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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Dr. Michael Morris’s Clinical Trial: Combining Taxotere + Xofigo

Dr. Michael J. Morris is a medical oncologist who specializes in prostate cancer at Memorial Sloan Kettering Cancer Center in New York City where he serves as the Prostate Cancer Section Head.

He spoke with Prostatepedia about a clinical he’s running that looks at combining Taxotere (docetazel) and Xofigo (radium-223).

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What attracted you to medicine in the first place? Why did you become a doctor?

Dr. Michael Morris: I came to medicine from a somewhat different background than many physicians. I grew up in a family that’s heavily focused on the humanities—history, culture, and literature. I inherited those genes from my family, but I also had a real scientific interest that I found to be equally compelling.

In college, I divided my time between literature and science. What attracted me to medicine was that it perfectly merged humanism and science – both patient care and research require an understanding of the history of a patient, his disease, and his treatments. The challenge of medicine is to creatively conceive how biology can be brought to bear to alter these for an individual and the field.

Have you ever had any patients over the years whose stories have changed how you view either the art of medicine or your own role?

Dr. Morris: Many people feel absolutely devastated when they get prostate cancer, which for many people can be a chronic disease. The anxiety provoked by a cancer diagnosis, and even by a detectable or rising PSA can be existential. One of my patients was a Vietnam War veteran. He had been through his share of battles before, and saw more than a few of his closest friends not live past early adulthood. For him, prostate cancer was a reminder to him of what he had survived already. He felt that he was lucky to have lived long enough to face prostate cancer as the primary threat to his life. He took his prostate cancer journey as the next opportunity to lead, to teach, and to be in charge of and help so many people through their disease. Even in our waiting room, he was guiding people and keeping everybody’s anxiety in line. That made a huge impression. People who have faced risks before can be incredibly helpful to those who are not experienced with the helplessness and fear that a cancer diagnosis provokes. We have a lot of first responders in our practice, and their experience managing risk and anxiety can be very helpful to those without those skills. They can help the care providers as much as the patients, too.

From a clinical trial standpoint, I’m struck by the selflessness of so many of our patients. They understand that their treatments are the result of the efforts of patients on studies who have preceded them, and they’re willing to volunteer so that we can learn how to best treat those patients who will follow them. They’re saying, “I’m going to give my body to a clinical trial so that the next generation of prostate cancer patients can learn from my experience.” That’s inspiring.

Talk to us about your Phase III trial combining Xofigo (radium-223) and Taxotere (docetaxel). Why this particular trial? Why now?

Dr. Morris: In general, my research focus is where nuclear medicine and medical oncology intersect. That is, looking at drugs that you can deliver systemically, that are targeted to either the prostate cancer cell itself or to the host organ of most metastatic disease which is bone. And that also means looking at combining those drugs with other drugs that can help patients either feel better or survive longer.

This trial comes out of a long history of work, trying to combine radioligand therapy, which are essentially liquid systemic radioactive drugs, with other systemic treatments, to target both the cancer cell itself and bone, which is the host organ to most metastatic disease.

Xofigo (radium-223) is a known, life-prolonging radioactive agent that targets metastatic disease to bone. Since most metastatic disease in prostate cancer is in the bones, you can really encompass most of the disease by targeting that one bony compartment. Within the bone is the cancer itself, and the chemotherapy is used to target the prostate cancer cell. It’s a concept of dual targeting, both the environment that the cancer is hosted in and the cancer itself. That’s why we’re using these two agents, one of which targets bone and the other cancer, and both of which prolong survival independently, to see if those effects can be amplified by giving them together.

What will you be doing step by step?

Dr. Morris: The first thing is, a man has got to qualify for the trial, which means that he has to have predominantly bone metastases because that is the target for the Xofigo (radium-223).

The second thing is that he can’t have a significant amount of soft tissue disease in either the lungs or the liver. He has to have progressed through standard testosterone-lowering agents, such as Zytiga (abiraterone) or Xtandi (enzalutamide). If that patient is otherwise a chemotherapy candidate, then the treatment involves giving chemotherapy once every three weeks and then the Xofigo (radium- 223) once every other chemotherapy dose, so every six weeks. They’re both IV agents. That’s the essence of the treatment of the study.

Xofigo (radium-223) is a unique radioactive drug. It emits an alpha particle, which releases a lot of energy in a very tiny distance, only a few cell-lengths deep. It has virtually no side effects, so it’s a well-tolerated, life-prolonging treatment.

Chemotherapy is standard first-line chemotherapy in the form of Taxotere (docetaxel). It’s given every three weeks. It’s life-prolonging as well, and is a member of a class of taxane-based chemotherapy.

What are the side effects like for that?

Dr. Morris: Primarily fatigue, but some patients can have tingling in their fingers and toes as well, and sometimes changes in taste. A very small number of patients can have their white blood cell counts suppressed.

How long are you going to be following these men while they’re on these two agents?

Dr. Morris: Patients receive a total of six doses of Xofigo (radium-223) and no more than ten doses of chemotherapy. After that, they’ve completed the treatment portion of the protocol, and they could go on, if they needed, to any other treatments. But we follow them for the rest of their lives.

Are there any fees associated with the trial? I’m assuming the Xofigo (radium-223) and the Taxotere (docetaxel) are provided.

Dr. Morris: The Xofigo (radium-223) is provided by the study, and the patient is responsible for the docetaxel, which is standard chemotherapy.

What else do you hope to learn from this study?

Dr. Morris: There are a whole host of innovative biomarkers and science that is built into this trial, so we learn as much as we can about each patient as they’re treated.

We’re looking at circulating tumor cells and cell-free DNA. We’re looking at the impact of the treatment using novel imaging techniques. We’re looking at quality of life. There’s a whole component of the study that will allow us to learn as much about the prostate cancer and the efficacy of the drugs as well.

Those will be covered under the trial as well, right?

Dr. Morris: Absolutely. Those are all covered by the study.

Is that information shared with the patient?

Dr. Morris: Any information we gather in real-time can be shared with the patient. Some of the scientific aspects of the trial will only be performed after the trial is done, so results from those will be delayed until after the study. But as we learn new information, we pass it on to our patients.

Join us to read the rest of this month’s conversations.

Dr. Alicia Morgans: Putting Chemo Into Perspective

Dr. Alicia Morgans is a medical oncologist at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago. She specializes in treating advanced prostate cancer and is particularly interested in addressing treatment side effects.

Prostatepedia spoke with her about chemotherapy for prostate cancer.

Why did you become a doctor?

Dr. Alicia Morgans: I’ve known since junior high school that I wanted to not only become a doctor but an oncologist. I knew I wanted to do something in science that engaged people on a personal level, and I had always admired the way physicians could do that. When visiting my grandmother during summers, I often went to her doctor appointments. I loved trying to understand things on a biologic level, and seeing the way the physicians she had listened and tried to help her. Even when they didn’t have a fix to a problem, they could at least serve as a witness to validate her experience and lend support in any way they were able. Oncology specifically has always been a really challenging puzzle to understand, and the best opportunity to form long-term relationships with patients.

Medicine is an amazing way for individuals to engage at a very deep level, not only with intricate and exciting science but also with really rewarding human interaction. I’m glad I made the decision.

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

Dr. Alicia Morgans: There are always patients who change how we move forward with the practice, art, and science of medicine. As it comes to chemotherapy, in particular, there are a number of men that come to mind who, when offered chemotherapy, said there was no way they could do it.

These statements come probably from their prior experience with family members or loved ones who have had bad experiences with chemotherapy. These are real experiences that certainly need to be acknowledged, but I haven’t met a person who we can’t get through at least one cycle of chemotherapy to see if they truly can’t manage it.

