Prostatepedia

Conversations With Prostate Cancer Experts


Leave a comment

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?

Not a member? Join us.

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.


Leave a comment

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).

Paller-20537-111ret

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.


Leave a comment

Dr. Ken Pienta: Chemo For Prostate Cancer

Dr. Kenneth J. Pienta, of the Johns Hopkins University School of Medicine, is an international expert in the development of novel chemotherapeutic agents for prostate cancer. He was the recipient of the first annual American Association for Cancer Research Team Science Award and is the author of more than 300 peer-reviewed articles. He frames this month’s conversations about chemotherapy for us.

Pienta_lab_Background

Not a member? Join us.

In 2018, chemotherapy for prostate cancer continues to be one of the many options we have to lengthen the lives of patients suffering from metastatic prostate cancer. There are still multiple other therapies that we don’t consider chemotherapy. Second-generation anti-androgen therapies like Zytiga (abiraterone), Erleada (apalutamide), and Xtandi (enzalutamide) are all now standards of care in castrate-resistant prostate cancer. We also have Xofigo (radium-223) as an option for patients with bony metastases.

There are two chemotherapies that have been approved for prostate cancer: Taxotere (docetaxel) and Jevtana (cabazitaxel). Now, the real challenge for patients and providers is when to use those chemotherapies.

Multiple studies have demonstrated that, when you’re newly diagnosed with metastatic prostate cancer, it may be beneficial to receive a limited number of doses of Taxotere (docetaxel) at the start of hormone therapy. That’s especially true if you have multiple places where the cancer has spread. That’s not correct for all people, but for some patients, it is a good option. More and more physicians are prescribing Taxotere (docetaxel) with a luteinizing hormone-releasing hormone (LHRH) antagonist at the start of therapy.

However, that doesn’t mean you cannot use Taxotere (docetaxel) after other things have failed. If you failed second-line hormone therapy or have failed radium therapy, Taxotere (docetaxel) is still a good option that helps people live longer.

Jevtana (cabazitaxel) continues to be a good chemotherapy option if patients have failed Taxotere (docetaxel).

Thank goodness we’ve seen over the last several years an increase in the number of drugs available to treat metastatic prostate cancer in addition to chemotherapy. Chemotherapy has been around for quite a while now, but there is still a role for it.

Again, the challenge for all of us is: when do we slot them in for you? The chemotherapy we use for prostate cancer is really a single agent chemotherapy, either Taxotere (docetaxel) or Jevtana (cabazitaxel). This is not the multi-agent therapy we use for other cancers, so the idea of major side effects is a bit overblown. For example, nobody vomits from chemotherapy for prostate cancer. The drugs we use to prevent that are too good.

We also have gotten much smarter about limiting the number of doses we use. We don’t necessarily give chemotherapy until it doesn’t work anymore. Often, we just give several doses and then take a break. If you get more than a couple doses of chemotherapy, you will still lose your hair temporarily.

Chemotherapy can make you feel more tired when it lowers your blood count, and it can make you more susceptible to infections, but people are very rarely hospitalized now for an infection from chemotherapy. It’s virtually unheard of that somebody would die as a side effect of chemotherapy.

The major side effect of Jevtana (cabazitaxel) tends to be diarrhea, but again, as we’ve learned about the dosing of that drug, that has become more manageable.

Another side effect of both drugs can be peripheral neuropathy, which is tingling in the fingers and toes. But we watch for that too. If you start to develop that, we tend to stop the drug. These are very tolerable medicines.

The word chemotherapy always evokes images of horror, but chemotherapy in 2018 is a lot different than it was even five years ago. We just know how to give chemotherapy much better. When I started in the field 30 years ago, if you had metastatic castrate resistant prostate cancer, survival was 6 months. Now, with the advent of all these newer therapies, we’ve gotten much better. The landscape of how to treat prostate cancer has changed completely in the last five years. It will change completely again in the next five years. The challenge is in what order are we going to use all these powerfully good drugs rather than having only one drug to give or none at all.

