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An interview with renowned urology researcher E. David Crawford, M.D., about the state of clinical trials on prostate health

Can hormone therapy extend the lives of men with advanced prostate cancer? Might a drug traditionally prescribed to treat benign prostatic hyperplasia (BPH) help prevent prostate cancer? Does a short course of hormone therapy prior to a radical prostatectomy prevent or delay cancer鈥檚 return?

Researchers have answered these questions 鈥� and countless others 鈥� through clinical trials, scientific studies that compare novel drugs and treatments with the current standard of care to determine what鈥檚 best for patients and improve medical practice.

But launching a clinical trial isn鈥檛 easy, and it requires more than simply coming up with a testable hypothesis. It鈥檚 costly, too. Today, a pharmaceutical company seeking to test a drug may spend tens of millions of dollars to recruit study participants, provide them with the drug, track their response to the drug over time, and analyze mountains of data.

Decades ago, individual investigators decided that they might find a cure for cancer more quickly if they collaborated on clinical trials. They started cooperative groups 鈥� networks of medical centers, universities, community hospitals, oncologists, laboratory scientists, statisticians, and administrators 鈥� to develop and sustain trials. The goal: find new strategies for the prevention, detection, and treatment of cancers and improve understanding of the biology of the disease. Several cooperative groups formed in the United States, Canada, and Europe, including the Southwest Oncology Group (SWOG), Eastern Cooperative Oncology Group (ECOG), European Organization for Research and Treatment of Cancer (EORTC), Cancer and Leukemia Group B (CALGB), and Radiation Therapy Oncology Group (RTOG).

At the American Urological Association鈥檚 annual meeting in May 2008, Dr. E. David Crawford, chairman of SWOG鈥檚 Genitourinary Committee since 1980, highlighted some of the current trials under way around the world in urologic oncology. He also spoke about the need to enroll more patients in clinical trials and the many challenges investigators face in completing a trial.

After hearing his presentation, editors at Harvard Medical School invited Dr. Crawford to share his thoughts on prostate research with readers. In addition to being a principal investigator on many studies that have shaped our thinking on prostate diseases, Dr. Crawford is a professor of surgery, urology, and radiation oncology, and senior associate director of the Comprehensive Cancer Center at the University of Colorado Health Sciences Center in Denver.

What is SWOG? Why should prostate patients have an interest in SWOG?

SWOG began about 50 years ago as a leukemia study group. It has evolved into a multidisciplinary group that studies melanoma, leukemia, and gastrointestinal, genitourinary, lung, and breast cancers. We also have committees focused on biology, pathology, and translational medicine, which focuses on moving discoveries from the laboratory bench to the bedside and vice versa. That鈥檚 an area of intense interest right now.

SWOG鈥檚 mission is to ask and answer difficult questions through clinical trials to advance cancer care. SWOG has several thousand members, representing just about every state in the United States and many countries around the world. Members include physicians, researchers, and clinical investigators who can enroll patients in studies.

What are some of the highlights of SWOG studies in general and with respect to prostate cancer? How has SWOG changed urologic practice?

Well, I think the first highlight has been our ability to bring together a strong multidisciplinary team, including medical oncologists, radiation oncologists, and urologists, to address important clinical issues. Urologists are an important part of the team because they often see the patients first. They鈥檝e contributed a lot to prostate research over the years. Many people in the Southwest Oncology Group have made significant contributions to our understanding of prostate cancer and have become internationally known.

In the area of prostate cancer, you鈥檙e probably very familiar with the concept of combined androgen blockade. Much of what we know about the combined androgen blockade comes from a study we did that was published in The New England Journal of Medicine.* More New England Journal of Medicine studies on hormone therapy followed that first one. Our work got the anti-androgen flutamide approved. And we鈥檝e also studied the use of chemotherapy prior to surgery.

Another one of the star trials that the Southwest Oncology Group did looked at the use of finasteride in preventing prostate cancer. In the Prostate Cancer Prevention Trial (PCPT), we showed that the drug could reduce the risk of cancer by about 25%. But because the initial analysis of the data also indicated the drug increased the risk of aggressive prostate cancer in a subset of men, its use for cancer prevention never caught on.

