Stopping the spread: New prostate cancer therapy
BACKGROUND: In the United States in 2012, an estimated 28,170 men died from prostate cancer and there were 241,740 new cases. (Source: www.cancer.gov) Prostate cancer starts in the prostate. The prostate is a small structure that wraps around the urethra and makes up part of the male reproductive system. Prostate cancer is the most common cause of death in men over 75 years old. A common problem in almost all men is an enlarging prostate, called benign prostatic hyperplasia (BPH). It does not increase the risk of developing prostate cancer, but it raises PSA blood test results (a screening for men for prostate cancer). PSA testing is responsible for detecting the cancer before symptoms occur. (Source: www.ncbi.nlm.nih.gov)
SYMPTOMS: Symptoms usually do not occur until prostate cancer is in a later stage. Symptoms relating to prostate cancer can also be caused by other prostate problems, including delayed or slowed start of urinary stream, dribbling or leaking of urine (usually after urinating), slow urinary stream, blood in the urine or semen, straining when urinating or not being able to empty out all of the urine, and bone pain or tenderness usually occurring in pelvic bones and lower back. If prostate cancer is suspected, then the doctor will have to do a biopsy to know for sure. (Source: www.ncbi.nlm.nih.gov)
TREATMENT: Treatment options have many factors to consider. For early-stage prostate cancer doctors recommend surgery, called radical prostatectomy, or radiation therapy, including brachytherapy and proton therapy. If the patient is older, then the doctor might recommend just monitoring the cancer with PSA tests and biopsies. In cases where the cancer has spread, treatment can include surgery, chemotherapy, and hormone therapy to reduce testosterone levels. (Source: www.ncbi.nlm.nih.gov)
NEW TECHNOLOGY: The problem with traditional treatment is the reoccurrence issue. It happens to about 30% of prostate cancer patients. A new therapy in its phase 3 trials, ProstAtak, might change the way prostate cancer is treated. The study is designed to compare two treatments, ProstAtak with external beam radiation therapy and Placebo with external beam radiation therapy. An estimated 700 people are involved in this study. In phase II trials, the rate of recurrence was reduced from 30% down to 10%. Based on an innovative technique called gene transfer technology, ProstAtak is used along with standard radiation therapy. The basic idea is to "jump-start" the body's own immune system so it can detect and kill remaining or recurring cancerous cells. If the outcome of the study is positive, then ProstAtak will most likely be approved for early stage prostate cancer treatment. (Source: www.drstevensukinurology.com)
Mark Buyyounouski, MD, MS, Associate Professor of Radiation Oncology and Director of Clinical Research at the Fox Chase Cancer Center, talks about a new and exciting treatment for prostate cancer.
Can you tell me what is so exciting about ProstAtak?
Dr. Buyyounouski: ProstAtak is a very exciting new treatment because it's an entirely different way to treat prostate cancer. ProstAtak is an adenoviral vector that expresses a herpes simplex virus thymidine kinase gene that helps not only kill prostate cancer within the prostate, but stimulates an immune response throughout the body to kill prostate cancer in the event that it spreads.
It actually works with the body's immune system then?
Dr. Buyyounouski: Right. The problem for most patients is that prostate cancer is below the radar. It's growing within their body and their prostate, but the immune system hasn't yet detected it to kill it itself. By combining ProstAtak and radiation together we hope to bring the prostate cancer into the patients' radar to ramp up the immune system to help better kill the cancer, not only in the prostate but throughout the body.
This is to prevent recurrence and it's for later stage prostate cancer, correct?
Dr. Buyyounouski: This treatment is to prevent recurrence but it's intended for patients with early stage prostate cancer. So that's the additional advantage of ProstAtak, this isan immunotherapy intended for early stage patients before there's definite evidence of spreading. The study targets patients who have about a one in four to a one in two chance of having prostate cancer recur in the future. We do intensive studies in the beginning when we diagnose patients to make sure there's no evidence of spreading, but we know, like weeds in a garden, if there are one or two cells that have escaped they could come back years from now. How ProstAtak may help these patients is by amping up their immune system to help better detect prostate cancer in the prostate and throughout the body in order to kill it.
