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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.


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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.


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Chemotherapy

Many patients fear chemotherapy not only because of its side effects but also because of what the need for chemotherapy implies about their prognosis. Fortunately, each physician we spoke with this month addresses both issues.

Taxotere (docetaxel), the chemotherapy drug most commonly used to treat prostate cancer, is usually used to treat patients with an aggressive form of this disease. However, multiple randomized trials have shown that this drug prolongs survival. We see the most dramatic impact in patients who have extensive metastatic disease at the time of diagnosis. The CHAARTED trial showed that initial treatment with Lupron (leuprolide) plus Taxotere (docetaxel) was markedly more effective than Lupron (leuprolide) alone in prolonging survival. There is a definite benefit to receiving the drug, if you need it.

The most common side effect of Taxotere (docetaxel) is fatigue, which is usually mild after the first dose, but worsens with each subsequent dose. Sometimes, this limits the total number of doses administered. Usually, this side effect disappears over time. Exercise lessens its potency, and each physician in this issue recommends exercise. Taxotere (docetaxel) damages the nerves in the hands and feet. This leads to a feeling of numbness and tingling in the fingers and toes called neuropathy. This grows in severity with each dose of the drug, but when stopped in a timely fashion, the side effect is reversible.

In 2003, Gedlicka et al. reported that alpha lipoic acid minimized nerve damage. Since the publication of this paper, we recommended two 300 mg tablets of time-release alpha lipoic acid twice a day during Taxotere (docetaxel) treatment in my practice. It appears to have a marked impact on the severity of this side effect.

Taxotere (docetaxel) damages the production of hair and nails. Hair loss can be prevented by chilling the scalp as the drug is administered. Chilling the hands and feet also seems to lessen the nail damage.

Prolonged Taxotere (docetaxel) treatment can also damage and block the tear ducts, causing tears to flow. Some physicians recommend inserting silicon rubber tubes in the tear ducts when the symptoms first appear. Once the tear ducts have closed, repair is much more difficult.

Many chemotherapy drugs cause a drop in hemoglobin, white cells, and platelets. While these can be a problem with Taxotere (docetaxel), it is milder than in the multidrug combinations used for other common cancers, such as breast cancer. Transfusions can be used if the drop in hemoglobin becomes clinically significant. Low white cell count can be managed with granulocyte stimulating factor (G-CSF). While a low platelet count can be managed by platelet transfusions, these lose their effectiveness over time. This can be a major problem in a few patients.

Patients on Taxotere (docetaxel) often experience inability to taste food. Patients have often reported that bland creamy foods are easier to eat.

Overall, the side effects of Taxotere (docetaxel) develop gradually as the number of cycles on the drug accumulates. If treatment is limited to six cycles, these side effects are usually mild and reversible. Most patients have nearly complete recovery within 6 months. If the cancer is still sensitive to the drug, a second round can be effective and well tolerated.

Read the rest of this month’s conversation about chemotherapy with:

  • Tanya Barauskas Dorff, MD: Chemotherapy
  • Alicia Morgans, MD: Putting Chemo in Perspective
  • Michael Morris, MD: Clinical Trial: Combining Taxotere + Xofigo
  • Julie Graff, MD: Chemotherapy, Xtandi, and Zytiga
  • Benjamin Gerendash, MSN, RN, NP Chemo: A Nurse’s Perspective
  • Catherine E. Guider, RN An Infusion Nurse’s Perspective
  • Patients Speak: Getting Chemo: My Story


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Clinical Trial: Free Genetic Testing

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

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

What attracted you to medicine?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Are there any fees for patients?

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

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

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

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

Dr. Cheng: Correct, yes.

Are you also cataloging the information that you collect?

Dr. Cheng: Yes.

What will you do with the data that you collect?

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

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

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

How many patients are you looking for, overall?

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

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

 


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Clinical Trial: Zytiga, Lynparza, + DNA Repair Defects

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

Prostatepedia spoke with her about a clinical trial she’s running, BRCAAway, that looks at Zytiga (abiraterone) and Lynparza (olaparib) in metastatic castrate-resistant prostate cancer (mCRPC) patients with DNA repair defects. (The trial has a ClinicalTrials.gov Identifier of NCT03012321).

What can you tell us about the trial that you’re running looking at Zytiga (abiraterone) and Lynparza (olaparib)?

Dr. Maha Hussain: In prostate cancer, and specifically in mCRPC, data emerging from multiple resources, including the Stand Up To Cancer initiative from a few years ago, indicate that greater than 20% of mCRPC cancer harbor DNA repair pathway aberrations. These types of defects in the tumor will allow the patient to potentially be a candidate for PARP inhibitors. In this regard, PARP inhibitors have had a track record in ovarian and breast cancer.

They’re currently undergoing multiple clinical trials, including Phase III clinical trials in patients with advanced disease and in different settings of the disease.

A couple of years ago, we published data from an NCI-funded clinical trial where patients with mCRPC underwent a biopsy of their metastatic cancer. The patients were then stratified by the presence or absence of ETS gene fusion and randomized to Zytiga (abiraterone) and prednisone with or without a PARP inhibitor called veliparib.