As you know, we went back and did a new analysis of the data and prostate tissue samples. In addition to reducing overall prostate cancer risk by 25% to 30%, finasteride showed no tendency to increase the risk of high-grade tumors. In fact, it decreased the rate of aggressive tumors by 27%. There鈥檚 nothing else out there that comes close to that.

What 鈥渃aused鈥� the aggressive tumors in the first analysis of the PCPT data? Why the discrepancy between the initial findings and the recent results?

If you put six needles in a prostate for a biopsy, you鈥檙e more likely to find cancer in a smaller prostate than in a larger prostate. Because finasteride shrinks the prostate, you have a higher chance of detecting cancer 鈥� including high-grade cancer 鈥� in men who take it compared with men who have larger prostates and don鈥檛 take the drug. It鈥檚 like looking for oil: if you can narrow your search to a smaller area, the more likely you are to find it.

Also, finasteride takes BPH out of the picture. When men take it, their PSA should drop by half. If it doesn鈥檛, you鈥檙e going to have a higher chance of detecting cancer. In my mind, there鈥檚 no discrepancy, but not everybody鈥檚 convinced of that.

Do you prescribe finasteride for all of your patients?

No, I don鈥檛. Nobody does. Finasteride and dutasteride, which belong to a class of drugs called 5-alpha-reductase inhibitors, are wonderful drugs. They can help men keep their hair,* prevent BPH from progressing and ease its symptoms, and reduce the risk of prostate cancer. But men aren鈥檛 going to go on them wholesale. I discuss these drugs with men who are over 50, have a family history of prostate cancer, or have urinary symptoms.

In the PCPT, we gathered a wealth of data, including lots of blood and tissue samples. Using that data, I think we will be able to determine who is at risk of prostate cancer and who will benefit from the drug.

How are you going to do that?

There are new markers coming out. You could have a molecular chromosomal profile to determine prostate cancer risk. Some people are doing that now, but I don鈥檛 know how accurate it is. We鈥檒l put PSA, family history, molecular information, and a bunch of other factors into a risk calculator. We鈥檙e not there yet, but I think we鈥檒l be able to tell a patient, 鈥淗ere鈥檚 what your risk is,鈥� and determine when it would be appropriate for him to go on a 5-alpha-reductase inhibitor like finasteride or dutasteride.

Do you receive requests to do clinical studies? How do you prioritize them?

We do receive requests. How do we sort them out? It鈥檚 a democratic system in that the information is passed around and discussed. Things have a way of either smelling good or smelling bad. Something may sound like a great idea at first, but once it gets circulated and people talk about what the challenges will be, you see that it is just not going to make it into development.

What resources do you need to complete a trial? For example, what did it take to complete the study of leuprolide plus placebo versus leuprolide plus flutamide?

Well, that鈥檚 an older study, and things have changed a lot since then. If you turn back the calendar to the 1980s when that study was designed, you had some physicians with enough data from patients to show that a certain dose of flutamide was safe and that it might be effective when combined with leuprolide. What they wanted to do was challenge the gold standard of taking leuprolide alone. So they did this pivotal study with leuprolide and flutamide versus leuprolide and placebo. It was pretty straightforward. The variable was an anti-androgen, flutamide. And it was relatively easy to enroll patients because, unless they wanted to go to Canada, they couldn鈥檛 get flutamide.

Now, it takes a lot more paperwork and effort to get studies approved by institutional review boards and activated. On the one hand, that protects patients and ensures that the data you collect are uniform and can be submitted as part of the drug-approval process. But that also means that the whole process has gotten extremely complicated and expensive. The amount of paperwork is just mind-boggling. So we have to pick studies very carefully. We don鈥檛 have unlimited resources.

How are the SWOG studies funded? How much does it cost to do a study?

We are supported almost exclusively by the National Cancer Institute. There鈥檚 a competitive renewal of grants every year. It鈥檚 hard to put a price tag on a study because it鈥檚 financed through a cooperative group, but it鈥檚 expensive. Trials are particularly expensive when they鈥檙e done by pharmaceutical companies. One trial sponsored by a pharmaceutical company that鈥檚 been ongoing in prostate cancer has cost over $300 million to do. I think trials are less expensive when they鈥檙e done through a cooperative group like SWOG because the investigators are already in place and all of the mechanisms are in place. But they鈥檙e still expensive and time-consuming.

