NCI clinician-scientists at the forefront of new prostate cancer diagnostics and treatment
At the 2013 annual meeting of the American Urological Association in San Diego, the company Invivo (a subsidiary of Philips Medical Systems) unveiled a product called UroNav. Resembling a stylized computer workstation on wheels, UroNav electronically fuses together pictures from magnetic resonance imaging (MRI) and ultrasound to create a detailed, three-dimensional view of the prostate, which physicians can then use to guide precision biopsies. Introduction of this commercial product was the result of nearly a decade’s research and development, principally conducted at the National Cancer Institute, whose investigators have no financial stake in UroNav. Three members of the team—diagnostic radiologist Peter Choyke, M.D.; interventional radiologist Brad Wood, M.D.; and surgeon Peter Pinto, M.D.—recently sat down, along with medical oncologist William Dahut, M.D., clinical director of NCI’s Center for Cancer Research, to discuss the challenges of prostate cancer screening, diagnosis, and treatment; benefits of image-guided biopsies; and the future of prostate cancer care.
From left: Peter Pinto, M.D., Brad Wood, M.D., Peter Choyke, M.D., in an operating room with a UroNav workstation.
How good is prostate cancer screening today?
Dahut: The digital rectal exam is useful only in very large, advanced cancers, so it’s a very poor screening test.
Pinto: When a doctor examines the prostate by placing a finger in the rectum, only the posterior half of the prostate can be assessed. Tumors in other areas of the prostate can never be felt.
Dahut: PSA [prostate-specific antigen] is not a particularly great screening test, either. The higher the value, the more likely one would find cancer upon biopsy. But there’s no actual safe PSA value, as prostate cancer can be detected even in patients with very low PSA values. In addition, even at very high PSA levels, not all patients have cancer. In the values we call above normal—which is a sort of artificial term, since there’s really no normal—if one does random biopsies, one detects cancer only about a third of the time.
Why is random biopsy difficult?
Choyke: Random biopsies mainly sample the back part of the prostate gland near the rectum and thus miss many tumors. At the same time, random biopsies diagnose many low-grade, inconsequential tumors that are then overtreated. Many of the more virulent prostate cancers, which should be treated, are found in the anterior part of the gland. The major reason not to biopsy there on a routine basis is the risk of going through the urethra, the tube through which urine leaves the body. Because the biopsies are done blindly, you’re not sure exactly where the needle is with respect to the urethra. There’s a lot of hesitation to put the needle in that deeply.
Once you find prostate cancer, should all men consider some form of treatment?
Dahut: Many men will have prostate cancer but will not have a lethal form of the disease and can live a normal life without prostate cancer treatment. However, what often happens clinically is that a screening PSA value is “abnormal.” This leads to a biopsy and often to the detection of prostate cancer. The power and fear of the word “cancer” drives men to opt for treatment. In certain cases, that’s probably the right thing to do. But in other cases, the men would have easily lived the rest of their lives without the need for any treatment. We have some pathological characteristics that are useful to predict which cancers are more likely to be lethal; the best known is what we call the Gleason score. Unfortunately, we all know of patients whose Gleason score appeared to predict a benign course but whose outcome was not favorable. Potentially this may occur because the area biopsied was not a lethal tumor. In this country, we are often reluctant to recommend “active surveillance” because of concerns that our biopsies may not find the most aggressive cancer in the prostate. This can lead to undertreatment. At the same time, we’re well aware that there’s significant overtreatment of men with prostate cancer.
Is the answer just to biopsy more areas of the prostate?
Choyke: It’s true that as you increase the number of biopsies from six to 12 to 18, you increase the rate of prostate cancer detection, but you don’t necessarily increase the rate of detection of significant cancers. You tend to increase the number of insignificant cancers. So, in some respects, increasing the number of biopsies doesn’t necessarily improve the outcome for the patient.
UroNav composite scan of the prostate to guide precision biopsy. The image outlined in green is an MRI fused with the image from an ultrasound.
Pinto: For most cancers—breast cancer and kidney cancer, for example—you first image the patient, see the tumor, and then place a needle directly into the tumor in order to diagnose the cancer. Doctors sometimes use prostate ultrasound to perform a biopsy, but that fails to find cancers inside the prostate. It does not have specificity or sensitivity; it lacks the imaging resolution to see tumors. Ultrasound alone does not allow urologists to biopsy the tumor specifically. Another imaging test patients think of is the CT scan. These scans also do not give enough detail and do not show the tissue characteristics of a prostate tumor. MRI can see tissue details very well, locating tumors even within soft tissue organs, and it works extremely well for the prostate. But the ability for MRI to consistently find cancer inside the prostate had not been established with enough confidence to change medical practice. With the help of our NIH prostate cancer patients who came to me for surgical treatment, we accomplished that task. The pathologic examination of each prostate from the men who had surgery here allowed us to confirm the MRI’s ability to detect their tumors. The MRI also allowed me to tailor my operation to their specific tumor and improve how we spare the nerves for erections and muscles for urinary control. Dr. Choyke’s team was able to fine-tune the MRI hardware and software, to provide me detailed imaging of the prostate and its adjacent structures, like the neurovascular bundle, rectum, and urethral sphincter, along with various abnormalities in the prostate. It wasn’t clear, though, if all those abnormalities were cancers.
