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Conversations With Prostate Cancer Experts


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Dr. Daniel George on PSA Recurrence

Dr. Daniel James George is Professor of Medicine and Professor in Surgery at Duke University.

Prostatepedia spoke with him recently about biochemically recurrent prostate cancer.

Have you had any patients whose cases have changed either how you view your own role as a doctor or how you view the art of medicine?

Dr. Daniel George: As we evolve new therapies and indications for treatment, it’s really interesting how that affects our relationships with patients. As an oncologist, my relationships with patients have become more longitudinal. What I mean by that is: people are living longer than ever. I’m beginning to recognize my treatments in the context of not just the short-term endpoint of how to control my patient’s disease in the next few months but in terms of the ramifications for his life and long-term survival. What does it mean in terms of his functional well-being, not simply now, but in a year from now or five to ten years from now?

In many ways, it comforts patients to hear the perspective, that I see them as a long-term survivor, and that I’m thinking about the implications of our treatments in a long-term perspective. That helps the patient invest in his own life and well-being for the long-term, whether that be diet, exercise, sleep, or all these other behavioral interventions that can really impact their quality of life.

You’re basically saying that prostate cancer is becoming more of a chronic disease.

Dr. George: It has been for some patients, and we’re beginning to recognize it more and more for all patients.

We used to think of short-term goals for some of our most advanced cases of prostate cancer—just in terms of disease control or palliation and not worry about the long-term implications of treatment. While on the other end of the spectrum we would have cases where we don’t have to treat the disease at all or maybe treat it minimally in others. Now I’m recognizing prostate cancer as a chronic disease for everybody, and so everybody needs to think of the long-term implications of treatments.

Likewise, we need to think of the implications of our sequential therapies and their cumulative side effects.

Can you define M0 prostate cancer, or biochemically recurrent prostate cancer, for patients?

Dr. George: This is probably confusing because of its name. We refer to prostate cancer in terms of stage. Stage refers to the extent of the disease. The Gleason Score or grade refers to how it looks under the microscope, its aggressiveness. But stage refers to the progression of this disease. Do they have bone metastases? Do they have distant lymph node metastases or other sites of disease? Or is it localized?

We usually use three categories: the T stage, which is the localized tumor, the N stage, which is the lymph node status, and then the M stage, which is the presence of metastases that are distant from the prostate. M0 refers to patients who have no distant metastasis. Think of M0 in terms of patients who are newly diagnosed with prostate cancer.

Recurrent prostate cancer patients are those who’ve had local therapy, surgery, or radiation, and who now have evidence of disease recurrence by PSA. After these treatments, we know that your PSA should be 0 or very low, and it should stay low. If your PSA rises and continues to rise, that’s an indication of disease recurrence. Yet, in many cases, they’re what we call M0 because, when we stage the patient with a bone scan or a CT scan, we can’t see any evidence of cancer. Many of those patients have what we might otherwise refer to as microscopic metastatic disease, disease that’s just below the level of detection. Some of them could have local recurrence or recurrence just within the pelvis and regional nodes that’s not distant. We now know from recent studies that the majority of those patients are going to relapse with distant metastatic disease. In other words, they have distant metastatic disease, but it’s just below the level of detection.

So, this is a bit of a misnomer because we’re treating them with systemic whole-body treatment therapy now because we recognize the risk of distant metastatic disease for the majority of these patients. We’re beginning to use newer imagining techniques, such as PET scans, that could be more sensitive at picking up this microscopic metastatic disease. That shouldn’t deter us from applying the current data to that patient population.

I think of M0 prostate cancer as being low-volume castrate resistant prostate cancer. When we think of it that way, it makes sense that the drugs we’re using work and work even better in that low-volume population. We should use them because M0 is just an early continuation of that metastatic process.

What are these systemic approaches that patients are likely to receive? What are the implications down the line in terms of side effects, and in terms of the longer longitudinal quality of life issues you mentioned earlier?