Most everyone can get through chemotherapy for prostate cancer because it’s different than chemotherapy for things like breast cancer or leukemia, where we use many drugs in combination that can be intense. This is typically one chemotherapy drug at a time, unless we’re specifically studying more intense combinations in clinical trials.

Most men do pretty well. There are several men who have been so sick from their cancer that, when I’ve given them chemotherapy, they actually feel a lot better, and that is really rewarding. It’s an experience that I use to guide conversations with patients who are frightened of chemotherapy. Sometimes the people who feel the worst at the start feel much better with chemotherapy.

Because the chemo’s killing their cancer?

Dr. Morgans: Exactly.

That’s a really important point you’re making. Just because, say, your neighbor had chemo for breast cancer and had a terrible time, that doesn’t necessarily mean that you will have a terrible time with chemo for prostate cancer.

Dr. Morgans: Absolutely, and there are a number of men who I’ve taken care of through chemotherapy for prostate cancer, men in their 60s and 70s, who have continued to work. Sometimes, men who are in that phase of their career have a little more flexibility with their job, and they can do half days or relax in the afternoon for a half hour and go back to work. Sometimes these are men with relatively physical jobs, and they’re still able to work, other than the day when they’re actually getting treatment, when they’re not able to be physically at work because they’re getting chemotherapy.

It is different than the treatments that we give to young women with breast cancer or people who are getting treatment in the hospital. This is an outpatient treatment. It typically takes about an hour to an hour-and-a-half to infuse. It’s something that we are sure to monitor very closely because we want to be safe, and we want to support people as they develop symptoms. For the most part, people do much better with this type of chemotherapy than they would expect.

At which points are men likely to encounter chemotherapy for prostate cancer?

Dr. Morgans: There are various points at which men can encounter chemotherapy in their prostate cancer journey. This has changed over the last few years. When men have metastatic disease today, whether that’s hormone sensitive or castrate-resistant, we recommend chemotherapy. As of yet, we do not routinely recommend chemotherapy for men who are having radiation for localized disease or for men with biochemical recurrent disease (though both of those populations have been studied in clinical trials, and there appears to be, at least in some of these patients, potential benefits related to that).

There have also been studies looking at neoadjuvant chemotherapy, which is chemo before prostatectomy. There appears to be a potential benefit to that, particularly in high-risk patient populations. But again, that’s not routinely recommended.

For the most part, men with metastatic disease are more routinely being offered chemotherapy, either in hormone-sensitive metastatic disease in the frontline setting or as one of the treatment options in metastatic castrate-resistant disease.

How is it usually sequenced? Or is there a usual sequence?

Dr. Morgans: There’s not a usual sequence, and every individual who is being treated for advanced prostate cancer is probably aware that we don’t have exact data to say which drug should be first, second, or third. These are conversations between men, their doctors, and their families to choose the treatment option that’s best for them.

For men with brand new prostate cancer that is metastatic from the get-go, or for men who have had prostate cancer treatment in the past and now have recurrent disease that’s metastatic but hasn’t yet been treated, we often recommend chemotherapy, particularly for men who have a high volume or high burden of metastatic disease. In that setting, we use six cycles of chemotherapy, and we can help men live longer and feel better. We have data on both the efficacy for improving survival and on the quality of life that show benefits in that population.

It’s important that we use it in that earliest stage of metastatic disease so that we only have to use six cycles of chemotherapy to get a pretty dramatic benefit whereas, if we use it in the later settings, we may use up to ten cycles of chemotherapy for lesser benefit. That’s a consideration when I’m talking to men with high-volume, hormone-sensitive disease.

In the later stages of disease, if we’ve used androgen receptor or hormonal therapies first, then often we switch to chemotherapy after that hormonal approach because it’s a novel mechanism of action and is expected to be more effective. Rather than continuing to hit on the same androgen receptor pathway, we’re using a different way to approach the cancer and overcome resistance.

What are the side effects of chemo like on its own? What about when you’re sequencing it either before or after hormonal therapy? Is there some sort of synergistic or cumulative effect to the side effects?

Dr. Morgans: Usually, we’re using chemotherapy alone with a gonadotropin-releasing hormone (GnRH) agonist or antagonist therapy. That would include therapies like Lupron (leuprolide), Zoladex (goserelin),

and Firmagon (degarelix), medicines that act to stop the testes from making testosterone. Then we add on Taxotere (docetaxel) chemotherapy when we choose the first chemotherapy for men with prostate cancer. The side effects are generally similar whether you use it earlier or later if you’re using it just in combination with that medicine.

With these injections, the most common side effect is fatigue. The next most common thing is neuropathy, which men would experience as a numbness or tingling in their fingertips or toes that, with repeated exposure, can go up into their hands or feet. It can become a more long-lasting issue, or eventually can lead to permanent numbness, especially as you get higher numbers of cycles. For example, if you use ten cycles in the metastatic castrate-resistant setting versus six cycles in the metastatic hormone-sensitive setting, you’re going to have a higher risk of things like neuropathy.

At any point when we’re using chemotherapy, we expect to cause blood counts to go down. Some men need a blood transfusion of either red cells for anemia or platelets for a low platelet count, though that’s relatively uncommon. What’s more common and possible is that the white count, the infection fighting cells, can go down with each dose of chemotherapy, and that count stays down until the bone marrow starts making more cells. We don’t have a transfusion we can give people to make that improve more quickly. That puts men at risk of what’s potentially a life-threatening infection when their blood counts are down, and the more cycles that they have of chemotherapy the longer it takes for their blood counts to recover. That’s another reason to think about using it when you only have to do six cycles as compared to ten.

As men get older, sometimes the side effect burden can become a little more noticeable to them. If we have the opportunity to use chemotherapy in men in their 50s or 60s as opposed to their 70s, we may see that there are fewer side effects. If they’re having a lot of side effects like loss of appetite and weight-loss, fatigue, and pain related directly to their cancer, the side effects of chemotherapy can actually be reduced fatigue, reduced pain, and improved quality of life between cycles.

Because as we said, it’s killing the cancer?

Dr. Morgans: Yes. There was a clinical trial that reported recently indicating that combined Xtandi (enzalutamide) and Taxotere (docetaxel) in addition to the GnRH agonist or antagonist therapy produced more side effects related to chemotherapy when we piled on an additional androgen receptor-directed therapy with the chemotherapy. Although the trial is done, and we see that people ultimately tolerated that more or less, because there was more toxicity and not a benefit to that triple-therapy approach, we’re not recommending that we do anything more at this point than chemotherapy with a GnRH agonist or antagonist. We’re not using a third androgen receptor-directed type medication in that cocktail, and that’s just to say that the more treatments that you add together, the more toxicity related to chemotherapy.

Is there anything men can do before getting chemo to prevent some of these side effects?

Dr. Morgans: One side effect I didn’t mention is that men can have some hair thinning. Usually, they don’t go completely bald, but they can have some hair thinning and some hair loss. Men can use a cold cap during each cycle of chemotherapy, which can reduce hair loss during chemotherapy.

I’ve had a number of patients whose job requires that they put forth a healthy image. We all want a healthy image, but for some men who work in financial spheres, trying to get people to invest in their companies, or if they work in investing, they have expressed to me that they can’t look sick, they can’t have hair loss.

They’ve used these cold caps and have not lost their hair. It’s impressive and surprising to me how effective the caps were for them.

That is something that they can do to try to reduce hair loss. Cold caps are approved for women with breast cancer who are receiving chemotherapy, and they also seem to work in men. They’re not always covered by insurance, but they can be really effective.

Cold caps were FDA-approved in 2017. You can read the FDA press release here: https:// http://www.fda.gov/news-events/ press-announcements/fda-clears-expanded-use-cooling-cap-reduce-hair-loss-during-chemotherapy.]

