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Conversations With Prostate Cancer Experts


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Chemotherapy: An Infusion Nurse’s Experience

Catherine Guider is an infusion nurse with Kaiser Permanente in Sacramento, CA.

She offers Prostatepedia her perspective on chemotherapy for prostate cancer.

Why did you become an oncology nurse?

Ms. Catherine Guider: I was interested in oncology even back in nursing school. I had a grandfather who had cancer and was given a very short timeline of survival, and he was one of those that beat the odds and made it to 93. I got to see a side to cancer that some people don’t get to see.

In nursing school, I did some time on an oncology inpatient floor and found it challenging and rewarding when it came to the personal relationships that I got to build with patients and their families.

When I came to Kaiser, I didn’t start in that department, but after a couple of years, I took an opportunity to move to the floor that does inpatient chemotherapy. A short time later, I was certified with chemotherapy and biotherapy, and I stayed there for many years. Now, I’m in the outpatient infusion oncology clinic.

Have you had any patients over the years who changed how you see your own role or how you see nursing in general?

Ms. Guider: Because I was in the inpatient side where sometimes people stayed for longer than a day or two, I saw the impact that we can have on their lives. I would spend my lunchbreak with some of our oncology patients, sharing lunches and time together, and I noticed that sitting with them would help them eat more and make them feel lighter. It’s gone both ways; they have enriched my life also.

There are definitely some who have impacted me. Being on the infusion oncology team, I’m part of a patient’s cheer group and their support group. When they cry, sometimes I cry, and sometimes that’s difficult. It’s definitely made nursing more personal for me.

What’s the process like for getting chemo for men with prostate cancer?

Ms. Guider: We have a good process here when it comes to onboarding new chemotherapy patients. Our doctors work with our nurse navigators, who then work with our triage on our medical assistance to get the patient scheduled for their chemo class and their first chemo treatment. All these people make sure that labs, pre-med home medications, and post-treatment meds are ordered with support. Overall, there are a lot of people involved to make sure that the patient and their family are well-informed. When they come in, they already have an idea of what that day and treatments are going to be like.

When they arrive, we make sure that a patient is up to chemotherapy. We make sure that they are physically and mentally well, and then we notify our pharmacy to make the medication. We have our own pharmacy within our department. If there is anything questionable, we get in contact with the patient’s oncologist, and they’re directly across the hall from us, so it’s very easy to do. All of that is addressed right then and there.

What is the infusion like? Is it painful?

Ms. Guider: No. You have to start an IV or access a port, which could be painful. But the majority of people don’t feel the chemotherapy. There’s always a potential reaction to certain medications, but we are good about how we handle those. We already have medications ordered that we can administer if someone has a side effect on the premises, and we can get that side effect reversed.

How long does the actual infusion last?

Ms. Guider: It all depends on the regimen. With prostate cancer, that’s normally Taxotere (docetaxel), and that is an hour infusion.

I have only given Jevtana (cabazitaxel) once or twice before, but I believe that’s an hour also. Taxotere (docetaxel) is still the first choice IV treatment.

What kinds of side effects have you seen patients deal with after chemo?

Ms. Guider: The normal: nausea. We send patients home with a list of medications to use for the nausea, and we recommend smaller meals throughout the day to stay ahead of it. There’s the hair loss, nailbed changes. You can have peripheral neuropathy with the chemotherapy. There’s fatigue, of course, and the impact on white blood cells, red blood cells, and platelets that we’re watching for as well.

Do you have any tips or advice for men to make the whole process of getting chemo easier?

Ms. Guider: Somebody’s mindset has a lot to do with how they come into it and how they handle it.

Somebody who’s active, eating a well-balanced meal, and good on their hydration normally does better than someone who isn’t. Some people don’t like to take additional medication, and so there is not that adherence there.

