On an early Tuesday morning, when many businesses are just ramping up, practice administrator John O’Rourke is wrapping up a briefing with a staff member. Their discussion includes the practice’s plan to begin administering Provenge, the prostate cancer vaccine, to their patients.

 spent at the more than 40-year-old practice, appointments with two of its senior physicians required rescheduling because both were called to consult in the operating room. Not to worry; two other partners graciously stepped in to discuss topics ranging from the establishment of the practice to the changing needs of urologic cancer patients in Tucson and beyond.

	“The physicians here will help each other out, whether it’s consulting in a patient exam room or in the operating room,” O’Rourke explained. “They consult each other constantly, despite the fact that the reimbursement system has made collaboration very complicated.”

	That’s no doubt one reason that in 2011, seven of the 11 top urologists in Tucson who were voted The Best Doctors in America were based at Urological Associates of Southern Arizona.

	In terms of urologic cancer care, the practice has also kept its eye on collaboration, seeking to form alliances with its fellow cancer specialists. The practice is in a unique position: Tucson is a microcosm of the rest of the United States, with a graying population that carries a higher cancer risk. And given its long history, the practice has seen many milestones reached for urologic cancer, particularly prostate cancer.

	O’Rourke and some of the physician partners shared their vision for their practice and how they are planning to thrive in an increasingly complex medical climate.

	Urological Associates of Southern Arizona was founded in the mid-1960s by Donald Gleason, MD, who came to Tucson from the East Coast. During that era, Tucson saw its population double, and the local medical community followed suit. Tucson became known as a “specialist” town, with the highest number per capita of board-certified physicians in the country. More than 850 physicians were serving the community of 200,000 residents in the 1960s.

	After Gleason established the practice, he called Robert J. Riley, MD, to join him. Practice lore has it that desert-based Gleason rang up his colleague from poolside on Christmas day, while Riley took the call in snowbound Connecticut.

	Throughout the next three decades, Riley and Gleason saw their practice expand, often merging with single practitioners like Thomas Hicks, MD, who joined in 1998.

	For Hicks, who spent six years as a solo practitioner, being a part of a large group held practical and professional appeal. “The physicians in this practice were interested in research, and I wanted to get more involved in research,” he said. “Joining a larger group practice also [offers] an efficiency of administration. For a solo practitioner to establish contracts is difficult, because you don’t have the leverage, so that’s another benefit of being in a larger group practice. The resources here and the collegiality of the physicians here appealed to me.”

	A wealth of resources has meant that the practice has been able to reach beyond the city: opening satellite clinics in the small southern Arizona towns of Safford and Willcox; acting as a teaching facility for urology residents from the University of Arizona School of Medicine (Stanley Suffecool, MD, serves as the practice’s clinical instructor); partnering with not one but three major hospitals in town; and conducting clinical trials.

	Curtis Dunshee, MD, joined the practice in 1993 and serves as one of the principal investigators of in-house clinical trials (Susan Kalota, MD, is the other PI). In fact, the practice is currently involved in a clinical trial of MDV3011, an investigational drug for men with metastatic castration-resistant prostate cancer that has progressed after treatment with docetaxelbased chemotherapy.

	The practice now boasts 12 full-time physicians, one nurse practitioner, and two physician assistants, based at two main Tucson locations.

	For urologists, treating cancer has always been a part of their specialty. After all, many urologic cancers are treated surgically or hormonally, and that’s been the domain of the urologists. “Only in the last few years have medical oncologists gotten the tools to take care of prostate cancer patients,” Hicks pointed out. “The same with renal cell carcinoma (RCC); in the last 10 years, medical oncologists have gained the tools to treat this disease. So before that, these cancers were taken care of primarily by urologists. We have the benefit of long-term experience with treating these cancers.”

	The physicians agreed that prostate cancer makes up the majority of the urologic cancer cases that they see now, followed by bladder cancer and RCC. It’s in the area of prostate cancer treatment that these urologists feel they have made the greatest strides.

	One advance was bringing Sanjay Ramakumar, MD, who came from the University of Arizona in Tucson, into the practice in 2007 (the year Riley retired). There, Ramakumar performed one of Tucson’s first laparoscopic prostatectomies in 2003. Since then, he has done nearly 500 such procedures.

	“Minimally invasive surgery has become so integrated into urology that you really can’t be a urologic oncologist without training in this area,” Ramakumar said. “Now prostate cancer patients are routinely offered [laparoscopic prostatectomy], and that’s a great advancement for them.”

	The widespread use of minimally invasive surgery for prostate cancer is just one area where urology has shown impressive progress, Ramakumar and Dunshee agreed. Another is the ability to offer treatment options for advanced prostate cancer.

	“The man who failed primary therapy, either radiation or surgery, had very few options,” Ramakumar said. “The main option was hormonal therapy, but it was of questionable benefit and came at such a high cost.”

	Partners at Urological Associates have made it a point to incorporate newer treatment methods into their armamentarium. For instance, Terry F. Favazza, MD, trained in brachytherapy in 2003. Partner Tristan T. Berry, MD, now specializes in robotic surgery for kidney cancer.

	And within the clinical trials, Dunshee has opted to reach out to a population that is often excluded from major research. “Ten years ago, I would have never considered enrolling a 90-year-old in a clinical trial,” he said. “But now I have a couple of [older patients] on clinical trials for castration-resistant prostate cancer who are doing well.”

	Healthcare reform has caused some physicians to circle the wagons, afraid of relinquishing turf and losing their livelihood. But Urological Associates has made it a point to reach out to other physicians and remind them that, as a profession, they will sink or swim together.

