When it comes to the personalized treatment of genitourinary cancers, biomarkers hold an immense amount of promise. Already, there are predictive and prognostic tools available to urologists.

In prostate cancer, either the old standby—prostate-specific antigen (PSA) testing&mdash;or the newer Prostate Health Index can help urologists determine when to biopsy a patient. When it seems a rebiopsy might be called for, doctors can use the ConfirmMDx test, which looks at DNA methylation; or, they can turn to PCA3, a urine test. Available to help urologists determine whom to treat are two additional tests: Prolaris and Oncotype DX.

But a host of new contenders are in development—in prostate cancer, so many that it can be difficult to keep track of all the tools and remember their specific indications. New tests are emerging in the pipeline for bladder, renal, and testicular cancers, as well, and urologists need to know the different options and how and when they should be used.

That’s why Urologists in Cancer Care has planned a two-part series exploring the use of biomarkers in the treatment of genitourinary cancers. To be published in the August and October issues of the magazine, the series will look at predictive and prognostic tests for all stages of prostate, bladder, renal, and testicular cancers, including tools already in use and others in development.

Our coverage will include the views of a variety of key opinion leaders on the promise of this burgeoning research pathway.

“There’s going to be testing that’s better than PSA to determine who needs a biopsy,” predicted Raoul S. Concepcion, MD, of Urology Associates in Nashville, Tennessee, and editor-in-chief of Urologists in Cancer Care. “If a biopsy shows a patient has cancer, then there will be testing to determine whether or not it’s aggressive, to predict who needs treatment and who is at risk of death. There will also be testing around a negative initial biopsy to see who gets rebiopsied, and then there will be a fourth category of tests to monitor the success of therapy.”

In the August issue, we will bring you a comprehensive article on available biomarker tests, as well as tests under development, specifically in prostate cancer. We will also present a summary of a recent OncLive TV Peer Exchange moderated by Dr. Concepcion, during which a panel of physicians discussed issues in metastatic castration-resistant prostate cancer, including the development and use of biomarker-based tools.

In October, we will follow that coverage with a definitive article about the current state of biomarker tools—both available and investigational&mdash;in bladder, renal cell, and testicular cancers. Also in that issue, we will offer an article exploring the challenges anticipated in obtaining health-insurance reimbursement for biomarker tests.

Dr. Concepcion hopes that the series on biomarkers will serve as a comprehensive guide for urologists on the use of prognostic and predictive tools.

“We see this as an opportunity to provide a thorough overview of what is available now, and what might be available in the next few years, when it comes to biomarker-based tools for prediction and prognostication in genitourinary cancers,” Dr. Concepcion said. “We hope physicians will read it, understand it, and keep it as a reference.”

Articles

Two-Part Series to Explore Use of Biomarkers in GU Cancer Treatment

Research from Chile suggests that low levels of free testosterone indicate that an apparently low-risk case of prostate cancer will require treatment.

Researchers from the Pontificia Universidad Católica de Chile studied 154 men whose prostate cancer qualified for active surveillance rather than treatment. The 54 men (35%) whose cancer eventually required active treatment had significantly lower starting free testosterone levels than those whose cancer was not reclassified and treated (0.75 vs 1.02 ng/dL, P = 0.03).

Men with free testosterone levels <0.45 ng/dL had a higher rate of disease reclassification than patients with free testosterone levels ≥0.45 (

 = 0.032). Indeed, free testosterone levels <0.45 ng/dL were associated with a several-fold increase in the risk of disease reclassification (OR 4.3, 95% CI 1.25—14.73).

“These results suggest low levels of testosterone are associated with more aggressive prostate cancer. This contradicts long-held beliefs that high testosterone is risky for prostate cancer, and low testosterone is protective,” said the study’s lead author, Ignacio San Francisco, MD.

Other than free testosterone levels, the researchers saw no significant differences among the men whose cancer eventually needed treatment and those whose cancer never did. The 2 groups had comparable mean age, prostatespecific antigen (PSA), PSA density, body mass index, and prostate volume.

Even total testosterone levels were comparable. It was only the free testosterone that varied. (Lower total testosterone levels did, actually, increase the risk for patients, but the numbers did not quite reach the level of statistical significance.) Researchers used receiver—operator curves to identify a free testosterone level of 0.45 ng/dL as the most appropriate threshold for further analyses—and the results were significant.

Among men with free testosterone levels >0.45 ng/dL (

 = 0.035), 36 of 98 moved from surveillance to treatment. Among men with free testosterone levels <0.45 ng/dL, 9 of 13 did. After finding that very low levels of free testosterone increased the odds that prostate cancer would eventually require treatment, the researchers looked to see whether high levels created any protective effect, but none was found.

The researchers acknowledged several limitations in their study, such as the relatively small cohort and the fact that free and total testosterone figures were available for most but not all of the men.

Moreover, they wrote, the limitations of retrospective analysis prevented them from analyzing things such factors as sex-hormone binding globulin (SHBG), luteinizing hormone, and estradiol, which affect testosterone physiology.

Still, they think the study may provide some practical benefit. Active surveillance is an increasingly popular option for men with low-risk cases of prostate cancer. Eventually, however, about a third of cases worsen to the point where treatment is needed. The ability to identify which cases are most likely to progress— and to treat them earlier&mdash;could improve outcomes, and the authors of this study think they may well have found a valuable tool in making such predictions.