Other than that, it’s important that men do their best to stay active. The more active they are before chemotherapy, the better able they’ll be to stay active while they’re getting chemotherapy and to make sure that their bowels are moving as regularly as possible. Some of the medicines that we use for even mild nausea associated with chemotherapy can cause constipation.

Download the issue to read the rest of Dr. Morgans’ comments.

Dr. Tanya Dorff On Chemotherapy For Prostate Cancer

Dr. Tanya Dorff is a medical oncologist who serves as associate clinical professor in the Department of Medical Oncology & Therapeutics Research and the Head of the Genitourinary Cancers Program at City of Hope, a research and treatment center for cancer based in Duarte, California.

Dr. Dorff’s research interests in prostate cancer range from clinical trials in PSA-recurrent prostate cancer to the role of fasting in chemotherapy tolerability to CAR T cells that are primed to target prostate cancer tissue.

She leads one of the largest clinical trial portfolios in genitourinary cancers.

Dr. Dorff spoke with Prostatepedia about chemotherapy for prostate cancer.

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Why did you become a doctor?

Dr. Tanya Dorff: When I was around three years old, I decided that what I wanted to do with my life was help people. And being a concrete thinker as a three-year-old, I felt like being a doctor was the only way to do that.

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

Dr. Dorff: There are so many who have influenced me. My mom had a rare form of leukemia when I was in college. It was uniformly fatal. But they had recently developed a new treatment with the discovery of a specific translocation of the retinoic acid receptor for acute promyelocytic leukemia (APL). All-trans retinoic acid was developed, and she received it as experimental (at the time) through compassionate access. She was cured, and she’s still alive today. That influences how I feel about clinical trials and translational science. If we hadn’t understood that biology, we couldn’t have designed the overwhelmingly effective treatment.

How is chemotherapy used today for men with prostate cancer?

Dr. Dorff: When I started treating prostate cancer, chemo was pretty much our only tool besides standard hormone therapy. It worked, but it was sort of end-of-the-line. People didn’t tolerate it very well, in part, because we used it in really advanced cases. Then, the drugs like Zytiga (abiraterone) and Xtandi (enzalutamide) came out, dramatically improved the situation for prostate cancer patients, and chemotherapy got pushed later and later.

The CHAARTED study was presented five years ago. That study showed that using chemotherapy early with the initiation of hormone therapy dramatically improved survival, above and beyond using it later. About 75% of the patients on the control arm got the chemo when they became resistant, so it was a pretty good experiment of now versus later, and not now versus never. To see that just using it early added an extra year or more of life for these men was really profound. That reinforced the strong role chemotherapy has in this disease.

With which other kinds of agents is chemotherapy frequently combined?

Dr. Dorff: Combinations with Taxotere (docetaxel) have never yet been successful in prostate cancer. There was Taxotere (docetaxel) with a high-dose Vitamin D, which was not only negative in that it failed to improve outcomes, but patients who received the combination actually fared worse. There was Taxotere (docetaxel) with Revlimid (lenalidomide), Taxotere (docetaxel) with atrasentan, Taxotere (docetaxel) with GVAX… All of these combinations have failed.

One of the ASCO presentations that prostate cancer physicians might remember most vividly is a slide presented by David Quinn in his presentation of the negative results of the SWOG S0421, the study of Taxotere (docetaxel) alone or with atrasentan. He showed a slide of a graveyard, implying that any drug tried in combination with Taxotere (docetaxel) is doomed to fail.

Why do you think that is? Is it just that the combination is too toxic?

Dr. Dorff: I don’t know. I don’t think it’s too toxic. All of these combinations go through safety before they go into Phase III, and you can combine them safely. I do not understand why combinations fail. Maybe it goes back to biology. Why would the combination succeed? You want something that makes the chemo work better, or you want the chemo to make the drug work better. That’s where we should probably start when planning combination studies. Even then, things that look good in early testing can fail in Phase III, so in some cases it may be that we need to sub-classify patients in order to design more successful trials.

Maybe a more interesting question when we’re talking about combinations is: how do we get the best use of the chemo and do the least damage to the patients?

At University of Southern California, we started a study looking at a fasting-mimic diet to make the Taxotere (docetaxel) better. We found preliminary evidence that fasting prior to chemotherapy reduced toxicity, and I envision that could have two specific benefits in men with prostate cancer who might get Taxotere (docetaxel).

One might be that if we could mitigate toxicity, more men would actually receive it. There was a lot of therapeutic nihilism out in the community about how chemotherapy doesn’t work so well for prostate cancer, or that these older patients can’t handle it. If we could ratchet down the toxicity, maybe more prostate cancer patients would actually get chemo.

The second benefit might be that if we could reduce toxicity to normal host cells, we would be more likely to get in full doses on time, which might make it work better against the cancer versus what happens now, which is that we frequently dose-reduce and dose-delay because of toxicities. The fasting-mimic diet study is still ongoing but these are the outcomes I was hoping for when designing it.

How long are they fasting before they start the chemo? What does that look like?

Dr. Dorff: They fast for 48 hours on a fasting mimic diet, which means they get vegetable broth and an energy drink. So, it’s a liquid, low calorie diet. It’s hard, so that’s part of why the study is still ongoing.

In our earlier trial, in which we did fasting with platinum chemo for up to 72 hours (48 before and 24 after the chemo dose), people really swore by it. They really felt like they had so much less toxicity compared to chemo cycles in which they didn’t fast.

With the fasting mimic diet (created by L-Nutra), because it’s not pure fasting, we extended it to three days before chemo. The first day is a fairly robust number of calories, just plant based and with specific amino acids left out, which is felt to be part of the effect. Then there’s the two days before chemo with lower calories, and one day after. After fasting or the fasting-mimic diet the body needs a bridging diet for the first meal, and the L-Nutra regimen also included supplements to replenish the body.

If someone reading this is interested in participating, can they contact you directly or should they contact someone else?

Dr. Dorff: Sure, they can contact me directly at tdorff@coh.org. But the trial is going on only at USC, so they may wish to contact the clinical trials office at USC or the medical oncology group at USC.

Are you combining diet with chemo instead of another agent?

Dr. Dorff: Yes.

What kinds of side effects can patients expect from chemotherapy? What are you hoping to reduce?

Dr. Dorff: One of the most concerning side effects is the peripheral neuropathy, which can become permanent, but I don’t want to scare any readers.

Can you explain what that is?

Dr. Dorff: It’s damage to the small nerves out in the fingers and toes that can manifest as numbness or pins and needles, burning kinds of discomfort. That can be permanent.

Is there anything patients can do before or during getting chemo to reduce the likelihood of that happening?

Dr. Dorff: Not that we know of.

There’s no way to predict who might suffer from that or not?

Dr. Dorff: It’s not a complete no. We know patients who already have some preexisting neuropathy, whose nerves are already damaged, are more susceptible, for instance patients with diabetic nerve damage. That’s one reason we might try to get them Jevtana (cabazitaxel) instead of Taxotere (docetaxel) because Jevtana (cabazitaxel) doesn’t impact the nerves in the same way. I’m not sure if that’s what patients worry about, but that’s one of my number one concerns because I’ve seen patients a few years after chemo who are still vexed by the neuropathy.

If Jevtana (cabazitaxel) doesn’t result in neuropathy, why wouldn’t you use that agent over Taxotere (docetaxel)?

