	In keeping with my recent missives and invoking some of my favorite music from the ’70s and ’80s, I was reminded recently by my good friend and colleague, Jim Bailen, MD, of the famous Gordon Lightfoot song, “The Wreck of the Edmund Fitzgerald.” Those of you who have ever had the opportunity to meet and interact with Jim (director of Clinical Research, First Urology, Louisville Kentucky), know that not only is he a great urologist and researcher, but one of the wittiest individuals you will ever have the pleasure to engage and an all-round good guy who I feel privileged to call a friend. And having been one of the founding partners of his group, he also possesses a very keen business acumen.

	At a recent meeting, Jim and I were talking about the changing environment of medicine and the challenges we as urologists are currently facing, especially in light of diminishing reimbursement, rising overhead, and increasing government regulations. He went on to explain to me that physicians tend to practice according to the “Edmund Fitzgerald principle.”

	For my fellow audiophiles and historians, many of you are probably aware that the Edmund Fitzgerald was an iron ore tanker that sank in Lake Superior in November of 1975, carrying a load from Wisconsin to Michigan in a particularly vicious storm of hurricane proportions, killing all 29 of its crew. Dr. Bailen, who had served as a physician in the Naval Hospital, Great Lakes north of Chicago prior to moving back home to Louisville, proceeded to tell me that it was commonplace and standard operating procedure that when these giant tankers encountered bad weather, they turned up their engines and tried to make port as quickly as possible. Many theories abound regarding what actually sank the “Pride of the American Flag,” but suffice it to say, the faster she went, the more water she took in, hastening her demise.

	We as physicians, especially surgeons, tend to operate on the same principle: When things go bad, especially when revenue goes down, we just work harder and see more patients, with the expectation that it will correct and we can maintain. The reality of the situation, however, is that despite our best efforts, doing what we know how to do and maybe not being fully equipped with all the correct data, we may in fact be losing money and be on board a sinking ship.

	Why do I bring this up? It is painfully clear that the solution goes well beyond just seeing more patients and operating more. Consider the following:	

			The government wants to move into alternative payment plans that go away from traditional fee-for-service options to those that are value-based, looking primarily at outcome metrics, as ill-defined as they may be, and patient satisfaction.

			As a result of the USPSTF “D” recommendation for PSA testing, the number of prostate biopsies is down across the United States, impacting revenue, whether it be in your lab, pathology division, or surgery center.

			With the number of biopsies down and more and more patients opting, appropriately so, for active surveillance for low-risk prostate cancer, the number of men choosing definitive therapy—whether it be surgery, radiation, or cryotherapy&mdash;is also on the decline, again impacting our practice revenue.

			With sequestration, the sustainable growth rate, Obama Care, the attack on the in-office ancillary services exception, electronic health record mandates, and the plethora of all the regulations we face on a daily basis, the cost to do business continues to rise and there is only so much we can trim.

	All of us need to critically examine how we are practicing in preparation for the changes that are looming. We should not compromise the care of our patients, but make sure that care makes fiscal sense. I know that some have abandoned in-house labs and advanced imaging. We have altered our policies regarding injections in the clinic, especially testosterone.

	As I talked about in previous articles, we all need to consider adopting therapies and service lines and partnering with other healthcare providers in our areas. Whether that means developing clinical research, advanced therapeutics for cancer care, or centers of excellence across many urologic disease states, it will put us in a better position to manage our patients at the time of diagnosis and through the continuum of care. This will be critical, especially with the push for accountable care organizations.

	Due to the nature of our specialty, we will more than likely always need hospital partners, and to continue to develop strategies that make it beneficial for us to co-exist. Remember that close to a third of new urology residents are signing on with integrated systems or hospital-funded groups directly out of their training. These systems represent the biggest threat to many specialties. I do not want the independent practice of urology to become flotsam and jetsam in the wreckage at the bottom of the healthcare system transformation, and the time to act is now, before the storm really builds.

Articles

We as physicians, especially surgeons, tend to operate on the same principle: When things go bad, especially when revenue goes down, we just work harder and see more patients, with the expectation that it will correct and we can maintain. 

Lessons From the Great Lakes

With the recent approval of a first-in-class radioactive isotope as a treatment for prostate cancer, urologists have a new weapon in their rapidly growing arsenal of therapies designed to fight this disease.

The intravenously administered treatment, radium-223 dichloride (Xofigo), is generating excitement among urologists and oncologists, and not just because it is the first alpha-emitting radiopharmaceutical ever approved by the FDA for use in humans. During the phase III ALSYMPCA trial that led to its May 15 approval, the drug prolonged survival and increased time to bone progression in patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases, and no known metastatic disease.

Now, practitioners will need to explore how the drug is going to best fit into their practices.