“In borderline cases,” San Francisco said, “the presence of low values of free testosterone may help determine whether it is more prudent to initiate treatment rather than continue observation.”

	San Francisco IF, Rojas PA, DeWolf WC, Morgentaler A. Low free testosterone levels predict disease reclassification in men with prostate cancer undergoing active surveillance. BJU Int. Published online ahead of print, May 4, 2014. doi: 10.1111/bju.12682.

Free Testosterone May Dictate Necessary Treatment in Prostate Cancer

The American Urological Association (AUA) has added recommendations for the use of radium-223 to its treatment guidelines for castration-resistant prostate cancer (CRPC), the organization announced May 14, during its annual meeting.

The CRPC guideline was released in 2013, and the amendments regarding radium-223 were added as part of the AUA’s ongoing review of the most recently published literature. The drug was not in the original 2013 guideline because it was not approved by the FDA in time for review and inclusion in the document, said Deepak A. Kapoor, MD, chairman and CEO of Integrated Medical Professionals, PLLC, in Melville, New York, and clinical associate professor of Urologic Surgery at the Icahn School of Medicine at Mount Sinai Hospital, in New York City. Radium-223 was approved by the FDA in July 2013.

“The AUA recognized that this is an important drug in the armamentarium of urologists who treat castrate-resistant prostate cancer, did an expedited literature review, and released an update to the guideline which allows for the use of radium-223 in patients with CRPC with symptomatic skeletal metastasis,” Kapoor said.

“We in New York have incorporated this into one of our clinical pathways for some months now, and have treated a number of patients with radium-223, and I can say that it’s an extremely effective form of therapy that has produced tremendous results. So, I applaud the AUA in taking the step in updating their guideline so rapidly.”

Radium-223 is the first alpha-emitting radiopharmaceutical approved by the FDA. In the ALSYMPCA trial, it demonstrated the ability to delay skeletal-related events and prolong survival in men with CRPC, symptomatic bone metastases, and no known visceral metastatic disease.

The full CRPC guideline, including new amendments, is available at 

www.auanet.org/education/guidelines/castration-resistant- prostate-cancer.cfm

All AUA clinical practice guidance documents, including guidelines, best practices and white papers, are available online at 

		AUA Recommendations for the Use of Radium-223 in CRPC

	Clinicians should offer radium-223 to patients with symptomatic, metastatic CRPC who have good performance status and have not taken docetaxel chemotherapy. These patients should have symptomatic bone metastases without known visceral disease.

	In patients who share the same eligibility criteria but have poor performance status, physicians may offer radium-223 in select cases, specifically when the performance status is directly related to symptoms associated with bone metastases.

	Patients in the same population who have good performance status and have received prior docetaxel can also be offered radium-223.

The American Urological Association (AUA) has added recommendations for the use of radium-223 to its treatment guidelines for castration-resistant prostate cancer

AUA Adds Radium-223 to Treatment Guidelines for mCRPC

I am sure that those of you who attended the AUA meeting in Orlando were struck by the number of presentations on the use of biomarkers and their role in better risk stratification and management of the urologic oncology patient.

Obviously, many of these investigations have been focused within the world of prostate cancer. Questions in this disease state abound. Is there a better test than PSA to determine who needs an initial biopsy? Given the severe limitations of transrectal ultrasound and sextant biopsy, what assay(s) might help us decide who is the prime patient for active surveillance, or who may need a repeat biopsy if the first was negative? Lastly and most importantly, what noninvasive methodology or lab testing can be utilized routinely to monitor our current therapies and patient response?

We are coming to an understanding that cancers have some commonalities across the board. For the most part, our immune system does a yeoman’s job of monitoring our microenvironment. It efficiently weeds out aberrancies and protects us from foreign invaders. But like any security system, there will be the occasional breach, which could result in a catastrophic event. As it relates to the human body, this would mean the creation of a rogue state with potentially unregulated malignant cell growth.

Fortunately for our patients, we continue to move in a positive direction as we gain a better understanding of this incredibly dynamic and complex process. Gone are the days of routine “bleeding” to rid our bodies of evil humors. Surgery and radiation continue to be mainstays of therapy for select tumors, but they, too, are on the decline as our therapies become more molecularly based. And, as we all know, traditional cytotoxic chemotherapy is being re-evaluated.

New therapies are being developed rapidly, and it is imperative that we adjust our mindset to look at cancer development and progression in a mechanistically different fashion.

Traditional cancer-center models and therapies revolve around the organ of origin. We view tumor types based on the organ in which they are discovered. Our clinical trials revolve around the same concept: Let’s get approval for this therapy in this particular organ in a patient with this particular cell type and clinical characteristics. But in reality, neither a cancer nor its treatment is about the organ of origin. We are now of the belief that cancers are driven by common pathways that may happen to start in the prostate, breast or lung. The tumors can unfortunately mutate, and resistance to therapy is due to a new or distinct pathway that allows escape. These mutations may in fact be due to selective pressure of the treatment being used. Thus, therapies need to be developed and tested to target these pathways and epigenetic factors.