So with traditional therapy you have surgery or radiation; can you talk a little bit about the traditional therapies and some of the misconceptions?
Dr. Buyyounouski: Conventional treatment for localized prostate cancer is surgery or radiation. Unfortunately there are misconceptions sometimes that if patients have treatment to their prostate, particularly cutting the prostate out with surgery, that means the cancer will never come back. Unfortunately the prostate cancer still can come back because many prostate cancers have already spread by the time we find them.
So that's the big concern?
Dr. Buyyounouski: The big concern is that there can be prostate cancer cells that have spread to lymph nodes or bones that's beyond our detection with conventional scans.
ProstAtak helps in that way to prevent recurrence and to help it from spreading, right?
Dr. Buyyounouski: ProstAtak works by a process called gene mediated cytotoxic immunotherapy, which helps stimulate T-cells throughout the body to better find cancer cell antigens in order to fight them, whether they are in the prostate, in lymph nodes, or in bones.
So if you were explaining this to your son, how would you explain it?
Dr. Buyyounouski: Conventional treatment for clinically localized prostate cancer is to radiate the prostate and the immediate area surrounding it. It's a highly effective treatment that in the vast majority of circumstances can cure prostate cancer. However, for many patients, about one in four, prostate cancer can come back. The problem there is radiation only works where you point it, and sometimes there are cancers that are too big for the radiation to kill. How ProstAtak may help is by injecting it in to the prostate to better kill the cancer cells within the prostate and to help better stimulate the immune system to fight the cancer itself.
Are there any results back yet from the trial?
Dr. Buyyounouski: There are preliminary results from Phase I and Phase II trials that have demonstrated this drug is safe and appears to be effective in killing prostate cancer. Compared to historical controls there were far fewer recurrences in the Phase II trial, which prompted this fast track Phase III trial comparing radiation alone with radiation and ProstAtak.
What about any side effects?
Dr. Buyyounouski: There are some side effects associated with treatment; they're mostly fatigue. There can be some low blood counts associated with the pro-drug that is used, Valacyclovie. Then the typical radiation type side effects, which are largely due to inflammation. They may need to increase daytime urinary frequency, urgency, or burning with urination. That's easily addressed with over the counter anti-inflammatories.
The side effects have been minimal?
Dr. Buyyounouski: Yes.
Is the trial still enrolling?
Dr. Buyyounouski: Yes. The trial is still currently enrolling throughout the country. Fox Chase is the cancer center that was selected in the region.
Do you know how long it should be running for? Do you think it's something that's going to be running for the next year or so?
Dr. Buyyounouski: It should still be open, yes. I would expect the targeted accrual is seven hundred and eleven patients. This is a very exciting time. There have been few occasions where we've been able to identify new treatments for prostate cancer, especially for clinically localized prostate cancer. There's been a lot of excitement about recent trials, immunotherapy trials or injected radio nuclear type trials, that have helped patients live longer much later in the course of prostate cancer when it's come back and metastasized. But this trail is looking to see if immunotherapy can help patients in earlier stages that may be potentially curative.
How long after the procedure does it take them to feel back to normal?
Dr. Buyyounouski: Well the great thing about radiation is there is very little recovery time needed. Most patients can continue doing all their daily activities, including work, throughout the course of treatment with no recovery time. The same holds true for patients who are receiving ProstAtak.
According to trials, it was a forty day regimen?
Dr. Buyyounouski: Yes. It's a daily treatment every day, Monday through Friday, five days a week; no weekends, no holidays for forty total treatments of radiotherapy. ProstAtak is injected in to the prostate on three occasions: one two weeks prior to the first treatment, on the day of the first treatment, and two weeks after. The injections have been well tolerated. It's a small gauge needle so it's not as traumatic as a biopsy where tissue is removed from the prostate. We're simply injecting four regions of the prostate with the drug and it's over in approximately thirty minutes.
What is Brachytherapy?