Choyke: The MRI allows us to define where the tumors are. It doesn’t actually diagnose the cancers, but it will show you suspicious areas that carry a risk for cancer. It’s possible to then go in under MRI guidance and stick needles into those lesions, but it’s extremely cumbersome within an MRI scanner to do this. An MRI is an enclosed chamber, and sticking needles into a patient in this enclosed chamber is very technically difficult, time consuming, and very expensive, because MRI time is very expensive. But the idea of targeted biopsies was good. There have been gradual improvements in the quality of the MRI. There have been improvements in the ability to transport high-density information around a hospital, or a medical system, electronically. And then there are developments in fusion algorithms that superimpose one kind of image on another kind of image very accurately. Those are the technologies that are in play here. They have come together relatively recently.
What difference does UroNav make?
Choyke: The essential innovation here is taking the MRI data, fusing it using software, to ultrasound data, thus enabling the urologist to perform the biopsy under what appears to be real-time MRI. The idea was to transfer high-quality MRI data to the ultrasound suite—which could be a urologist’s office or a procedure room somewhere else in the hospital—and fuse the MRI to the ultrasound, enabling the biopsy to be performed under the ultrasound technique, which takes 10 to 15 minutes.
From a patient’s perspective, what is the process like?
Choyke: Let’s take a patient who has had several biopsies already, but his PSA has progressed from four to six to eight to 10. That’s a pretty typical patient for us.
Dahut: This often occurs in men in their 50s or 60s, but can occur in men in their 40s or even younger.
Choyke: There’s no prep for the MRI. We do get some blood work, to make sure that it’s safe to inject contrast media. They fill out a brief survey. Then we place an endo-rectal coil probe in the rectum of the patient while he’s on the MRI table and put another coil over the surface of the lower abdomen. Then the patient goes into the scanner, whereupon we do about an hour’s worth of scanning. After that, the coil is removed and the patient can go home. There are several outcomes.
Dahut: When the images are done on the MRI, they’re looked at in terms of low, intermediate, or high likelihood of cancer.
Choyke: If the patient does not have any suspicious lesions, notwithstanding the rising PSA, we’ll turn the patient back to his regular care. If there’s a focal lesion that’s of concern, we generate a PowerPoint of the lesions and immediately e-mail Dr. Pinto and his team that this is a suspicious lesion. The patient returns. The UroNav procedure is done while the patient is completely awake. There’s no sedation unless there’s an unusual case. Dr. Pinto or Dr. Wood will administer local anesthesia into the prostatic area to reduce the pain associated with the procedure. A 3D ultrasound is performed. That’s simply putting the ultrasound probe in the rectum, slowly pulling it back, and acquiring images all the way through. Those images go to the UroNav workstation, where the MRI has already been transmitted. The MRI data have been segmented so only the prostate is showing. The lesion has been demarcated on the screen by our team. The 3D ultrasound image is also segmented, which means just outlining where the prostate margins are, and that is done semi-automatically. The machine itself takes those segmentations and fuses them together, and in so doing, brings the site of the lesion onto the ultrasound screen. Everything that was done on the MRI is now transferred over to the ultrasound image. At that point, every time you move the ultrasound probe in any direction, you move a virtual MRI image in the exact same way. The procedure can be done as if you are looking at the MRI, whereas the information is really coming from the ultrasound. The lesion is lined up—there’s a biopsy guide that is built into the ultrasound device that projects where a needle will go. That can be lined up with the target that’s been identified on the MRI. Several biopsies are obtained from those lesions.
Peter Pinto, M.D., Urologic Oncology Branch, NCI, in prostate surgery suite with UroNav readout and probe.