Dr. George: This is an important aspect of the care for these patients because we have two studies—and a third will soon be reported—that demonstrate a clinical benefit from using what we have broadly termed secondary hormonal therapies, therapies that we add to primary androgen deprivation (ADT) or testosterone suppression.

Patients for whom testosterone suppression has failed can respond to another hormonal intervention later. These are drugs that target the androgen receptor, the protein that testosterone binds to, and inhibits it from signaling. It shuts off what seems to be the most common mechanism for resistance to testicular testosterone suppression. That is an overexpression or overabundance of this receptor, which makes prostate cancer cells sensitive to low levels of residual testosterone in the body.

Xtandi (enzalutamide) and Erleada (apalutamide), in two separate Phase III studies, have demonstrated a clinically significant benefit: a delay in the time to metastasis. The FDA has accepted this as a meaningful endpoint because of the degree of delay. It was associated with about a two-year delay in the time to metastasis in this population.

Patients who were at high risk for developing metastatic disease were in the control arm and developing metastatic disease within about a year of coming on the study for the placebo arm. For the treatment arms, with Xtandi (enzalutamide) or Erleada (apalutamide), we’re seeing a delay of about two additional years. That means three years until the time of metastasis.

The results suggest that we’ve changed the progression of this disease dramatically. In addition, both studies showed a strong trend in favor of the treatment arm for improved overall survival associated with this delay in metastasis. Even though the data may not be as complete because it takes a longer time to report, we’re seeing this correlation in metastasis-free survival, if you will.

Again, I caution the semantics here because these patients do have metastases; they just can’t be seen yet. But the delay in that radiographic appearance of metastasis is associated with an improved survival.

What’s the approach to finding smaller metastases earlier on with the newer imaging techniques? And if they are very small, do you treat them aggressively with radiation, do you continue using the systemic therapies, or do you use a combination?

Dr. George: There is a mix of presentations of patients. When we image with a novel PET-imaging tracer, we’re going to see more than one site of disease in most patients. We’re going to see multiple lymph nodes, multiple bone metastases, or maybe lymph and bone metastases.

For a subset of about 20 percent of patients, we see this disease limited to only lymph node disease or only one or two bone metastases. We refer to this as oligometastatic disease, which we have yet to biologically define. Clinically, we know that it’s associated with a longer survival.

Oligometastatic prostate cancer raises the question of whether or not these patients could be managed with therapy localized to those sites, therapy that does not necessarily expose them to further systemic therapy. We don’t have a lot of data in the castrate-resistant setting, but in the hormone-naïve setting, there are some data that suggest that there can be a delay in the time to initiating subsequent hormonal therapy by doing that.

There’s a study out of Europe, but the median effect was relatively small, just a few months. It’s not clear that this is going to be a meaningful difference for most patients, but it is something that can be discussed.

A lot of those treatment approaches can be done with minimal intervention, external radiation, ablations, or limited surgery. Those will be options. But in the majority of these patients that we do this molecular imaging for, we’re going to find evidence of more than one site of disease or multiple lesions. This suggests that they need a systemic therapy approach.

It’s reasonable to extrapolate this data because we know from the placebo arm of these studies that these patients went on to develop metastases in their bone scan or CT scan within months, 50 percent of them within a year, and many of them in just a few months of their subsequent scan. The likelihood is, if we’d done the molecular imaging at baseline on these patients,we would have seen it. Yet still, in this population, we’re seeing a treatment effect.

We see the treatment effect regardless of what level of PSA doubling time you have. In patients who have a PSA doubling time of just two or three months, we see a dramatic treatment effect. In patients who have a doubling effect of eight or ten months, we still see a dramatic treatment effect in terms of prolongation in the time to metastasis—fewer events in those cases, but still, we see that treatment effect.

The PSA doubling time is an important parameter that we’re using now, in addition to these imaging stats, to determine who we should treat with these drugs and their prognosis.

Isn’t doubling time an indication of the aggressiveness of the disease?