Dr. Buyyounouski: That's another type of way of delivering radiation, but it still has the same limitations in that it only works where we put the radioactive seeds. The whole advantage of ProstAtak is that it helps kill the prostate cancer where we're not radiating, and that's the Achilles heel in prostate cancer, particularly in the intermediate and high risk population that this study is targeting. By evaluating the patient's PSA, Gleason score, or physical exam, we've determined that these patients are at an intermediate or high risk of recurrence. Recurrence is largely driven by prostate cancer cells which we don't see now that are lingering, hiding out in lymph nodes and bones throughout the body, that if left untreated will come back some day and grow and metastasize. By giving ProstAtak today we may be able to cure these patients, prevent these cancers cells from coming back by helping the immune system to fight it, itself. The one nice advantage of the ProstAtak trial is that for patients who choose to participate, chances are they receive the investigational drug because the randomization is two to one. So, for patients who are interested in radiation, who understand that there's a risk of recurrence of the cancer coming back in the future and are willing to undergo maybe a few more side effects including fatigue or nausea due to the study drug and may wish to squeak out the one or two percent possibility of having the cancer not be cured, then participation in this trial might be a good thing for them.
What's the one to two percent exactly?
Dr. Buyyounouski: This is an ideal study for patients who are interested in receiving radiation but also understand that because of cancer cells that may have already spread, they have a risk of cancer coming back in the order of one in four to one in two. They're also willing to maybe have some additional side effects due to ProstAtak, maybe fatigue or maybe nausea, in order to increase their chance of curing the cancer. What about the other twenty-five percent? There are some patients who say, "seventy-five percent, that sounds great! I'll have radiation I can avoid a surgery, sign me up." Then there are patients who come in they are sixty, fifty, and say, "I really don't want to have the surgery, I'd like to have radiation but I'd also like to know that maybe I'm going to be doing better than seventy five percent." If they understand that and they're willing to maybe have some additional side effects like fatigue or nausea due to the ProstAtak with the hope of changing that seventy five percent to eighty five or ninety percent, then I think participation in this study would be something good for them.
What's the percentage with surgery if they were to go for that?
Dr. Buyyounouski: It is the same.
So they have a twenty-five percent of recurrence?
Dr. Buyyounouski: Right.
You're saying one in four to one in two; would that be a twenty-five to fifty percent chance of recurrence?
Dr. Buyyounouski: Yeah, twenty-five to fifty percent chance of recurrence.
They can't narrow that down a little bit more?
Dr. Buyyounouski: Well it depends on the Gleason score, the PSA, and the exam, so all comers. Basically, patients who are intermediate risk or high risk are eligible for this study. On average, intermediate risk patients have a risk of recurrence of one in four, so twenty-five percent. High risk patients: one in two, or fifty percent.
What would you choose if you came down with prostate cancer?
Dr. Buyyounouski: I would probably have prostate brachytherapy, radioactive seeding. It has the lowest incontinence rate. It doesn't have incontinence as low as erectile dysfunction rates and it's just as curative as surgery. It is a great treatment, that's probably what I would do. Unless I was in the unfortunate circumstance where I had a high risk of spread, so no matter how many radioactive seeds I put in the prostate it's not going to address this issue which I keep getting to about spread throughout the body. In that case this is something that is critical; it's a tool we need for the future to make treatment for prostate cancer better.
So maybe for the general population the one that you mentioned would be better, but if you're a high risk person you think this would be?
Dr. Buyyounouski: If you're low risk, yes. If you're in the low risk group we think there's a low propensity for spreading beyond the prostate. Local therapies like surgery, radiation, whether it's external beam or prostate seeding, are excellent choices. But for patients who present with intermediate or high risk prostate cancer where there's a growing concern for prostate cancer beyond the prostate to lymph nodes or bones, then we need to start thinking about other treatments.
Right now are there any treatments?