According to Oliver Sartor, MD, medical director, Tulane Cancer Center, and professor of Cancer Research in the Departments of Medicine and Urology at Tulane University School of Medicine in New Orleans, Louisiana, an important basic guideline is that radium-223 is not a replacement for older therapies for prostate cancer, but instead complements many existing treatments extremely well. While Sartor, who helped design and run the ALSYMPCA trial, doesn’t recommend using the drug with other radiopharmaceuticals, or with chemotherapy until more research is conducted, he noted that the field beyond that is fairly open.

“I don’t use radium-223 in and of itself—I am always using it with another therapy, typically hormonal therapies,” said Sartor, who was the trial’s North American principal investigator. “In keeping with the design of the trial, patients can get best supportive care, manipulate their hormones, or take bisphosphonates if they want while radium is administered. So the nice thing about this drug is that it works well with other treatments. Today, many of these patients are managed with new hormone therapies like abiraterone and enzalutamide, and administering those in combination with radium, quite frankly, is a smart thing to do.”

Furthermore, oncologists who had early access to radium-223 during and after the trial agree that the drug is easy to administer and boasts a good safety profile.

Nicholas J. Vogelzang, MD, a medical oncologist at Comprehensive Cancer Centers of Nevada (CCCN) and a clinical researcher at US Oncology in Texas, was a bit startled when he heard data in 2007 about radium-223 in prostate cancer.

“I saw the first report of the drug being effective and was intrigued, because who would have thought that a radium associated with atom bombs and radioactive fallout would be useful for treating cancer?” recalled Vogelzang, who participated in the ALSYMPCA trial in its final months, when CCCN joined as an expanded access site. “When I was growing up, we had to hide under our tables for atom bomb testing, and one of the things we were told to do was to take a shower if we were exposed to nuclear fallout. A shower washes off the alpha particles, which are in the dust and will burn the skin.”

When it’s directed toward an appropriate target within the body, though, radium-223 has proven quite safe, Vogelzang said.

While gamma particles penetrate tissue the most deeply and beta particles have a more limited penetration, alpha particles— which are the largest&mdash;are the most superficial in their reach, Vogelzang explained. At the same time, they’re powerful, he said, meaning they can pack a punch without hitting far beyond their target.

“It’s really very safe, but when it does hit something it’s like a bowling ball hitting a piece of glass: The glass shatters,” Vogelzang said. “The DNA is damaged very easily by these big alpha particles. You can give it in the vein, and it doesn’t burn the vein. Even if you inject it under the skin it doesn’t really burn the skin very much, but it localizes to where bones are being made. That’s important, because where bones are being made is where the cancer sits.”

Consisting of two protons and two neutrons, an alpha particle is able to kill cancer in and around bone because it is a calcium mimetic, going where calcium does—preferentially targeting sites of osteoblastic metastasis where there’s a lot of bone turnover, rather than normal bone or marrow, Sartor explained.

“In the osteoblastic metastases, you have a lot of osteoblastic activity laying down an organic matrix and then an inorganic matrix,” he said. “The organic matrix is filled with hydroxyapatite, and the radium binds to the hydroxyapatite. It’s very nice because the radium doesn’t actually bind with the tumor, but with the regions around the tumor. These areas are exactly where it needs to radiate, and it does so very well.”

An injected radiopharmaceutical like radium-223 differs from external-beam radiation and brachytherapy because it’s “liquid radiation that homes to the bone spots,” Vogelzang said.

It is less likely than external-beam radiation to damange normal tissue and, unlike brachytherapy, radium-223 does not have to be surgically placed; rather, it can be given intravenously in any vein, Sartor said.

The drug, which has a physical half-life of just over 11 days, “prolongs survival in patients with advanced bonemetastatic CRPC unlike any other form of radiation,” he added.

Previously approved radiopharmaceuticals for the treatment of prostate cancer—samarium 153 (Quadramet) and strontium 89 (Metastron), both beta emitters&mdash;ease pain, but don’t prolong survival, Sartor explained.

“I used strontium 89 many years ago, and it was very effective, but you couldn’t give it more than once or twice,” Vogelzang recalled. “Then came samarium, which is still on the market. I still use it from time to time because it’s very effective in controlling pain. I remember a schoolteacher who was in a lot of pain, didn’t want to quit school, and didn’t want to take chemotherapy. I gave him that drug, and he was able to go back to school the next week.

“Those drugs work, and the approval of radium-223 builds upon that—without the burden of side effects that those other drugs gave us,” Vogelzang said.

Sartor added that radium-223 has an advantage at the molecular level.

at a single-cell level from the bloodstream,” Sartor said. “The interesting finding is that, from the same patient, one cancer cell and the next cancer cell are not necessarily the same; heterogeneity extends down to the cellular level. One of the reasons I like radium is that it has the ability to overcome some of the problems with genetic heterogeneity. The alpha particle really doesn’t care what type of mutation you have; it will pretty much kill them all.”

Radium-223 was approved 3 months prior to the mid-August decision date originally anticipated by the FDA.

Neal D. Shore, MD, who treated patients with radium-223 as part of an early-access program, posited that the early approval was based on the strength of the data supporting the drug’s usefulness.