Dr. Dorff: Because insurance typically won’t cover it. Head-to-head, they were compared in the FIRSTANA trial, and they were equally effective; one wasn’t much better than the other. So, insurance companies can say that Jevtana (cabazitaxel) is not more effective; it’s equally effective. Taxotere (docetaxel) is a fraction of the price because it’s off-patent, and Jevtana (cabazitaxel) is actually approved specifically in post-Taxotere (docetaxel) patients, so it’s off-label to use it first-line. You can make a case when you have a guy with neuropathy, but even if you have a guy without neuropathy, you sure would like to leave him without neuropathy at the end of his treatment.

We start to see the neuropathy around dose five. If you stop, it’s more reversible, but if you keep going, that’s where it can become permanent, and so again, when we’re getting to how we can enhance the efficacy, if we could get more doses in without being limited by neuropathy, maybe we would do better with the drug, or maybe we just avoid the neuropathy, have equal efficacy and patients suffer less. There’s two ways we can win.

Equal efficacy and side effects are a huge issue for men.

Dr. Dorff: Patients really worry about hair loss. I don’t think we’re impacting that with the diet, unfortunately. That is reversible. They also complain about the taste changes and mouth sensitivity because that really impacts eating.

Does that go away once chemotherapy is finished, or does that linger after?

Dr. Dorff: That goes away.

It’s just while they’re getting chemo that they lose sense of taste?

Dr. Dorff: Yes, but it’s a long time to not be able to taste.

And the hair loss only happens while they’re getting chemo, too? It comes back?

Dr. Dorff: Yes, it grows back.

What combinations with Taxotere (docetaxel) do you think will work best?

Dr. Dorff: The ongoing combinations that I think people are still interested in are platinum with taxane and carboplatin with Jevtana (cabazitaxel). That’s an important combination for the more aggressive variants.

Part of how we think Taxotere (docetaxel) chemotherapy works is that it interferes with antigen receptor (AR) translocation in the cell to the nucleus, because the microtubules are needed for that. It still may be more for patients whose cancer is using a lot of AR signaling whereas platinum is more for cancer that might not be as dependent on that mechanism. That combination is pretty important.

There are some other biologics being studied together with Taxotere (docetaxel), but I’m not sure that those will be successful. There’s Taxotere (docetaxel) with immunotherapy, but we have the negative GVAX trial that tried combining vaccines with Taxotere (docetaxel). We are also combining it with Xofigo (radium-223), which is a little interesting, but I don’t know why those agents would necessarily help each other. Again, when you’re looking at a combination, it’d be nice if there were a reason to expect synergy.

What about favorite sequences?

Dr. Dorff: We know that after you’ve had Zytiga (abiraterone) or Xtandi (enzalutamide), you can induce the androgen receptor splice variants such as AR-V7. These are associated with less responsiveness to Zytiga (abiraterone) or Xtandi (enzalutamide). Patients might want to go from Zytiga (abiraterone) straight to Xtandi (enzalutamide), but we know there’s a lower likelihood of success, and we know AR-V7 is a big part of that. If we sequence in chemo, since they’ve shown that AR-V7 positive patients still benefit from chemo, I view the optimal sequence as Zytiga (abiraterone) or Xtandi (enzalutamide), followed by wiping out the AR-V7 population with a chemo drug, and then going to Zytiga (abiraterone) or Xtandi (enzalutamide) next. We don’t know for sure if that’s what happens when we use that type of sandwich approach, but it has theoretical appeal, and that’s how I talk to patients about it. The other way to go is a clinical trial, especially for combination with Zytiga (abiraterone) or Xtandi (enzalutamide).

What about the side effects profile when you do those kinds of sequencing?

Dr. Dorff: Hormone drugs like Zytiga (abiraterone) and Xtandi (enzalutamide) have much better side effect profiles, generally speaking, but the chemo side effects are largely reversible, and we tell patients that it’s not forever. There are good days and bad days, so it’s important to note that most people are not feeling bad every single day that they’re on the chemo. I don’t think the side effects vary based on sequence.

Some of my colleagues feel that when they use chemotherapy up front like in the CHAARTED study, they see more side effects if they start the chemo right away, but they see fewer side effects if they wait a month or two into the hormone therapy to add the chemo.

Is that because the patients become used to the side effects and learn how to manage them before you add something else?

Dr. Dorff: No, because the side effects are totally different between the two treatments. This is speculative, but I think you debulk. I think that part of the reason people get a lot of chemo side effects is that when we’re killing a lot of cancer there’s a big inflammatory reaction. You can feel sick from it, and we see that anecdotally in certain patients. If you can debulk the cancer a little bit with a couple months of hormone therapy, and then give the chemo, it might be better tolerated.

That’s interesting. So as the cancer’s dying, it throws off some kind of signal?

Dr. Dorff: It does. There’s a lot of dead stuff that has to be cleared by the body, and maybe that means it doesn’t have as much attention to do the healing that it needs to do with the chemo. I don’t know; that’s purely speculation.

Is there anything else you think men should know about chemotherapy for prostate cancer?

Dr. Dorff: First and foremost, chemo is effective. People downplay the role but CHAARTED really showed us that this is a good tool. We are working on tools that have fewer side effects. I’m working on whether diet can help mitigate side effects, and other people are looking at things like exercise, but the bottom line is that chemo is a good tool.

But still some patients draw a line in the sand and say they’ll never receive chemo because they’ve seen other patients getting chemo for other cancers. The chemo we use for other cancers is different than what we use for prostate, and every person’s reaction to chemo is different. Of course, you can’t erase that impression that’s made on you when you see someone who you care about struggling through chemo, but it doesn’t mean that’s what your experience is going to be.

Your doctor’s job, and your oncologist’s job, is to make it livable, to allow you to still do the things you want to do and to keep you safe and healthy through your chemo. There are tricks up our sleeves that we use to make that happen.

Sometimes patients are surprised to hear that they can actually feel better on chemo.

Why would that be?

Dr. Dorff: Because sometimes the cancer’s driving their side effects. It’s a catch-22. There are patients who might want to wait until they’re feeling better to get chemo, but if they’re feeling bad from the cancer, it’s really the chemo that’s going to make them feel better.

I have patients who’ve been unable to eat, in too much pain to really get out and do anything, and when they start chemo, they feel better, they eat better, they have more energy, and they can do more. If you take someone with no cancer symptoms, sure, the chemo’s going to make them feel worse. But if you take somebody with cancer symptoms, they may actually feel better.

That’s interesting because there’s this whole cultural perception of chemo as being catastrophic. The idea that chemo would make you feel better seems bizarre, but it makes sense the way you explain it.

Dr. Dorff: Yes, I think a lot of patients are shocked to hear it, and I think that’s a good thing to put out there.

Do you have any suggestions for men as to how to handle side effects before going into it?

Dr. Dorff: Communication with your doctor is the way to be successful in your chemo. A lot of people don’t want to bother the doctor, or they want to tough it out, but the earlier they tell the doctor that there’s a side effect, the easier it is for the doctor to intervene and reverse it. There’s no medal at the end of chemo for not having had to take a treatment for a side effect or not having called the doctor. Just pick up the phone and call. That’s how your doctor can do their best by you, and how you can be most successful with your treatment.

Aside from that, staying active is really important. Getting out and walking, even if you’re not exercising per se, but just moving around and not being sedentary is important for circulating the blood. We don’t want you to get a blood clot during chemotherapy because you’re not moving. It helps you expand your lungs, so maybe it can help keep your respiratory tract and heart healthier. Go into chemo as fit as possible, and try to maintain activity and mobility during treatment.

Read the rest of this month’s conversations about chemotherapy for prostate cancer.

Patients Speak: Getting Chemotherapy

Bill R. found out he had prostate cancer about a year and a half ago. He’s been on Taxotere (docetaxel) and has just started Jevtana (cabazitaxel).