We give patients a list of antiemetics to use if they become nauseated. Sometimes, they take them that first or second day, just as a safety measure to keep the nausea away. Some people don’t like to do that. But it’s always better to stay ahead of the nausea than let the nausea set in because it’s hard to play catch-up and get it to go away once it’s there. Nausea doesn’t only make patients feel unwell, but they’re not going to drink the amount of fluids that they need or eat the meals that they need if they’re nauseated. Coming in with all of that already in place, makes somebody tend to do better.

What role do you see the caregivers playing in the whole chemo process?

Ms. Guider: We invite caregivers to the chemo class. It’s always up to the patient if they want their caregiver to come to join them. Sometimes people and their family members come for the first appointment, and then after a while, the patients come by themselves. We have other people whose family members come every time. It all depends on the role that they already have in the relationship.

Sometimes caregivers are more of the voice for the patient. Sometimes they speak up and say that the patient is having a difficult time getting their food in, or they’re having this nausea afterwards, but the patient is not telling us.

Other times, caregivers are the cheerleaders who will bring a sandwich, and when the patient eats half, they’re the cheerleader saying “why don’t you take just one more bite? Don’t quit yet.” They all have different roles.

We also have caregivers who take an unproductive role, and that’s probably been in the relationship. Encouraging people to do better or take that next bite is very different than a person saying: “you need to eat that.”

Presentation can be huge, and if that avenue isn’t already developed between them, then sometimes we’ll see people bicker over how much they drank the day before.

I guess any conflicts that are already in the relationship will be highlighted by a situation like this, right?

Ms. Guider: Yes, along with the stressors of all of it.

Any other tips you have for men who are about to get chemo or maybe have already had chemo and are struggling with side effects?

Ms. Guider: When it comes to the side effects, you don’t have to struggle through them. Your team is there for you if you speak up. We can change pre-medications around. We can change medications at home. We can try completely different meds. We also have a social worker. We have nutrition. We have mental health. We have various support groups. Be open to reaching out.

Be open to asking questions, getting things clarified, and gathering more information, especially if it’s researched-based. There’s a lot of misinformation on Google that can backfire. You need to make sure that your information is based on research.

We all come in with a different knowledge base, so when it comes to what’s on the internet, sometimes it’s written for a certain group only, and at times there’s not even anything factual.

It’s great to talk to other people who have gone through cancer and treatment, but always keep in mind that every body is different. You could have the same people going through the same exact treatment, and for whatever reason, their side effects will be different, and how they handle them will be different. It’s not a cookie cutter.

Just like everybody comes in with a different level of fitness and a different mindset, right?

Ms. Guider: Yes, and it’s the history of how they took care of their bodies. The other comorbidities that they might have will factor in how they’re going to physically handle the chemotherapy. There’s the whole emotional side of handling the cancer itself. Just the word brings so much with it.


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Chemotherapy, Xtandi, and Zytiga

Dr. Julie Graff is a medical oncologist at Oregon Health & Sciences University.

Prostatepedia spoke with her recently about chemotherapy, Xtandi (enzalutamide), and Zytiga (abiraterone) for prostate cancer.

Why did you become a doctor?

Dr. Graff: Even as a child, I wanted to become a doctor, so my whole life I thought about it. Then I went to college, I fell in love with science, and I thought I would get a job somewhere working in a lab.

During college, I volunteered for a hospice, and I realized how much I love patients, how special people are, and how people with cancer are among the strongest people. I was drawn to work with them, and also, my scientific side could still be engaged in research.

Have you had any patients over the years who stand out in your mind as having either changed how you see your own role as a doctor or how you view the art of medicine in general?

Dr. Graff: I’ve had multiple patients who’ve meant a lot to me over the years. Someone I met in hospice stands out. The first time I met him, he said, “I know that I’m 80. You look at me, and what you don’t realize is that I want to live just as much as you do.” He had emphysema and was dying, but the drive to live can stay so strong, even at 80. Your body’s not even working that well anymore, and you’re suffering. Still, just this drive to stay alive is important. I’ve kept that in mind since then.