“I’m not part of the FDA panel, but I think it’s always really great to see the FDA moving with alacrity for a very unique and novel therapeutic that’s going to help our patients with advanced prostate cancer,” said Shore, medical director of Atlantic Urology Clinics in South Carolina and its independent clinical research arm, the Carolina Urologic Research Center. Those organizations partnered with the Coastal Carolina Radiation Center, in North Carolina, to offer the fledgling drug, and after its approval, Shore was the first physician worldwide to administer the radiopharmaceutical to a patient.

“The FDA saw not only its clear efficacy in terms of improvement in survival and delay in skeletal complications for patients with bone metastases in the CRPC population, but it also saw that it’s very well tolerated,” Shore said of radium-223. “It’s remarkable in that we didn’t see any of the significant myelosuppression that we’re familiar with when giving the beta and gamma particles. In addition, this radioisotope is cleared through the intestinal tract, so it’s excreted fecally and we saw very, very low levels, or mild events, of diarrhea.”

The double-blind, randomized, mutinational ALSYMPCA trial compared radium-223 against placebo and best standard care in patients with CRPC and at least two bone metastases. According to updated results presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO),

 patients in the radium-223 arm of the study experienced a median overall survival of 14.9 months compared with 11.3 months in the placebo arm (hazard ratio [HR] = 0.695; 95% CI, 0.581-0.832; P = .00007). In the radium-223 arm, the time to the first skeletal-related event was a median of 15.6 months, a significant improvement over the 9.8 months in the placebo arm (HR = 0.658; 95% CI, 0.522-0.830; 

According to the FDA, the most common side effects reported during clinical trials were nausea, diarrhea, vomiting, and swelling of the leg, ankle, or foot. The most common abnormalities detected in blood tests included anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia.

“This 900-plus patient trial showed that patients who got the radium lived longer than those who did not get the radium,” Vogelzang said. “They had reduced pain. They had reduced blood cancer markers, and they needed less opium or morphine. Their side-effect profile actually reduced, because in a majority of the patients, what we describe as side effects come not from medication, but from the cancer itself. They needed fewer x-rays, and they didn’t break their bones as often.”

Those benefits led to delays in the need for additional treatment, Shore said, including “a delay in the onset of a radiation requirement for painful bone metastases and other delays in skeletal events, such as surgical intervention and core compression.”

“This is the ideal drug that the FDA should approve,” Vogelzang said, “and they did.”

About 70% of men with advanced metastatic CRPC will be eligible for radium-223 at some point in their lives, Sartor said. Although patients need to be symptomatic to receive the drug, he noted, symptoms don’t have to be severe.

“Symptoms don’t mean you are taking morphine opiates all the time,” he said. “Symptoms can mean that you are taking something like acetaminophen or even another steroidal, aspirin, Advil, ibuprofen, or something like that. It turns out that you don’t have to be very symptomatic in order to benefit, because this is a drug that prolongs survival. Yes, it does relieve pain, but it prolongs survival.”

The drug was particularly effective in study participants with a fairly early stage of prostate cancer that had spread to bone—even if they were older, Vogelzang said.

“The trial allowed men who didn’t want chemotherapy, or who were not fit for chemotherapy,” he said. “We know that many of these men are very old and not healthy and are not good candidates to be treated with chemotherapy, but in fact they had more benefit than the men who had previous chemotherapy.”

Patients on the other end of the symptom spectrum, however, may end up frustrated if they’re hoping to take radium-223, Vogelzang said. The drug doesn’t work at all in tumors outside bone, he pointed out.

Sartor and colleagues presented a post-hoc analysis of pain parameters in ALSYMPCA at the 2013 ASCO annual meeting, confirming that treatment with radium-223 reduced pain and opioid use in CRPC patients with bone metastasis.

“The pain analysis is a verified questionnaire, a validated composite of four questions that assess pain,” Sartor said. “In this context, there were two findings: (1) that use of radium-223 would decrease the amount of pain, and (2) very importantly, that it would have an opiate-sparing effect. That means that people who receive the radium are less likely to require opioid analgesics. I think it is a very important message, particularly in our elderly patient population.”

In another analysis, Sartor and coauthors considered bonealkaline phosphatase (ALP) as a prognostic factor for the success or failure of radium-223 in patients with metastatic CRPC.

 They concluded that higher baseline levels of total ALP were associated with an increased risk of death, and pointed out that because patients on the ALSYMPCA trial experienced a decline in ALP, further analysis is warranted to determine whether there is a correlation between total ALP dynamics and survival.

In another study presented at ASCO this year, Vogelzang and colleagues analyzed whether prior docetaxel use had any impact on the effectiveness or safety of radium-223 in the study’s population.

 The authors found that, while the use of the radiopharmaceutical significantly prolonged overall survival and was safe in patients regardless of prior docetaxel use, those who had used the chemotherapy faced a slightly increased rate of grade 3/4 bone marrow suppression when using radium-223.