For us as physicians, it’s an exciting time to take care of men with prostate cancer.

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


Leave a comment

Us TOO: Mark Slaughter’s Prostate Cancer Story

Mark and Denise Slaughter talk about their experience with chemotherapy for prostate cancer.

DSCN7750 (ed) Denise & Mark

Not a member? Join us.

The C word. No one can imagine beforehand the horror of being told you have cancer.

My problems began with urinary troubles: middle of the night urges, frequency, and the inability to go, start, or finish a urine stream. My primary care physician recommended a urologist.

My urologist was awesome and earned my confidence and trust with his approach. He explained he was trying to see a picture rather like a jigsaw puzzle, but in order to see the picture clearly, he needed more pieces of the puzzle. He convinced me to let him do a digital rectal exam (DRE).

The result was not good. On a 0-10 scale, 0-5 would indicate no problems and 5-10 would range from concern to panic. He said mine was about a 7 or 8. Very smooth everywhere, no evil nodules or lumps, but way too hard. Unlike the softer part of your thumb near the palm of your hand (like it should be), it felt like the harder area of your thumb where the bone is located. It was definitely a reason for concern.

Next, he talked me into a PSA test. I was one of the men who, about seven or eight years ago, read the controversial studies about PSA tests and unreliable results, and I took them to heart. Many organizations were saying PSA was overrated and shouldn’t even be used. So, I had stopped letting doctors test mine. My PSA was tested and came back very bad. It was 259. To see more of the picture, my doctor needed to do a biopsy. He respectfully listened to all of my logical arguments.

No number of needle probes will show you enough of the prostate. Too many and you can damage a fragile little organ. Besides, you would access a sterile body part by going in through a sewer. He held his ground and said he really needed this important piece of the puzzle. My wife and I thought about it overnight and agreed to let him do the biopsy.

My biopsy procedure was a piece of cake. I was given an antibiotic before the procedure. An ultrasound device accurately guided the doctor, and he was able to get 12 samples: 6 from each side of the prostate. Of the 12, I was really only hurt by one of them. Each felt like someone quickly poked me with a pencil. I heard the device click. I required no pain medication and passed a little blood during urination for a few days afterwards.

Then the results came. Of the 12 needle biopsy locations, nine were found to contain high-grade cancer. Of those nine, eight had a Gleason score of 8, and the last one was scored at 7. The range for cancer is 6 to 10, so we knew this was a bad score. It meant the cancer had spread beyond the prostate gland. My doctor said that the next step was to get CT and bone scans that, together, would show us where the cancer had spread in my body. My next stop was the hospital for the scans. The procedures were simple and easy enough. The results were another story.

February 8, 2018 is a day emblazoned in my memory, a day I will never forget, the day time stopped. That was the day I was told I have the big C word: I have cancer.

My doctor was tactful but did not mince words. The CT scan showed cancer in my lymph nodes, in my groin, and up my back on both sides of my spine. The bone scan showed lesions in four places on my pelvis and six places on my ribs. The tests all showed that I have advanced Stage IV metastatic prostate cancer. There is no cure. But we can manage it with hormone treatments and chemotherapy. With no treatment, I might only have a couple of years to live. With treatments, perhaps three to five years.

Upon hearing this news, my first thought was: I am dead. I had been standing next to my wife Denise, who was seated at her desk as we listened on the speakerphone. I collapsed into a seated position on the floor and reached out to catch Denise as she fell out of her chair. We crumbled to the floor together, sobbing and wailing with wrenching heaves of our chests. Squeezing each other as though life had ended that very moment. We embraced. We cried. We cried. We cried. Time stopped.

We laid together in a heap on the floor for a long time. By the time we climbed to our feet, we could hardly breathe. My face hurt from all the tears. Our eyes were swollen, our faces red below our eyes and otherwise colorless as though life itself had drained from our faces. It was like our lives were over.

