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When a patient develops advanced prostate cancer, that doesn't mean his urologist needs to bid him farewell.
Raoul S. Concepcion, MD
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—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—cardiothoracic surgery, for example—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—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)—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.”1
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—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.”
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—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.