He spoke with Prostatepedia at length about his experiences with chemotherapy for prostate cancer. How did you find out that you had prostate cancer?

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Bill R.: We had just moved from California to Arizona for my retirement when I was diagnosed. I got to the point where I couldn’t pee, so I ended up at the urologist. After a bunch of tests, the urologist said, “You’ve got an enlarged prostate. You can either run around with a bag of pee tied to your leg for the rest ofyour life, or we can do a transurethral resection of the prostate (TURP) to cut part of it out.” They did the TURP, and they biopsied it.

That’s when they called me with the bad news. I had Stage IV prostate cancer that had metastasized. It was well along. It’s not been a year and a half.

What was your reaction?

Bill R: It was a surprise, certainly not expected. It takes a while to internalize it, and the first question you ask is: how long have I got? That’s like asking how to push a piece of string uphill. Nobody really knows the answer. They said that it’s very aggressive and, without treatment, probably two years or less.

What kinds of treatment did you have?

Bill R: Everything happened almost immediately because they said it was aggressive, and I couldn’t screw around. I was on androgen deprivation therapy (ADT): Lupron (leuprolide), which suppresses the testosterone, and Xgeva (denosumab). At the same time, I started chemo because the protocols at that time said the two of these together seemed to extend life.

Which chemo drug did you go on?

Bill R: Taxotere (docetaxel).

What was that like?

Bill R: Initially, I was in pretty good shape, and once I got diagnosed, I worked out even harder. I was swimming half a mile per day and more. I figured I had the strength in my body to get through this. Through the first three or four treatments of chemo, I had some of the usual effects, like constipation, occasional nausea, and stuff like that. I took a probiotic during treatment. That seemed to help. Other than that, I really didn’t have much of a problem, although, each chemo session beats you further down into the dirt. It’s once every three weeks, so you get weaker as you go through it.

Right, of course.

Bill R: They were going to do six chemo sessions, but my PSA just would not come down. They had expected it to drop close to zero, and we got down in the 20s, but that’s about where it ended up. They wanted to do two more chemo sessions, and I agreed to that. At that time, I had six chemo sessions, and the last two were pretty hard. It really did wipe me out in terms of energy and everything else. I didn’t have a lot of reaction to it, though.

I had a moustache that got so thin, I just shaved it off. The hair on my head thinned, but I didn’t lose all of it. It got very sparse, and I had little bald spots, but it was short and fuzzy. It all grew back differently. I now have a bunch of cowlicks, where before, I had nice straight hair. Chemo usually causes the fingernails to look awful for a while, and I lost my two big toenails, but they have now grown back, more or less.

The chemo started in September 2016 and ended February 2017. After the last chemo session, my PSA was still up at around 23 or 24. They worked on getting me approved for Provenge (sipuleucel-T), which is an early immune therapy. They extract your white blood cells and send them to a lab, where they do something, and then put them back in. I did that in the summer of 2017.

Over the next several months, my PSA came down. It got to a low of about 11, but that’s as low as it ever got. There were times when the chemo was bad. In the beginning, I didn’t realize how much you had to stay hydrated.

I didn’t know that.

Bill R: Yes. They offered for me to come in a day later, and they pump you full of a liter of saline.

Were you able to keep going about your daily activities or were you incapacitated?

Bill R: It slowed me down. First of all, you don’t know what you don’t know, so you’re not really prepared for this.

Chemo causes constipation, and if you’re prepared for that, it’s not a problem; you take laxatives ahead of time. But if you don’t know that, it’s a pretty miserable couple of days. From that standpoint, it slowed me down, but it didn’t stop me from going about our daily routine.

For the first month or two, I continued to swim, though not as much as I had been. I assumed that if I stayed active it would help me through the chemo. I was never incapacitated in that sense. There were a few days where either I didn’t feel well or was really tired, so I didn’t go out and pound the pavement or anything. In retrospect, it was hard to tell in the first month or so whether the chemo or the Lupron (leuprolide) was causing more issues.

Because you were taking them simultaneously?

Bill R: Yes. You’re doing everything at the same time. I guess, in retrospect, I slowed down and had a few days of down time. But it didn’t stop me from doing what I wanted to do.

I went out and bought a custom chopper motorcycle, and after my Provenge (sipuleucel-T) treatment in the summer, I took a 3,500-mile ride up to Sturgis, out through Yellowstone, and home. Two weeks later, we spent a month in Europe. It was hard for me, but maybe it wasn’t as hard on me as it might have been on others, simply because I was in pretty good shape when I started. If you’re not in good shape, it could be tougher. They give you some steroids to help you through this, and in the beginning, it took a while to get the steroids adjusted. They gave me too much, and I got mouth sores for a while. Once the steroids got adjusted, that was fine. The worst part of the whole thing was after it was over. Inside of a week, I started to retain water. I put on 20 pounds, and it was all water. I’m not a big guy at about 150 pounds and 5’8”, but I looked like the Pillsbury Doughboy. Living in Arizona, you run around in shorts all the time, and even the cargo shorts that I wore were so tight that they’d leave marks on my legs.

Were you able to start exercising again after everything was done?

Bill R: Yes. I started swimming again and working out. When I did the Provenge (sipuleucel-T) in the summer, that wasn’t so bad, I guess. It’s something that most people don’t want to go through—let me put it that way. There were days I was extremely tired and didn’t feel well. I was able to get back on my feet, exercise, and lead a normal life.

Doing that again, with what I know now, it probably would have been less of an impact on me. That’s the challenge for a lot of people. You go into this, and you don’t know what you don’t know. The doctors don’t really know how you’re going to react to some of this either.

Right, because everybody is different.

Bill R: Exactly. They had to adjust things like the steroids, and then things were better. They expected my water retention. I had some neuropathy damage in my feet, which is permanent. When I walk around, I feel like I’m walking on water bubbles all the time, so I’m not really stable. That took a while to get used to. Staying active will make you feel better, even if it’s just going out for a walk every day, so you’re not sitting there thinking, “I’m going to die, and this is awful.”

Right. It’s not good for anyone to dwell on that.

Bill R: Right. As soon as you head down that path, you’re toast. You’ve got to find a way to live your life. It forces you to get all your affairs in order because you realize that you’re going to pass away before you expect to. I’m starting Jevtana (cabazitaxel) in a few months because the cancer has progressed.

I’ve heard people can tolerate Jevtana (cabazitaxel) a little better. The side effects are not as severe as Taxotere (docetaxel).

Bill R: That’s what they’re telling me, that I shouldn’t expect things like water retention and so on. I am going through that now, so the doses are once every three weeks for six rounds. We’ll see how that goes. But it is what it is. I tell everybody if you live long enough, you’re going to get prostate cancer.

That’s actually true.

Bill R: It’s only a question of when. If you get it like I did, earlier in life, it shortens your life. But if you get it when you’re 90, nobody knows and nobody cares. Hopefully I’ve helped people a little bit.

A lot of it is mental. If you swear that this is going to be miserable, everything you look at will contribute to that feeling. Whereas, if you’re determined to get through it with a positive attitude, it’s not as bad. There’s a lot in the mental side that really helps you get through it.

Join us to read the rest of our August conversations about chemotherapy.

Dr. Vogelzang Offers Advice for Men Prescribed Chemo For Prostate Cancer

Dr. Nicholas Vogelzang is a medical oncologist at Comprehensive Cancer Centers of Nevada. He is a member of the 2018 Class of Giants of Cancer Care, a designation awarded to healthcare professionals advancing the field of oncology by their contributions in research and clinical practice.

He also serves as Associate Chair for the Genitourinary Committee of US Oncology, the Vice Chair SWOG GU committee, and the Associate Editor of Kidney Cancer Journal and Clinical Genitourinary Cancer.