We know that immunotherapy is here to stay. Targeting the patient’s own immune system makes complete sense, given its role in surveillance, whether that be active or passive. Therapeutic vaccines, checkpoint inhibitors, advanced monoclonal antibodies: All will hopefully have a role in the management of our patients as we turn more and more toward precision medicine and the development of orphan drugs that target specific biomolecular targets. The field of “omics”—genomics, proteomics, and metabolomics&mdash; will hopefully become part of our nomenclature. Ideally, this will be the new paradigm as we move forward.

It's Not About the Organ

When a patient develops advanced prostate cancer, that doesn’t mean his urologist needs to bid him farewell. Urologists should consider treating their patients with prostate cancer from diagnosis to death, rather than sending them to oncologists when their illness progresses, as long as that plan makes sense within their business models and cultures, several speakers suggested in May during a course offered at the 2014 Annual Meeting of the American Urological Association (AUA).

With that principle in mind, the 2-hour course—whose faculty included Raoul S. Concepcion, MD, of Urology Associates, a 34-member practice in Nashville, Tennessee, and editor-in-chief of Urologists in Cancer Care&mdash;outlined how to establish an advanced prostate cancer clinic in the community setting. “We are the experts of this disease, without a doubt,” said faculty member Basir U. Tareen, MD, of the 22-member Metro Urology in Minneapolis/St. Paul. “We see this disease from the beginning, with an elevated PSA [prostate-specific antigen], to the biopsy and to the treatment.

So it naturally holds that, even once we get into the advanced stages of the disease, we should be the ones that are managing it—it provides better continuity of patient care. We don’t want to suffer the same fate as many other specialties&mdash;cardiothoracic surgery, for example&mdash;where you get stuck being a technician, and sooner or later you have a lot of other specialties taking away this disease that we really are the experts of.”

Concepcion added that retaining these patients is vital to the survival of community urology practices.

“I challenge all of you, especially those of you in independent and community practice, to look at the revenue that is generated in your practice that is directly or indirectly related to prostate cancer, whether it’s lab work, visits, surgery, imaging, or pathology,” he said. “It’s a significant number, and may range anywhere from 25% to 50% of the revenue in your practice. Yet I will speculate that we’re a couple of tests away from potentially losing prostate cancer if we don’t grasp things like the use of multiparametric MRI, a better way to biopsy. Potentially, we could lose the whole disease.”

Remaining the primary specialty that treats prostate cancer will depend on urologists understanding and using not only new imaging modalities, but also the seven novel treatments for advanced prostate cancer that were approved since 2004—most, in fact, in 2010 or later. Doctors will also need to set up procedures in their offices for making that care available, emphasized the speakers, who included Greg Hanson, MD, also of Metro Urology. During the course, the speakers outlined the factors doctors will need to consider, and the tasks they will need to complete, in order to offer their patients comprehensive prostate cancer treatment in community practices.

Urologists have traditionally been excellent at diagnosing and treating early prostate cancer, but after the chemotherapy docetaxel (Taxotere) was approved in 2004—because many did not understand its benefits&mdash;doctors sometimes spent too much time using hormonal treatments such as bicalutamide (Casodex) in an attempt to control progressive disease and manipulate PSA kinetics without a survival benefit, Concepcion said.

“I’m sure many of you heard from your medical oncology colleagues that the urologist always sent patients too late,” he said. “Ultimately, what happened is that we sent PSAs sky high.”

That may explain why it requires an adjustment in thinking, now, for urologists to consider continuing to treat patients with prostate cancer throughout the course of their disease, Concepcion said.

But with the rapid, recent approval of a host of new agents for advanced prostate cancer, each of which can offer a survival benefit of about 3.5 to 5.5 months, he said, expectations for what is possible within a urology practice have changed. “I think it’s important for us to understand all these drugs—not only their mechanisms, but more importantly [in what settings] they are approved by the FDA,” Concepcion said. “If you have an interest in this, it’s worthwhile taking the time to learn about these agents. It’s incumbent upon the urology world now to identify these patients earlier, because we all know there is plenty of data out there that suggest that the earlier we can identify patients with metastatic disease, the earlier we can start many of these patients on some of the various therapeutics that have a better survival benefit.”

That’s crucial, because castration-resistant prostate cancer (CRPC) has a high mortality rate, Hanson added. Of patients with M0 CRPC, Hanson said, 46% will develop metastatic disease by 2 years, and 80% over the long term. The 2-year mortality rate for M0 patients is 33%, for asymptomatic M1 patients is 71%, and for symptomatic M1 patients is 80%, although those numbers in recent years may have dropped slightly, he said.

In a time of such change, Concepcion entreated urologists to “be thinking about guidelines”—such as the treatment recommendations issued by the AUA or the National Comprehensive Cancer Network (NCCN)&mdash;rather than caring for patients a certain way “because that’s our gestalt, or that’s the way we learned it back when we were training.”

Based on NCCN guidelines, Concepcion gave an overview of how and when to use the new medications for CRPC, a condition he said is characterized by testosterone <50 ng/dL and a rising PSA in a patient taking hormone therapy for the disease. While in the past urologists might not have scanned patients for advanced disease at that stage, it makes sense to do so now that there are treatments available in that setting, Concepcion said.

When PSA reaches 2 ng/mL in those men, he said, “I just want you to start looking, whether you use sodium fluoride PET, which is the newest and latest technology that’s out there, or traditional CT bone scan.”