	One example of this came in 2011 with the US Preventive Services Task Force (USPSTF) recommendation against routine prostate cancer screening with prostate-specific antigen (PSA) testing. After the recommendation came out, Urological Associates saw a drop in the number of patients referred to their practice. So they sent letters to all of the primary care physicians in southern Arizona, urging them to continue with PSA screening.

	“We said, ‘It is a mistake to take the only screening tool we have for the number one cancer diagnosis in US men, and the number two cause of cancer-related death, and stop screening with it,’” Ramakumar explained. “The task force is not speaking untruths, but how you look at the data, and how that data impacts a practice and the patients on a day-to-day basis, are two different things. Perhaps the agenda of the government is not the same as the agenda as a clinician who cares for patients who die of prostate cancer.”

	It’s this type of communication that Ramakumar and his colleagues want to see happen in all specialties, and especially among all the doctors who treat urologic cancers. Given the multiple options that prostate cancer patients now have for their disease, coordination of care is vital, he explained.

	“Compartmentalized medicine has worked in the past, but that can lead to duplication of services,” he said. “We need to really think integrated care. If you have two specialists performing the same test, it’s a waste. It’s not that we are going to start doing chemotherapy, but we are going to coordinate with those physicians who do. This is a solution to deal with rising healthcare costs.”

	O’Rourke came to Urological Associates in 2010, when the healthcare reform movement was in full swing. One of his first tasks was to determine how to make sure that the practice was ahead of the curve.

	“There’s an emphasis in healthcare today on cost-effectiveness and cost cutting,” he said. “Some people feel the price for more efficiency is patient care. One thing I’ve done is look to best practices in other industries and start making little adjustments to bring ourselves into line with those best practices.”

	One thing I’ve done is look to best practices in other industries and start making little adjustments to bring ourselves into line with those best practices”

	One area that O’Rourke drew inspiration from was Six Sigma, a business management strategy that emphasizes quality management control and eliminating errors. To that end, the practice’s focus in 2012 will be the implementation and streamlining of systems and tools, he said.

	ï»¿“Our goal has been to make the systems that surround the patient more efficient,” he said. “For instance, we are in the process of introducing a wireless tablet system into our check-in process. This will facilitate faster patient intake and enhance the communication system outside of the exam room between the staff and the physicians.”

	The benefit here is that once the systems are working efficiently, the patientdoctor experience can play out exactly how it needs to in the exam room. “Each patient is unique, and there’s no point in trying to pigeonhole patients into some kind of formula,” O’Rourke said. “But if we build a more efficient system, then we have the best of both worlds: cost-effective care along with putting the patient first.”

	In cancer care, the practice has two major projects under way. First, there’s the introduction of Provenge (sipuleucel-T) for patients with early-stage metastatic prostate cancer. Before offering the vaccine to patients, practice nurses will undergo training in the infusion process at a facility that already delivers Provenge.

	The second project is to set up a bone health clinic for their prostate cancer patients. Putting the program in place will be a group effort, but once the clinic is a go, its administration will be turned over to the people who are best equipped to manage it.

	“I firmly believe in finding the one person in a practice who is passionate about a particular project and letting them be the strongest advocate for it,” O’Rourke said. “So that’s what we are doing with the bone health clinic. Once we’ve established the clinic with everyone’s input, and set up the clinical pathway for running it, we’ll turn it back over to the physician assistants and nurse practitioners to manage.”

	Last year, the practice renovated its older office, relocating all of the administrative offices to an offsite location, and then converting the space into more exam rooms. “We are in the business of patient care, so we needed to emphasize that with our physical location,” O’Rourke stated.

	With multiple projects, locations, and physicians to manage, O’Rourke said he makes it a point to keep everyone in contact with each other, through Web conferences, clinical roundtables, and, when possible, face-to-face meetings.

	Without a spirit of collaboration, the practice will not continue its success. O’Rourke recalled recently seeing an example of what happens when the shareholders in a practice are completely disengaged from one another.

	“I was recently at a conference where I watched the CEO of a very large East Coast practice address the physicians— they had about 20 doctors and at least that many locations&mdash;and I could just see that there was a complete disconnect between her and the doctors,” he said. “These were very good doctors, and she was a good CEO, but they just weren’t communicating and working as a whole. That kind of disconnect is ultimately going to breed inefficiency in a practice, and the patient experience will suffer.”

Articles

At Urological Associates of Southern Arizona, "collaboration" is not just a buzzword, it's part and parcel of the daily practice.

Desert Harmony: Urological Associates of Southern Arizona Strives for Collaborative Cancer Care

	A multidisciplinary audience gathered in New York City for the 5th Annual Interdisciplinary Prostate Cancer Congress. The meeting provided an opportunity for medical oncologists, radiation oncologists, and urologists to review the latest strategies and therapeutic agents available for patients with prostate cancer and fostered discussion to build consensus about best treatments.

	Three case studies focused on how best to sequence therapy in prostate cancer were presented by Daniel P. Petrylak, MD, and discussed by a panel that included Robert Dreicer, MD, and Oliver Sartor, MD. The audience voted on the treatment options they would have chosen for the patients whose cases were presented.

The patient is a 72-year-old man with a PSA score of 80. A biopsy of the prostate reveals Gleason score 10 adenocarcinoma with small-cell components. A bone scan demonstrates extensive metastatic disease, and a CT scan of the abdomen/pelvis demonstrates three hepatic metastases.

Which of the following treatment options would you recommend?

		Combined androgen blockade with carboplatin/etoposide

		Combined blockade with carboplatin/docetaxel

When you see a patient like this, with hepatic metastases and a hint of small-cell pathology, you worry about a mixed lesion because that is more typical biologic behavior. So, clearly, androgen-deprivation therapy (ADT) is appropriate. Every once in a while, a patient will show up with liver metastases from the adenocarcinoma component, so I think it’s reasonable to start with ADT. I’d probably re-image the patient in eight to 10 weeks, assuming he is asymptomatic. Obviously, if there are symptoms, you’ll start systemic therapy.