Dr. George: It is. We knew this earlier in disease prior to hormones. PSA doubling time was very prognostic for time to metastasis and overall survival. It’s been less studied in the castrate-resistant setting, when patients have progressed on primary hormonal therapy, but we’re still seeing it there. In fact, the results are really dramatic.

There were some abstracts at the Genitourinary Cancer Symposium (GU ASCO) around this data. There have been reports from these two Phase III studies with Xtandi (enzalutamide) and Erleada (apalutamide) that demonstrate this. We believe there is a strong correlation between a shorter PSA doubling time—a shorter time to bone metastasis—and shorter overall survival.

Just to put these studies into context, the requirements were that PSA doubling times were less than ten months. If doubling time is a year or longer, these are slow-growing cancers. Even though they’re castrate-resistant, these are patients who will live for many years with no metastasis, so it’s reasonable just to observe their disease. For the studies, the median or 50th percentile PSA doubling time was around four months. That’s really short and aggressive.

That’s why we saw that the average time to metastasis was just about a year in the control arms. It’s important to recognize where your patient is in this continuum because it guides whether we should treat him like we did on the study, or if their disease is too slow growing to justify the treatment.

What other considerations are important for patients who fall into this category?

Dr. George: The important thing for patients to know: not to worry. I know that as a physician, it’s easy to say ‘don’t worry about your rising PSA level,’ but as a patient, it is hard to ignore.

Join us to read the rest of Dr. George’s comments about biochemically recurrent prostate cancer.


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Join A Clinical Trial For Biochemically Recurrent Prostate Cancer

Dr. Rahul Aggarwal is an Associate Clinical Professor of Medicine in the University of California, San Francisco Genitourinary Oncology and Developmental Therapeutics programs. He’s keenly interested in developing novel therapeutics and imaging strategies for men with advanced prostate cancer.

Dr. Aggarwal is a Co-Investigator in the ongoing Prostate Cancer Foundation’s Stand Up To Cancer-funded West Coast Dream Team prostate cancer consortium.

Prostatepedia spoke with him about his clinical trial on hormonal annihilation in men with high-risk biochemically recurrent prostate cancer.

Not a member? Join us.

What is the thinking behind your clinical trial on hormonal annihilation in men with high-risk biochemically recurrent prostate cancer?

Dr. Aggarwal: This trial is for patients with prostate cancer who previously had what we call a radical prostatectomy, or the prostate was removed, as their primary treatment and then subsequently had evidence of cancer recurrence as indicated by a rising PSA. We’re specifically looking at patients with a PSA that is rising quickly with a PSA doubling time of nine months or less.

We know that this group of patients is at risk for subsequent development of metastases as well as at risk for prostate cancer-related mortality. One standard treatment approach is to use intermittent hormone therapy, which can suppress the cancer for a period of time. Inevitably, though, the cancer becomes hormone or castration-resistant.

Once that happens, patients have fewer treatment options remaining and a shorter prognosis.

The main goal of the study is to use some of the more potent hormonal therapies that have been developed, including Zytiga (abiraterone) and Erleada (apalutamide). and apply them to this situation to see if we can durably suppress the patients’ prostate cancer in a finite period of treatment. Rather than treating indefinitely, we treat everyone on the study for 12 months, and then we stop and let their testosterone levels recover and any side effects related to hormone therapy stop or lessen. Hopefully, we can see long-term control of patients’ PSA levels or maybe for some prevent the need for future treatment.

In this way you would also lessen some of the side effects associated with these treatments?

Dr. Aggarwal: Exactly. Then the total duration, or percent time, spent on hormone therapy would be shorter. Even though we’re giving more potent hormone therapy, this would actually translate into less overall treatment and less medical burden from a side effect perspective. Some of the other studies that have come out using medicines like Zytiga (abiraterone) and Erleada (apalutamide) in the hormone sensitive or castration resistant settings do seem to suggest there is a benefit to giving these medicines earlier in the treatment course. I think it fits with what we’re seeing in terms of the general trends in the use of these medicines and the management of prostate cancer.