My doctor referred us to an oncologist. We couldn’t stand him. He was rude and dismissive as he explained the chemo treatment plan and the poor prognosis for the remainder of my life. It is an understatement to say that he lacked a good bedside manner. Several friends immediately recommended we get a second opinion.

A friend of mine, and my former primary care physician when we lived in Atlanta, told me to forget that guy and get myself to another center. I did just that. I did just that and found an incredible doctor who was instrumental in the CHAARTED study that showed excellent results of early chemotherapy treatment combined with hormone therapy for the treatment of advanced metastatic prostate cancer.

My first appointment with this doctor was an education in prostate cancer. He explained the course of the disease, different methods of treatments, and answered each and every question I had. He described the treatment options as the tools in his toolbox. Whenever one might fail to produce results, he would reach for another one. He explained new drugs, such as hormone therapy, and he explained chemotherapy. Some people prefer chemo because it is six treatments and you are done. Other people would rather take pills for the rest of their lives. No study showed any real difference in the outcome of chemo versus hormone therapy. At first, I was going to go the hormone therapy route. I was terrified of chemo because of my preconceived notions and the horror stories from people I had known who went on chemo and suffered horrendous side effects before dying painful deaths.

But there was a major snag in my getting approval for hormone therapy. Because I am on Medicare and have the Part D drug coverage, I was not eligible for any financial aid from the pharmaceutical companies or from any other charitable organizations for hormone therapy.

Consequently, it was going to cost me in the neighborhood of $5,000 per month for the rest of my life. This was a huge blow to overcome mentally and financially. There was no way I could afford that.

My doctor reassured me again that the results of chemo are as positive as those from hormone therapy. Medicare would pay for the chemo. Because of these two considerations, I chose to take the chemo. Believe me, nothing about taking chemo comes close to the fear and angst of anticipating it.

I am currently undergoing chemo. I am through the fourth of six cycles of Taxotere (docetaxel). The biggest side effect for me has been the infamous cancer fatigue, especially during the first week after chemo. It takes about all the energy I have to walk from my chair to my bed to take a nap.

My doctors gave me Compazine (prochlorperazine), which prevents nausea and has worked extremely well for me. I also take Lupron (leuprolide), which has caused some hot flashes, mostly in the late afternoon and evening. Sometimes

I have night sweats. Cramps of my ankles are a bothersome little issue several times a week.

One thing I have not had at all is neuropathy. My wife read about studies done in Canada, the United Kingdom, and France that indicate icing of the fingers and toes during chemo infusions prevents any changes to fingernails and toenails as well as neuropathy. I asked my oncologist and he said although there are no definitive studies in the United States that show results, he didn’t object to my doing it. My wife has faithfully kept my hands and feet iced during treatments. It’s not pleasant, but it’s certainly tolerable and offers a big pay-off. To me, it’s like a kid playing in the snow with no mittens.

Each of my sessions lasts about 1.5-2 hours. Once in a while, when it feels too cold, I take my hands or feet out of the ice for a short break. Overall, my treatments have been far less of an ordeal that the initial fear of treatment.

Another side effect: hair loss. I have had heavy, patchy hair loss on my head that started about 13 days after my first chemo treatment. The afternoon when large patches of hair began falling out into my hands in the shower, I decided to take action. The next morning, slowly, deliberately, I dressed, collected my wallet and keys, walked to the garage, got in the car, drove to the nearest barber and got a buzz cut. I didn’t think about it. I just did it. And it was one of the best decisions I have made. It is far easier to manage quarter inch long hair than patches of messy hair. I would say to any guy, wait and see if your hair begins to fall out, then just accept the fact and manage it.

As for sexual function, I am 66 years old and have suffered from erectile dysfunction for six or seven years. Hormone therapy is medical castration. The result is loss of sexual function. I rarely have any kind of erection, and even the size of my genitals has shrunken somewhat.