What鈥檚 the largest phase III SWOG prostate cancer study under way now?

The one that鈥檚 ongoing right now will be another blockbuster trial. It was designed to answer the question of whether intermittent hormone therapy might be better than continuous hormone therapy for patients with advanced disease.* We鈥檙e looking to enroll about 2,300 participants in this study.

We鈥檝e been wondering whether we could cycle patients on and off hormone therapy, not only prolonging survival, but reducing side effects and costs as well. It鈥檚 a great question. The idea was put forward to develop a clinical trial, and we did it. There wasn鈥檛 a lot of argument about it 鈥� the idea was very well received. There was discussion, though, about how long people should be treated, how long they should be off treatment, and what the PSA nadir should be before temporarily halting treatment.

The trial has been activated, and it鈥檚 been accruing pretty steadily, though not as rapidly as we鈥檇 like to see. One reason is that if people think they know the answer to the question about which treatment regimen is better, they are going to pursue that regimen on their own. Given a choice, patients will say, 鈥淚 know I want this, not that, so I鈥檓 not going to enter the trial.鈥� The second reason is that the pool of patients with advanced prostate cancer has shrunk substantially. We just don鈥檛 have as many as we used to. And even though they鈥檝e been diagnosed with advanced prostate cancer, a lot of them don鈥檛 have any symptoms. But I think we鈥檙e just about done enrolling patients now. We鈥檙e waiting for the Data Safety and Monitoring Committee to say that they have some preliminary results.

What hormonal therapies were chosen for the trial?

It鈥檚 a combined androgen blockade for nine months. After that, those with a PSA less than 4 ng/ml randomly receive either continuous or intermittent hormone therapy, with a combined androgen blockage throughout.

There are parallel studies ongoing in another cooperative group in Canada. They are looking at intermittent versus continuous hormone therapy for biochemical failure after radiation, so we should get some answers there, too.

Can you ask multiple questions or test multiple hypotheses in one trial?

Well, we do collect a lot of data that we mine for other information. For example, one of the things that came out of a recent trial that was presented at a meeting of the American Society of Clinical Oncology is that people with metastatic disease who lowered their PSA to undetectable levels lived longer than people who didn鈥檛 get their PSA to less than 4 ng/ml.* So we defined a very high-risk population among patients newly diagnosed with metastatic disease. Researchers are now interested in doing clinical trials to evaluate drugs in these patients.

Does time to nadir have any effect at all on prognosis?

We don鈥檛 have all that data yet, but yes, it does. The faster you reach your nadir, the better your outcome 鈥� as long as the PSA nadir is undetectable.

Do you always get enough patients to enroll to have statistically significant results?

Occasionally 鈥� and more often than I like to see 鈥� we have great ideas and activate studies, but we don鈥檛 get patients enrolling. One example is the START study. This is a phase III randomized trial comparing active surveillance with radical treatment 鈥� either surgery or radiation therapy. It鈥檚 an excellent, state-of-the-art study attempting to answer critical questions, but since it started about a year ago, I think only a few dozen men have enrolled.

Another example is a CALGB study called the PUNCH trial. It鈥檚 comparing the rate of biochemical progression鈥揻ree survival in high-risk patients with localized prostate cancer who have a radical prostatectomy with or with out chemotherapy and hormones beforehand. We need to know if giving chemotherapy with hormones before surgery slows the cancer鈥檚 possible return; it鈥檚 a critical question. But this study is not accruing well either.

I think it鈥檚 sad that these studies exist but patients aren鈥檛 enrolling. These important trials are just languishing and dying on the vine because of a lack of accrual and support.*

Why do you think that鈥檚 the case?

Because people want to pursue active surveillance. Or they want treatment. People have strong feelings both ways.