I’m thinking there are probably two components to the tumor. If small-cell is 80% on the biopsy, that pushes me a bit more toward combined androgen blockade with carboplatin/etoposide.

The patient was treated with combined blockade with six cycles of carboplatin and etoposide up front. His PSA normalized, and a CT scan of the adenocarcinoma showed that his liver metastases went away completely. He was maintained on combined blockade. After one year, his PSA rises to 40 and his liver metastases comes back. He also develops symptomatic bone pain.

		Combined blockade with carboplatin and docetaxel

Fifty percent of the audience chose abiraterone acetate, and 39% selected carboplatin and docetaxel.

To me, that PSA rise indicates that the androgen axis is still intact. So I feel that bringing an additional way to attack the androgen axis, like the abiraterone, is very reasonable. We don’t have a lot of data in this sort of setting—in fact, we have almost none&mdash;and I wouldn’t fault anybody who would go with the carboplatin/ docetaxel.

It still may be that what we’ve seen here is just mostly adenocarcinoma, so if at this juncture he’s symptomatic, I think abiraterone is a very reasonable choice. I probably would again give him four weeks of therapy and see whether or not there’s any clinical response.

The patient was treated with abiraterone/prednisone. On that treatment, his PSA dropped from 120 to 30, but a CT scan shows continued progression of the disease in his liver. Do you think the patient has a small-cell component at this point? Do you think he has an adenocarcinoma?

Approximately 67% of the audience said they’d treat with carboplatin/docetaxel, 17% said carboplatin/etoposide, 10% said irinotecan, and 7% said oral etoposide.

Is there a role for measuring chromogranin A or neuronspecific enolase? Would that help determine whether to do a re-biopsy at that point?

I’ve found it to be all over the place, and you can’t really get into a trend. Doing another biopsy is not unreasonable, but at the same point, is it going to alter your therapy that much that you want to delay and arrange for a CT-guided biopsy?

The patient was treated with carboplatin and docetaxel, and responded to treatment. The liver lesions are completely gone, although the cancer did progress into his lymph nodes, so he’s now on cabazitaxel.

I’d like to comment some more on carboplatin/docetaxel. We’ve published studies on that, and it turns out from a PSA perspective that it’s really quite an active combination. We were using it second-line and have some patients getting some pretty reasonable responses. Nobody has pursued this because it’s an old drug and old drugs die, but it’s not a bad combination at all.

How would a re-biopsy change your decision?

Well, I think that you may not go forth with a small-cell regimen if you saw that the cancer was adeno-dominant.

The optimal time to do that would have been up front, because if you’ve demonstrated a small-cell component, you already know what you’re going to do. And if it was a pure adenoma, you’d also do something different. By the time you go downstream, you’re really talking about palliation.

The patient is a 73-year-old male who underwent a radical prostatectomy for a Gleason 9 adenocarcinoma, stage T2N1M0. He undergoes adjuvant androgen blockade because of his positive lymph nodes. His PSA begins to rise from 0.8 to 1, and then one month later it’s 2.3. His bone scan demonstrates no evidence of metastatic disease, and his CT scan of the abdomen/pelvis is negative.

		Enter the patient in a phase II study for abiraterone in castration-resistant, nonmetastatic prostate cancer

I think the trial is reasonable, but there’s a risk that some patients may be directed away from it because Medicare is paying for the sodium fluoride PET scan on the basis that eligible patients will then be treated with sipuleucel-T. That’s just one of the issues being raised by these sensitive tests that can detect growing cells in the bone marrow or the bone cortex. They may be detecting disease earlier so you can get more of a treatment effect, or is this going to translate into a stage migration? We really do need to evaluate these properly to see if we’re actually doing any good by using these more expensive tests.

I agree that abiraterone on an investigational basis is absolutely the right thing to do. There is at least theoretical rationale that abiraterone may have some meaningful impact. And you have a trial, so that would be the answer.

But what will that mean for the patient if he fails abiraterone? In a retrospective study, Johann S. de Bono, MD, MSc, PhD, [of The Royal Marsden, London, England] looked at his patients who progressed on abiraterone and went on to receive docetaxel. And what he found was that their survival was reduced to about 13 months, and the PSA decline rate was somewhere around 28% to 30%, lower than you would have expected. It’s a small cohort of patients, and it wasn’t a randomized trial, so you have to take that for what it’s worth. But it may imply that you are making these patients resistant to docetaxel, so then what do you do? We don’t have a good answer, but it needs to be followed up as a study.

At least a theoretical rationale is that docetaxel may actually be operationalizing as an androgen receptor-targeted therapy as opposed to a cytotoxic. That’s the issue that’s underpinning this, and that’s theoretically why another androgen receptor- targeted therapy following a first one might be less effective.

Isn’t abiraterone approved by the FDA only after docetaxel, and if so, are the insurance companies paying for abiraterone ahead of chemotherapy?

Yes, it’s approved post-docetaxel. With regard to prechemotherapy uses, it’s very regional. About four months ago I started using abiraterone in a pre-chemotherapy setting, and I’ve actually had very little difficulty getting it reimbursed for what I felt were appropriate patients. But I know that there are certain parts of the country where there’s essentially no chance of getting it approved.

So who would you consider an appropriate patient for abiraterone before docetaxel?

The patients I will treat typically have rapidly progressive disease but no symptoms. These are patients I would not routinely treat with chemotherapy, but if I had a therapy that was effective (ie, abiraterone), then I would treat them.

What has been your experience with response rate to abiraterone after someone was refractory to androgen blockade?