But, with a loving partner, these things have not been so hard to accept. I still have the good feelings two people share in intimacy. I would rather be alive than fully-functional, sexually. I do admit my history has made this easier to accept than it might be for some younger men. The key here is perspective. Some choices in life are just hard. You have to decide what matters the most.

The biggest positive about chemo is that you do it and it’s over forever. For me, six cycles of three weeks, then never again. This compared to a lifetime of multiple pills on a daily basis, worrying all the while about how long they might be effective.

On the down side, you have to get your head around walking into a room feeling good and letting them inject you with strong chemicals that will make you feel bad. It’s rather bizarre. I live about 200 miles from my cancer treatment center, so the car trip and hotel stay give me way too much time to let bad thoughts get in the way before each treatment. Again, it’s all about controlling your thoughts and attitude. I know it sounds trite, but holding onto a positive attitude really matters.

The routine at each treatment is: a lab test for blood markers, doctor appointment, and chemo infusion. If my blood looks good, the doctor approves the chemo, then the chemo is prepared and infused. I know it’s working because the blood tests show positive results. My PSA has dropped from 259 to 20, 5, 2, and 1.7 over the first 4 treatments. Similarly, my testosterone has dropped from around 500 to less than 20, which the doctors consider insignificant. They tell me my testosterone level is that of a prepubescent boy, which is good because loss of testosterone starves the cancer.

My oncologist has not even discussed AR-V7 biomarkers with me because, so far, my cancer has been responsive to chemo. We have had some general discussions about castrate-resistant prostate cancer and that there are other options for continued hormone treatments after the Lupron (leuprolide), should it become ineffective.

I have a wonderful support group. First, my loving wife of 46 years is a registered nurse and the best advocate anyone could ever ask for. Second, I live in an active adult community of residents over 55. So many of my neighbors have been supportive and shared their own experiences with cancer. Third, I have a strong faith. My church friends have been amazing with calls, cards, food, gifts, and time for visits. It has been humbling to see how many dear friends I have and how supportive they are in my time of need. I think this is one of the biggest keys in getting through cancer.

I have to mention some of the person-to-person connections I have been provided with through Us TOO have helped greatly in terms of information and support.

My advice to anyone facing chemotherapy is to first go to the nearest national cancer center, get a top-rated oncologist who specializes in your particular cancer, ask questions, listen to suggestions, and make a shared decision with your oncologist and caregiver. Ask your team of doctors and pharmacologists for all information about drugs and their most common side effects.

Each person’s cancer is unique and your responses to drugs will also be unique.

The Grim Reaper follows us all. Most of our lives we ignore the inevitable fact that everyone will die. With a chronic, terminal diagnosis, the Grim Reaper comes up closer behind us. The key to survival is to never look back. Focus forward. Look to the light of day. Focus on the here and now. Enjoy life.

In a strange way, having advanced Stage IV metastatic prostate cancer is a gift. It has changed the focus of my life in positive ways. Because now, more than ever before, I live in the present. And life is more intense, fuller, and more complete than I could have imagined.

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


Leave a comment

The Genomic Revolution Comes To Prostate Cancer

Dr. Oliver Sartor, the Laborde Professor of Cancer Research in the Medicine and Urology Departments of the Tulane School of Medicine, is one of the leading researchers in advanced prostate cancer today. He is also the editor-in-chief of Clinical Genitourinary Cancer and the author of more than 300 scientific papers.

Dr. Sartor puts this month’s conversations about prostate cancer genomics into context for us.

“We can divide genomics into two different categories. The first category is germline genomics, which is the DNA with which you’re born. It’s clear that about 12% of people with advanced prostate cancer will have alterations in their inherited DNA, in particular in genes involved with DNA repair. Most common of these alterations are BRCA2. There are a variety of others that are somewhat prevalent, including ATM, CHEK2, and BRCA1. There are others that are more rare.