 Vogelzang and coauthors found that, while the use of radium-223 and docetaxel were the strongest prognostic factors for decreases in neutrophils and platelets in the study’s population, participants still faced a low risk for hematologic adverse events.

So how will radium-223 fit into community practice? The drug is easy to administer, given intravenously over the course of 45 to 60 seconds once every 4 weeks for a total of six doses, Shore said.

“From the patient’s perspective, you walk in, you get it, and you go,” Vogelzang said. “You don’t have to worry about nausea, vomiting, or hair loss. It’s a really easy drug for older patients. They literally can drive into our office, get weighed, get their blood count checked, get the drug in their vein, and say ‘See you next month.’”

However, the new drug must be administered by someone with the appropriate licensure—typically, a radiation oncologist or nuclear medicine radiologist.

“I think the practical and clinical applications for administering this therapy are not going to be daunting whatsoever,” Shore said. “Initially, people might see it as an obstacle and hurdle that the drug needs to be administered by someone licensed to handle radiopharmaceuticals. However, some of the larger urology and medical oncology groups are integrated, or they’re multidisciplinary, so they have radiation oncologists built into their practice. Where that’s not the case, I think there are many urologists and medical oncologists who have great affiliations with their hospital-based nuclear medicine radiologists.”

A more provocative question, Shore suggested, is how practitioners should combine, or sequence, radium-223 with other drugs.

“The fun question is, ‘How can I give this, or can I give this, with some of the other newly approved therapies that have come along since 2010 that help our patients with CRPC, such as sipuleucel-T, abiraterone, enzalutamide, docetaxel, and cabazitaxel?’” Shore said. “In the ALSYMPCA trial, patients were just stratified to have received or not received docetaxel or zoledronic acid, because when that study was done, these other therapies weren’t available. So, I think it will be important to have investigator-initiated trials, and perhaps cooperative group studies or industry-sponsored studies, to give us a greater comfort level. It doesn’t strike me that there should be a challenge, intuitively, in giving these other therapeutics concomitantly, but we have to get the data, we have to do the studies, and that’s very important.”

Until there are guidelines, physicians should use their judgment to make case-by-case decisions about combinations and sequencing involving radium-223, and also be sure to give the new drug strictly according to its label, Shore said.

Looking ahead, Sartor noted, there may be other uses for radium-223 in cancer treatment.

“There is a series of trials for radium-223 being conducted in breast cancer (NCT01070485),” he said. “Plus, there is a lot of discussion about trials at this point in multiple myeloma. There certainly needs to be more work done, and there are no phase III trials, so that is an area of interest that is going to take more planning.”

			Parker C, Nilsson S, Heinrich D, et al. Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer patients with bone metastases (ALSYMPCA). 

			Nilsson S, Sartor AO, Bruland OS, Fang F, Aksnes A-K, Parker C. Pain analyses from the phase 3 randomized ALSYMPCA study with radium-223 dichloride in castration-resistant prostate cancer patients with bone metastases. 

			Sartor AO, Amariglio R, Wilhelm S, et al. Correlation between baseline variables and survival in the radium-223 dichloride phase III ALSYMPCA trial with attention to total ALP changes. 

			Vogelzang NJ, Helle SI, Johannessen DC, et al. Efficacy and safety of radium-223 dichloride in castration-resistant prostate cancer patients with bone metastases who did or did not receive prior docetaxel in the phase 3 ALSYMPCA trial. 

			Parker C, Garcia-Vargas JE, O’Bryan-Tear CG, Fang F, Vogelzang NJ. Hematologic safety of Ra-223 dichloride in castration-resistant prostate cancer patients with bone metastases from the phase 3 ALSYMPCA trial. 

First Approved Alpha Emitter Bolsters Arsenal Against Prostate Cancer

The words “north” and “south” may conjure up images of the Civil War that divided, and then eventually reunited, the country. For Urologic Specialists of Oklahoma (USO) in Tulsa, the merging of north and south was free of such conflict and turmoil, yet still rooted in long-held personal ties and shared history.

USO co-founders John Forrest, MD, and Robert Bruce, MD, have known each other since the fourth grade. They both attended medical school at the University of Oklahoma and, after some time away from home, ultimately joined two different, well-established practices in north and south Tulsa

“Over time, we came up with the idea to merge our two large practices into one larger group,” Forrest explained. “It’s always been my feeling that with the changes in medicine, practicing in a larger, highly structured group was the wave of the future. It allows you certain positions in the marketplace in terms of how you practice medicine, how you respond to payers, and how you manage regulatory issues. We believed that being a large group would make us more agile to respond to changes in healthcare while providing a high level of expertise and service.”

The advantages of this model, Forrest explained, include shared, structured decision making; the ability to offer an array of ancillary services on site; and timely access to the latest healthcare management practices, such as electronic medical records.