On the other hand, I’ve had some patients who say that years don’t matter—it’s quality of life. I can appreciate both sides. When I talk to patients, even those who say they want to live forever, I tell them that what we want to do is help them live as long as possible while maintaining a quality of life that they can enjoy.

I guess each person falls somewhere along that spectrum.

Dr. Graff: Exactly. As a doctor, you really just have to educate people, and tell them, “I know you want to live and that you think it’s a good idea to get surgery, even though there’s a 50% chance you could die during surgery or whatnot. But what are your real goals, and how can we help you reach them?” We want to move the focus of the conversation a little bit.

Can you give us a brief overview of how and when chemo is used for prostate cancer. I know it’s different from how and when chemo is used in other cancers.

Dr. Graff: In prostate cancer, there are a couple of settings where chemotherapy is used. We’ve been using the drug Taxotere (docetaxel) for 15 years now. It used to be something we gave at the very end of the disease course, when the hormone shots stopped working, but as of 2015, we use it early in the disease also.

Chemo has a bad rap in some ways. It’s thought to be something you should avoid at all costs, but what people don’t realize is that, when symptoms of the cancer (such as bone pain) get bad, chemo can help. The type of chemo we use in prostate cancer is not as toxic as we do for other cancers. We just use one drug. It doesn’t cause a lot of nausea and vomiting, which is a lot of patients’ worst nightmare. We use it in early and late settings, and I don’t think anything’s going to replace it. Even though we have other drugs now, we run out of hormonal options, and chemo’s a decent option.

When and how are Zytiga (abiraterone) and Xtandi (enzalutamide) used in prostate cancer?

Dr. Graff: Zytiga (abiraterone) and Xtandi (enzalutamide) are similar to chemo in that, initially, they were used at the very end of the disease. Now they can be used up front when people are diagnosed with metastatic prostate cancer, so it depends.

Most people get some mileage out of one or the other, but there is a large degree of cross-resistance between the two. It’s not likely that people would get good cancer response out of both of them. It’s going to be interesting to see what happens to Xtandi (enzalutamide) now that there are other drugs that target the same pathway.

What is androgen-receptor splice variant 7 messenger RNA (AR-V7), and what is its role in resistance to Zytiga (abiraterone) and/or Xtandi (enzalutamide)?

Dr. Graff: The androgen receptor has several domains, and one of them is the ligand-binding domain, which is very important. As this androgen receptor floats around in the cell, the androgens (male hormones) bind to that ligand-binding domain, and so does Xtandi (enzalutamide) for that matter. Cancer cells can lose that part of the androgen receptor, then lose their dependence on the androgens that are circulating and lose the target for Xtandi (enzalutamide). The AR-V7 splice variant can predict resistance to both Zytiga (abiraterone) and Xtandi (enzalutamide), and it might be a reason why there’s cross-resistance between them.

What role does chemotherapy play in this resistance to Zytiga (abiraterone) and/ or Xtandi (enzalutamide) that we see?

Dr. Graff: Fortunately, chemotherapy is still active in people whose cancers are resistant to Zytiga (abiraterone) and Xtandi (enzalutamide), so it still plays an important role. It can be very useful when people have prostate cancer-related symptoms.

We use chemo early on in metastatic disease, right after diagnosis. There are three studies presented in the past year in which they use chemo followed by Xtandi (enzalutamide) or a drug like it. It might be more effective in combination with those other drugs. We’re trying to learn still.

Can chemo reverse resistance to Zytiga (abiraterone) and/or Xtandi (enzalutamide), or does it play any role in that scenario?

Dr. Graff: I don’t know if it can reverse it. I have seen data showing that, if you’re on Xtandi (enzalutamide) and the cancer cells become resistant to that, then if you put a patient on chemo, some of those cells that aren’t resistant to Xtandi (enzalutamide) might come back, and it might be reasonable to re-treat it then. That’s not carved in stone.