The implications of these germline mutations are significant for the patient: in certain configurations they may predispose a cancer to be sensitive to certain therapies, such as PARP inhibitors or platinum-based chemotherapy or (rarely) immunotherapy. There is more complexity, but knowing the germline mutation helps the informed clinician make decisions. In my practice, we test all patients with advanced prostate cancer for these germline mutations. (A National Comprehensive Cancer Network guideline suggests the same approach.)

These germline mutations represent the DNA with which you’re born. That DNA is going to have repercussions if also mutated in your family members. Men who have some of these DNA repair mutations have an increased risk of prostate cancer. In addition, there is a small increased risk of pancreatic cancer and male breast cancer for those with some of the germline mutations. Around 30% of men with BRCA2 will be diagnosed with prostate cancer in their lifetime, but that cancer is more likely to be aggressive if diagnosed. With regards to females, it’s particularly important. Females with DNA repair defects are more likely to have breast and ovarian cancer. Female with DNA repair mutations, in particular BRCA1/

BRCA2, ought to consider having their breasts or ovaries removed at an appropriate time. Prophylactic surgery has been demonstrated to be potentially life-saving for those individuals. The risk of breast cancer may be as high as 70% and the risk of ovarian cancer may be as high as 40%.

Thus, for these germline mutations there are implications for treatment and implications for the patient’s family.

We should be doing prostate cancer screening earlier in men with these DNA repair defects for prostate cancer; we should be doing biopsies at a PSA of 3 or higher, and perhaps even lower, for younger men known to be at risk. Starting screening at age 45 has been suggested by some. In addition to germline genomics, we need to also talk about somatic genomics. Data indicates that about 60% of individuals who have a DNA repair germline mutation are likely to have another second genetic mutation occur within their tumor. In addition, many of the tumors can acquire an alteration in their tumor DNA even when the germline is normal.

Taken together, about 20 to 25% of men may have DNA repair mutations in their tumor’s DNA. That makes them particularly sensitive to certain therapies such as the PARP inhibitors, as I mentioned earlier, or platinum chemotherapy. When you have two DNA repair mutations in the same cell, the likelihood of response to these agents appears fairly high.

There are also other DNA defects of considerable interest, such as alterations of the mismatch repair genes MSH-2 and MSH-6. When these alterations do occur, there is a potentially increased probability of responding to immunotherapy such as the new PD-1 inhibitors.

Overall, the guiding light today in genetics in my practice is to look at both the germline DNA and the tumor DNA. I choose to look at the tumor DNA circulating free DNA (cfDNA) tests, in particular the Guardant Health assay. The ability of other assays to corroborate the Guardant Health findings is not yet clear. There is clear data to indicate that different assays give different results, but nevertheless, I think in the early exploratory phase we’re in now, it’s important to begin to test patients in order to better understand their genomics and hopefully guide us towards better therapies. This will happen part of the time but certainly not all of the time.

There is more to the story of prostate cancer genetics. We’ve looked at androgen receptor mutations that can have implications for a response to Androgen Receptor directed therapy, such as Xtandi (enzalutamide), Zytiga (abiraterone), and Erleada (apalutamide). We’re dissecting a number of permutations that occur. It’s a complex scenario, because very few men have only one mutation. Most have multiple mutations. And in most cases, these mutations are not targetable with current therapies. This is very important for people to know.

Everybody thinks if they get a genomics test that means they’ve got a treatment. It’s not the case. Many times we get the genomics results and find that there are no known treatments we can use for that man’s particular alteration. That said, there is a subset of men who will have informative genomics while many more people will have non-informative genomics.

There is a final issue I’d like to discuss. There is currently a bit of a debate amongst physicians over the utility of PARP inhibitors such as Lynparza (olaparib) as compared to platinum chemotherapy. But it is noteworthy that platinum-based chemotherapies are inexpensive compared to PARP inhibitors. This does not require a clinical trial. (Most men will access PARP inhibitors through a clinical trial, although sometimes insurance companies are willing to try.)

