Sorting Out What Makes Sense in Diagnosing, Treating Prostate Cancer

Evidence-Based Oncology, February 2014, Volume 20, Issue SP2

In the fall, The American Journal of Managed Care convened an expert panel to address emerging issues in the treatment of prostate cancer. According to a 2012 report from the American Cancer Society, prostate cancer is the most common cancer among men, accounting for 43% of all cancer cases among men in the United States.1 Panelists addressed current controversies over when and how often to screen men for prostate cancer, as well as which treatments should be given to which patients. This transcript has been condensed.

The discussion was chaired by A. Mark Fendrick, MD, co-editor-in-chief of The American Journal of Managed Care.

Participants were:

E. David Crawford, MD,

head of Urologic Oncology at The University of Colorado at Denver, University of Colorado Hospital,

Daniel J. George, MD

, Duke Cancer Institute, and

Neal Shore, MD,

medical director, The Carolina Urologic Research Center, Myrtle Beach, SC.

Prostate Cancer Screening: Is the PSA Test Still Valuable?

A. Mark Fendrick, MD, opened the discussion by asking panelists to respond to the controversy surrounding the 2011 recommendation from the US Preventive Services Task Force (USPSTF), which called for not screening men without symptoms using the prostate-specific antigen (PSA) test.2 The recommendation has been criticized in some circles and was followed with a separate recommendation from the American Urological Association (AUA) that screening on asymptomatic men not occur until 55 years.3 As Fendrick explained, the apparent competing recommendations “have made it quite confusing for general internists like myself,” as well as stakeholders—including payers who must decide whether the PSA test will be covered. Dr Fendrick invited comment from Neal Shore, MD, and E. David Crawford, MD. Dr Crawford has published on this topic and is currently involved in the PLCO trial (prostate, lung, colorectal, and ovarian screening).

Dr Crawford:

This is one of the more controversial areas in prostate cancer and early detection. In 1989, prostate cancer became the most common cancer in American men, and the second leading cause of death. Most of the cases that were diagnosed were advanced. When the maximum PSA test came out, the thinking was that mortality rates could be reduced with screening for early detection.

What happened was we were too successful—the pendulum swung from late diagnosis to an over-diagnosis of cancer. We were finding small cancers and overtreating people. The real controversy is very simple, I think, you need to separate diagnosis from treatment.…

The backlash occurred, and it needed to occur, but now we need to get some equilibrium and really identify who will benefit from treatment. Thirty thousand men are still dying from prostate cancer, and we need to whittle away at that.

Dr Shore:

I completely agree. We have this conundrum: We have many patients who do not need treatment, and yet we have many patients who need aggressive treatment. We have 250,000 men who get newly diagnosed with prostate cancer, and much of the data would suggest anywhere from 30 to 50% have a very unaggressive or low-grade form of the disease and would benefit from monitoring, or what some call active surveillance. We have not done a great job of that, but we now are on the cusp of doing a much better job with additional biomarkers and assays.

At the same time, there are 50 to 60% of men who need active interventional treatment, whether it is surgical removal or radiation or cryoablation. And so the task force recommendation of D (which states there is “moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits”) has uniformly been met with disdain and shock by the urologic community, because it was just too severe.

Team-Based Approach

Dr Fendrick asked for comment on the emerging concept of a “team-based” approach to cancer treatment, which encourages greater integration and cooperation among all those involved in a patient’s care, including medical oncologists, urologists, radiologists, and even nurse practitioners.

Dr Crawford:

We have had a multidisciplinary team in place for several decades.… It is tough to get all of the specialities together, and we do not all agree. Now what we have shown, and this has been shown not only with our group… is that folks who are treated in our multidisciplinary clinic actually have better survival rates than do patients in Colorado who do not. It is not just that selection bias, because we do get some tough cases.…This does make a difference, and men appreciate it.

What sometimes happens, unfortunately, is that if the practice has a robotic machine and everybody needs to get a robotic prostatectomy, you think it is great. If you have IMRT (intensity-modulated radiation therapy) or protons, then that is what you do.…

There are multiple ways people can be treated and you have to be honest with them. Often with early prostate cancers, the cure rate is the same with all of the treatments; there are just different side effects. When people exaggerate the lack of side effects, that leads to some of the controversy that exists right now in prostate cancer.