What can a patient expect to happen step by step if he ends up participating?

Dr. Aggarwal: The treatment phase of the study consists of monthly visits for a year in which patients are getting hormone injections. Then it is a randomized study, so in the standard of care arm men would be getting the hormone injections alone once a month for a year. Then there are two experimental, or investigational, arms with added hormonal therapy. One arm has added Erleada (apalutamide). The third arm adds Erleada (apalutimide) plus Zytiga (abiraterone).

Patients have a two in three chance of being on one of the added hormonal treatment arms.

This is an open label trial, meaning there is no placebo. Everyone will get active treatment, so there’s no risk that their PSA levels won’t go down. Every patient responds initially to hormone therapy, or nearly everyone. We see patients monthly for hormone treatments. We evaluate them for side effects. At four or five time points throughout the study, we have patients fill out questionnaires regarding their symptoms. We do want to understand from a patient perspective what quality of life and symptoms are like during the course of treatment.

After one year of treatment, assuming the PSA is not rising, patients will then enter a follow-up phase which we try to make easy. We check patients’ PSA and testosterone levels once a month, but we don’t require any mandated in-person visits to allow more flexibility for those who live far away from the study center where they were treated.

At the time that the PSA rises to above 0.2, that’s the cut off for what we call PSA progression, which is the primary endpoint of the study. After that treatment is per the discretion of the patient and treating doctor. We still follow patients long term for metastases free and overall survival. The treatment options at that point are completely up to whatever is decided upon between the patient and his doctor. It’s flexible on the backend too if his PSA were to rise.

Join us to learn more about Dr. Aggarwal’s trial and how to participate.


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Prostate Cancer Dormancy + Disseminated Tumor Cells

Dr. Julio Aguirre Ghiso is a Professor of Medicine, Hematology and Medical Oncology and Oncological Sciences at Ichan School of Medicine at Mount Sinai in New York City. His research explores why and how in some patients disseminated tumor cells can remain dormant for years after initial treatment before reactivating to form incurable metastases.

Prostatepedia spoke with him about his research and about a clinical trial testing his findings that is currently looking for prostate cancer patients.

To  learn about a clinical trial for prostate cancer patients that Dr. Aguirre-Ghiso is running: Join us or download the issue.

Why did you become involved in cancer research? What is it about cancer research that has kept you interested?

Dr. Julio Aguirre-Ghiso: When I was an undergraduate student, I was looking for challenging problems to solve in biology. Serendipitously, I started working and volunteering for a cancer biology team in Argentina, where I trained. I became very interested. I was working on tumor immunology. Then I became very interested in the cell biology of cancer cells. At some point, I realized that it didn’t really matter if it was cancer or Alzheimer’s or some other basic biological questions on other organisms; what I really was curious about was solving tough problems and answering questions. This was a good mix where, if I were able to do it, I would also be helping people with cancer in the future.

Focusing on cancer would give me an opportunity to apply my curiosity to something that is relevant for people. That was the original intention. Since I was not an MD, my curiosity was about mostly biological questions. This was a fitting problem to go after.

Let’s talk about the concept of disseminated tumor cells. Can you explain to us how that works and how it is related to the development of metastasis?

Dr. Aguirre-Ghiso: Patients usually present with what’s called a primary tumor. That’s the first cancer lesion ever found in that patient. At that time, doctors will do certain tests on that primary tumor to understand if it had gone through certain changes that would make it able to spread. When cancer cells grow, they may acquire certain abilities that allow them to spread from that primary site—from, let’s say, the prostrate or the breast—to other parts of the body.

The disseminated tumor cells are these cells that have spread throughout the body. They have disseminated from the primary tumor to other organs in the body. Those could be the bones; the liver; the brain; or the lung. When they arrive to those organs, they’re not immediately able to grow. Since they’re usually solitary cells–that’s how we find them in the patient samples and in the mouse models that we’ve used—we call them disseminated tumor cells. They’re not yet metastases, but they’re not in the primary tumor. They’ve left and arrived to other organs. That’s the definition of these disseminated tumor cells.