As it turns out, neither the platinum-based chemotherapies nor the PARP inhibitors will be effective forever, so we do need strategies to manage patients after PARP inhibitors or platinum-based chemotherapies fail. Currently, that space is unexplored. We have to gather much more data before we can make conclusions about those with underlying DNA repair defects who have failed platinum-based chemotherapy or PARP inhibitors.

This is an area of active and important investigation that represents a conundrum for many patients today. I’ve got a patient right now going through this. We’re debating what to do next. I’ve tried to be as honest as I can when I say, “I don’t know what to do, but we’ve got to try something.”

We are in the middle of a revolution, but the parts and pieces are not yet clear. For some, understanding tumor genetics at the current level is helpful. For others, it is perplexing and expensive.

Join us to read this month’s conversations about prostate cancer genomics.

(Already a member? You can read all conversations in your copy of April’s Prostatepedia.)


1 Comment

Dr. Charles Ryan: Why Oncology?

Dr. Charles J. Ryan is the Clinical Program Leader for Genitourinary Medical Oncology at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.

He primarily treats men with advanced prostate cancer. His research focuses on novel therapies for advanced prostate cancer.

Not a member? Join us to read Dr. Ryan’s conversation in our March issue on cancer recurrence.

Why did you become a doctor?

Dr. Ryan: I grew up in a medium-sized city called Appleton, Wisconsin. My father was the first medical oncologist and the first prescriber of chemotherapy in our town. He never did a fellowship because they didn’t exist when he finished his training.

I’m the youngest of four kids. By the time I was in junior high school, all of my siblings had gone away. My mother is a nurse, and she was working for hospice in our community. Sitting around the dinner table, it was just the three of us.

The dinner conversation was frequently about cancer, hospice, medicine, and things like that. That’s what shaped me at the time. I decided to become a physician in college, but I had given a lot of thought to oncology and medicine well before making the decision.

I guess medicine is the family business?

Dr. Ryan: Yes. It is sort of a family business. When I started my medical training, I felt a kinship with the medical oncologists I interacted with at the University of Wisconsin. I was randomly assigned to work in an oncology clinic and a prostate cancer clinic. I just felt like: these are my people. The timing was right for me to make a decision. It’s what I wanted to do with my life. I found the disease itself biologically compelling, and the emergence of new therapies and the community of physicians and researchers who worked on it were an interesting group of people. It was a natural decision.

Join us to read Dr. Ryan’s thoughts on Xtandi (enzalutamide) and Zytiga (abiraterone.)


Leave a comment

Living With Neuroendocrine Prostate Cancer

Stan P. has neuroendocrine prostate cancer. He spoke with Prostatepedia about his experiences with this aggressive form of prostate cancer.

How did you find out that you had prostate cancer?

Stan P: It was a PSA taken by my primary physician. It was taken kind of late. It came out to be 6.2, which is fairly high. After that, I started consulting around trying to find a doctor to treat me. That was back in 2006.

How did you find out that you had neuroendocrine prostate cancer? Was that when you were first diagnosed or was that after you’d been on some kind of treatment?

Stan P: I was taking Zytiga (abiraterone) for almost two years. The physician was also running blood tests. One of the substances in the blood test that stood out was this bone-specific alkaline phosphatase. It started to go up while at the same time my PSA was undetectable. It had reached undetectable status about a year after taking Zytiga (abiraterone).

The physician saw this one level going up, so he prescribed an F18 sodium bone scan along with a couple of other specialized blood tests. One of the blood tests was LDH, which I think detects cellular injury. Another was chromogranin A that detects neuroendocrine tumors. The third one was CEA, carcinoembryonic antigen, a marker for colon and thyroid cancer.