Dr Fendrick then asked Dan George, MD, to comment specifically on whether the teambased approach was “an outlier or the norm.”

Dr George:

I think this is becoming more and more the expectation for patients. This goes beyond prostate cancer. If you look at cancer in general more and more of our therapeutic modalities; from pancreatic cancer, rectal cancer, or esophageal cancer… (we are moving toward) the multidisciplinary approach. There is a growing expectation for cancer patients that they are going to be cared for by a team, it is not a single-doctor management plan any more.…As Dr Crawford said, it is hard to get everybody together. One of the big advantages we have in academic medical centers is the opportunity under 1 roof to have shared clinics and shared infrastructures, so that with 1 visit patients can see multiple specialists.…

It is our credibility as care providers for this patient new to cancer to know that he is getting the best choice based upon all of the options presented, and that he is not just hearing a biased presentation on how he should be managed.

As you have heard, with screening we are going to have patients who do not need treatment at all, or need minimal, single modality treatments; those patients with more locally advanced cancer are really going to need a multi-modality approach to management and treatment. For patients to really understand and accept where they are in that spectrum we have to have credibility. For most educated cancer patients, this is now the expectation. And I think you will see the community doctors more and more finding ways to provide that in their environment.

Shared Decision Making in Selecting Treatment Options

Dr Fendrick next asked for comments about benefits of shared decision making, in which the patient is engaged in the discussion of which treatment choice makes sense for his particular cancer. Despite a more patient-centered approach in academic centers or large practices, he said that AJMC tends to receive papers that illuminate Dr Crawford’s observation: if a prostate cancer patient sees a radiation oncologist, he is more likely to receive radiation therapy; if he sees a surgeon, he is more likely to end up having surgery. Do large groups tend to realize early on that a given patient may benefit from particular type of care? Dr Shore responded first.

Dr Shore:

Historically, we have practiced in silos in the community, but what we are seeing now is the aggregation of large groups, particularly in medical oncology and urology communities. Large group practices—which are probably defined as anything more than 10 physicians— afford a level of subspecialization.…I am seeing more large urology groups, as well as medical oncology groups, hire radiation oncologists and hire urologists within a medical oncology group and vice versa....

Getting back to the decision regarding the patient’s best treatment choice: I would hope that this would prevent that patient from just getting siloed into having his prostate removed, or being radiated if he only saw the physician who only offered that 1 form of therapy. I think throughout all of medicine we have recognized that we have to do a better job of making sure all options are explained to patients.…

Both in academia and in the community, we have not paid enough attention to outcome data and quality measures. We are really starting to see that now; and from a payer’s standpoint that has huge implications. We have a finite amount of resources to allocate to these therapies.

Dr Crawford:

One of the challenges that I see, and this is actually being commented on by the Office of the Inspector General, is that a group gets an IMRT machine and all of a sudden the reimbursements are terrific for that....The number of cases they refer internally for IMRT goes up, and other things go down. What are your comments on that?

Dr Shore:

Perhaps you are alluding to a recent report by the (Government Accounting Office) GAO, but (that report was) lambasted because the results were not evidence-based.…We certainly can do a better job of policing outliers; those in our subspecialties and specialities who are not following best practices.…There is no doubt we have outliers, every profession does; historically we have not done a good job (of policing them) but I think we are recognizing the importance of doing so. But the in-office ancillary exception is vital as far as I am concerned, absolutely vital, to the future of the independent practice of medicine. There are those who would take the outliers and use that across the board and take away physicians’ abilities to have an integrated facility. That I think would be incredibly detrimental in the long run for the future of independent practices of medicine.

Dr Fendrick asked the other panelists to respond, and to discuss what tools are used to ensure shared decision making, to ensure that prostate cancer patients get an unbiased description of their treatment options.