Why are they important? We and others have provided compelling evidence that these cells are the source of the metastases. Those are the cells, not all of them, but some of them, that are able to eventually grow into metastases that affect the functioning of the organ, and sometimes systemically, the functioning of the patient. That’s what leads to death. That’s why these cells are important.

Do all disseminated tumor cells eventually grow into metastases?

Dr. Aguirre-Ghiso: No.

How do you know which disseminated tumor cells are going to grow into metastases and which are not?

Dr. Aguirre-Ghiso: Well, that’s been a major challenge and a major push from my program: to try to get in early and identify those disseminated tumor cells so that we have some idea if a patient carries disseminated tumor cells that are not going to do anything and the patient doesn’t have to worry, or if the patient carries some cells that look like they’re switching and they’re going to form metastases.

That has been our goal. It’s not yet a clinical test, but that’s why we have pushed the boundaries of our research to get to that point as fast as possible because we think that instead of waiting and not doing anything or treating blindly and then waiting until those metastases grow, we can intervene earlier. We would like to be able to say that this patient has only dormant cells and they don’t look like they’re going to reactivate based on certain markers or gene signatures.

That patient would then only need to be monitored, but new treatments may allow eliminating even those cells. If another patient has a mixture of cells some of which are fully dormant and some of which look like proliferative cells, we would treat him in a different way.

We have provided data for this from our mouse models and from clinical patient samples in prostate cancer. We published two papers in 2014 and in 2015 on this.

Not all cells are going to grow.

In fact, if you look at early lesions in breast cancer, for example, disseminated tumor cells are found in the bone marrow of 13-15% of women with ductal carcinoma in situ but only a small fraction of that 13-15% will develop metastases. It’s not a given that if these cells are there they’re going to grow, but if they are there, there is a higher risk of metastases. That has been proven by large population studies that have been published in The New England Journal of Medicine. This is true for not only breast cancer but for other cancers as well. The goal and the challenge is to have enough information to be able to predict accurately what those cells are going to do when you detect them.

Where we are in the timeline of being able to predict which patient is carrying potentially dangerous disseminated cancer cells and which is carrying dormant disseminated cancer cells?

Dr. Aguirre-Ghiso: We have different areas of research into these disseminated tumor cells. Why they are dormant? Why do they sleep in the body for a long time and then awaken? We discovered a marker in 2015 that could distinguish these deep-sleeping cells in both prostate cancer and breast cancer models. If the cells had this marker, they would behave in this dormant way, and if they didn’t have this marker, they would look more like a proliferative or an about-to-reactivate cancer cell.

At that time, it was correlative between just two groups of patients. Last year, we published a paper on breast cancer where we used the same marker detected in tumor cells disseminated to the bone marrow of breast cancer patients. We were able to show that if patients had this marker they were much less likely to relapse with bone metastases than if they didn’t have this marker. In 2015, we’ve published the original finding where we just said this is probably a good marker; we understand how it works in mouse models. In 2018, we showed that the presence of the markers can distinguish retrospectively how patients behaved. Now the challenge is for people to start using the markers prospectively to see if it helps them make decisions on how to treat or monitor patients. We are very much at the early stages of applying the information that we have generated and bringing it into the clinic.

On the other hand, in that same 2015 paper, we were able to show that if we use two drugs that are FDA-approved and combine them in sequence, we can turn on these dormancy mechanisms in different types of cancer cells—i.e. breast, prostate, and head and neck cancer cells. Because these drugs were available—and there are independent studies showing that when prostate cancer patients are treated with hormonal therapy and anti-androgens, they turn on this marker of dormancy that tells you the cancer is deciding to go into sleeping mode— we wondered if we could repurpose those drugs and treat prostate cancer patients at risk of developing metastases to see if we could delay the onset of metastasis and keep the disseminated tumor cells in a dormant state.