USO formed in 1996 with nine doctors on the north side of town and four on the south side, housed in multiple locations, said Steve Dobbs, the practice’s CEO. In 2004, the 52,000-square-foot main campus was built, bringing the majority of the physicians and staff under one roof (the practice also maintains a small satellite office in another part of Tulsa). USO now has 20 physicians and will be welcoming two more later this year. Its areas of specialty include general urology, urologic oncology, pediatric oncology, renal transplantation, and a division devoted solely to female pelvic medicine.

 about how the practice came together, how it maintains its union, and why outreach is a major part of its expansion plan.

Beyond Forrest and Bruce’s long-term friendship, USO has many connections that give the practice its united front. But getting to the point of cohesion did require some adjustment.

Dobbs joined USO in 2011 and checked in with some of the veterans of the practice to learn more about the challenges it faced when first merging. Not surprisingly, one of the main issues was integrating the different cultures of two independent practices that had been around since the 1960s.

The practice managers looked to one of the driving principles of real estate to circumvent any culture clash: location, location, location.

“When they designed [the current] building, they strategically put one doctor from the north side and one doctor from the south side next to each other in a pod,” Dobbs said. “That way, people would ‘click’ together. In fact, even now, in every one of our pods, there are physicians who came from the south side practice and doctors who came from the north side. Of course, after all these years, north and south is a non-issue, but it was a smart way to get everyone to start working together as a group.”

In fact, USO physician-partners have taken that “all for one” philosophy even further with their salary structure. “We have a pooled income model,” Forrest said. “Basically, all of the full partners make the same amount of money. It’s not driven by patient volume, compensation formulas, or relative value units. We all subspecialize, but ultimately, our contributions are equal, so our income model reflects that.”

The shared income model is “all about doing the best we can for the patient,” Dobbs echoed. “If one of our physicians sees a patient, and determines that person would be better served by one of his partners, then that patient is referred. I see it happen every day.”

In addition to its central location and an egalitarian income model, the practice boasts other connections: Physicians David Confer, MD and Stephen Confer, MD are father and son, while physicians Oren Miller, MD and Curt Powell, MD served in the military together.

USO also includes many physicians with Oklahoma roots. “Of the two physicians we recruited this year, one grew up in Tulsa. So he’s coming into a community where many people have known him for years,” Dobbs explained. “The other is from a town about 60 miles away from here. He’s done a fellowship in urology trauma and he wanted to come into a practice where he could really use that knowledge. These are both people who we recruited from major training programs in the country, but who have a relationship with Oklahoma and want to give back to their community.”

Indeed, physician recruitment is an area where the practice has excelled. Forrest attributes that to the practice’s size, which he said offers it clout and an array of helpful contacts. The group’s success in recruiting new members is particularly notable at a time when there is a shortage of urologists due to more physicians opting to become hospital employees. Having been in the healthcare industry for nearly 40 years, including several as a hospital CEO, Dobbs acknowledges the appeal of the hospital model, but said he asks potential partners to look beyond the paycheck.

“So many doctors become hospital employees so they don’t have to worry about the business side,” he said. “I understand that. But I ask them to think, how do they want their partner relationship to work? Do they want to work with people who have their backs? In a dynamic, large group like ours, if you need help, your partners will step up and help you. In a hospital setting, those personal relationships aren’t always as easy to establish.”

As part of its plans for expansion, USO will continue its outreach program to other towns in Oklahoma, either because those communities have no urologists or their urologists are about to retire.

As part of their routine, all USO partners participate in the outreach program, traveling to towns 20 to 100 miles away from Tulsa to provide general urology services.

“For instance, Vinita, Oklahoma, is about 60 miles away, and it did not have a practicing urologist in town or nearby,” Dobbs explained. “McAlester, which is a large city near the Choctaw Nation, is about 100 miles away, and that community of 20,000 has no full-time urologist. We usually partner with a local hospital so that we have a space to consult and treat these patients.”

From a clinical standpoint, outreach also includes talking to patients about their overall health and any associated risk for urologic disorders, including cancers.

“The biggest health challenge in the US now is the management of obesity, which is a risk factor for prostate cancer, stone disease, recurrent urinary tract infections, sexual dysfunction, and incontinence,” Forrest said. “But patients don’t always see those relationships, and that’s part of our job, to help them understand that.”

The outreach also includes helping to raise the awareness of patients and the general public about other urologic cancers that typically don’t gain as much attention as prostate cancer. For instance, a study presented at the 2013 American Urological Association meeting showed that testicular cancer rates have been steadily rising.

 Yet public awareness of this disease is minimal, Forrest said.

The same holds true for renal cell carcinoma and bladder cancer, he pointed out. “The rate of finding renal cell cancer is up because of ubiquitous CT scanning; renal lesions are found earlier. But the rate of high-stage, renal cell carcinoma is still going up. In terms of bladder cancer, those rates are not going down, most likely due to smoking and some other environmental factors. It can take up to 20 years for that malignancy to show up, even in someone who has quit tobacco use.” Fortunately, urologists now have much better tools to treat these cancers, Forrest said, such as ablative techniques and laparoscopic or robotic partial nephrectomy. “Also, we’ve had the introduction of three to five new oral agents that have slowed the growth of metastatic renal carcinoma, adding years of survival to these patients’ lives,” he said.