If a patient in this population has a positive bone scan, he should be maintained on LHRH [luteinizing hormone-releasing hormone] therapy, ensuring that his testosterone level is <50 ng/dL, and also given bone-targeting therapy such as zoledronic acid (Zometa) or denosumab, Concepcion said, since “the minute you put patients on LHRH therapy there is significant bone marrow density loss. Plus, if they have metastatic disease to the bone, you put them at tremendous risk for skeletal-related events.”

Then, if the patient is asymptomatic, Concepcion continued, “there is category 1 evidence to use sipuleucel-T (Provenge), abiraterone acetate (Zytiga), secondary hormonal manipulations, and clinical trials. If he is symptomatic, then what has category 1 evidence are docetaxel, radium-223, and abiraterone.

“Enzalutamide (Xtandi) right now is not approved by the FDA in the pre-chemotherapy space, although if a patient doesn’t want chemotherapy, doesn’t want anything like abiraterone and there’s a reason why they can’t take it, you could actually write for enzalutamide," Concepcion said. "Many people believe enzalutamide will probably get approval in the pre-chemotherapeutic space sometime this year.” If patients fail or do not tolerate chemotherapy, they can be given abiraterone acetate, cabazitaxel (Jevtana), enzalutamide, radium-223, and, in some cases, immunotherapy sipuleucel-T (Provenge), Concepcion added.

Hanson offered some reassurance about starting to use newer drugs, noting that reservations in his practice about prescribing abiraterone—mainly because it must be paired with prednisone&mdash;turned out to be unfounded.

“We don’t write prednisone often, and I think there was a momentary sense of panic among some of my partners about getting calls at night from patients on prednisone, and how we would manage them,” Hanson said. “After the first year, we looked back. The incidence of side effects has been remarkably low. We have not had to adjust for any hepatic issues at all.”

	How to Structure an Advanced Prostate Cancer Clinic

When the idea of starting an advanced prostate cancer clinic was broached in Hanson’s practice, “we didn’t have a lot of takers,” he recalled.

Once the clinic did get off the ground, he said, some guiding principles emerged.

Since advanced prostate cancer is very different from earlierstage prostate cancer, practices will do well to consider it a separate disease state and assign designated physicians to handle it, Hanson said.

Ideally, those few members of the practice—doctors who are comfortable treating these patients&mdash;will act as “physician champions” for the advanced prostate cancer clinic, he said. In his practice, two or three providers out of 22 are fulfilling that role.

“For us, this is where it took a lot of time, having a lead physician or a couple of lead physicians in the group to really spearhead this,” Hanson said. “In our group, we have a cancer committee that meets every 3 months. That’s where we brought a lot of this information and disseminated it out and answered questions. The further we got along, the more the partners have been receptive to this.”

A clinic of this type should use a multidisciplinary approach, Hanson added; his practice consulted with colleagues in medical oncology at nearby facilities to explain what the clinic would handle and discuss any overlap between the specialties. Metro Urology also refers patients, when needed, to an in-house bone health clinic run by a physician assistant, and staff members in the practice’s business office have excelled at working with specialty pharmacies and patient assistance services when administering drugs such as abiraterone.

When patients visit the clinic, they start with a consultation, during which they hear data about available treatment options and receive baseline imaging, if needed. If they have evidence of metastatic disease, doctors initiate treatment with sipuleucel-T, then transition to abiraterone after that series of treatments has been completed. A frustration for urologists with the newer treatments is that they are all indicated for patients with at least M1 disease; there are no FDA-approved therapies in the M0 setting, Hanson and the other speakers said.

Hanson added that issues related to the high costs of these medicines will have to be worked out, since there are still questions about how these treatments will fit into accountable care organizations and whether urologists or other specialists will write most of the prescriptions for these drugs.

Effectively imaging men with prostate cancer is the key to making sure they get the treatments they need—and avoiding therapies that won’t help them, Hanson said.

To determine which patients need a practice’s advanced prostate cancer clinic, he said, “We really want to focus on detecting recurrent disease after biochemical failure—the detection of any bony lesions or metastatic disease. When patients go from M0 to M1, that’s the definition that we need [to start treating for CRPC].”

There are a fairly large number of imaging modalities available, or being investigated, for use in tracking locally advanced metastatic prostate cancer, including the promising multiparametric MRI, Hanson said—although the jury is still out on when to apply many of these in the course of the disease, and how often.

Particularly promising technologies are the sodium acetate and choline PET scans, he said.

“These are highly avid markers for prostate cancer, even lowgrade,” he said. “They are very useful for recurrent disease. They are much more sensitive than FDG [fludeoxyglucose]. The uptake does occur in the metastatic cells prior to any osteoblastic changes; they find it a lot earlier.”

Hanson also discussed sodium fluoride PET CT, “a highly sensitive bone-seeking PET tracer useful for detecting osteoblastic new bone formation. It’s similar to technitium 99 but it’s taken up twice as much. It has better sensitivity and specificity and allows us to see lesions earlier in the disease process.” The technique, which combines PET and CT images, works most accurately in patients with PSAs of 1.5 to 2 ng/mL, especially those with quicker PSA doubling times, he said.