Pinto: Prostate cancer has been treated for over a century by removing the whole prostate. One could argue that a skilled surgeon can spare the nerves that cause erections, can spare the urethra that keeps a man dry and prevents leakage of urine, and remove all the cancer safely. But that’s a very difficult operation to perform. At many institutions, even with robotic surgery technology, men still suffer from incontinence and erectile dysfunction. It always struck me that, in an era of PSA-diagnosed, early-stage cancers, why haven’t we changed how we manage prostate cancer? Why do we still remove the whole prostate, why do we still radiate the whole prostate, if the tumors found at a lower stage put most men at risk for the side effects of treating the whole prostate? The reason was because we could never see the tumor in the prostate, until now. Based on this advanced imaging, we developed a device to specifically biopsy a visualized prostate tumor. That’s the UroNav platform. Patients have since come to me and asked, “If you can see the prostate tumor, if you can place a biopsy needle into it and confirm it is a cancer, why take out or radiate the whole prostate and risk incontinence and impotence? Why not just go in and destroy the tumor?” That was in 2011, when we started a new prostate cancer treatment protocol based on our imaging research, a Phase I feasibility trial to place a laser fiber into the prostate cancer and destroy the entire tumor. This allows us to target only the cancer inside the prostate for destruction. This image-guided focal therapy for prostate cancer can avoid the side effects of whole gland therapy, erectile dysfunction and urinary incontinence. Although this tumor-specific treatment has been used in the past for kidney and breast cancer, this concept of focal therapy for prostate cancer is very new. It’s been shown to be very safe and feasible here at NIH. As a result, we are expanding this to many more patients here, opening up a Phase II trial to confirm its cancer effectiveness.
Is this just a stopgap, while we’re waiting for a genetic or a blood test?
Dahut: Unfortunately I don’t see a perfect test likely to be available any time soon. I think we are going to need imaging, pathology, as well as knowledge related to inherited genes and the genomics of the tumor. I think a blood test, to say, “Is my cancer going to be the one that’s going to kill me or not?” is not realistic. Any future blood or genomic tests will need to be put in the context of all other available information such as pathology and imaging. In general, it may be easier to determine the very high risk tumors and those with the most benign characteristics, both pathologically and based on imaging criteria. A real challenge will be to better differentiate the intermediate-grade tumors in order to determine those which may need more aggressive treatment from those in which we can potentially defer therapy.
What exactly do we mean when we talk about interventional radiology, and what is the state of the art in that field?
Wood: Interventional radiology is minimally invasive, image-guided therapy, often using needles, catheters, or minimally invasive equipment, guided with imaging or video-game like software, that can integrate and fuse CT, MRI, ultrasound, X-ray, or 3D X-ray. Interventional oncology applies these tools in a multidisciplinary team to better diagnose and treat cancer. We watch as we do minimally invasive procedures, with continuous feedback on the effects of what we’re doing while we’re doing it, so we can modify that process and do it a little better. Information is power. Why not use that information when we need it most, while the patient is on our table? Much of what we study and help develop is focal or regional therapy, where we deliver chemotherapy to the liver, for example, through a catheter. We use the blood vessels as a roadmap to get to the liver. We also put needles into tumors to cook them with radio-wave frequency energy (or microwaves, lasers, cryoablation to freeze, or focused ultrasound, which is completely non-invasive). The non-invasive ultrasound waves can kill tissue, deliver drugs or increase the sensitivity to other treatments like radiation. The National Institutes of Health provides fertile ground for first-in-human, multidisciplinary teams to develop translational tools based on team science. The UroNav was over a decade of NIH teamwork, from concept to system to pre-clinical to patient to commercialization, and now changing the standard of care in certain settings. NIH team science!
Where might the future of prostate screening and detection lie?
Pinto: PSA alone has not performed as well as we all would have liked. Ideally a screening test would only find the clinically significant aggressive cancers, thereby not subjecting men to repeated negative biopsies, overdiagnosis and overtreatment. As a result, the medical community has recently recommended against the use of PSA for prostate cancer screening. If you were to use MRI with PSA, we may see the performance of PSA improve. Also it may be that some day MRI could be an opportunity for screening by itself. Breast cancer screening is solely based on imaging via mammography. Some types of colon cancer screening are also based on imaging, in one example via direct visualization of the tumor during colonoscopy. In a similar fashion one could imagine a day when based on a man’s family history, health status, and risk factors for prostate cancer, he could have a prostate MRI at a certain age and, if negative, have repeat imaging at some later dates, so he can avoid the many negative prostate biopsies caused by a high PSA. In men that we image at NIH, who are known to have prostate cancer detected by our MRI, it often takes two or three years for the tumor to change at all. MRI helps us better select those men for active surveillance who do not need to treat their prostate cancer and to avoid the frequent biopsies that are required without the use of prostate MRIs.
Wood: The real interesting stuff is the patients who are currently, maybe, some would say, over-treated by radiation or surgery. Perhaps those patients who had non-aggressive prostate cancer can go on active surveillance, and can be potentially monitored with MRI. For certain patient populations, this technology has a huge impact. We’ve seen a number of patients who had a decade of negative biopsies—six, seven, eight negative biopsies—but the tumors are just sitting in there. There they are, growing inside, and many times, very significant tumors. For those patients it’s key.
Why does the involvement of NIH or NCI matter?
Choyke: I once was told when I first got to NIH, “Remember, it’s the National Institutes of Health, not the National Institutes of Science.” Our mission is to get this stuff out to the public. It doesn’t do any good for us to just publish in our academic journals.
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