In bladder cancer, preoperative chemotherapy prior to cystectomy has been refined over the years, while in early-stage testicular cancer, active surveillance is a viable option, he added.

Since the doctors at USO forge longterm bonds with their patients, they are able to present a variety of such options at the most appropriate times.

“What’s interesting about the practice of urology is that we take care of some of these patients for many years, so we watch their health change over time,” Forrest said. “Not many other specialties have the ability to make those connections.”

			Nigam M, Shikanov S, Aschebrooke-Kilfoy B, Eggener S. The increasing incidence of testicular cancer in the United States from 1992 to 2009. Presented at: the American Urological Association Annual Meeting; May 4-8, 2013; San Diego, CA. Abstract 933.

USO co-founders John Forrest, MD, and Robert Bruce, MD, have known each other since the fourth grade. They both attended medical school at the University of Oklahoma and, after some time away from home, ultimately joined two different, well-established practices in north and south Tulsa.

United in Tulsa: Urologic Specialists of Oklahoma Is a Model of Collaboration

At a time of controversy regarding the value of prostate-specific antigen (PSA) screening in the early detection of prostate cancer, the American Urological Association (AUA) has issued a new clinical guideline on the subject and launched an educational campaign designed to share the information with urologists and their patients.

As compared with previous AUA recommendations, the guideline more narrowly defines the profile of the asymptomatic patient who should receive PSA testing; at the same time, the guideline reaffirms the organization’s belief that the test has value, despite a government recommendation that its use be stopped altogether.

According to the Clinical Guideline on the Early Detection of Prostate Cancer, screening with PSA tests should focus on men aged 55-69 years, the age group most likely to benefit.

Routine screening is not recommended for average-risk men 40- 54, after age 70, or for men with an average life expectancy of less than 10 to 15 years. The AUA has recommended against screening PSA tests for men younger than 40.

Irrespective of patient age, a screening PSA test should not occur without a thorough discussion of the risks and benefits of screening between patient and physician, the guideline states.

The document emphasizes a more selective, evidence-based approach to PSA testing as compared with recent recommendations from other organizations, most notably the United States Preventive Services Task Force (USPSTF), said J. Stuart Wolf, MD, chair of the AUA Practice Guidelines Committee.

“The USPSTF essentially said that physicians should not offer screening PSA tests to any men,” Wolf said. “The AUA does not agree with that. We feel that PSA screening is a reasonable discussion to have between a physician and a patient. Our guideline emphasizes offering PSA tests to appropriately selected candidates.”

Even with appropriately selected patients, physicians should carefully discuss the potential risks and benefits of PSA testing and make a shared decision about proceeding with a test—or deciding against it.

“The average-risk man, 55 to 69, needs to be discussing the pros and cons of PSA testing,” said Stephen J. Freedland, MD, associate professor of Urology at Duke University in Durham, North Carolina, and a member of the writing committee for the PSA testing guideline. “Men at high risk—because of family history or African- American race&mdash;need to have this discussion earlier.”

Moreover, the guideline does not preclude testing for men who are outside the high-risk age range, he added. A man who is age 70 or older, wants a PSA test, and has been appropriately educated about the process should not be excluded from testing.

“The key—regardless of a man’s age&mdash;is to discuss PSA testing with a physician and then make an informed decision,” Freedland said.

The guideline replaces a 2009 AUA best practices statement, which went beyond prostate cancer detection and included aspects of treatment and monitoring. In the practice statement, the AUA lowered the recommended age for a baseline PSA test to 40 and eliminated use of a specific PSA threshold for triggering a biopsy. The 2009 document had replaced earlier practice statements on the same topic.

Updating of the practice statement began about 2 years ago and was ongoing at the time the USPSTF announced its recommendation against routine PSA screening tests for asymptomatic men of any age.

“It was just time in the cycle for updating the best practices statement,” Wolf said, “so our practice guideline was not developed as a response to the USPSTF recommendations. Howewver, we did review the recommendations and used the clinical guideline to address what we considered to be some deficiencies in the USPSTF recommendations.”

The practice statement was based primarily on consensus and expert opinion. To develop the clinical guideline, the AUA commissioned an independent study of available evidence, as recommended by the Institute of Medicine. The review covered published literature from 1995 to 2013, a period that encompasses the introduction, evolution, and widespread use of PSA testing in clinical practice.

The review of evidence resulted in a detailed discussion of the potential risks of PSA testing, but also the limitations of the data and their sources. Consistent with the emphasis on shared decision making, the guideline includes a section called “What a Man Needs to Know Prior to Making a Decision About Testing.”

The AUA has distanced itself from routine screening in any age group, including the 55 to 69 group. Instead, the guideline recommends individualized decision making, noting that screening intervals of 2 years or longer might be appropriate for some 55- to 69-year-old men.