Hanson noted that this technique may have to be used selectively until it is more widely available, and because it is relatively expensive. While an MRI of the prostate costs about $400 or $500, or $300 through Medicare, and a full body scan with technicium 99 costs about $232 via reimbursement from Medicare, a sodium fluoride PET CT costs about $1200, he said.

However, he said, there is money available for reimbursement for sodium fluoride PET scans through the National Oncology PET Registry (cancerpetregistry.org), which is tracking how the use of these tests affects treatment decision-making to determine whether they should be routinely covered via Medicare. Medical oncologists and radiologists should be able to help urologists get their patients signed up for the registry, Hanson said.

Hanson added that it may be worthwhile to speak with colleagues in medical oncology, who order a lot of PET scans, to ask if they might find it useful to invest in a sodium fluoride PET CT machine, which would in turn create an opportunity for urologists to refer patients for scanning.

When it comes to image scheduling and frequency, Hanson said, clinical symptoms and PSA absolute doubling time are helpful indicators. Concepcion suggested beginning to image when PSA hits 2 mg/ nL and, if scans are negative, checking PSA every 3 months. If scans remain negative when PSA hits 5, he said, additional scans should take place every time PSA doubles.

“If you just use that, if you get in the habit of scanning, you will pick these patients up,” Concepcion said.

Hanson noted that the PREDICT trial (NCT01981109), sponsored by Dendreon and currently enrolling, “is going to probably look at optimal timing for imaging in M0 patients. That will probably give us some guidelines.”

When putting together an advanced prostate cancer clinic, an important piece of the puzzle involves administering the sipuleucel-T. To do that, the speakers recommended creating a sipuleucel-T clinic within each larger prostate cancer clinic, saying that model can bring significant returns.

Based on reimbursement for infusion and medication charges for the nearly $100,000 course of treatment, “our practice, on average, gets a net profit of $17,000 per infusion. We do three infusions, so that’s $51,000 per patient,” Tareen said. “It really is pretty impressive, considering it doesn’t require a lot of manpower. There are not a lot of new areas in urology where you can generate revenue in your office, and this is one area where you can.”

He added that, “Among the 49 patients we’ve infused, I don’t know that anyone’s ever paid more than $100 out of pocket. Dendreon has very good assistance programs.”

The first step in setting up a sipuleucel-T clinic is to identify patients with asymptomatic or minimally symptomatic metastatic CRPC who can benefit from the drug, Tareen said. His practice identified existing patients who were on long-term leuprolide (Lupron) and had PSAs greater than .5 ng/mL, and then determined their eligibility for the drug by imaging them, if that hadn’t been done recently.

Setting up the infusion clinic is simple, Tareen said. “You need a room that you can use for 90 minutes, a comfortable chair, an IV pole, and a nurse or somebody in your office that is capable of starting an 18-gauge peripheral IV. Then you should have some Demerol on hand in case there is an infusion reaction. And that’s really about it,” he said.

He said that patients tend to feel comfortable getting their infusions in the urologist’s office they have been regularly visiting. “They sit in a chair. It’s daytime, so they watch their 'Price is Right.' A family member will sit with them. We usually have some juice and cookies. We run the infusion over 90 minutes, and they go home.”

Since sipuleucel-T is created individually for each patient using leukapheresis, urology practices must be prepared to oversee that process, Tareen noted.

On day 1 of the process, cell collection is conducted at the nearest office of the American Red Cross. The Red Cross sends the cells to a lab where the medication is manufactured, and the patient is infused at his urologist’s office on day 3 or 4. Then, the cycle is repeated two more times. The entire process takes 5 weeks.

It’s important to tell patients how many appointments they will have, show them and their families the infusion room, and disperse educational handouts about the treatment, Tareen said.

Explaining that the drug offers a 4-month survival benefit can be tricky, he noted. “All the patient hears is, ‘I’m only going to live 4 months.’ You can say, ‘This is 4 months longer than however long you are supposed to live. It’s not that you are going to be dead in 4 months.’ I also make sure to tell them that, when you sub-stratify the data out for patients who have been treated with Provenge and have PSAs less than 20, the survival advantage can be up to 7 months.”

The administration of sipuleucel-T takes very little physician time, Tareen said. Infusions are typically directed by a nurse practitioner, he said, with the urologist dropping by briefly to check in.

“You do need to have a very strong ancillary support staff, just like anything else in urology,” Tareen said. “I think it’s important to identify one nurse champion, give them some ownership of this, and make them responsible for explaining the protocol, asking patients to fill out enrollment and patient-assistance forms, and discussing the price of the treatment and how it will be covered.” The nurse champion should schedule infusion dates based on doctor and nurse, or physician assistant, availability; call the Red Cross to coordinate leukapheresis; and set up a lab visit 10 to 14 days prior to the patient’s first Red Cross appointment so that a baseline CBC can be drawn and a vein assessment performed. In rare cases, a port may need to be placed in a patient so that the drug can be infused via a central line.

Where a practice does need to invest physician time is in choosing one or two physician champions who will conduct all patient consultations prior to the start of sipuleucel-T.

“You want to make sure, especially when you are dealing with an expensive drug, that all the FDA indications are met, that the person doing this is really familiar with the proper patient selection,” Tareen said. “They are going to be the first line of defense to verify that these patients are hormone-refractory and have metastatic disease without any visceral metastases, and will be educating the office staff and partners. The physician champion can reassure everyone that sipuleucel-T is well-tolerated and not really any more morbid than BCG [bacillus Calmette-Guerin], which we routinely give.”