Is it being explored in any clinical trials that you know?

Dr. Graff: I hope so. I don’t know which trials those would be.

What about the side effects of these various agents?

Dr. Graff: It’s complicated. Chemotherapy can cause some low blood counts and a risk of neutropenic fever, but then it has other side effects, like neuropathy in the hands and feet, that don’t just reverse automatically. There is also some tear-duct scarring and watery eyes. These might get a little better off the chemo, but they could be permanent side effects for the patients.

This type of chemo doesn’t hurt the kidneys, you need good liver function to get it, and it doesn’t seem to cause hypertension. In those ways, chemo is a good option for elderly men with prostate cancer.

Zytiga (abiraterone) can cause mineralocorticoid excess, which means the adrenal glands aren’t functioning normally. You could get too many of one type of hormone that causes high sodium and low potassium. Zytiga (abiraterone) can also irritate the liver, so we’re careful to watch for the liver function. It can also exacerbate the hormonal side effects of castration.

Xtandi (enzalutamide) is known to cause profound fatigue, which was its dose-limiting toxicity. Of course, it’s linked to seizures, but in people without a history of seizures, that’s pretty unusual. And just like Zytiga (abiraterone), it can cause hypertension. Management of blood pressure and cognitive decline is critical. People have reported that they feel a bit foggier on Xtandi (enzalutamide), and they have also reported increased falls, especially in the elderly. Once you’re off Xtandi (enzalutamide), some of those things will reverse, but it’s possible that being on Zytiga (abiraterone) and Xtandi (enzalutamide) could result in muscle mass loss or other things that won’t recover off those treatments.

What would you suggest to manage those side effects?

Dr. Graff: Exercise is critical for any prostate cancer patient. The drugs we use—even just the initial hormone therapy of turning off the testicles —lead to so many side effects like thin bones, muscle loss, weight gain, and all those things can be mitigated with some exercise. They won’t be taken away, but they could at least be improved. That exercise should continue on the other drugs.

It’s really hard to exercise when you’re on these drugs because you’ve got more fatigue. A lot of patients with prostate cancer have arthritis or some barrier to exercise that makes it difficult for them, but as much exercise as possible is important.

I guess any exercise is better than none, right?

Dr. Graff: Exactly.

Do you have any further thoughts about chemo, Zytiga (abiraterone), or Xtandi (enzalutamide) that you think patients should know about or might not be aware of?

Dr. Graff: They’ve been out for a while now. Any prostate cancer patient starts with a blank slate and has to learn all this stuff with the help of the provider. Think about your goals in life and if these drugs are going to interfere with those. If your goal is to continue working as an architect or something that requires a lot of thought and careful planning, maybe Xtandi (enzalutamide) is not the best choice, and maybe Zytiga (abiraterone) is a better choice.

Some of these drugs are contraindicated in certain patients. A patient with bad heart function, like congestive heart failure or something, should not be on Zytiga (abiraterone), and a patient with a history of seizures should not be on Xtandi (enzalutamide). A lot of thought should go into picking these. The first drug you use is likely to be the most effective, and then as you go down the line, they become less effective.

As a prostate cancer patient, you have several options now; it’s not just chemo or nothing once the prostate cancer becomes resistant to the androgen blockade. Consider lifestyle when making a choice.

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Clinical Trial: Free Genetic Testing

Dr. Heather Cheng is an Assistant Professor at the University of Washington and Fred Hutchinson Cancer Research Center, and the Director of the Seattle Cancer Care Alliance Prostate Cancer Genetics Clinic.

Prostatepedia spoke with her about a clinical trial she’s running that looks at inherited genetics of men with metastatic prostate cancer.

What attracted you to medicine?

Dr. Heather Cheng: There are a couple of things I love about medicine and especially oncology. One is getting to know patients, finding out what’s most important to them as people, and using that information to help guide discussions and decisions about their treatment in a way that is true to what is most important to them. These days I guess you call this shared decision-making. That’s the most rewarding part about what I do.