Dr George:

I think we are recognizing that there are different ways of presenting this information, and we are becoming a little bit more sophisticated in doing this.…In an ideal world you do not need a multidisciplinary clinic. In an ideal world any one of us as prostate cancer providers ought to be able to equally represent the other choices, the other modalities and approaches. But to Dr Crawford’s point, that is not the world we live in; we all have biases whether we admit them or not. A multidisciplinary clinic allows us to balance those out. A benefit of a multidisciplinary clinic is that it regrounds us on the data from these other fields, and in tools like this to understand how best to present treatment choices to patients. Once you start practicing this way, it affects how I talk to patients in my own clinic when I am seeing them as the only cancer specialist.…

Dr Crawford:

I would agree and disagree when we talk about multidisciplinary clinics. You cannot expect me to know what a medical oncologist knows; you cannot expect a medical oncologist to know what I know. I think the benefit of a multidisciplinary clinic is that it starts out with pathology. I am not a pathologist, but we will see 1 or 2 patients a month who were advertised as having prostate cancer, but do not have prostate cancer; instead they have ASAP (atypical small acinar proliferation) or PIN (prostatic intraepitheial neoplesia).…The pathologist is important here; the radiologist is also important in picking up lesions and things like that; the medical oncologist can talk about trials and outcomes.

I think that Dr George is right, we all have a knowledge of a little bit about radiation, but it is not perfect.

Dr Fendrick agreed with their points, and then asked, based on unmet needs and challenges, where research and development efforts should be aimed.

Dr Shore:

We have this odd spectrum of aggressive to indolent disease in prostate cancer, as opposed to many other solid tumors that tend to be more uniformly aggressive. How do we decide who the men are in the 50 to 60% of newly diagnosed cases that need aggressive treatment? How do we best treat them? That’s where we have to have the multidisciplinary philosophy that we just discussed....

In addition, we are now entering new metrics. The metrics we have historically used to decide on aggressiveness of therapy have been age and actuarial survival comorbidities; specific to prostate cancer, we have looked at histopathology, the Gleason Score, and the stage of the disease— which mostly involves the digital rectal exam and PSA. Now we are looking at genomic assays and other biomarkers to help us decide additional testing or aggressiveness of therapy.

We really are now entering into a new world, and I think it is incumbent upon not just urologists and medical oncologist, but also primary care physicians to understand that we can do a much better job in selecting patients who require more aggressive therapy. We still have patients who, if we fail to do appropriate targeted screening, then we will miss further opportunities to help the men who need aggressive therapy early on.

Dr George:

I agree 100%. I think that is our biggest risk—that we make a blanket decision not to screen. I think there are a lot of people in primary care who have already come to that conclusion, and their patients are going to suffer. We are not reflexively treating everybody with surgery or radiation therapy, and there are growing numbers of patients with active surveillance, which is affording us to be aggressive in treating the patients who need it.

The Large Urology Group Practice Association will have additional recommendations that will give greater clarity and specificity, to help the clinicians better understand that PSA does have value if used judiciously.

Dr Fendrick:

I completely agree, and I think ultimately the idea of targeted screening will not just be used in prostate cancer screening, but will be used other screenings as well. We have seen advances in human papilloma virus (HPV), and now our cervical cancer screening rates have changed. Obviously, you all know of the great controversy in breast cancer screening—when to start and how often.

Disparities in Screening and in Treatment

Dr Fendrick asked whether the new treatments and diagnostic tools available for prostate cancer, which can invite a more targeted approach, are cause for optimism, or whether treatment gaps—and differences in mortality— existed for certain groups.

Dr Crawford

clarified that there have always been calls for more focused attention to high-risk groups, including African American men and those who were exposed to Agent Orange in Vietnam. “This is not new; this has been around for a while but people have just not paid attention.” Conversely, no professional society endorsed practices like PSA tests for elderly men on oxygen, and yet those things happened. What’s happening now is that efforts by the American Cancer Society and USPSTF are forcing physicians to adhere to long-standing best practices. Dr Shore responded.

Dr Shore:

There are some great advances though, and there are still some additional low-hanging fruit. Dr Crawford mentioned the challenge with the African American community. If you look at all of the up-to-date most recent American Cancer Society statistics the disparity and mortality for prostate cancer…there is virtually upwards of a 100% differential in mortality through much of the southeast of the United States and in urban areas. It speaks to receiving inadequate care, inadequate screening, inadequate treatment, and that is real low-hanging fruit to do away with that disparity.

Dr Fendrick asked whether the disparities were due to a more aggressive disease at diagnosis, or whether these differences played out regardless of how advanced the disease was at diagnosis.