Sixty-five percent. The tumors are unequivocally going to respond to abiraterone at a vigorous rate in the secondary hormonal setting. One of the things I’ve noted, though, and it’s more of a question I’m asking the group as a whole, is that when we look at this group of patients and they begin to fail abiraterone and those types of agents, the progression of their disease is very explosive.

That’s the point of the randomized stage II trial that was mentioned before. We may get an answer from that.

The patient is a 68-year-old male diagnosed five years ago with a Gleason score 9 adenocarcinoma of the prostate. Two years ago, the cancer became metastatic to bone, and he started combined androgen blockade. When the anti-androgen is withdrawn, his PSA rises to 2 over a six-month period. A CT scan of the abdomen and pelvis demonstrates no visceral metastases, and metastatic disease to bone.

You decide to treat the patient up front with:

This is the classic patient with whom, if one is going to give immunomodulatory therapy, sipuleucel-T is clearly appropriate to discuss. When we don’t have any data, for those patients who get sipuleucel-T and who are appropriate to receive additional therapy, abiraterone is perfectly reasonable. I’m not an immunologist, but immunologists tell me that 5 mg to 10 mg of prednisone, at a basic science level, really doesn’t compel one to think that it would alter an immune response. If I were going to give subsequent therapy, I would use abiraterone and prednisone. I think that’s a reasonable sequencing if one is going to use those therapies.

We’re assuming that testosterone level is castrate. And that’s something that we don’t talk about enough, because I’m running into more and more people, particularly on six-month luteinizing hormone-releasing hormone (LHRH) analogs, that are not bottoming out their testosterones where we think we should. And I think that’s important to check, particularly for urologists.

I saw a patient on Wednesday who had forgotten to go back to his urologist and was late getting his shot. I checked his testosterone level and it was 70. So he may not be actually castrate- resistant, but he presented to me as a castrate-resistant case. So I agree with measuring testosterone.

You’ve got to watch out for this, because you can get very easily fooled in missing a primary hormone failure versus somebody who did not normalize the testosterone.

I participated in the Eligard (leuprolide injection) trials, and I remember that one patient simply did not suppress. There are these rare patients out there, and you don’t know who they are until you measure their testosterone.

We even thought he was taking a testosterone supplement, like dehydroepiandrosterone sulfate (DHEA).

	The last comment to make is if you read the package for every LHRH analog or LHRH antagonist, all say you should be checking testosterone levels. It’s probably a good idea to periodically check testosterone levels, even with a routine patient who is doing well, to make sure you’re getting an optimum decline.

The patient received three treatments with sipuleucel-T. Three months later, his PSA has crept up a bit to 3. His bone scan and CT scan results are unchanged.

Approximately 73% said they would observe, 18% chose abiraterone/prednisone, 10% chose chemotherapy, and nobody chose ketoconazole.

Just a quick comment on the early use of abiraterone, and this is something I’ve seen in my older patients. A cautionary issue, and this is anecdotal and not documented in any clear way, is that these patients end up losing muscle mass. I think extreme androgen deprivation might affect the muscles a little bit more than our usual androgen deprivation.

Nobody really knows what the effect of total androgen suppression is going to be on a 20-month basis versus a four- or five-month basis.

When patients come off of a compound like abiraterone, they tell you how fatigued they were while they were on it. There’s no free lunch here. It’s a very important class of agents, but, like anything else, we’re going to have to be thoughtful, not just because of the economics but because of the impact on quality of life.

The patient was, in fact, treated with ketoconazole 200 mg PO TID. Ten months later, this patient had visceral progression, and his PSA rose to 30. He was treated with docetaxel and prednisone.

The important issue is: How do you sequence them? We don’t have biological markers. We’re all doing this based upon moving from lesser toxicity to greater toxicity.

You touched earlier on the duration of chemotherapy, and mentioned a guideline of 10 cycles of docetaxel based on the results of a trial. But I would like to know from the panel members what they do in practice if the PSA is continuing to decline and the patient is past the typical number of drug cycles and still tolerating the treatment.

First of all, I don’t follow PSA. When I’m using cabazitaxel, I’m treating patients with advanced disease who are symptomatic. So I use therapy based on symptoms. If the patient comes back and says, “Hey, Doc, I have less pain,” or “I feel better, my appetite is up, I gained a pound or two,” and he’s tolerating therapy, that’s a rationale.

What is the minimum and the maximum number of cycles if a patient is responding?

I do the same thing with docetaxel. Like many of us, I treat symptomatically, so with docetaxel I’ll say, “Look, I’m going to try to give you six cycles of therapy, and if you have clinical response, I’m going to stop,” because I’m a believer in a re-treatment paradigm. Cabazitaxel is a different story. Although there is a survival benefit, I’m treating for symptomatic benefit. You don’t need a rocket scientist to tell you when you reach maximal therapeutic benefit and the treatment window says, “If I give you another cycle, I’m defeating the purpose here.” That’s how I use cabazitaxel.

I think one of the questions you’re asking is, “Do you stop at 10 if you have a patient who is benefiting?” The answer is I do not. I have patients now on cycles number 18 and 19. I use growth factors according to the FDA guidelines, and I’ve been surprised how nontoxic they are.

Three case studies focused on how best to sequence therapy in prostate cancer were presented by Daniel P. Petrylak, MD, and discussed by a panel that included Robert Dreicer, MD, and Oliver Sartor, MD.

IPCC Case-Based Discussion: How Should We Sequence Therapy?

In men with primary squamous cell carcinoma of the penis who have undergone surgery that removed all glanular epithelium and who have nodal (N) stage 0/1, a maximum 12-month follow-up period is recommended, provided that patients are recurrence-free throughout the first year of the surveillance period, according to United Kingdom researchers.