Have you had any patients over the years who have changed how you see your own role or how you view the art of the medicine?

Dr. Cheng: I have a lot of patients who fit those criteria. My interest in this area started when I was a first-year Hematology and Oncology fellow. I was in the clinic and it was when we were at the beginning of this wave of new exciting drugs that prolong survival, such as Zytiga (abiraterone) and Xtandi (enzalutamide).

I met this patient who was 43 years old; he had new, aggressive metastatic prostate cancer. His disease blew through every one of the new drugs. It was extremely humbling and disappointing because we were so excited about these drugs, but they didn’t do much to slow his disease. And it was heartbreaking because he was so young. He had a family history of cancer but not prostate cancer. He had a teenaged son. We had a lot of discussions about the effect of his disease on his son. I wondered if there was something genetic, something that was making his cancer so aggressive. And then, what could this mean for his son? His memory has stuck with me.

When I think about the work and research that I do, it’s not just for the individual patient in front of me. I’m also thinking about how we can improve things and advance the field so things can be better for the next generation. How can we make progress as quickly and with as much positive impact as possible?

I met another patient who had a great effect on me. He had just been diagnosed with high-risk prostate cancer, Gleason 9. He was planning to get radiation. As part of a research study, we offered to sequence the DNA of his cancer because he had an unusual appearance of his cancer– ductal histology. He was kind and generous enough to volunteer and participate. It wasn’t going to affect his treatment, but he agreed to help us learn more.

In his cancer, we found a mutation in the BRCA2 gene, the one that many people may have heard of because of its association with breast and ovarian cancer risk. There was suspicion that the mutation could be inherited, so we brought him back for dedicated genetic testing for inherited cancer risk. And, it turns out he did have an inherited version of that mutated BRCA2 gene. He was the first person in his family to be found to carry the mutated version of BRCA2. Neither he nor his family would have known until later if we had not looked in his tumor.

After this, some of his relatives had genetic counseling and were also tested. The sister who had breast cancer had a recurrence and was found to carry the BRCA2 mutation. This information was important for her because it offers additional treatment opportunities for her cancer that might not have otherwise been considered. His daughter was also found to carry the BRCA2 mutation and after learning of this, had a mammogram and was diagnosed with breast cancer. She’s still curable, so she’s going through treatment, but it is possible that she might not have known until much later otherwise.

The importance of test results can extend to relatives in a way that might help more than one person, not just the person that I see in the clinic, but other members of their family. I do want to be clear that these mutations are not found in most people— even those with cancer—but for the people who have these mutations, it can be life saving information for their family members.

What will you be doing, and what can men expect to happen, during your clinical trial?

Dr. Cheng: You can learn about the study from your doctor, support group, or by visiting our website, http://www.GentlemenStudy.org. There is information about the study. You can consent online, confirm that you have metastatic prostate cancer, and check that you’re interested in genetic testing for cancer risk.

There is a questionnaire that many take about 40 minutes to complete, that asks about your knowledge of genetics, basic health, family history of cancer, and demographic information about where you live.

You can upload supporting information about your diagnosis, or you can check a box saying you’d like help from the research team to gather that information on your behalf. Because there are strict privacy laws around medical records, you need to give permission to our team to get medical information for the study on your behalf.

To be eligible, you must have metastatic prostate cancer and must live in the United States. There’s one other exclusion, which is that if you have some blood disorders such as leukemia, we cannot be sure that the test results are valid.

If you meet criteria, you will be mailed a saliva kit, a medical-grade genetic test through Color Genomics, with instructions on how to provide a saliva sample. Follow the instructions carefully and then mail the kit back. Results are typically available within 4 weeks. You will have access to a genetic counselor following your results, and you are invited to follow up in person to our clinic if you live in the area. If you don’t live near us, we can direct you to resources to find a genetic counselor for in-person visit or by telehealth.