The most common side effects of the drug occur during infusion, and include nausea, chills, fever, and malaise, Tareen said. “You can infuse the 250 CCs over 60 minutes, but we’ve found if we do it over 90 minutes, the reaction is much less,” he said. “We pre-medicate all our patients with Benadryl, Tylenol 1000 mg, and Pepcid as soon as we put the IV in, and you need to have Demerol on hand.”

Once a course of sipuleucel-T has been completed, Tareen added, it will be up to the physician champions to coordinate patients’ care by prescribing oral therapies or administering other follow-up treatments, and knowing when to refer a man to a radiation or medical oncologist.

			Crawford ED, Stone NN, Yu EY, et al. Challenges and recommendations for early identification of metastatic disease in prostate cancer. 

When a patient develops advanced prostate cancer, that doesn't mean his urologist needs to bid him farewell. 

Advanced Prostate Cancer Clinics Keep Urologists, Patients Together

Two recently approved drugs for the treatment of advanced prostate cancer—radium-223 (Xofigo) and abiraterone acetate (Zytiga)&mdash;will be studied in combination in a phase III clinical trial. The trial (NCT02043678) of abiraterone with or without radium- 223 has begun enrolling men with castration-resistant prostate cancer that has spread to bone, not yet been treated with chemotherapy, and is causing no or mild symptoms, according to a description on the website Clinicaltrials.gov.

The endpoint of the randomized, double-blind, placebo-controlled study will be symptomatic, skeletal, event-free survival at 3 years, or, more specifically, whether the addition of radium-223 to standard abiraterone will prolong life and delay the time to skeletal-related events such as painful fractures or bone pain, according to the website.

Secondary endpoints include overall survival, time to opiate use for cancer pain, time to pain progression, time to cytotoxic chemotherapy, radiological progression-free survival, and number of participants experiencing adverse events.

The trial could help urologists unravel some of the mystery surrounding how to best combine or sequence the half-dozen new therapies for advanced prostate cancer that have been approved by the FDA since 2010, including abiraterone and radium-223.

Radium-223 has been shown to delay the time to a patient’s first skeletal-related event, as well as to prolong survival, in patients with CRPC, symptomatic bone metastases, and no known visceral metastatic disease. Abiraterone has been shown to prolong survival men with metastatic prostate cancer in whom the disease has progressed while receiving treatment with androgen deprivation therapy.

The trial is expected to enroll about 800 patients at 150 centers, with a study completion date of July 2020 and the collection of final data for the primary outcome by July 2017.

Patients will be randomized in a 1:1 ratio to receive either radium- 223 or placebo in addition to abiraterone acetate plus prednisone/ prednisolone, in combination with best supportive care, for the first 6 cycles, followed by abiraterone acetate plus prednisone/ prednisolone thereafter. Treatment will continue until an on-study symptomatic skeletal event occurs or other withdrawal criteria are met, the website explained.

The study is sponsored by Bayer in collaboration with Janssen Research & Development, LLC.

	Clinicaltrials.gov. National Institutes of Health. Radium-223 dichloride and abiraterone acetate compared to placebo and abiraterone acetate for men with cancer of the prostate when medical or surgical castration does not work and when the cancer has spread to the bone, has not been treated with chemotherapy and is causing no or only mild symptoms (ERA 223). Clinicaltrials.gov. http://tinyurl.com/qew8l58. Published January 1, 2014. Updated May 8, 2014. Accessed June 4, 2014.

Two recently approved drugs for the treatment of advanced prostate cancer-radium-223 (Xofigo) and abiraterone acetate (Zytiga)-will be studied in combination in a phase III clinical trial.

Radium-223, Abiraterone to be Studied in Combination

Androgen-deprivation therapy (ADT) is a mainstay of treatment for prostate cancer in a number of settings, so managing its side effects is becoming increasingly important for urologists in collaboration with oncologists and primary-care physicians.

The issue is of particular concern due to the availability of newer agents that decrease testosterone levels for longer periods of time, and also with the use of ADT in non-metastatic prostate cancers, which ultimately lengthens the time men spend on antiandrogen drugs, according to Leonard G. Gomella, MD, chairman of the Department of Urology at Thomas Jefferson University Hospital, in Philadelphia.

ADT can involve bilateral orchiectomy or the use of estrogens, luteinizing hormone-releasing hormone (LHRH) agonists or antagonists, antiandrogens, newer agents such as abiraterone, or the secondary administration of ketoconazole, said Gomella, who addressed the topic during the 7th Annual Interdisciplinary Prostate Cancer Congress, held March 15 in New York City. The strategy, he said, is most appropriately used upon diagnosis of metastatic prostate cancer; with radiation in intermediate- to high-risk prostate cancer; to stimulate volume reduction before brachytherapy; and after treatment failure in localized disease, although the timing in that setting is controversial.

With increased use of the strategy have come growing concerns over side effects including hot flashes, loss of libido, fatigue, anemia, muscle loss, osteoporosis, and bone fracture.

Adverse events can also include depression, memory difficulties, and emotionality, as well as metabolic syndrome, which comprises obesity/sarcopenia, diabetes, and cardiovascular disease. While giving ADT on an intermittent schedule can help ease these side effects, the jury is still out on whether that method is as effective in treating prostate cancer as continuous therapy, Gomella said.