	Importantly, they noted, this subgroup accounts for 54% of all patients with invasive penile cancer. “We recommend a maximum follow-up of one disease-free year in this population, which is far less than the five-year surveillance period recommended by the EAU,” said Hussain Alnajjar, MD, a research fellow in Urology at St. George’s Healthcare NHS Trust in London, at the European Association of Urology (EAU) 27th Annual Congress in Paris in February.

	Alnajjar pointed out that the EAU guidelines are very broad and do not take into account the different disease stages and risks.

	He and colleagues prospectively reviewed all newly diagnosed cases of primary squamous cell carcinoma of the penis treated surgically at their institution over a recent 11-year period. They found few recurrences overall in this group of patients, and most recurrences occurred within 12 months of the definitive primary treatment.

	The analysis included all patients regardless of tumor grade who had had penile surgery leaving no residual glanular epithelium, with clear local margins, fully-staged regional nodes, and pathological N stage pN0/pN1.

	In addition, follow-up protocols are generally predicated on small retrospective studies. And under current guidelines, patients have to present for follow-up consultation and clinical examination about four times a year. This can be especially difficult for patients who are elderly and/or live far away from specialized centers.

	The study was undertaken to provide more stratified follow-up arrangements based on risk of recurrence derived from a large contemporary series of patients treated at a single supra-network center. St. George’s Healthcare NHS Trust provides highly specialized penile cancer healthcare services to a population of 10 million.

	“In essence, we wanted to see if there is an identifable group of lowrisk patients who have had their glans epithelium removed totally by total glans resurfacing, glansectomy, partial penectomy, or even total penectomy and who have N0/N1 inguinal node status,” Alnajjar said.

	Overall, 228 of 420 patients with newly diagnosed squamous cell carcinoma of the penis satisfied the inclusion criteria. In the first 12 months of surveillance, there were five local, two regional, and two distant recurrences (3.9%). Two patients developed late local recurrence (17 months and 29 months), and both had G1T1 lesions locally excised. No patient had nodal or metastatic disease after 12 months. The remaining 217 (95%) patients remained disease-free at a mean of 44 months follow-up.

	“Based on our observations, we recommend that these low-risk patients be followed for a maximum of one year provided they are recurrence-free,” Alnajjar said. “They can then be discharged in the community and followed by their general practitioner. In addition, we recommend that patients perform routine self-examination.”

	Alnajjar HM, Perry MJA, Rees RW, et al. Optimal follow up arrangements for invasive squamous carcinoma of the penis. Presented at the European Association of Urology 27th Annual Congress; February 24-28, 2012; Paris, France. Abstract 523.

In men with primary squamous cell carcinoma of the penis who
have undergone surgery that removed all glanular epithelium a maximum 12-month follow-up
period is recommended.

Maximum 12-Month Follow-Up Suffices in More than Half of Men with Surgically-Treated Invasive Penile Cancer

Specialty-focused cancer treatment centers are designed to be extensions of the practices that they serve. If you are part of a urology clinic that has pathology, radiology, and lab services in-house, then you already function as a multispecialty practice. Operating inside a full-service urology practice, radiation oncology is a different kind of service center that is unique because in this setting it is not attached to a hospital and is considered free-standing.

	Integrating radiation or medical oncology into the mix can challenge even the most seasoned CEOs, both operationally and financially. Everything from scheduling and tracking cross-specialty referrals to billing audits requires special knowledge and skills unique to cancer care. As the person ultimately responsible, you have two options—recruit and hire someone with this knowledge base or hire a consultant.

	Speaking from experience, the best solution might be both. The commitment to hiring a specialist who is dedicated to the practice is a wise choice. However, finding the right person or persons is a different story and is largely dependent upon the market and availability. On the flip side, hiring a consultant who is an expert in the subject matter is also practical, but it can be expensive when services are billed by the hour. In the area of coding, both for compliance and economic reasons, this is one instance where hiring an internal expert and an independent consultant is well-advised.

	Your system for billing should include a two-part process, combined with an internal audit mechanism. Because cancer care— and specifically radiation oncology&mdash;includes both technical and professional services, documentation of services comes from the electronic generation of billable services produced by the equipment, plus those documented by the providers. A well-trained billing specialist verifies the billing sources using the technical records and electronic health record or paper chart.

	Compliant processes include an internal billing audit that occurs monthly, in conjunction with month-end closing procedures, performed by someone other than the cancer center billing specialist. Typically, this is the billing supervisor or manager. I recommend that specialty-focused cancer centers also employ the services of an independent coding expert, as a way of ensuring that correct coding guidelines are being followed. Coding rules are subject to frequent changes, and are often susceptible to interpretation.

	When you consider how complex the system is, and how little training physicians get in medical school about coding, it stands to reason that practice leadership must emphasize its importance.

	The American Medical Association maintains the nomenclature known as Current Procedural Terminology, or CPT codes. In practice management, it is the sole source of how we define services provided to patients. Our entire business is dependent upon the ability to choose the proper code so that reimbursement from payers and patients alike is accurate and appropriate.

	Urologists utilize about 350 codes on average. In fact, most specialists have a procedural repertoire of about 400 codes, out of a universe of nearly 10,000 codes. When you consider how complex the system is, and how little training physicians get in medical school about coding, it stands to reason that practice leadership must emphasize its importance.

	This is especially true when urologists establish a new service line, such as cancer care. In particular, radiation therapy is more unique, by coding standards, than people realize. Sequencing and grouping of CPT codes has an impact on compliance and reimbursement. The algorithms should be evaluated annually, if not biannually.

	If you use a consultant for expert advice on coding guidelines, be sure to check qualifications thoroughly. Interpretation of coding criteria can be subjective, and may range from conservative to marginal on the compliance scale. Even if you do employ an expert, get a second opinion from time to time. Identify an expert within your practice, and support continuing education for that person. I am always surprised when I learn of practices that do not employ at least one certified coder, particularly in the area of cancer care.