“The main point is that PSA testing for early detection of prostate cancer has an important role in maintaining the health of American men,” Wolf said. “Clearly, it has been overused in the past, but we feel it is a grave mistake to react to that overuse by completely getting rid of any early-detection efforts at all. We feel that a more balanced approach—selecting men at higher risk&mdash;is a more appropriate way to go.”

As an aid to shared decision making about prostate cancer screening, the AUA has developed an education program with information for providers and patients. As part of that effort, the AUA is offering a free toolkit to doctors and patients that includes a frequently asked questions document; a flow chart that explains who is a good candidate for PSA screening (

); a brochure; a fact sheet; a checklist; and a patient booklet (

). “Because the AUA’s primary audience is urologists, the educational materials have been developed for urologists to distribute to patients during office visits,” Wolf said. “The materials are designed to facilitate discussion between providers and patients, because we recognize the discussion is not an easy one for providers who are unfamiliar with the issues and considerations that go into making a decision about PSA testing.”

Clinicians and patients can access the entire guideline on the AUA website (www.auanet.org), which also has a link to the Urology Care Foundation, an AUAsponsored initiative developed specifically for patient education. Additional patient-oriented material is available at KnowYourStats. org, a website that builds on the organization’s longstanding prostate cancer awareness campaign developed in conjunction with the National Football League.

“To achieve the goal of a balanced approach to use of PSA testing for early detection of prostate cancer, the patient and physician bear a pretty high burden for education,” Wolf said. “That is the basis for the public education program. Urologists need to know a lot and patients need to know a lot.”

Clinicians and patients also should recognize that the clinical guideline is just that—a guideline.

“This is not a mandate or a requirement. It’s a guideline,” Freedland said. “Patients who are outside the guidelines, and understand the risks and benefits of testing, may say ‘I want to be tested.’ From the perspective of a practicing urologist, I am not going to use a guideline to say ‘No, you cannot do this’ or ‘Yes, you must do this.’ The guideline provides a starting point for the discussion between physician and patient.”

		Figure. Is Prostate Cancer Screening Right for You?

		This wall chart is part of the toolkit being offered by the AUA to spread the word about its guideline on PSA screening

At a time of controversy regarding the value of PSA screening in the early detection of prostate cancer, the AUA has issued a new clinical guideline on the subject and launched an educational campaign designed to share the information with urologists and their patients.

AUA Issues Recommendations for PSA Screening in Prostate Cancer Detection

 Marijuana users had a small but statistically lower risk of bladder cancer compared with people who smoked tobacco or did not smoke, a large retrospective cohort study showed.

The overall cohort had a bladder cancer risk of <1%. Nonetheless, cannabis (marijuana) users had an incidence of 0.3% compared with 0.4% among nonusers. The difference represented a 45% reduction in the hazard ratio (HR) for bladder cancer.

The magnitude of risk reduction appeared to increase with the frequency of cannabis use, Anil A. Thomas, MD, reported at the American Urological Association meeting in San Diego, California, in May.

“The full effects of cannabis use are not known, and Kaiser Permanente does not promote nor condone the use of cannabis,” said Thomas, an endourology fellow at Kaiser Permanente Los Angeles Medical Center. “However, our findings demonstrated a reduced incidence of bladder cancer among cannabis users, which could lead to further investigational studies to determine if cannabinoids, the active components of cannabis, have biologic activity against bladder cancer. Future research may eventually lead to the development of new targeted therapies for patients with bladder cancer.”

Bladder cancer is the fourth most common cancer in men, and tobacco use is a recognized risk factor for developing the disease. Whether that risk extends to cannabis use had not been examined in large epidemiologic studies. To address the issue, Thomas and colleagues analyzed records from the California Men’s Health Study (CMHS), a multiethnic cohort study that focuses primarily on prostate cancer, but also on the etiology of other cancers and non-cancerous conditions.

		Table. Bladder Cancer Risk Based on Smoking Patterns

					Hazard Ratio, as Compared with Nonsmokers

The bladder cancer study involved 84,170 men from the Northern and Southern Kaiser Permanente health regions participating in the CMHS. After excluding 680 men with a history of bladder cancer, investigators analyzed data for the remaining participants.

According to self-reported information provided by the participants, a total of 71% of the men were smokers (41% cannabis, 57% tobacco and, included in those numbers, 27% both substances). Meanwhile, 29% used neither cannabis nor tobacco. During follow-up for as long as 11 years, 279 study participants (0.3%) developed bladder cancer. Cannabis users accounted for 89 (0.3%) cancers and nonusers (including tobacco users) for 190 cancers (0.4%, 

An analysis adjusted for age race/ethnicity, and body mass index showed that exclusive tobacco use was associated with a bladder cancer HR of 1.52 compared with nonusers (

 <.007). In contrast, exclusive cannabis use was associated with a reduced risk of bladder cancer (HR=0.55; 

 =.0484). Men who reported use of tobacco and cannabis had a bladder cancer HR of 1.28, which was not statistically different from that of nonusers (

In another adjusted analysis, men who reported using cannabis once or twice had no reduction in bladder cancer risk (HR=1.07; 

 =.760), whereas men who reported use in excess of 500 times had a bladder HR of .66, which still did not achieve statistical significance (P =.175).