The one that stood out was the chromogranin A. It was high. At the same time, the F18 scan showed two neuroendochrine tumors. One was in the ileum (the end of the small intestine) and the other one was in the C5 vertebrae. With the undetectable PSA, these results from the scan, and some of the blood results, the physician suggested that it was probably neuroendocrine, which I didn’t even understand at the time.

He said something about adenocarcinoma being differentiated into this neuroendocrine tumor. From that point, his recommendation was to try some platinum-based chemo. I was not feeling any symptoms. I was not in any pain, and I was still doing my normal thing. He recommended that I undergo Xofigo (radium-223).

Were you still on the Zytiga (abiraterone) at this point or did he take you off the Zytiga?

Stan P: I was still on Zytiga (abiraterone) when all this happened. He took me off later because my kidneys started to show side effects from it—high creatinine. He took me off of that to see if it would lower the creatinine levels, and it did, so he kept me off it. I continued to take an androgen agonist (degarelix), which I’m still taking.

What was your initial reaction when you heard all this? Did you immediately start researching about neuroendocrine prostate cancer? How did you respond?

Stan P: I had no idea what a neuroendocrine tumor was. I didn’t even know what a PSA was. I got this medical explanation, and then when I started delving into it on the Internet, I found out that only 1% of the prostate cancer patients get this or have this condition. Then I knew it was serious.

There really are no cures. I consulted with two other prostate specialists. One was the chief of hematology and the other was the chief of prostate cancer research at a teaching hospital. One doctor said that he treats this through standard-of-care treatment, which means platinum-based chemo. The other doctor told me to go back on the Zytiga (abiraterone), which really didn’t make any sense. My understanding is that this neuroendocrine tumor does not have any androgen receptors. But the real issue is there aren’t many doctors around who spend a lot of time with this type of cancer.

What is your current doctor’s plan going forward?

Stan P: I just went through six months of Xofigo (radium-223) and completed that at the end of March. The recommendation has been to wait for three months and get a scan then. In the meantime, I take Firmagon (degarelix). During the six months on Xofigo (radium-223), I had a couple of scans. One was a technetium-99 bone scan, which was performed after two treatments with Xofigo (radium-223).

The strange thing was they only found one neuroendocrine cancer in the ileum. They did not find the one at the C5 vertebrae. Maybe the F18 was oversensitive to the scan. I don’t know.

At the same time, I entered a clinical trial for C11 Acetate PET/CT scan. They were giving me these C11 Acetate PET/CT scans every month, and I decided I should stop doing that because it was affecting my blood counts too much. I had two C11 Acetate PET/CT scans, and both were uneventful. They didn’t find anything, which I kind of expected because my PSA is undetectable. They did not detect any of the neuroendocrine tumors either.

Since ending the Xofigo (radium-223), I have not had any scans. I’m waiting another month, and then I’ll get another scan to see the effect of that. During the time I was undergoing Xofigo (radium-223), the blood tests were becoming much more positive. The bone-specific alkaline phosphatase went down to normal levels. That indicated that maybe the tumor was not growing anymore. The plan right now is to just stay on Firmagon (degarelix) and get another scan in another month. Treatment will be scheduled then.

Do you have any advice for other men who have been told that they have neuroendocrine prostate cancer?

Stan P: First, make sure you actually have a neuroendocrine tumor. Then consult with a doctor who specializes in neuroendocrine prostate cancer. I found a nationwide list on the site carcinoid.org. And just keep the faith. I have a positive outlook that something’s going to come to help me either put off the growth of this tumor or to cure it. I keep looking, and that’s about all I can do. Just keep the faith.

What about any advice for doctors treating patients like you?

Stan P: I would recommend that the doctors educate themselves on the ongoing clinical trials for this disease. Even if they don’t know about any while the patient is visiting them, they should at least tell the patient that they will do research themselves. I’m sure doctors have a better way of finding these things out than the layman.