The testing for this study is not recreational testing. It is not the same as Ancestry.com or 23andMe. This is clinical, medically appropriate testing if you have metastatic prostate cancer.

Do you share this information with their doctor, or is it up to them to share the information with their doctor?

Dr. Cheng: We strongly encourage participants to share the results and information with their doctors, but our ethical board does not allow us to do this for participants without their specific consent.

Are there any fees for patients?

Dr. Cheng: There is no fee for the patient.

It sounds similar to the process for the Metastatic Prostate Cancer Project, except I don’t think they share their results.

Dr. Cheng: Yes, it is similar to that project. The difference is that the patient or the participant gets results that apply to them individually. The Metastatic Prostate Cancer Project, which is fantastic and an important and innovative study, is de-identified, and the patient doesn’t get individual-level results back.

Their goal is to amass as much data as they can for research.

Dr. Cheng: Correct, yes.

Are you also cataloging the information that you collect?

Dr. Cheng: Yes.

What will you do with the data that you collect?

Dr. Cheng: We’ll be looking at demographics, the proportion of people who have mutations (pathogenic variants), information about family history, and validated measures of knowledge, distress measures and satisfaction with testing.

If patients consent to re-contact, they will be contacted at the conclusion of the study. If there are other follow-up studies, they can opt to learn about those. There will also be an invitation for those who agree to subsequent studies, like treatment studies or PARP-inhibitor studies, for example.

We’re still learning about certain genes, such as ATM mutations and CHEK2 mutations. As we learn more, we may want to update participants on what the field has learned. There are still many important questions that the field needs to answer, and patient engagement and participation will make this happen more quickly. There will be opportunities for those downstream studies.

How many patients are you looking for, overall?

Dr. Cheng: The plan was for 2,000. We have sent kits out to over 350. We still have room for participation!

Join us to read the issue and learn how to participate in Dr. Cheng’s study.

 


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Prostate Cancer Genomics

This issue is devoted to the genetics and genomics of prostate cancer, which is one of the most promising and exciting areas of prostate cancer research. Already, this line of investigation is having a major impact. For example, by better defining the genomics of patients entering clinical trials, there can be a marked reduction in the number of patients needed to reach statistical significance. This can potentially reduce the costs of drug development dramatically.

Research into the role of genetics and genomic alterations in the biology and treatment of prostate cancer are still at a much earlier stage than it is for breast cancer. While laboratory studies have discovered a wide range of genes that might act to determine prostate cancer behavior in the clinic, proof that these changes actually determine outcome in the clinic are rather limited. There are even fewer examples where drugs attacking these changes have been FDA-approved for the treatment of prostate cancer.

The PD-1 inhibitor, Keytruda (pembrolizumab) is at present the only example. In 2017, this drug was approved to treat cancers that show mismatch repair or microsatellite instability. These mutations are found in a small proportion of prostate cancer patients.

There are a number of mutations targeted by drugs that are in advanced testing, so this list may expand rapidly. One of the more promising targets is BRCA2. Mutations that alter the function of this gene are known to be involved in breast and ovarian cancer. Cancer cells with these BRCA2 mutations become dependent on the protein, PARP, for their survival and drugs that inhibit PARP can be effective therapy. Studies on patients with advanced prostate cancer show that altered BRCA2 is found in 10-30% of cases. PARP inhibitors have shown significant activity in early clinical trials. Randomized controlled trials needed for FDA-approval are in progress.

Genomic information can also be used to determine how likely prostate cancer is to behave aggressively. This can help identify patients who are likely to do well with active surveillance or to be at low risk for recurrence after an initial attempt at curative treatment.

While genomics promises to revolutionize the treatment of prostate cancer, this revolution requires support from the patient community. The key studies can only be done if patients elect to participate in these trials. For this reason, we made sure to provide you with information on how to become involved in this process.

Not a member? Join us to read more about prostate cancer genomics and prostate cancer genomics clinical trials.


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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.