He suggested that urologists enlist the help of primary-care physicians in monitoring the possible development of ADT side effects by referring patients to be followed with screenings.

Gomella explained that gonadotropin-releasing hormone (GnRH) agonists increase cholesterol and triglycerides,

 boost obesity,and heighten insulin resistance

 in men with prostate cancer, potentially leading to diabetes mellitus, coronary heart disease, and myocardial infarction.

To monitor for signs of diabetes, urologists or primary-care physicians should conduct blood screens for glycated hemoglobin, diabetes, and pre-diabetes on these patients at baseline and then yearly, and should promote weight loss and physical activity,

Tracking potential cardiovascular complications should involve screening for fasting lipoproteins at baseline, 1 year, and then every 5 years, and assigning a target LDL cholesterol level based on major risk factors for coronary heart disease, Gomella said. Prevention in this setting, he said, should focus on the treatment of hypertension, tobacco cessation efforts, the promotion of healthy lifestyle choices, and the use of first-line statins for hyperlipidemia when needed.

While a normal man loses 0.5% of his bone density in a year,

 men on ADT lose 4.6% of their bone density in that period,

 a trend that “adds up over the long term and has the potential to cause great morbidity and in fact mortality,” Gomella said. After being on these medications for 10 years, 80% of men have osteoporosis,

One study found that the likelihood of experiencing a bone fracture between 1 and 5 years after treatment with a GnRH agonist increased 6.8%, to a frequency of 19.4%, in patients with prostate cancer who received ADT as compared to patients with the disease who were not treated with ADT; in the ADT group versus the non-ADT group, 5.2% versus 2.4% of patients experienced fractures that required hospitalization.

 Fractures in areas such as the hip can significantly decrease a patient’s longevity, and men fare much worse in that situation than women do, Gomella noted.

 Monitoring bone mineral density (BMD) remains the gold standard for diagnosing osteoporosis in clinical practice, the doctor said, as it is one of the best ways of determining bone strength and predicts fracture as reliably as blood pressure predicts stroke. A DEXA bone scan T-score of <-2.5 indicates osteoporosis, he said. He added that the World Health Organization has a fracture risk assessment questionnaire that physicians might find helpful.

In general, he said, osteoporosis prevention should start with “the easy stuff” before more complicated interventions are used.

One simple tactic for prevention is the administration of vitamin D, which at 700 to 800 IU per day can lower the risk of bone fracture by 26%, Gomella said.

Along with that, calcium can help, but in doses above 1000 IU it comes with a side effect of its own—a 20% increased risk of cardiovascular disease mortality in men, Gomella said.

 As a result, he said, it is now considered best for patients to get about 400 mg of calcium from their diets, with supplementation at 600 mg daily.

By inhibiting osteoclast activity, bisphosphonates such as zoledronic acid, pamidronate, alendronate, and risedronate can reduce bone resorption and turnover, slightly increasing BMD in the hips and spine and reducing the incidence of vertebral fractures by 40-70%, Gomella said. However, these drugs should not be given if a patient’s glomerular filtration rate is <30, and a dental exam should be given before starting, and again every 6 months, to limit the risk of osteonecrosis of the jaw, a potential side effect with this drug class.

Other side effects can include dysphagia, nausea, uveitis, hypocalcemia, renal impairment, and musculoskeletal pain, Gomella said.

Some bisphosphonates are approved only for women, he cautioned, and drugs in this class that are approved for men tend to be applicable in very specific settings, such as osteoporosis but no metastases, or vice versa.

Also potentially useful in this population is the monoclonal antibody denosumab (Prolia, Xgeva), which can increase bone density at the spine by 6.7% after 2 years and decrease the incidence of vertebral fractures by 68% and hip fractures by 40%, Gomella said.

Potential side effects include osteonecrosis of the jaw, hypocalcemia, and new primary malignancy, Gomella pointed out.

 Other potential treatments for bone metastases and/or osteoporosis include the parathyroid hormone teriparatide, although it is not appropriate for men who have undergone radiation and is typically not used in urology; estrogen or testosterone, which are not FDA-approved in these settings and are controversial; and the nonsteroidal antiestrogen toremifene, which is not FDA-approved for use in men, Gomella said.

To best prevent and track osteoporosis in men taking ADT, doctors should conduct BMD testing on all such patients at baseline, after 1 year of treatment, and then every 2 years, Gomella recommended. He said that prevention and early treatment should include exercise, prevention of falls, smoking cessation, decreased alcohol intake, 1000 mg a day of calcium, and 1000 IU a day of vitamin D3. Drug therapy should be considered in patients who are age ≥50 years and fit at least one of the following categories: history of hip or vertebral fracture; T-score of ≤-2.5 at the femoral neck or spine; a 10-year ≥3% probability of hip fracture according to the World Health Organization’s questionnaire; or a 10-year ≥20% probability of a major osteoporosis fracture according to that scale.

Gomella concluded his talk with a discussion of hot flashes, which affect 50% to 80% of men taking ADT.