	Sometimes I am asked whether it pays to become a coding expert, as a physician, or if it makes better sense to simply hire good help. First, remember that as a physician, you are ultimately responsible for any code you or your practice submits for payment, whether you coded the services or had help. Second, you are the only person who really knows what service was performed. If you document those services thoroughly, then a coder can help tremendously. If you are poor at documentation, then a coder cannot help you. It’s either your risk or your gain.

	Free-standing specialty-focused cancer treatment centers provide one of the best patient experiences available. They serve an important niche in today’s healthcare market. Developing and managing a successful center requires attention to detail. As leaders, we are not expected to know everything, but securing the proper resources is key to long-term success.

	Joyce Vollmer is the CEO at Winter Park Urology Associates and has worked in urology practice management for 15 years. She is based in Orlando, Florida, and specializes in process improvement and change management.

When you consider how complex the system is, and how little training physicians get in medical school about coding, it stands to reason that practice leadership must emphasize its importance.

The Importance of Correct Coding in Specialty-Focused Cancer Treatment Centers

		Scanning electron color-enhanced image depicts prostate cancer cells.

Photo courtesy Annie Cavanagh/Cell Image Library

	Unlike other cancers, the treatment options for prostate cancer have remained fairly consistent over the last decade. Research has been stymied by the bland molecular sub-characterization of prostate cancer in contrast to other cancers. For example, breast cancers may or may not express hormone receptors, and various expressions are strongly linked to response. Prostate tumors—all of them&mdash;have androgen receptors. All first-line treatments have been androgen-directed, especially initially.

	Urologists and oncologists have had several treatment protocols to choose from, all approximately the same in terms of overall efficacy, although patient response has been variable. The general treatment steps have been androgen deprivation, second-line hormonal manipulations, and chemotherapy. Throughout, bone health has been a concern.

	Now, with four new agents approved in the last two years (

) and two promising agents in the pipeline, therapy selection and potential outcomes are changing.

	Each of the four newest therapies has been proven to improve overall survival or to delay skeletal-related events better than the standard therapies available prior to their approval. According to Oliver Sartor, MD, Laborde Professor for Cancer Research and medical director at the Tulane Cancer Center, New Orleans, Louisiana, “Urologists make strong bonds with their patients, and often follow them for years. All of these agents will be useful to urologists, although they may prefer to have patients with advanced disease treated in the medical oncology setting.”

	This autologous cellular immunotherapy induces an immune response targeted against an antigen expressed in 95% of prostate cancers, prostatic acid phosphatase (PAP). The FDA approved its use for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (CRPC).

	Sipuleucel-T offers a new option—immunotherapy&mdash; between initial androgen deprivation and second-line hormone manipulation. Using multiple agents to attack different parts of the neoplasm’s growth cycle is a general approach in most cancers. The sipuleucel-T trials enrolled patients who were either taxane-naïve or who had been treated with a taxane, but were fairly robust. To enroll, patients had to have no or minimal cancer symptoms, no visceral metastases, no regular opioid use, good performance status and organ function, and a washout of three months after prior cytotoxic therapy. Patients who are in earlier stages of disease and fail androgen-deprivation therapy (ADT) possess better innate immunity, which is needed to mount an immune response to this “vaccine.” More robust responses increase the likelihood of extended survival.

		Table. New and Investigational Therapies for Prostate Cancer

					An autologous cellular immunotherapy that targets PAP

					A monoclonal antibody that binds to RANK ligand, decreasing bone resorption and increasing bone mass and bone strength

					A semi-synthetic taxane developed to overcome taxane resistance

					An oral second-generation androgen synthesis-inhibitor that targets the dual-enzyme complex CYP17

					An irreversible androgen receptor antagonist and androgen receptor signaling inhibitor

					Investigational, Ra-223 or Alpharadin, Bayer HealthCare

					Delivers alpha-particle radiation to the bone and prostate cancer bone metastases

		PAP indicates prostatic and phosphatase.

	Many urologists are administering sipuleucel-T in the office, an approach that requires good planning and communication with patients. Patients undergo a leukapheresis procedure approximately three days before receiving each sipuleucel-T infusion. Urologists need to stress to patients that punctuality for the leukapheresis procedure and office infusion is essential, since leukapheresis and infusions must be appropriately spaced and sipuleucel-T expires quickly. Patients receive three doses at approximately two-week intervals.

	Sipuleucel-T is well tolerated. The most common adverse reactions, reported in up to 15% of patients, include back pain, chills, fatigue, fever, headache, joint ache, and nausea. Most patients report these as mild or moderate in severity, and most reactions occur within a day of infusion and resolve within two days. Approximately one-quarter of patients experience serious adverse reactions, defined as grade 3 or greater; these include acute infusion reactions and cerebrovascular events. Several notable single-case reports (eosinophilia, myasthenia gravis, myositis, rhabdomyolysis, and tumor flare) have been reported. 

	This monoclonal antibody binds to RANK ligand, a protein essential for osteoclast formation, function, and survival. Denosumab decreases bone resorption and increases bone mass and bone strength. It is FDA-approved for two indications: to increase bone mass in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer who are at high risk for fracture, and for prevention of skeletal-related events in patients with bone metastases from solid tumors.

	In these patients, denosumab also reduced the incidence of vertebral fractures. Between 50% and 60% of patients with CRPC currently receive a bisphosphonate. Denosumab is a superior osteoclast inhibitor compared with the current standard for patients with bone metastases, zoledronic acid (Zometa).

 According to Emmanuel Antonarakis, MBBCh, assistant professor of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland, “Xgeva [denosumab] is given subcutaneously and doesn’t require creatinine monitoring, so it’s somewhat easier to use than Zometa. It can be administered with ease in outpatient settings.”