As part of that study, we also looked at other tumor genomics when extra tissue was available. We discovered that the patients who had tumors with DNA repair defects seemed to respond much better to treatment with Zytiga (abiraterone) with or without veliparib as opposed to the patients who did not have that. This is not something that anyone knew before. After we had published our data, the Johns Hopkins team published data they had on patients who had undergone germline testing and who had received Zytiga (abiraterone) or Xtandi (enzalutamide). They reported similar observations.

This leads me to the current trial, which we call BRCAAway. BRCAAway is a prospective clinical trial for patients who have developed mCRPC for which they have not yet received any specific treatment. Patient will undergo a biopsy, unless they have previous tissue available from either the primary or metastatic disease, and the tissue will then be evaluated for the presence of specific DNA repair defect alterations. Per the US FDA guidance, patients who have BRCA1, BRCA2, and/or ATM are randomly assigned to either Zytiga (abiraterone) + prednisone, Lynparza (olaparib), or combination Zytiga (abiraterone) + prednisone and Lynparza (olaparib). Any patient whose tumors have other DNA repair defects (not BRCA1, BRCA2, or ATM) are enrolled into an exploratory arm where they will receive Lynparza (olaparib). Lynparza (olaparib) is provided by the study. The patients who are randomized to the arm of the Zytiga (abiraterone) or Lynparza (olaparib) can cross over to the other treatment if their cancer is progressing; i.e., if a patient who is randomized to Zytiga (abiraterone) and prednisone and then develops progression of the cancer is interested and his physician deems it appropriate, he can switch over to Lynparza (olaparib). The same is the case for patients who are randomized to Lynparza (olaparib) if they progress on frontline Lynparza (olaparib), they can switch to Zytiga (abiraterone) and prednisone per standard-of-care.

Are you assuming that these patients have already been tested for BRCA1, BRCA2, and ATM, or will you be testing for that?

Dr. Hussain: So long as it was done in a certified and appropriate lab, we can accept the data for patients who have been tested. The study covers a biopsy and the genomic testing for the patients.

Are there any fees associated, or is everything covered?

Dr. Hussain: Anything that’s standard-of-care is billed to insurance. Anything that is a research procedure, as in the biopsy and the genomics testing, is covered by the study. The Lynparza (olaparib) is provided by the study, but the Zytiga (abiraterone) is not because that’s part of standard-of-care. All of these tests to assess the cancer, assess tolerance, and assess the cancer progression in terms of scans, things like blood work or anything for safety assessment, per CMS rules, are billed to insurance.

How many patients have you already enrolled, and how many are you looking to enroll?

Dr. Hussain: In the arm with the BRCA1, BRCA 2, and ATM, we need 60 patients. We’re about halfway there. We have enrolled 40 patients to date. For the exploratory arm, we have expanded our limit, and we’re growing that arm. So far, we have plenty of room to accrue more patients.

How many sites do you have?

Dr. Hussain: We currently have 15 active sites.

That’s a lot.

Dr. Hussain: It’s a lot of sites, but as I’m sure patients appreciate, part of it is that by the time we see an eligible patient, they have to have the specific mutations, whether it’s on new tests or based on previous tissue. When we test, it’s roughly one in five who will likely be positive. Of course, they have to qualify by other criteria, so we have to screen many patients. We’re on track as we forecasted, and we’re hopeful to finish enrollment by a year from now. We also hope to have some important data to share.

Wow! That’s fast.

Dr. Hussain: Of course we need adequate follow-up to assess clinical benefit and its duration. I’m thinking 2020 will be the end of the study, and if there are signals earlier, we will be reporting the data. The Prostate Cancer Clinical Trial Consortium (PCCTC) is acting as the coordinating CRO. The institutional review board (IRB) of record is Northwestern University IRB. If you’re interested in learning more, please visit https://clinicaltrials.gov/ct2/show/ NCT03012321?term=brcaaway &rank=1 or email cancertrials@ northwestern.edu.

Is there anything else you want patients to know about this particular trial or about the context in which it’s occurring?

Dr. Hussain: This and other clinical trials are important options for patients to consider. Clearly, they have access to regular standard-of-care treatment. The hope is that we can do better than standard-of-care. We are also trying to validate earlier observations that I mentioned regarding whether the patients who have DNA repair defects have better response to Zytiga (abiraterone) and how does this response compare to Lynparza (olaparib) versus the combination.

Lynparza (olaparib) is a drug that’s available on the market for breast and ovarian cancer, so there’s a fair amount of experience with it. It is not yet FDA approved for prostate cancer, but we have a reasonable understanding for the potential side effects. Certainly, there are multiple clinical trials that are looking at it and other PARP-inhibitors in prostate cancer.

Zytiga (abiraterone) is standard-of-care and FDA approved. It’s been around for many years. All treating oncologists should be very familiar with it and how to monitor and what to expect.

It looks like an exciting trial.