Prostatepedia spoke to him recently about the development of chemotherapy for prostate cancer. He also offers advice for men prescribed chemotherapy and thoughts on a new class of drugs called PARP inhibitors.

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Do you have any advice for men who have been prescribed chemotherapy? For many patients, it’s a frightening thing. There’s a cultural concept that chemotherapy is terrible.

Dr. Vogelzang: I understand how seriously patients take this issue, although it’s an unfounded fear. I have a patient who is dying. He’s a retired pilot. He refused to take chemotherapy. Yet, he went to the Philippines and spent $30,000 on some herbal potion rather than go on chemotherapy. He came back far worse than when he left. At this point, he’s trying chemotherapy, but he’s just taken too long to get it.

There are a couple of things I’d say. Number one: don’t wait too long. Take chemotherapy when you’re strong. Number two: all the side effects are reversible. You don’t suffer the whole time, although fatigue is real. You’ll have nausea for a day and some folks get bad diarrhea. We have developed dramatically effective drugs to prevent diarrhea, nausea, and vomiting. You don’t vomit anymore. You may not even get nauseated. About the only thing you get is fatigue. Taxotere (docetaxel) can cause hair loss, but Jevtana (cabazitaxel) does not.

If you use an ice cap, like women do with breast cancer, you don’t lose your hair. You can get some numbness in the fingers, but you can prevent that by using ice on your hands. There’s even a product on the market now, called the cold cap, that you can buy for $300 or so that you wear on your head. It looks like a World War I flying cap from the Red Baron. You put it on your head during the one hour of chemotherapy. It virtually prevents the hair loss.

There are also mittens and stockings that protect against fingernail and nerve damage in the hands and feet. You can do it the inexpensive way and put your hands and feet in ice. People come into my clinic and ask what all those guys are doing with their feet in ice? It’s to prevent nerve damage from the chemotherapy.

Like I said, Jevtana (cabazitaxel) avoids those side effects. I try to give Jevtana (cabazitaxel) whenever I can first for that reason. Usually, the insurance requires Taxotere (docetaxel) first because Jevtana (cabazitaxel) is a lot more expensive. Jevtana (cabazitaxel) can be really well tolerated for a long time. I have one patient who is a rancher originally from Minnesota. He is on dose number 27 of Jevtana (cabazitaxel). His PSA started in the high hundreds and now it’s 11. In some patients, chemotherapy is highly effective, long lasting, and is clearly not to be feared.

It’s just urban legend that somehow chemotherapy is bad. We figured out many years ago that chemotherapy is not to be feared.

Join us to read the rest of Dr. Vogelzang’s comments on chemotherapy for prostate cancer.

Switching from One Chemo Drug to Another

Dr. Emmanuel Antonarakis is an Associate Professor of Oncology and Urology at the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center.

Prostatepedia spoke with him recently about his work on the benefit of switching men from Taxotere (docetaxel) to Jevtana (cabazitaxel)— or vice versa—if his PSA doesn’t go down by 30% in the first twelve weeks of treatment.

You’ve published a paper on switching patients from Taxotere (docetaxel) to Jevtana (cabazitaxel) and vice versa. What is the thinking behind switching chemotherapeutic agents? Why would you want to switch agents earlier as opposed to when the first chemotherapy drug stops working?

Dr. Emmanuel Antonarakis: The motivation behind this paper was that the FDA-approved recommended dosing schedule for both Taxotere (docetaxel) and Jevtana (cabazitaxel) is a course of ten doses, given three weeks apart. When patients begin FDA-approved Taxotere (docetaxel) or FDA approved Jevtana (cabazitaxel), they’re often told by their oncologists that they should expect to receive this chemotherapy once every three weeks for up to ten doses. A patient may not receive ten doses or might stop the therapy before he reaches ten doses because he cannot tolerate the therapy and has unmanageable side effects, or his cancer begins to progress before he ever get to dose number ten. If his PSA begins to increase again at dose six or seven or the tumors begin to grow again, his oncologist might ask him to stop chemotherapy.

We then wondered whether the ten doses was a reasonable time to wait or whether there could be an early indicator, or an early sign, of therapy resistance or therapy futility without having to go through six, seven, eight, nine or ten doses.

The idea that we had was to test an early intermediate marker of sensitivity or resistance to the chemotherapy. The best marker of early sensitivity or resistance that we could think of was whether or not a patient had a 30% PSA drop within the first four cycles of therapy. As you recall, if the therapy is given once every three weeks, four cycles basically means 12 weeks, which roughly equates to about three months.

The decision to use this intermediate endpoint was not arbitrary; it was based on some large retrospective meta-analyses that have shown that the strongest predictor of overall survival in patients receiving both Taxotere (docetaxel) and also separately Jevtana (cabazitaxel) was whether or not patients had a 30% PSA reduction after 12 weeks.

Patients who do achieve at least a 30% or greater reduction in the first 12 weeks have a survival that’s longer than patients who don’t achieve that endpoint. We thought, well if this endpoint is strongly correlated to survival, perhaps we can use it as a decision point. If after four doses of therapy or 12 weeks of therapy a patient don’t achieve a 30% reduction in PSA perhaps we should switch him to the other chemotherapy, rather than sticking with it and just waiting for either the toxicity to develop or the PSA or the radiographic disease to progress. That was the hypothesis.

We designed a relatively small study of about 63 patients. We used a 2:1 randomization so they were twice as likely to get Taxotere (docetaxel) compared to Jevtana (cabazitaxel). Approximately 41 patients got Taxotere (docetaxel) first. The other 22 patients, got Jevtana (cabazitaxel) first. Irrespective of which arm they were randomized to, they received the first four doses of chemotherapy in 12 weeks. We checked their PSA every three weeks.

At the end of the fourth dose, if the PSA level had dropped by 30% or more, the patients would continue on the same therapy on which they started. However, if patients did not achieve a 30% reduction or more, they would be switched to the other chemotherapeutic agent.

If a patient had a 25% reduction, we would switch him to the other agent because we thought that was not good enough. If someone received Taxotere (docetaxel), and their PSA dropped by 25%, even though it dropped by 25%, it did not meet that 30% threshold so they would then switch for the fifth dose to receive Jevtana (cabazitaxel) for the remainder of their chemotherapy. The inverse was also true. If the patient received Jevtana (cabazitaxel) first and also did not get a 30% reduction by week 12, in other words four doses, they would also switch to receive Taxotere (docetaxel). The interesting thing that we found in both treatment arms was that the chance that a patient had a favorable PSA response, which was defined as a 50% or more decrease, was higher than we had seen in historical trials using each drug by itself without switching. To put some numbers on that, we found that there was about a 54% chance that patients would have a 50% reduction in PSA if they had to the opportunity to switch from one chemotherapy to the other, compared to about a 45% chance of PSA reduction in the historical data where patients did not switch.

Did it matter if they got Jevtana (cabazitaxel) first or Taxotere (docetaxel) first?

Dr. Antonarakis: What we found out is a bit of a paradox: people could benefit from the switch in both down over time and the availability of non-chemotherapy agents is going up. A lot of these patients who may not have a 30% PSA reduction with one chemotherapy, might choose to do another hormone therapy, a radiopharmaceutical drug like Xofigo (radium-223), immunotherapy like Provenge (sipuleucel-T), or even a PD-1 inhibitor, or potentially a PARP inhibitor.

It might be difficult to convince a patient who has just failed one chemotherapy after four doses to go immediately to a second chemotherapy. I’m not 100% sure what the future will hold. I also don’t think this is a trial that we could have conducted today.

What would you say to a man reading it? That this is worth talking to his oncologist about or is this just something interesting for him to know about?