Palliative measures should include suggesting that men identify and avoid their hot-flash triggers and keep their environment cool, Gomella said. He added that reassuring patients that hot flashes may subside over time “usually does a lot of good.” While hot flashes can interfere with a patient’s daily activities, Gomella continued, they are difficult to treat because there are no FDA-approved medications for this condition in men, and many of the therapies that are available can result in side effects.

 and medroxyprogesterone acetate at 400 mg/d

 have been fairly effective, but cause weight gain, Gomella said. Other treatments being tested or used in this setting include estrogens, antidepressants, neuromodulators, and acupuncture—which so far seems promising for its efficacy and lack of side effects, Gomella said. He added that soy products contain phytoestrogens that might decrease hot flashes and improve cardiac and bone health.

			Smith MR, Finkelstein JS, McGovern FJ, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab. 2002;87:599-603.

			Smith MR, Lee H, Nathan DM, et al. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab. 2006;91:1305-1308.

			Keating NL, O’Malley AJ, Smith MR, et al. Diabetes and cardiovascular disease during androgen deprivation for prostate cancer. J Clin Oncol. 2006;24:4448-4456.

			Saylor PJ, Keating NL, Smith MR, et al. Metabolic complications of androgen deprivation therapy for prostate cancer. J Gen Intern Med. 2009;24 (Suppl 2):S389-S394.

			Kanis JA. Osteoporosis. Blackwell Healthcare Communications Ltd; 1997:22-55.

			Maillefert JF, Sibilia J, Michel F, et al. Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma. J Urol. 1999;161:1219-1222.

			Morote J, Morin JP, Orsola A, et al. Prevalence of osteoporosis during long-term androgen deprivation therapy in patients with prostate cancer. Urology. 2007;69:500- 504.

			Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med. 2005;352:154-164.

			Trombetti A, Herrmann F, Hoffmeyer P, et al. Survival and potential years of life lost after hip fracture in men and age-matched women. Osteoporos Int. 2002;13:731-737.

			Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson- Hughes B, et al. Fracture prevention with vitamin D supplementation; a meta-analysis of randomized controlled trials. JAMA. 2005;293(18):2257-2264.

			Larsson, SC. Are calcium supplements harmful to cardiovascular disease? JAMA Intern Med. 2013;173(8):647-648.

			Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Eng J Med. 2009;361(8):756- 765.

			Smith MR, Egerdie B, Hernandez Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Eng J Med. 2009;361(8):745-755.

			Irani J, Salomon L, Oba R, Bouchard P, Mottet N. Efficacy of venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for the treatment of vasomotor hot flushes in men taking gonadotropin-releasing hormone analogues for prostate cancer: a double-blind, randomised trial. Lancet Oncol. 2010;11(2):147-154.

			Jones JM, Kohli M, Loprinzi CL, et al. Androgen deprivation therapy-associated vasomotor symptoms. Asian J Androl. 2012;14(2):193-197.

With ADT in PC, Managing Side Effects Increasingly Important

The world’s largest gathering of urologists, the annual meeting of the American Urological Association, offered an array of information relevant to those who practice in the community setting.

was on site during the meeting, held May 16-21 in Orlando, Florida, to cover presentations of data from recent research studies, as well as in-depth courses teaching urologists to pursue a variety of new paths in their day-to-day practice.

This month, we present that coverage both in 

Covered in these publications is a study demonstrating that carefully trained German shepherds are able to detect prostate cancer with 99% accuracy by sniffing men’s urine samples. Also in the area of prostate cancer, we offer information about a new way of examining prostate-specific antigen dynamics to determine when the disease is likely turn aggressive; data on the success of intermittent dosing of the gonadotropin-releasing hormone antagonist degarelix (Firmagon); and the addition of recommendations for the use of radiopharmaceutical radium-223 to the AUA’s guideline for the treatment of metastatic castration-resistant prostate cancer.

The AUA meeting also offered a plethora of information about other diseases treated by community urologists. Here, we summarize studies that considered the cost-effectiveness of testicular self-examinations; the use of a cell-cycle gene array test to predict metastatic progression of renal cell carcinoma after surgery; and the value of physical activity in preventing death from bladder cancer.

In separate conference coverage, we offer articles about some of the most intriguing genitourinary-related presentations made at the May 30-June 2 annual meeting of the American Society of Clinical Oncology—including data showing a nearly unprecedented increase in median survival for men with newly diagnosed metastatic, hormone-sensitive prostate cancer when chemotherapy was added to standard hormone therapy.

Elsewhere, we focus on the ongoing quest to understand how best to combine and/or sequence treatments for prostate cancer—in part through a physician-authored column on radium-223. Further, we offer a look at novel imaging techniques for use in patients with prostate cancer; a discussion of how to treat the side effects of androgen-deprivation therapy; a primer on how to launch an advanced prostate cancer clinic; and insights into how to use social media as a marketing tool for large urology group practices.

We also have a profile on the life’s work of Lawrence H. Einhorn, MD, who helped develop a cure for testicular cancer. For his contributions, Dr. Einhorn was named one of OncLive’s Giants of Cancer Care in 2013.

We hope this array of information reflecting the constant evolution of genitourinary cancer care provides strategies our readers can apply immediately, in addition to an understanding of promising new tactics in the pipeline.

The world's largest gathering of urologists, the annual meeting of the American Urological Association, offered an array of information relevant to those who practice in the community setting. 

June 2014 | Oncology Live Urologists in Cancer Care®