Dr. Hussain: We are very excited. What is clear from the experience with prostate cancer is that one size does not fit all, this is one of the first examples of precision medicine in front line mCRPC. Our goal is to better personalize care and significantly impact disease outcomes.

The patient is our partner. We cannot succeed and deliver better treatments to patients without their partnership, so we are very grateful to them for their participation.

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Frontiers In Prostate Cancer Genomics

Dr. Felix Feng is a physician-scientist at University of California, San Francisco (UCSF) keenly interested in improving outcomes for patients with prostate cancer. His research centers on discovering prognostic/predictive biomarkers in prostate cancer and developing rational approaches to targeted treatment for therapy-resistant prostate cancer. He also sees patients through his prostate cancer clinic at UCSF.

Prostatepedia spoke with him about the state of genomics for prostate cancer today.

Not a member? Read the rest of this month’s conversations about prostate cancer genomics + prostate cancer genomics clinical trials.

What would you like prostate cancer patients to know about the state of genomics for prostate cancer today?

Dr. Feng: Genomics is becoming an important reality for patients with prostate cancer. We’ve talked about genomics for years in the context of research and possible advances for patients, but we are now reaching the era when these advances are being used in clinical practice or being assessed in clinical trials.

For patients with metastatic prostate cancer, patients with alterations and mismatch repair genes should be treated with immunotherapy (checkpoint blockade) at some point in the course of their treatment. At some point in their treatment, patients who have alterations in the BRCA1 and BRCA2 genes or other DNA repair genes should also enroll on a trial involving a PARP inhibitor.

There are many other trials testing specific biomarkers for selection for patients. For example, a few years ago, Prof. Johann de Bono presented the results of a study looking at an AKT inhibitor for patients with PTEN deleted prostate cancers. That’s currently being explored in a Phase III trial, and we’re eagerly awaiting the results of that.

In addition, the presence of androgen receptor (AR) splice variants is being used to select patients for studies. These need to be tested out. Some are molecular biomarkers rather than genomic biomarkers. But for patients with metastatic prostate cancer, we can point to definite examples where science is becoming clinical reality.

In the context of patients with localized prostate cancer or non-metastatic prostate cancer, we’re also seeing a number of advances. There are several tissue-based biomarkers that are now covered in various contexts by insurance companies, and they can be ordered as standard-of-care clinically.

In one of my roles, I chair the Genitourinary Cancer Committee for the Clinical Trials group NRG Oncology. A number of our national trials are Phase II and now also Phase III. The trials that we’re developing incorporate these genomic biomarkers for patient stratification or patient selection. When you start to see genomic markers like Decipher incorporated into NRG or PAM50 trials, it means that, sooner or later, these will become standard-of-care, assuming that the trials are positive.

Are there any open and enrolling clinical trials that either focus on prostate cancer genomics or incorporate genomics into their design that you think men reading this may either want to look into or ask their doctors about?

Dr. Feng: Two of the most promising studies are in patients who have had surgery for prostate cancer and now have a PSA recurrence. They are both actively enrolling.

The first trial that I would highlight is NRG-GU006. This study is open at hundreds of hospitals in the United States and Canada; it takes men who have a PSA recurrence after prostatectomy. We go back, we profile the prostate cancer sample from those patients, and we assess a biomarker called the PAM50 classifier, which we helped validate in prostate cancer as predicting response to hormonal therapy. Patients get stratified by this biomarker and are then randomized to standard-of-care, which is radiation alone, or to radiation plus the next-generation antiandrogen Erleada (apalutamide). They get both genomic testing with the PAM50 classifier and randomization, as well as the opportunity to be on Erleada (apalutamide).

Another trial that is actively enrolling is the NRG-GU002 trial, which takes patients who have very aggressive recurrences of their prostate cancer after surgery, and tests them using the genomic classifier Decipher. In the control arm, those with aggressive disease get randomized to radiation and hormone therapy or radiation and hormone therapy plus chemotherapy with Taxotere (docetaxel).

We and other groups have many other trials in development trying to incorporate these biomarkers, but those are the two trials that are open and accruing.

Who are the lead investigators on these two trials?

Dr. Feng: On NRG-GU006, the co-leads are Dr. Daniel Spratt from the University of Michigan and me. On the NRG-GU002 trial, the lead is Dr. Mark Hurwitz from Thomas Jefferson University.

Is there anything else that patients might want to consider?

Dr. Feng: For patients with metastatic disease, there are a number of PARP inhibitor studies in development right now. We’re looking to move PARP inhibitors into earlier and earlier disease spaces in select patients, largely based on the presence of DNA repair alterations.

This study using the Genentech AKT inhibitor is exciting to me. It’s a Phase III study for patients with PTEN alterations. Not all prostate cancers are the same, but we have traditionally put prostate cancer into one disease. But the many different cancers that comprise prostate disease could be genomically selected or stratified.

That is the future, right? Smaller and more precise categories?

Dr. Feng: Yes.

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Prostate Cancer Genomics

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

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

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

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

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

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

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