Dr. Buyyounouski: Yes there are, but the benefit is not well understood. Hormone therapy is a treatment that is currently being used to address this risk of spread. It's routinely recommended for high risk patients where it's given for two to three years. For intermediate risk patients it's sometimes used but is currently the subject of ongoing clinical trials. The problem with hormone therapy however it has quite an extensive side effect profile, which has been talked about quite a bit recently because of some of the potential cardiac affects that could be fatal in addition to factors that affect quality of life, such as menopausal-like symptoms due to the low testosterone level. Charles elected to get the hormone therapy which is allowed on this study, but not everybody has to have the hormone therapy. Hot flashes, weight gain, sleeplessness, difficulty with erections, thinning of the bones, loss of muscle mass, and fatigue are associated with hormone therapy. It's not part of the ProstAtak scene, so that's a potential advantage too.
Is this more for a higher risk group of recurrence?
Dr. Buyyounouski: Whenever we learn about prostate cancer, the first thing we do is group patients into risk groups based on the risk of spread: low risk, intermediate risk, or high risk. They're based on three factors: the PSA level, the Gleason score, and the exam. PSA's less than ten are low, ten to twenty is intermediate, and more than twenty is high. Gleason scores six and less are low, seven is the middle, and eight, nine, and ten is high. For the physical exam, generally speaking patients who have palpable nodules that are outside of the prostate, they are considered high risk. If you're low risk, surgery, external beam radiation, or brachytherapy by themselves without hormonal therapy are all equally effective in curing the prostate cancer and do so on average about ninety-five percent of the time. For intermediate risk patients the risk of recurrence with either surgery or radiation is about twenty-five percent, or one in four. For high risk patients it's as much as fifty percent. The ProstAtak study is targeting intermediate and high risk prostate cancer patients. The idea is that by injecting ProstAtak into the prostate and combining it with radiation we'll be able to better eradicate the cancer cells within the prostate and stimulate the body's own immune system to help fight the cancer by showering the body with fragments of the prostate cancer cells which it can detect and fight so that it will kill cancer cells not only in the prostate but anywhere in the body where the prostate cancer can be lingering. This study is ideal for patients who are looking to avoid a surgery and have decided to have external beam radiation treatment, but are looking to help increase the odds of curing the cancer. The hope is that we can improve our cure rates from seventy-five percent to maybe eighty-five percent or higher.
Provenge is for metastatic disease?
Dr. Buyyounouski: Yes, it is.
Which is different?
Dr. Buyyounouski: It is for a different population. Provenge was shown to improve survival in the metastatic setting. These are patients much further down the road, so Mr. Ken for example: if his prostate cancer were to come back we would first know about that because he would have an elevation in PSA, a blood test; that's how we monitor all of our patients. As the PSA levels increase, we may learn that it has spread to the bones at which time he might choose to have hormonal therapy, which is highly effective but only works for an extended period of time. At which point we usually have to go to second treatments like chemotherapies, and that's where Provenge comes in. Provenge can help extend men's survival, I think by about three months, once they have hormone refractory disease. Which is great, but the big goal is to have fewer patients with metastasis, fewer patients with hormone refractory disease, by curing more of them the first time around when we're treating them with radiation.
So Provenge is for once the recurrence has happened?
Dr. Buyyounouski: Right. So this trial may define a new standard of care in the treatment of clinically localized prostate cancer. It's standard treatment radiation with or without hormone therapy at the patient and physicians choosing versus radiation with ProstAtak. If we find that the patients who receive ProstAtak are less likely to have their prostate cancer come back, that will be the new treatment recommended to all men with newly diagnosed prostate cancer.
Does it look like it's heading in that direction?
Dr. Buyyounouski: Yes it does. There is convincing evidence and what supports that is this trial was formulated together with the FDA on what is called a fast track. So when very promising results are presented and there's a perceived benefit to patients, they like to institute this fast track mechanism so that we can learn the answer sooner than later. So that is exactly how this trail is being put forth.
If it does get approved, when can we expect it?
Dr. Buyyounouski: Hopefully the trial will be completed by twenty fifteen, but this is big stuff, very big. This is the only trial I'm aware of that is looking at combining immunotherapy with radiotherapy in the Phase III setting and only one of a handful of trials exploring systemic agents like ProstAtak with radiation. There may be more studies in the future, but right now there are very few studies that may change the face of prostate cancer treatment.
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Fox Chase Cancer Center
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