Part of the problem is also that even though we have well-designed studies, we don鈥檛 market them. By 鈥渨e,鈥� I mean cooperative groups, individual researchers, and, to some degree, pharmaceutical companies. This is where we fall behind. We don鈥檛 have CDs, pamphlets, or reminders. If you have materials that you can pass out to investigators and to physicians in busy clinics, patients are more likely to enroll. The materials are marketing aids. If Procter & Gamble comes out with a new soap and doesn鈥檛 market it, the soap doesn鈥檛 sell. Unfortunately, that鈥檚 what we do. We think that investigators will remember all of the studies and enroll patients. But we know from experience that that doesn鈥檛 happen.

Do studies ever get cancelled due to lack of enrollment?

Unfortunately, yes. It鈥檚 not that they close because we aren鈥檛 asking great questions. We are. It鈥檚 that patients don鈥檛 know about the trials or that they aren鈥檛 willing to enroll. One trial that closed was SWOG 8890, which looked at radiation versus surgery, an age-old question. But investigators didn鈥檛 put patients on it. Another such trial was to compare brachytherapy with surgery. That one didn鈥檛 accrue enough patients. Another one was looking at hormone therapy prior to radical prostatectomy. That one didn鈥檛 accrue enough patients.

For SWOG, it used to be that I would decide that pursuing the trial was futile, or the genitourinary committee would. Now, the Data Safety and Monitoring Committee tracks accrual. If it looks like we鈥檙e not going to have enough people, they say it鈥檚 futile and the trial closes.

One of the more recent trials to close was sponsored by a pharmaceutical company. They were studying Taxotere (docetaxel), a type of chemotherapy, in high-risk patients after radical prostatectomy. The trial was supposed to accrue several thousand patients, but only about 1,700 enrolled in a few years, so the company closed it. As for when to close a trial, that varies, but you get to a point where you realize that you鈥檙e not going to have enough patients to get a statistically significant answer. Continuing the trial at that point is a waste of resources and not the right thing to do for patients.

So patients should ask their primary care physicians and specialists about participating in studies?

Yes, readers should consider clinical trials when they鈥檙e available. Clinical trials ask cutting-edge questions, and participants receive excellent medical care.

Prostate research is about 10 to 15 years behind research into breast and colorectal cancers because, in general, men are more reluctant than women to participate in clinical trials. If you look at the number of women who go on breast cancer trials versus men on prostate cancer trials, you are looking at about 30,000 versus 9,000 a year. That鈥檚 why we鈥檝e learned so much about breast cancer in recent years. Hopefully, we can encourage more men to consider participating in a clinical trial.

What exciting developments can prostate cancer patients expect in the next five years? What does the future look like in terms of prostate cancer treatment?

I think we鈥檙e going to continue finding prostate cancers early on, but we鈥檒l use less aggressive treatments than we have right now. All of the talk has been about surgical robots and how much radiation we can use without destroying surrounding tissues. But robots in particular have been a lateral step, not a step forward, in the treatment of prostate cancer. There鈥檚 no question that in some people鈥檚 hands, robotic surgery may be a little bit better than a traditional approach. But it鈥檚 the person who performs the robotic procedure that matters, not the robot. That鈥檚 becoming clearer.

I think we could have made more progress by focusing on other areas, such as less aggressive treatments with targeted, or focal, therapies. I think we really need to look at whether we can treat just part of the prostate 鈥� something equivalent to a lumpectomy, instead of a mastectomy, in women with breast cancer.

You鈥檝e talked about the male lumpectomy in the past and now it seems to be coming to fruition.

Yes, the train has left the station, so to speak. The problem is that people are doing it, but I don鈥檛 think some of them are doing it right. Some people are looking at eight biopsies, or cores, in a patient with prostate cancer; most of those biopsy samples were probably taken from one side of the prostate or were only positive on one side of the prostate, so they only treat half of the prostate. We鈥檝e shown that that isn鈥檛 going to work because small but significant cancers can be missed. You simply can鈥檛 rely on a few biopsy samples.

We鈥檝e shown and published that you need to do biopsies at 5-millimeter intervals aided by a grid like those used for placing radioactive seeds during brachytherapy.* If you biopsy every one of those 5-millimeter holes where the seeds would go, you will not miss the cancer. We found this out through autopsies of men who weren鈥檛 known to have prostate cancer and from men who had a radical prostatectomy. That was the first thing I did before we embarked on focal therapy: prove that we weren鈥檛 going to miss the cancer.