To read the rest of our conversation and to learn about a clinical trial for prostate cancer patients that Dr. Aguirre-Ghiso is running: Join us. Or download the issue.


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Dr. Maha Hussain On Biochemical Recurrence

Dr. Maha Hussain is the Genevieve Teuton Professor of Medicine in the Division of Hematology, Department of Medicine, and the Deputy Director of the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine.

Prostatepedia spoke with her recently about biochemically recurrent prostate cancer.

What is biochemical recurrence?

Dr. Hussain: A biochemical recurrence implies that an individual with prostate cancer who has received therapy now has evidence of disease activity as reflected by their PSA blood test. In the context of negative imaging, the PSA is a flag. It generally indicates a relapse. Generally speaking, when the patient has a rising PSA, they get imaged. If the scans are negative, then this becomes purely biochemical recurrence.

Why is this a disease state that we’re particularly focused on? What are some of the key issues in how we approach treating these men?

Dr. Hussain: There are two settings of biochemical recurrence. One is the non-metastatic hormone sensitive setting. This means a patient has had local therapy with surgery and their prostate was taken out, or they’ve had radiation therapy with or without hormonal treatment, and now they have a PSA that’s going up. This implies there is cancer activity. Generally, imaging is done, and most of the time, conventional imaging such as bone and CAT scan are negative.

While not imminently harmful, non-metastatic hormone sensitive biochemical recurrence has significant psychological implications for the patient because it reminds them that there is cancer activity in their body that’s growing.

With regard to management, salvage radiation plus hormone therapy is the standard of care for patients who developed PSA-only relapse post radical prostatectomy as it reduces risk of mets and improves longevity. While there are options for patients who had radiation therapy plus hormonal therapy, they are not optimal.

For example, while hormone therapy is an option for patients whose PSA started to increase after salvage radiation and hormonal therapy, the totality of the data to date does not suggest significant benefit for early hormone therapy versus waiting until there’s a reason to treat.

This population; non-metastatic hormone sensitive PSA relapse, tends to live quite long, and some may not develop visible mets. The speed by which the PSA starts to go up and how fast it increases—what we call doubling time—can imply earlier versus later development of metastatic disease. Detailed discussion is needed to address options, pros and cons of treatment, and potential options for clinical trials.

The other setting of biochemical recurrence is the non-metastatic but castrate-resistant setting, which differs from the previous setting in that patients were treated with hormone therapy and now their PSA is rising while on therapy; that is the rising PSA is occurring despite the fact that hormone therapy has lowered their testosterone levels to the castration range. This is a different clinical phase of disease where the cancer has shown that it is no longer responsive biologically to the hormonal therapy that they are receiving. We know that, given enough time, cancer will show up. We know also that the speed by which the cancer is growing, as reflected by the PSA rate of increase, has an implication as to how soon the cancer will show up on the scans.

This is an area of an unmet need for decades, until last year when two drugs were FDA-approved for this particular patient population, specifically Erleada (apalutamide) and Xtandi (enzalutamide) based on significantly delaying time to development of metastasis. At this year’s American Society of Clinical Oncology GU (ASCO GU) conference, there was also positive data from another trial with Darolutamide in this disease setting. I believe the drug is in front of the FDA at this moment for review.

These three trials were done in a population of patients who had a worse prognosis as reflected by their fast PSA doubling time—a doubling time of 10 months or less. This is because these patients are likely to show metastases within an average of about two to two and a half years.

The issue is whether there is benefit for people who don’t have that kind of PSA doubling time. What if the doubling time is one or two years? It certainly is an area where we need to think about value to that patient.

For both Erleada (apalutamide) and Xtandi (enzalutamide), the FDA approval did not specify the doubling time requirement. The FDA approved it in all patients who have non-metastatic castrate-resistant disease. Clearly one size does not fit all. It’s critical to make shared decisions between the patient and the treating physician with regard to the value of the treatment, the risks from the cancer, the risks from the treatment, the treatment objectives, and when to initiate therapy.