Dr Shore:

It is a great question. It is multifactorial, and it is potentially an earlier, more aggressive disease for some. It is being diagnosed too late for many. It is receiving inadequate therapy for many, both in localized as well as in advanced disease. This allows us to segue into the burgeoning advancements of advanced prostate cancer therapies. Obviously we are thrilled over (this), for advanced prostate cancer is clearly one of the best examples of tremendous advancement from preclinical to clinical or from bench to bedside, where we are doing a markedly better job in keeping men alive and maintaining quality of life. Among African American men, many of them have not been brought into the trials that have shown these advancements and still are not receiving therapy. In my own state of South Carolina, Medicaid lags behind in offering advanced therapies to patients who could benefit from FDA-approved therapies. It is a multifactorial issue for certain populations, no doubt.

Excitement Over Emerging Agents

Dr Fendrick asked about coverage for new therapies, such as abiraterone and enzalutamide, and invited panelists to comment on clinical data on emerging agents.

Dr Crawford:

In the last 3 to 4 years there have been 7 new drugs that have been introduced in the arena of advanced prostate cancer, with more to come. There was a dearth of activity for decades; we had LHRH (luteinizing hormone-releasing hormone) antagonists, and we had mitoxantrone, and we have other types of chemotherapy with taxotere. Now we have these new drugs and the interesting thing is all of these drugs are different. They are immunotherapy, they are new chemo, they are anti-androgens, LHRH antagonists; they are radionucleotide, bone preserving agents. It is an exciting time (Table).

Dr Crawford then asked Dr George to comment on how all these new drugs are integrated. Are they sequenced? Are they used together? And Dr Crawford raised the issue of cost, as many cost up to $100,000 per year.

Dr George:

You bring up all of the critical issues in 1 question—it is a little daunting. This is a time of excitement, and a little bit of anxiety as we see a sudden explosion of treatment options all at once. And the reason that is a challenge is that they are developed largely in parallel, so we do not necessarily have the data of using these agents in sequence or in combination.

Dr George explained having 7 new therapies at once, with relatively few data on how they should be used in sequence or in combination, presents challenges for practitioners. Which patients need which therapies? He noted several points: (1) Most of the new therapies are based on overall survival (OS) improvement. (2) These therapies work through different mechanisms— these are not “me, too” drugs. Immunotherapy, for example, is in a class by itself. He continued:

Dr George:

It really is a fantastic opportunity, but it is a real challenge to understand: do these disparate mechanisms actually add to each other in sequence? What is that sequence, and are they overlapping when you block the testosterone pathway with an androgensynthesis inhibitor, such as abiraterone? Does that somewhat negate the benefits of subsequent enzalutamide, or vice versa? I think those are some of the challenges that we face right now, which I think payers are going to face, in helping us justify the sequence that we do.

Dr Fendrick noted that previously, medicine did not worry about cost-effectiveness until there was a well-known and rigorously established benefit. Having so many new drugs at once makes that impossible.

Dr Fendrick:

Dr George, you mentioned the melanoma example; this is not dissimilar to a discussion we had recently where the enthusiasm was high, the science was fascinating, but at the same time while the potential was clear, there wasn’t a lot of clinical experience using these drugs in sequence or in combination— even though the theory would suggest that they would work better together than alone.

Dr George:

We do have some sequence data; it is not obviously complete, but we do have some. For instance, the immunotherapy sipuleucel-T was largely given to a patient population that had not received chemotherapy. Eighty-five percent of the patients had never received chemotherapy for prostate and showed a significant survival advantage in that population. Incidentally, that percentage improvement in survival looked similar in the 15% that did receive chemotherapy. So, it looks like you could give that therapy either before or after chemotherapy, but the strongest data is giving it before chemotherapy.

Among our secondary hormonal therapies, abiraterone acetate, which is an androgen-synthesis inhibitor, and enzalutamide, which is an androgenreceptor antagonist, have both shown significant improvement in survival in patients that had received prior chemotherapy. This suggests that chemotherapy is not selecting out resistance for those strategies. Abiraterone has also gone on to show a significant clinical benefit to a broader patient population, those patients who had never received chemotherapy.