Dr. Antonarakis: Patients who are beginning their first chemotherapy should discuss this trial with their oncologist, and together with the oncologist decide in a joint fashion whether switching from one chemotherapy agent to another after four doses might be right for him, especially if he’s tolerating the chemotherapy well. If he tolerates the drug and his PSA has not dropped by 30% or is continuing to increase, then in my opinion rather than continue with the potentially futile therapy, a patient and his oncologist may wish to consider using this trial to guide or justify their choice of switching drugs earlier rather than later. directions. That was fascinating to us because, as we all know

Jevtana (cabazitaxel) was specifically approved by the FDA as a second-line curative therapy only indicated in men who have failed Taxotere (docetaxel) first. Based on that reasoning, one might expect Jevtana (cabazitaxel) to work better after Taxotere (docetaxel) but not Taxotere (docetaxel) after Jevtana (cabazitaxel).

This is not what we found.

We found that in both directions, both from the Taxotere (docetaxel) to Jevtana (cabazitaxel) switch, but also in the Jevtana (cabazitaxel) to Taxotere (docetaxel) switch, there was a significant amount of patients, approximately half, who were salvaged by the crossover therapy. By salvaged, I mean those who did not achieve a 30% PSA reduction with the first drug but did achieve a PSA reduction of 50% or more after crossing over to the second drug.

As I mentioned before, this occurred in both directions, both in patients receiving Jevtana (cabazitaxel) after Taxotere (docetaxel) and Taxotere (docetaxel) after Jevtana (cabazitaxel).

Are the side effects of Jevtana (cabazitaxel) a little bit easier to take than the side effects of Taxotere (docetaxel)?

Dr. Antonarakis: Interestingly, the side effects of Jevtana (cabazitaxel) in the published literature indeed appear to be slightly better. In this particular trial, which was very small obviously, they seemed comparable. In other words, we did not see any appreciable difference between the Taxotere (docetaxel) and the Jevtana (cabazitaxel) overall in terms of side effects. Taxotere (docetaxel) had a little bit more neuropathy nerve damage, which Jevtana (cabazitaxel) did not do. On the other hand, Jevtana (cabazitaxel) had a little bit more neutropenia, while the Taxotere (docetaxel) did not.

I would say that when patients receive these agents in a first-line setting, in other words, when they had not received another chemotherapy previously, their side effects were fairly comparable. I don’t think there was a clear signal in terms of one drug being clearly safer than the other.

Does it matter which you get first?

Dr. Antonarakis: From a side effect perspective, they’re both fairly equivalent in terms of tolerability, with slight differences in neutropenia, which is worse with Jevtana (cabazitaxel) and neuropathy, which is worse with Taxotere (docetaxel).

What is the next step? Are you going to run a similar trial with more patients?

Dr. Antonarakis: One question that arises is if this small randomized trial is enough to change practice. Should a community oncologist or urologist give Taxotere (docetaxel) for four doses and wait to see if the patient’s PSA drops by 30% or more? If it doesn’t drop to 30% or more, should he to switch to Jevtana (cabazitaxel)?

I have to admit that this is something that I have done in my practice a few times, but I really don’t believe that this is ready for clinical practice yet. Yes, in this trial, we showed that the PSA response rates could potentially be improved by this switch strategy. What we did not demonstrate was whether this improves overall survival.

The ultimate question is does switching chemotherapy agents after four doses improve survival, compared to just waiting until we see radiographic or clinical progression to switch agents. That would, as you mentioned, require a larger Phase III randomized study. The idea of study design would be to randomize patients to the switch strategy versus no-switch. We would randomize one group of patients to receive chemotherapy and switch if their PSA did not drop by 30%. The second group of patients would start chemotherapy but would not be given the opportunity to switch, even if their PSA did not drop by 30% or more. The randomization would not necessarily be the randomization to the chemotherapy, but would be randomization to a switch strategy versus a stick-with the first-chemotherapy strategy.

Sanofi, which makes both Jevtana (cabazitaxel) and Taxotere (docetaxel), have not been eager eager to respond to such a study because of financial considerations and also because the patent life of Taxotere (docetaxel) is over and the patent life of Jevtana (cabazitaxel) will be expiring soon.

Unfortunately, we might be left with a Phase II study that may, potentially, not translate into a Phase III study. I think individual patients and individual oncologists may look at these data and might be convinced that some patients might potentially benefit from a switch strategy, especially those who did not have any degree of PSA reduction after four cycles.

An added complexity is that the popularity of chemotherapy is going down over time and the availability of non-chemotherapy agents is going up. A lot of these patients who may not have a 30% PSA reduction with one chemotherapy, might choose to do another hormone therapy, a radiopharmaceutical drug like Xofigo (radium-223), immunotherapy like Provenge (sipuleucel-T), or even a PD-1 inhibitor, or potentially a PARP inhibitor.

It might be difficult to convince a patient who has just failed one chemotherapy after four doses to go immediately to a second chemotherapy. I’m not 100% sure what the future will hold. I also don’t think this is a trial that we could have conducted today.

What would you say to a man reading it? That this is worth talking to his oncologist about or is this just something interesting for him to know about?

Dr. Antonarakis: Patients who are beginning their first chemotherapy should discuss this trial with their oncologist, and together with the oncologist decide in a joint fashion whether switching from one chemotherapy agent to another after four doses might be right for him, especially if he’s tolerating the chemotherapy well. If he tolerates the drug and his PSA has not dropped by 30% or is continuing to increase, then in my opinion rather than continue with the potentially futile therapy, a patient and his oncologist may wish to consider using this trial to guide or justify their choice of switching drugs earlier rather than later.

Join us to read more conversations about chemotherapy for prostate cancer.

Managing Chemotherapy Side Effects

Dr. Cy Stein is a medical oncologist at California’s City of Hope hospital. He routinely advises his fellow doctors to, “Never think about yourself. It’s only about the patient.”

Prostatepedia spoke with him about dealing with the side effects of chemotherapy for prostate cancer. Why did you become a doctor? What was it about medicine that drew you in? What keeps you there?

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What are the most common chemotherapy drugs that men with prostate cancer are likely to encounter today?

Dr. Cy Stein: It all depends on what your definition of chemo is, but I take a very narrow definition that I think most of the community would take. There are two chemotherapy drugs that exist for prostate cancer. One of them is called Taxotere (docetaxel). The other is Jevtana (cabazitaxel). I don’t consider drugs like Lupron (leuprolide) to be chemotherapeutic agents. We consider them to be hormonal agents because they act directly on testosterone. Testosterone, as I’m sure everybody knows, is the male sex hormone. In order to get responses in prostate cancer, physicians have to lower the patient’s level of testosterone in their blood. That’s not a chemotherapeutic way of doing it; that’s a hormonal way of doing it.

Similarly, the newer drugs that have come out recently are not chemotherapeutic agents either. I’m referring to Zytiga (abiraterone) and Xtandi (enzalutamide). We call them oral hormonals. Provenge (sipuleucel-T) is a kind of tumor vaccine, so it’s really immunologic oncology. Xofigo (radium 223) is also not a chemotherapeutic agent, so we’re down to two.

What are the differences between the two. When would Taxotere (docetaxel) be used over Jevtana (cabazitaxel)?

Dr. Stein: Taxotere (docetaxel) was first developed in 1995-1996 and has been on the market for a long time. It was originally used in breast cancer and lung cancer as well. Then it was introduced for use in prostate cancer.

There is significant amount of toxicity with Taxotere (docetaxel), although it is a very good drug. It is different from Jevtana (cabazitaxel), even though both of the drugs are formed to the same general class of molecule, which we call taxanes. They both come from, ultimately, the needles of the Pacific Yew tree. Even though the names sound similar, these are different drugs with different toxicity profiles.