Some good news about this disease phase is, because it’s invisible cancer, and while this means there’s micrometastatic disease, the patient has some time to think about things and also monitor carefully.

In my experience, probably about 8 to 9 out of 10 patients elect to be on treatment because of the concern over worsening disease and the value based on the clinical trials. There are some patients who feel great, and if they’re not going to have an issue tomorrow, then they want to wait a few months before deciding on treatment. That’s perfectly reasonable.

Isn’t that true for a variety of situations in prostate cancer, that you have time to gather a variety of opinions?

Dr. Hussain: Correct in general, but specially for this disease space because no one is going to die overnight from a PSA that’s not controlled. That’s to put it bluntly. There is that room. Patients should talk with their physician about that and discuss risk-benefit ratios as all therapies have side effects.

For certain patients, those side effects might be more important, especially for those who have significant cardiovascular disease. It becomes important to incorporate risk-benefit and close monitoring, but it doesn’t mean that no treatment should ever be done.

Do you have any other advice for men in this situation?

Dr. Hussain: One thing to remember for men with hormone-sensitive biochemical recurrence who have had salvage therapy or post radiation and hormonal therapy is that if therapy is to be done, it ought to have a good reason. Lowering the PSA alone is not the objective; clinical benefit should be the objective.

There is potential harm from treatment in the absence of proof that giving hormone therapy for a PSA of let’s say 0.5 or 0.6 will have a benefit. One has to balance the risks from the treatment and both physical and monetary risks to the patient and ultimately implement a shared decision.

These conversations with patients can be long and potentially stressful to the patient. Yes, hormone therapy can be given. The issue is not whether it can be given but whether it should be given, and if so, when.

There’s a fair amount of population-based data that suggests there’s no clear advantage, but there’s limited prospective clinical trial data. I would encourage patients to discuss these issues with their physicians, understand the upsides and downsides, and also discuss opportunities for clinical trials. Clinical trials are one space in which we need informative data and partnerships with patients to come up with better answers.

For patients who had radical prostatectomy (surgical removal of the prostate), and then their PSA is going up, their best treatment option is salvage therapy, which involves radiation with hormonal treatment.

Based on the more recent data from Radiation Therapy Oncology Group (RTOG), the radiation involves the prostate bed and the pelvis to include the pelvic lymph nodes with four to six months of hormone treatment. This is something that should be discussed with the care team. Radiation alone is not enough, and certainly the data indicate the combination is better with regard to outcomes. If the patient doesn’t want to do the hormones, that’s fine, but the hormones can reduce risk of progression and potentially add to overall survival.

The other side would be situations where patients have had radiation therapy and have received hormonal treatment as part of their primary treatment. Then they stopped the therapy, and now months or years later, the PSA is rising. That’s a different scenario. The issue is whether to resume hormone therapy or not. That’s when a careful conversation is necessary between patients and their physician because there is no compelling data that say it’s necessary to do the hormone therapy.

So, there are a variety of situations.

Dr. Hussain: Yes and/or access to clinical trials. We know the phases of prostate cancer now. The same disease state now has multiple phases, and it’s becoming complicated. That’s important because this speaks to the importance of personalizing care for the patient at all levels.

We’re becoming more and more personalized about how we categorize the different disease states.

Dr. Hussain: Yes, absolutely, and we do individualize the care. A 50-year-old who comes in with non-metastatic castrate-resistant prostate cancer and no comorbidities has a very different disease than someone who is 85, had a stroke, and is in a wheelchair.

Patients should ask their physicians specifically about the type of biochemical recurrence they have, their expected prognosis based on their PSA doubling time, their risk-benefits ratio, and which scientific information from prospective clinical trials can help guide their decisions. Patients should ask for educational material, and doctors should help patients make a decision that’s not based on being afraid but being informed about the choices, pros, and cons.

Would you give similar recommendations to anyone along any stage of the disease progression?