	The most common adverse reactions reported for denosumab include back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis. Serious adverse reactions are possible and include hypocalcemia, serious infection, skin rash and dermatitis, osteonecrosis of the jaw, and pancreatitis. Calcium and vitamin D supplementation is essential, and urologists need to counsel patients carefully about seeking prompt medical attention if they develop signs or symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps.

	This semi-synthetic taxane was developed to overcome taxane resistance. Compared to mitoxantrone, cabazitaxel significantly improved survival in patients with metastatic CRPC who had previously received docetaxel. Mortality on this agent is approximately 5%, however.

	The FDA approved cabazitaxel in combination with prednisone for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel regimen. Dosage is individualized based on body surface area (25 mg/m2) every three weeks. Cabazitaxel requires dose adjustments in hepatic impairment.

	This oral second-generation androgen-synthesis inhibitor targets the dual-enzyme complex CYP17. Some experts call it a “better ketoconazole” due to its more specific and potent androgen suppression. It has been FDA-approved in combination with prednisone for metastatic CRPC patients who have received prior docetaxel. Abiraterone severely inhibits testosterone production by the adrenal gland and in the tumor itself. However, it also increases mineralocorticoid production, creating the need to administer it together with prednisone to abrogate the clinical effects of mineralocorticoid excess. In the pivotal clinical trial for abiraterone, patients treated with abiraterone acetate/prednisone lived a median of 14.8 months compared with 10.9 months for placebo/prednisone.

	Abiraterone is usually given as a 1000-mg once-daily dose in combination with prednisone 5 mg twice daily to ameliorate hypertension and hypokalemia. Patients receiving GnRH agonists must remain on them for the entire course of treatment with abiraterone and prednisone. Periodic liver function monitoring is needed.

	Abiraterone is approved for use in patients previously treated with docetaxel, but recent findings in chemotherapy-naïve patients have been positive. COU-AA-302, a large (N >1000) phase III trial of abiraterone/ prednisone versus placebo/prednisone in chemotherapynaïve patients, was unblinded in March 2012 because of the positive trend toward response in the abiraterone group. An analysis of interim evidence found that abiraterone/prednisone effectively treated mildly symptomatic or asymptomatic metastatic CRPC patients who had not gone through chemotherapy. The most common adverse events were hypertension, fluid retention, hypokalemia, and cardiac events, although there were no significant differences in grade 3-4 events in the treatment-versus-placebo group.

This investigational agent is an irreversible androgen receptor (AR) antagonist and AR signaling inhibitor, and represents an advance from the nonsteroidal AR antagonists flutamide, bicalutamide, and nilutamide. MDV3100 has redundant mechanisms: It blocks testosterone binding to the AR, impedes the movement of the AR to the nucleus of prostate cancer cells, and inhibits binding to DNA.

 In November 2011, the data and safety monitoring committee unblinded Medivation’s phase III AFFIRM trial when a planned interim analysis revealed that the estimated median survival was 18.4 months in MDV3100-treated patients compared with 13.6 months for placebo-treated patients. In addition to this 37% reduction in risk of death with MDV3100, the drug also caused tumor shrinkage in approximately 30% of patients and a 50% decline in prostate-specific antigen level.

	This drug delivers radiation to the bone and prostate cancer bone metastases. In a phase III clinical trial conducted in men with bone-metastatic CRPC who were docetaxel-refractory or docetaxelineligible, Ra-223 improved patient survival by an average of three months. In addition, Ra-223 drug therapy delayed bone damage or the need for surgery or radiation by more than five months.

	As new agents emerge and offer promising results, one concern that has arisen is cost, especially in the freestanding urology practice. “Some of these agents are extremely costly, and practices will need to plan ahead and work with both the drug companies and insurers to make sure that their cash flow is protected,” Sartor said. “And dosing needs to be scheduled carefully—a practice can lose thousands of dollars when even one dose is wasted.”

	The availability of several new treatment options for advanced CRPC presents urologists and their patients with another dilemma: Sometimes, clinical evidence may be insufficient to make informed decisions. One example is a case in which a patient with advanced disease no longer responds to standard hormonal therapies but has not been treated with docetaxel. Some physicians might want to use abiraterone, given current early evidence that this type of patient might respond to abiraterone, but the therapy has not yet been approved for use in this setting. This type of off-label use may not be covered by insurance. Approval of earlier use of abiraterone may depend upon the recently unblinded COU-AA-302 study. If and when that happens, however, physicians will then have the choice of whether to use sipuleucel-T or abiraterone first, or whether the two agents can be safely combined.

	In addition, noted Antonarakis, urologists who use these new agents will need to pay attention not only to dosing and side effects, but also to drug interactions. “Although the FDA has approved these new therapies for very specific indications, we can expect them to be used earlier in the disease as new data emerge. In addition, ongoing clinical trials will eventually identify new combinations of these drugs. For example, while only single-agent trials using Radium-223 have been completed thus far, a phase I study using Radium-223 in combination with docetaxel is now recruiting,” Antonarakis said. Experts believe that novel sequencing of treatments may improve survival rates for men with metastatic CRPC over the next few years. The optimal sequencing is being studied, and several studies are under way or being planned that examine concurrent or sequential use of novel agents with older therapies or with each other.

			Provenge [package insert]. Seattle, WA: Dendreon Corporation; April 2010.

			Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castrationresistant prostate cancer.

			Beinart G, Rini BI, Weinberg V, Small EJ. Antigen-presenting cells 8015 (Provenge) in patients with androgen-dependent, biochemically relapsed prostate cancer. 

			Rini BI, Weinberg V, Fong L, Conry S, Hershberg RM, Small EJ. Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (Provenge ) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy.