The important thing for a patient to remember is that, even though these drugs have side effects, at times we see spectacular responses from both of them. The side effects are manageable and definitely worth the effort for the patient because of the potential for the response that you can get. Taxotere (docetaxel) has more side effects than Jevtana (cabazitaxel). Taxotere (docetaxel) seems to have more toxicity, and most important, the toxicity seems to get worse as patients age. Therefore, I find it extremely difficult, if not impossible, to give Taxotere (docetaxel) to men who are over 80.

What toxicities are we talking about?

Dr. Stein: For Taxotere (docetaxel), the major dose-liming toxicity is fatigue. People are not going to feel anything on the day that they get the Taxotere (docetaxel). The day after, they’re going to feel pretty tired, and most men will want to just stay in bed. Their partners don’t particularly like that, but it’s probably best to leave them in bed because they’re not going to be very functional for a day or more on Taxotere (docetaxel).

It’s not uncommon for a man to say, “For three days after I get this drug, I’m very wiped out.” I’ve even heard them say, “Five to seven days after I get this drug, I feel very wiped out.” Then the men will get better, and eventually they will come back for their next cycle, and we’ll do it all over again. It doesn’t happen quite so much with Jevtana (cabazitaxel) because it is a little easier on the fatigue.

In terms of other side effects, one of the side effects that Taxotere (docetaxel) has, only in about 10% of cases, is febrile neutropenia. That is the white blood cell count goes down seven to nine days after getting the chemotherapeutic drugs and leads to an infection. The patient will have a fever of 100.4 or greater, and the febrile neutropenia requires antibiotics. With Jevtana (cabazitaxel), the incidence of febrile neutropenia is much, much higher. What I do is I make sure that all of my patients have Neulasta (pegfilgrastim) applied before they get the chemotherapy, to prevent their white count from going down.

There are some patients who may not need Neulasta (pegfilgrastim), but I prefer to sleep calmly at night. I don’t want to worry about a patient getting febrile neutropenia on Jevtana (cabazitaxel), so I treat every one of my patients with Neulasta (pegfilgrastim).

In terms of other toxicities, many men say that Taxotere (docetaxel) also causes food to taste like cardboard. Their hair will certainly thin, but it probably won’t all fall out. They may get tearing of the eyes. They may get changes in their nails such as brown bands that horizontally cross the nails. These disappear after discontinuation of treatment. They can also, potentially, get a little bit of fluid in their lungs, although in my experience that hasn’t been a clinical problem. They can also, potentially, develop neuropathy.

It sounds rough, and for some men it is, but a lot of men go through it very well. They can have a tremendous response. I’ve seen any number of individuals have responses of 75% and even 90% in their PSA. These are the kind of individuals who live a great deal longer than if they didn’t respond.

Jevtana (cabazitaxel) is a very similar story, except the fatigue is much less. The neuropathy is significantly less, although I have seen patients with neuropathy on Jevtana (cabazitaxel). The nail banding does not happen. The poor taste doesn’t happen. The hair loss is greatly reduced. Fatigue is also significantly reduced, but there is still fatigue in some patients.

Because the toxicity profile is better with Jevtana (cabazitaxel), I don’t hesitate giving this drug to patients who are over 80 years old. In my opinion, they seem to tolerate it better. I had a patient who was 90 years old and of sound mind and body. He didn’t have much of a choice; he had two sons who were doctors. We talked it over and he said, “I want the drug.” He got the drug, and I started him with a much lower dose than the full recommended dose. I titrated him up to tolerability, and he received 13 consecutive cycles of Jevtana (cabazitaxel). All his pain went away, and he lived an extra year.

Jevtana (cabazitaxel) has a lower dosage option that has just been approved. What has been the impact for your prostate cancer patients?

Dr. Stein: I use two doses of Jevtana (cabazitaxel): 25 mg/m. and 20 mg/ m.. The overall survival with both doses is identical, but at 25 mg/m., the PSA is more affected as opposed to the 20 mg/m.. In other words, you have more PSA decline on the 25 mg/m. than you have on the 20 mg/ m.. Of course, you have less toxicity on the 20 mg/m.. For those men who really follow their PSAs very closely, I might, all other things considered, recommend the 25 mg/m.. For most men, I think the 20 mg/m. is just fine. For Taxotere (docetaxel), the full dose is 75 mg/m.. There’s little evidence that you lose much in the way of efficacy if you go to 50 mg/m. to avoid toxicity, and I’ll do that frequently.

Is there anything men can do to prepare themselves for these side effects?

Dr. Stein: Aside from communicating with their doctors and taking Claritin if you’re receiving Neulasta (pegfilgrastim), I’m not sure there is anything you can do.

Is there anything else you’d like patients to know about chemotherapy for prostate cancer?

Dr. Stein: These are very realistic options for patients. Men can tolerate Taxotere (docetaxel) for maybe six to eight cycles. It’s hard for men to get more. With Jevtana (cabazitaxel) it’s unbelievable how much people can get because the toxicity is less. I know of a man who received 55 continuous cycles of Jevtana (cabazitaxel) and did extremely well. My own personal record is 33 cycles. In one of those cases, the patient had a 99% response in his PSA; he lived three extra years. He did extremely well. I had another man who also got 33 cycles. His PSA was roughly 50 to 70 and it stayed that way for 33 cycles before he started to progress. I have seen quite a few remarkable responses.

Join us to read the rest of this month’s conversations about chemotherapy for prostate cancer.

Clinical Trial: Intravenous Vitamin C + Taxotere (Docetaxel)

Dr. Channing Paller, an Assistant Professor of Oncology at Johns Hopkins University School of Medicine, focuses on translational research and clinical trials of developmental therapeutics in prostate and other solid tumors.

She is keenly interested in the rigorous evaluation of natural products in cancer treatment.

Prostatepedia spoke to her about her Prostate Cancer Foundation instigated and Marcus Foundation funded clinical trial on combining intravenous Vitamin C with Taxotere (docetaxel).

Dr. Channing Paller: One of my interests is studying natural products that people take as dietary supplements. We don’t know whether they work or whether they cause harm, so I test them. Several of my clinical trials study these compounds rigorously in a placebo-controlled fashion, as we would with any cancer treatment.

I knew about a recent randomized study of high dose intravenous ascorbic acid (vitamin C) in ovarian cancer patients, which showed that ascorbic acid treatment combined with standard chemotherapy reduced toxicities from the chemotherapy and also trended towards improved overall survival. Vitamin C enabled the patients to receive more cycles of chemotherapy, and that was associated with longer overall survival.

In response to the findings in ovarian cancer, the Prostate Cancer Foundation sent out a request for proposals for early stage research on vitamin C’s role in treating prostate cancer. We decided to initiate a large (60 patient) placebo-controlled trial with co-primary endpoints of quality of life and cancer response to the combination of intravenous (IV) vitamin C and chemotherapy. We are extremely grateful to the Marcus Foundation for supporting the trial.

We chose Taxotere (docetaxel) because it was first line and an easy place to start to answer the question. Jevtana (cabazitaxel) would have worked just as well.

What can patients expect to happen during the trial?

Dr. Paller: We are conducting a randomized placebo-controlled Phase II trial of standard-of-care Taxotere (docetaxel) for metastatic castrate resistant prostate cancer with either ascorbic acid or placebo, which is electrolytes and hydration, given twice a week in between the cycles of chemotherapy every three weeks. Some people say that this is too big a commitment, so they get to take breaks if needed. They can miss a session or two here or there. They can even take two weeks’ break, if needed. We’re trying to help people live better, not chain them to the clinic.

Join us to read more about Dr. Paller’s trial.