I should point out that in prostate cancer, only about half of the patients ever go on to receive docetaxel-based chemotherapy or other chemotherapies, so when we look at a post chemotherapy patient population we are looking at a relatively narrow field of patients, who are somewhat healthier but more aggressively treated. When we look at a pre-chemotherapy population of patients, we are looking at a much broader cross section of the population of castration-resistant prostate cancer (CRPC) patients.

There, too, abiraterone showed significant clinical benefit. This was not necessarily a statistically significant improvement in OS because the study was stopped short of that end point, but for all of the clinical end points before that—disease progression, time to chemotherapy, pain, and other deterioration in performance status—all strongly favored abiraterone over prednisone alone. This is suggesting, again, we are changing the natural history of this disease by using a drug like that early.…

The Challenge of Personalized Medicine Dr Fendrick asked the panelists to address how clinicians and payers can deal with the “moving target,” the challenge of matching the appropriate treatments to the right patients with limited data.

Dr Crawford responded by saying it was time to think “outside the box.” For years there very few treatments, and the discussions were along the lines of “pain or no pain.” Dr Crawford highlighted how the discussion of treatment costs has shifted; years ago, he was an author on a paper in the New England Journal of Medicine about men paying $240 a month to extend survival by 6 months, and that was considered expensive. Today, he said, instead of $240 the costs are “tens of thousands” of dollars a month.

Dr Crawford:

Is there a rationale for using some of these new agents, the C17-20 hydroxylase agents, such as abiraterone, early? Maybe, as there was a study that was just done that will have some results. Should you do that early, should you use an antiandrogen receptor different from casodex and other ones? There is a rationale for combining abiraterone with enzalutamide. So, in the real world, I would say okay, we can study this all, but is it going to take 15 years?

Dr Crawford says years ago, leukemia researchers were criticized for going from a single drug to 3 or 4 to obtain data, but that may be the way to convert prostate cancer into a chronic disease, rather than a fatal one. Giving a patient sipuleucel-T will not react with other treatments, for example.

Dr Fendrick responded that this approach reveals the challenges with so many therapies: “The more we get and take advantage of this personalized medicine the harder it is…to educate the payer community on this idea.…This is about trying to get the right agent or the right treatment to the right patient at the right time.”

He asked Dr Shore to discuss whether guidelines from the National Comprehensive Cancer Network (NCCN) are keeping pace with cutting-edge science. “It seems from the operational standpoint to be really challenging.”

Dr Shore:

Organizations such as the NCCN, which do have CRPC Guidelines based upon their panel of key opinion leaders, do try to give guidance to urologists, medical oncologists, and radiation oncologists on how to best deal with these newly approved, very exciting, highly individually unique mechanism of action therapies—which also have price tags.

Also, we recently saw publication of the American Urological Association CRPC Guidelines, and they described 6 different index cases starting from the patients who are CRPC rising PSA, with a castration level of testosterone and no radiographic evidence of disease and asymptomatic, to the patients who are at the very end who are after chemotherapy who are progressing as well. It is a very nice breakdown, and of course since its publication in May 2013, right afterward we already had the approval of Xofigo or Radium-223. This speaks to what was said earlier, where we are continuing to develop new therapies to add to our armamentarium, which adds to the confusion on how to sequence combinatorial strategies.

This can potentially create confusion from the payer’s side as to when they should be providing reimbursement. The bottom line is there are now very well described recommendations by the AUA CRPC Guidelines Committee, as well as the NCCN on what the Level One Evidence is and what is less than Level One Evidence for making decisions.

In my mind, the best methodology right now from a payer’s standpoint to say, OK, we understand the FDA-Labeled Indication and therefore we should respect the labeled indication and where they fit in to those 2 discrete guidelines. I think as long as we follow that, then we are not going to have clinicians and patients be disappointed that they do not get adequately supported by their payer.

Dr George:

I agree, but there is a limitation; and I appreciate that the guidelines just did not reproduce themselves. I thought the AUA did a really nice job of doing something different from NCCN. As much as I respect the NCCN guidelines they are not helpful to clinicians, because all they do is recapitulate the level 1 evidence we have and then the level 2 evidence is basically just consensus building....I think what the AUA put together is much more contextual and helpful in helping clinicians say, “Oh, my patient looks like this scenario or that scenario, and I am going to follow that approach.”