			Xgeva [package insert]. Thousand Oaks, CA: Amgen Inc; November 2010.

			Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. 

			de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. 

			Scher HI, Logothetis C, Molina A, et al. Improved survival outcomes in clinically relevant patient subgroups from COUAA- 301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel-based chemotherapy. 

			Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration- resistant prostate cancer. 

			Zytiga [package insert]. Toronto, Canada: Pantheon; April 2011.

			Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castrationresistant prostate cancer: a phase 1-2 study.

			[No author.] J&J unblind Zytiga phase 3 trial in pre-chemotherapy castrate-resistant prostate cancer. March 8, 2012. Available at 

http://pharmastrategyblog.com/2012/03/jj-unblind-zytiga-phase-3-trial-in-pre-chemotherapy-castrate-resistant-prostate-cancer.html.

			Safety and Efficacy Study of MDV3100 in Patients With Castration-Resistant Prostate Cancer Who Have Been Previously Treated With Docetaxel-based Chemotherapy (AFFIRM). 2009. Available at: 

http://clinicaltrials.gov/ct2/show/NCT00974311

			Nilsson S, Strang P, Aksnes AK, et al. A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer. 

			[No author.] Radium-223 plus chemo shows clear OS benefit. 

			Nilsson S, Franzén L, Parker C, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. 

			Parker C, Heinrich D, O’Sullivan JM, et al. Overall survival benefit and safety profile of radium-223 chloride, a first-in-class alpha-pharmaceutical: results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases. 

. 2012 (suppl 5; abstr 8 ). Available at 

http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=116&abstractID=89142

Now, with four new agents approved in the last two years and two promising agents in the pipeline, therapy selection and potential outcomes are changing.

New Therapies for Prostate Cancer: The Practicalities

	Men with low-risk prostate cancer who have opted for a strategy of active surveillance are about half as likely to experience pathologic progression or abandon active surveillance if they take a 5-alpha reductase inhibitor (5-ARI) as men who are not taking a 5-ARI, Canadian researchers announced at the European Association of Urology (EAU) 27th Annual Congress held in Paris in February.

	Antonio Finelli, MD, University Health Network, Princess Margaret Hospital, Toronto, Ontario, Canada, and colleagues reviewed outcomes in men who were taking a 5-ARI while on active surveillance for prostate cancer and men who were not undergoing 5-ARI treatment.

	More than 200,000 new cases of prostate cancer were diagnosed in the United States in 2010, and low-risk prostate cancer accounted for roughly half of the new diagnoses, Finelli said. Active surveillance is gaining traction in this population, given that surgery and radiation have an adverse impact on quality of life. Both the National Comprehensive Cancer Network and the National Institute for Health and Clinical Excellence have recommended that active surveillance be considered a first-line strategy for patients with low-risk disease, he said.

	Treatment with 5-ARIs inhibits the conversion of testosterone to dihydrotestosterone, which drives both benign and malignant growth of prostatic tissue, Finelli said. These drugs, which are indicated for the treatment of benign prostatic hyperplasia, were associated with a roughly 25% relative reduction in prostate cancer diagnoses compared with placebo in two large randomized, controlled trials. However, no studies to date have demonstrated an effect for 5-ARIs on individuals diagnosed with low-risk prostate cancer.

	The study included men with a prostate-specific antigen (PSA) <10 ng/mL, clinical stage T1c/T2a, Gleason score ≤6, and ≤3 cores positive cores with no more than 50% of a core involved at initial diagnostic biopsy. The primary endpoint of pathologic progression was defined as Gleason score >6, or maximum core involvement >50% or >3 positive cores on a follow-up prostate biopsy.

	A total of 288 men on active surveillance satisfied the inclusion criteria. The median follow-up was 38.5 months. Overall, 93 men (32%) experienced pathologic progression and 96 men (33%) abandoned active surveillance. Only 13 (18.6%) of 70 men taking a 5-ARI had pathologic progression versus 80 (36.7%) of 218 men not taking a 5-ARI (

	The median time to progression was longer in the 5-ARI group than the non-5-ARI group (42.5 months vs 31.5 months; 

 < .026). The 5-ARI group was also less likely to abandon active surveillance (20% vs 37.6%; 

	On multivariate analysis, lack of 5-ARI use was the strongest predictor of pathologic progression (odds ratio [OR], 2.98; 95% CI, 1.5—5.9), followed by age and baseline maximum percentage involvement of any biopsy core.

	Finelli said that study limitations included its retrospective design and the lack of uniform duration of 5-ARI therapy or type of 5-ARI used. He added that these findings are supported by the double-blind, placebo-controlled Reduction by Dutasteride of Clinical Progression Events in Expectant Management of Prostate Cancer (REDEEM) trial, which was recently published in 

	Finelli A, Trottier G, Lawrentschuk N, et al. 5-alpha reductase inhibitors diminish the rate of progression in men with low risk prostate cancer on active surveillance. Presented at the European Association of Urology 27th Annual Congress; February 24-28, 2012; Paris, France. Abstract 1092.

Men with low-risk prostate cancer who have opted for active surveillance are about half as likely to experience pathologic progression or abandon active surveillance if they take a 5-ARI.

5-alpha Reductase Inhibitors Help Prostate Cancer Patients on Active Surveillance

	It is with great pleasure that I welcome you to the inaugural issue of 

. As all of us are so keenly aware, the beauty of our field is the diversity of patients who walk through our doors on any given day with a vast array of symptoms and disease states that we need to manage or diagnose. Whether our patients are male or female, adult or pediatric, symptom- or lab-driven or confirmed diagnosis, surgical or medical, we represent a true hybrid specialty that relies upon our cognitive and technical skills to adequately manage our patient population.

It is with great pleasure that I welcome you to the inaugural issue of Urologists in Cancer Care.