Dr. Hussain: Absolutely. Informed decisions are critical in every disease setting. But biochemical recurrence is a complicated phase of disease. In the setting of metastatic disease, it’s relatively easy in that there is no question regarding the disease risks. Earlier therapy, before symptoms or before the disease worsens, is better generally. This a disease setting that is likely to cause harm if therapy is delayed significantly.

But with non-metastatic hormone sensitive biochemical relapse, a patient can go for years without having any visible metastasis. It’s more complicated when there’s no imminent danger. At the end of the day, I tell patients with non-metastatic hormone sensitive disease in whom there is no clear data to support benefit from systemic therapy, that this is a gray area where we don’t have compelling data to say that giving hormone treatment is going to give a meaningful benefit. Therefore, one option is we monitor closely with interval PSA checks and periodic imaging. Based on doubling times and trends, what new evidence that comes up, and patient comfort we can watch. Once the patient is informed about the specifics, it is fascinating that the majority tends to be comfortable with watching and about a third are not comfortable with not getting therapy. There is not a one-size-fits-all approach. Personalized shared decision is critical.

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Biochemical Recurrence

In March, we’re talking about biochemical recurrence.

Dr. Snuffy Myers frames the issue for us below.

Not a member? Join us to read conversations with Drs. Daniel George, Pedro Barata, Julio Aguirre-Ghiso, and Rahul Aggarwal.

Pp_March_2018_V4_N7

This issue focuses on treatment issues for men with an increasing PSA after prostatectomy or prostate radiation. In this introduction, I will review some basic concepts that should help you follow the discussion more easily.

If surgery has successfully removed the prostate gland, the only source of PSA will be surviving cancer cells. After radiation, there can be normal prostate cells in addition to cancer cells. However, prostate cancer cells differ from normal prostate cells because the cancer cells are able to grow in a particular manner. Cancer cells grow by doubling: 1 cell becomes 2; 2 become 4; 4 become 8. Cancer cells do this at a constant rate.

For example, if the cancer cells double every year, then on subsequent years, the number of cancer cells would be 1, 2, 4, 8, 16, 32, 64, 128, 256, and so on. As a general rule, it takes 15 doublings to go from 1 cancer cell to a mass 1 centimeter across. At 1 centimeter, cancer masses generally become detectable by CT scan. As a rough rule of thumb, it takes another 15 doublings to reach a lethal cancer burden.

The implication is that half of the cancer growth occurs below the level of detectability.

Unlike most cancers, our ability to follow prostate cancer is not limited to imaging tools like the

CT or bone scans. We have PSA as a biochemical marker that can be used to follow the cancer. The PSA is a much more sensitive indicator of cancer presence than both CT or bone scan and can indicate the presence of recurrent cancer months to years earlier.

In most patients, the PSA level is roughly proportional to the size of the cancer mass: if the cancer doubles in size, the PSA will double. Thus, the PSA doubling time is thought to provide an estimate of the cancer doubling time. PSA doubling times faster than 3 months usually indicate rapidly growing disease associated with short survival unless treated aggressively. PSA doubling times slower than 9 months usually indicate much less aggressive cancers. PSA doubling times greater than two years are associated with prostate cancers that can take a decade or more to cause metastases detected by the scans.

As a result, it is common to see men after surgery or radiation who have an increasing PSA, but no other evidence of disease. In those patients, PSA doubling time represents the only well established tool to determine the aggressiveness of the cancer and how soon metastatic cancer might manifest itself.

PSA, however, provides no information about the location of the cancer. Is it present in bone, lymph node, liver, or lung? The recent advances in PET scans mean that the cancer can now be detected while it is much smaller than would be the case with CT or bone scan. However, clinical trials have yet to prove this early detection improves the outcome of treatment.

Finally, there is the problem of late relapses. After surgery, patients can have an undetectable PSA for years—even more than a decade— and then recur. What was going on during that silent interval and what changed to trigger recurrent cancer? This phenomenon is called cancer dormancy and is also reviewed in this issue.

Charles E. Myers, Jr., MD