Dr George explained it is one thing to tell practitioners when to start a therapy; it is quite imanother to tell them to stop, or when to switch. In this area, there is very little guidance.

Dr George:

The payers cannot say anything there, because there are no data one way or the other. Once they have paid for a medicine they are not going to stop paying for it, so there is no pressure on that side, either.

Offering Guidance for Payers

Dr Fendrick said that precedents exist for payers in other chronic conditions, such as hepatitis C, in which if markers do not respond treatment is stopped. He encouraged each panelist to offer advice to payers on how to decide what to cover in the new world of prostate cancer treatment, and laid out the extremes:

Dr Fendrick:

Clearly we cannot give every drug every time to anyone. Nor do we want to get to a situation where you are going to have to call us for a prior authorization every single time.

Dr Crawford said he disagreed somewhat with Dr Shore about the value of NCCN guidelines, and to an extent with the AUA guides. The issue, as he sees it, is not whether there is a guide for one drug following another, but that the guides do not address “what I think we all believe is the bright future.” Cures may be possible where they were once not.

Dr Crawford:

We need to think outside the box and take some chances. The chances we are taking to test this cancer, and putting together bleomycin and cisplatin when these were monotherapies, and then people did doublets and triplets....Well, I think we have to do that in prostate cancer.

Yes, it is going to be extremely expensive; it could be $400,000 a year, but we have the American ingenuity and the wherewithal that we will find better ways to do it, or there will be other drugs that come along that are less expensive in the same category.

I think we really owe that to men with advanced prostate cancer, to make that step and start doing this and seeing how it goes.

Dr George:

I would echo that. There is a very important point here, and that is that we cannot be complacent with prostate cancer.…We have not cured anybody with this disease, and even patients who go through all of these therapies; I have plenty of patients who have gone through all of them and they are still dying of prostate cancer, and they could still benefit from additional treatments.

This is a research question, and the national research agenda of our cooperative groups, of our industry, of the federal government or the US Department of Defense, needs to get behind those kinds of initiatives for sure, and maybe the payers do, too.

Dr George agreed that practitioners need better predictive markers to match treatments with patients, as well as more guidance on when to stop or switch therapy. The PSA, he said, is a “pretty good marker of response to those agents that are targeting the testosterone and androgen-receptor pathways, but it is not perfect.”

Dr George:

I think there is a blend here of continuing to do the envelope-pushing combination strategies, with cost to the wind—let’s try to cure the disease—because that is going to be the most cost-effective manner of managing these patients in the long run.

Dr Shore:

I would like to respond to the 2 of you disagreeing with me. I think when you say “real world” that really is interesting to me, because 80 to 85% of cancer is practiced in the community, not in academic centers.

The real world is fighting to get patients reimbursement for these expensive newly approved therapies. I am in those trenches and I see how that happens, but I am not sure that in the academic centers you see it to the same degree. Perhaps you do, but in the community you really come to it in a more direct way. And so the question that I was asked was, “What are guidelines for payers?” or “Are there guidelines for payers?”

It is a law that if there is a level 2 recommendation by NCCN, then the (Centers for Medicare & Medicaid Services) has to reimburse. So, for the payer population that is going to be hearing this, that is very important. It is a separate issue to think about and to discuss issues of predictor response, and resistance, combinatorial, and sequencing strategies.

The question that was asked is, “How are we going to pay for this, and what would be the recommendation to the payers regarding these new novel and newly approved therapies?” and, “Where do they best fit in based upon the guidelines?” When NCCN gives something a level 2, by law CMS has to pay for it, so that actually is federal policy. That I think was the point I was trying to make.

Dr Fendrick:

EBO

I want to thank all of you for this really robust conversation on not only where we are, but where we are going and where we need to push the envelope on prostate cancer.

References

1. American Cancer Society. What are the key statistics about prostate cancer? http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics. Updated August 26, 2013. Accessed January 4, 2014.

2. Moyer VA. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157(2):120-134.

3. Carter HB, Albertson PC, Barry MJ et al. Early detection of prostate cancer: AUA guideline. J Urol 2013;190(2):419-426.