So that means we might do 60 to 90 biopsies, or more specifically, mapping biopsies. We map very precisely where the cancer is in three dimensions and then treat just the cancer, not the whole prostate.

How do you treat just the cancer?

Right now, we鈥檙e using cryotherapy to freeze cancerous tissue. We will be using HIFU, which stands for high-intensity focused ultrasound, to heat tissue. We will also be using a technique called irreversible electroporation, which uses two electrodes and an electrical current to 鈥渄rill鈥� microscopic holes in tumor cell membranes. The cells die from the damage to the cell membrane. If we can kill all the cancer cells with electrical pulses, we wouldn鈥檛 need to use toxic chemotherapy drugs. That鈥檚 why this is such exciting technology.

Who is a candidate for targeted focal therapy?

The average patient I see right now is a 58-year-old man with a PSA of 5 ng/ml and one positive biopsy with a Gleason 6 cancer. This patient will generally have a radical prostatectomy or radiation therapy and be cured. But then I start wondering whether I鈥檝e overtreated the patient. So what I do is take patients who probably have low-risk cancers and do the mapping biopsies. We find that about 60% of them have bilateral disease 鈥� cancer that鈥檚 on both sides of the prostate 鈥� that鈥檚 more extensive or of a higher grade than we originally thought. I don鈥檛 think we can accurately treat them with targeted focal therapy. But about 40% of patients who have mapping biopsies have low-risk cancers that can be treated this way.

Aren鈥檛 those patients also candidates for active surveillance?

Yes, they could pursue active surveillance. But most men, given the choice between active surveillance and focal therapy, will choose focal therapy because they want to do something. That鈥檚 what makes focal therapy so appealing.

What鈥檚 on the horizon in terms of advanced disease? What about hormone therapy and chemotherapy?

In terms of advanced disease, I think we鈥檝e come as far as we鈥檙e going to go with chemotherapy. It鈥檚 just going to be a matter of reducing toxicity. In the future, we鈥檒l be looking more at combining chemotherapy with other, targeted agents, such as agents that target blood vessels feeding the tumors or the spread of cancer into bone. I think we鈥檒l also see chemotherapy used earlier on in high-risk patients and not just in patients who have exhausted other treatment possibilities.

There is renewed interest in androgens and androgen receptors. It鈥檚 almost as if we鈥檝e rediscovered that the lower a man can get his testosterone and the longer he can keep it down or block it, the better off he is. And people whose cancers would have been considered hormone-refractory in the past really aren鈥檛 termed that anymore. They are now hormone-insensitive cancers. We can try different hormones for them. We鈥檙e also developing new agents to attack testosterone development early on.

Can you make some comments about your work on BPH and what you see on the horizon there?

I think that we have made a great deal of progress in the understanding of BPH over the years, and we understand a lot more about the role of medical therapy in treating BPH. Patients don鈥檛 need to wait until their symptoms are so bad that they need surgery. Medication can help with symptoms like urinary retention.

One thing that we鈥檝e been able to do is identify men who are at risk of progression 鈥� men with BPH who have a PSA of 1.6 ng/ml or greater and a prostate that weighs 31 grams or more.* They are on the slippery slope, meaning that they are more likely to have continued prostate growth and urinary retention and need surgery. So it鈥檚 important to identify men in that group and institute medical therapy.

The two most common therapies are alpha-1 blockers 鈥� the most common of which is tamsulosin (Flomax) 鈥� and 5-alpha-reductase inhibitors 鈥� the most common of which is dutasteride (Avodart). These drugs are capable of arresting the disease and providing almost instant gratification in terms of symptom relief.

We need to get the word out to family practitioners that an elevated PSA is a surrogate for an enlarged prostate. Even if you don鈥檛 have symptoms, if you have an enlarged prostate, then you鈥檙e at risk of having a problem with progression of BPH.

Any parting comments?

We鈥檝e made a lot of progress against prostate cancer in the last two decades. Screening has resulted in the discovery of early-stage disease. And we鈥檝e made strides in hormone therapy and established the value of chemotherapy in men with advanced prostate cancer. With new biomarkers and targeted therapies on the horizon, the future looks even brighter.