“While a cause-and-effect relationship has not been established, cannabis use may be inversely associated with bladder cancer risk in this population,” Thomas said. “Additional research is needed to determine if there is indeed a biological effect of cannabis to prevent or delay the development of bladder cancer.”

	Thomas A, Wallner L, Quinn V, Slezak J, Chien G, Jacobsen S. Association between cannabis use and risk of bladder cancer: Results from the California Men’s Health Study. Presented at: the American Urological Association Annual Meeting; May 4-8, 2013; San Diego, CA. Abstract 1290.

Marijuana users had a small but statistically lower risk of bladder cancer compared with people who smoked tobacco or did not smoke.

Lower Bladder Cancer Risk Seen in Marijuana Users

A cocktail of herbs and vitamins lowered prostate-specific antigen (PSA) in more than a third of patients with biochemically recurrent prostate cancer (bcrPC), and thus may be a good alternative to observation in this population, according to study results published in conjunction with the 2013 Annual Meeting of the American Society of Clinical Oncology.

Since there is no standard for the treatment of bcrPC, and androgen deprivation therapy (ADT) has not been proven to prolong survival in these patients and may have “deleterious effects,” “a non-hormonal, non-toxic agent to reduce PSA would be a welcome alternative to observation,” wrote authors Tanya B. Dorff, MD, assistant professor of Medicine in the University of Southern California’s Keck School of Medicine, and colleagues. Their phase II study was not presented during the annual meeting, but was published in conjunction with the event.

The supplement used in the study was Prostate Health Cocktail, made by OncoNatural, which contains vitamins D and E, saw palmetto, lycopene, green tea, and soy extracts. The primary endpoint of the study was PSA decline.

To be eligible, men needed to have rising PSAs whose value doubled within 3 to 36 months and no evidence of metastases. Among the 40 men who participated, median age was 67 years and median baseline PSA was 2.8 ng/mL. Twenty-three percent of the men had Gleason scores between 8 and 10. Of the participants, 23% had been treated with primary radiation only, 25% with prostatectomy only, and 52% with both.

The men were given three PHC capsules daily for a median of eight 4-week cycles. PSA tests were done after cycle 1, and then every two cycles thereafter.

The investigators found that 37.5% (15) of participants experienced a decline in PSA of 55% or less, and of 35 men evaluable at 12 weeks, 9 men (25.7%) had PSA decline. The median “best” PSA change was 3.7% (range, -55% to 34.3%) and the median change in PSA at 12 weeks was 17.9% (-17.5% to 78.0%), Dorff said. Fortythree percent of study participants stopped therapy due to PSA progression, with a median time to progression of 10.2 months.

As of early July, 2 men were still in the study, 3 were continuing on the protocol after completing the trial, 3 had been lost to followup, 19 had developed metastases, and 13 were off study without having developed metastases

There was no significant change in testosterone or dihydrotestosterone during treatment, the authors reported.

Toxicities that may have been associated with PHC, none higher than grade 2, included transient liver enzyme elevations, gastrointestinal symptoms, weakness/dizziness/pain, and fatigue, the authors wrote.

“PHC is a potential alternative to observation in select patients with bcrPC,” the colleagues concluded.

In addition, the investigators suspect that PHC could be useful as an alternative to ADT. They plan to study PHC in comparison with placebo to determine not only whether the cocktail delays the time to metastasis, but whether it delays the need to start ADT, Dorff told 

Nicholas J. Vogelzang, MD, head of the Genitourinary Cancer Program at the Nevada Cancer Institute, who referred patients for enrollment in the study, said it was easy to find eligible men interested in participating.

“We picked patients whose PSA was rising after radiation or surgery who were not ready to have their testosterone lowered,” he said. “Most men are attached to their testosterone—it’s part of their life&mdash;so many who have a rising PSA don’t want to have their testosterone lowered. That’s why an alternative to that, in the form of a pill or a vitamin, is very attractive.”

	Dorff TB, Tsao-Wei DD, Howes D, et al. Final results from a trial of a combination herbal supplement for biochemically recurrent prostate cancer. 

A cocktail of herbs and vitamins lowered PSA in more than a third of patients with biochemically recurrent prostate cancer, and thus may be a good alternative to observation in this population.

September 2013 | Oncology Live Urologists in Cancer Care®

Lessons From the Great Lakes

First Approved Alpha Emitter Bolsters Arsenal Against Prostate Cancer

United in Tulsa: Urologic Specialists of Oklahoma Is a Model of Collaboration

AUA Issues Recommendations for PSA Screening in Prostate Cancer Detection

Lower Bladder Cancer Risk Seen in Marijuana Users

Herbal Supplement Could Outperform Observation in Some Patients With Recurrent Prostate Cancer