Pain medication will be used in the removal of the prostate has been linked to cancer

Use the anesthetic management of patients with prostate cancer, to surgical methods and control pain, prostate gland cancer affecting their long-term cancers result when removing, guided by a Mayo Clinic study has found. Suppress the ability of the immune system to fight cancer cells after opioid, usually specified when, after painkillers. To radical prostate removal except before in research reduce opioids patients need surgery after the spinal or epidural associated complement and painkillers combined with General anesthesia, found this lower risk of cancer recurrence is suggested. Survey results will be published online in the British Journal of anaesthesia.

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History of Prostate Cancer Tied to Higher Odds for Melanoma

Studies followed thousands of white male health professionals

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Fewer weeks of hormone therapy before radiation reduces side effects in intermediate risk prostate cancer

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A shorter course of androgen suppression therapy prior to radiation therapy, when compared to a longer course of androgen suppression therapy, yields favorable outcomes and fewer adverse effects for intermediate-risk prostate cancer patients, according to research presented at the American Society for Radiation Oncology's (ASTRO) 55th Annual Meeting by researchers from the Mayo Clinic. The study confirmed a disease-specific-survival (DSS) rate of 95 percent when patients received fewer weeks of neoadjuvant (NEO) total androgen suppression (TAS).

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Unstable chromosomes linked to less favorable response to radiation therapy and surgery in prostate cancer patients

Sep. 25, 2013 — Detailed evaluation of a prostate cancer tumor biopsy may predict treatment outcomes for image-guided radiation therapy (IGRT) or surgery for prostate cancer, according to research presented today at the American Society for Radiation Oncology's (ASTRO's) 55th Annual Meeting. The study results indicate that patients who have abnormal levels of breaks at common fragile sites (CFSs), sites within the chromosomes that are sensitive to DNA damage, are more likely to have their cancer to return -- treatment failure. These CFS break abnormalities are usually associated with instability of the cell's DNA, a phenomenon that is particularly associated with cancer.

In this study, researchers assessed the outcomes of 280 prostate cancer (Cap) patients, and reviewed the DNA "fingerprints" of each patient's tumor (using the patient's initial diagnostic core biopsy) to determine if gene copy number alterations (CNAs), or breaks in CFSs, were related to a less positive response to treatment. Two groups were analyzed: 126 localized intermediate risk CaP patients who had received image-guided radiation therapy (IGRT) treatments, with a mean dose of 74.6 Gy; and 154 localized intermediate and high risk CaP patients who had undergone radical prostatectomy (RP), which is the surgical removal of the entire prostate gland.

Utilizing an array comparative genomic hybridization (aCGH), DNA from frozen needle biopsies of the RT patients was analyzed for 13 previously characterized CFSs: FRA2G, FRA3B, FRA4F, FRA6E, FRA6F, FRA7E, FRA7G, FRA7H, FRA7I, FRA7K, FRA8C, FRA9E, FRA16D. The effect of having at least one CNA in any CFS was assessed using the Kaplan-Meier method and Cox proportional hazard models.

The data revealed a pattern in which the patients who failed treatment had abnormal levels of CNAs at CFSs. In the IGRT group, CNAs in CFSs occurred frequently, with 80 of the patients (64 percent) having a CNA in one or more CFS locations (median was 1, and the range was 0 -- 10).

Each patient's biochemical relapse-free rate (bRFR) was gauged, because if a patient relapses biochemically, his prostate specific antigen level has risen significantly and this is a reasonable indicator that the cancer has recurred. Thus, a high bRFR is desirable. On univariate analysis, patients with a CNA in at least one CFS showed a decreased 5-year bRFR (64 percent), compared with the bRFR of patients without genetic alteration in CFSs (90 percent; HR = 2.13, 95% CI: 1.17-3.86, p = 0.011). After adjusting for clinical factors in a multivariate model, a CNA in a CFS was determined to be a significant independent predictor of decreased response to radiation therapy and higher incidence of recurring cancer. (HR = 2.94, 95% CI: 1.51-5.75, P = 0.0016).

The results of the 154 patients in the RP group were compiled using the publically available Memorial Sloan-Kettering Cancer Center (MSKCC) aCGH database of patients. CNAs in CFSs were also frequent in the RP group, with 81 patients (53 percent) having a CNA in one or more location (median was 1, and the range was 0 -- 6). These results also correlated to decreased 5-year bRFR rates of 68 percent, compared to 82 percent for RP patients without genetic alterations in CFSs (HR = 1.79). Despite this strong trend, after adjusting for clinical factors in a multivariate model, a CNA in a CFS was not a statistically significant predictor of cancer recurrence (HR = 1.52, 95% CI: 0.77-3.02, P = 0.23).

"We thought that patients who have CFS breaks might be more sensitive to radiation therapy-induced DNA damage," said the lead author of the study, Robert G. Bristow, MD, PhD, a Professor within the radiation oncology and medical biophysics departments at the University of Toronto; and a Clinician-Scientist at the Princess Margaret Cancer Centre in Toronto. "We now think that the CFS breaks are a signal that the cancer cell has acquired numerous genetic changes that lead to more aggressive cancer cells that can spread early and outside the prostate gland. Our data suggest that the patients failing treatment are due to early metastatic (distant spread) disease. If we validate this study in similar, but larger groups of patients, we can develop a test based for CFS breaks; the results would allow us to place patients in one of two categories: those whose tumors do not have CFS breaks and who would likely do well with local treatment alone (e.g. radiotherapy or surgery); and, those patients whose tumors do have CFS breaks and would need a more complex treatment protocol, in addition to RT or surgery, to combat distant spread."

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Test could identify which prostate cancers require treatment

Sep. 11, 2013 — The level of expression of three genes associated with aging can be used to predict whether seemingly low-risk prostate cancer will remain slow-growing, according to researchers at the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center. Use of this three-gene biomarker, in conjunction with existing cancer-staging tests, could help physicians better determine which men with early prostate cancer can be safely followed with "active surveillance" and spared the risks of prostate removal or other invasive treatment. The findings were published today in the online edition of Science Translational Medicine.

"Most of the 200,000 prostate cancers diagnosed each year in the U.S. are slow growing and will remain so, but the three-gene biomarker could take much of the guesswork out of the diagnostic process and ensure that patients are neither overtreated nor undertreated," said study leader Cory Abate-Shen, PhD, Michael and Stella Chernow Professor of Urological Oncology at CUMC.

"The problem with existing tests is that we cannot identify the small percentage of slow-growing tumors that will eventually become aggressive and spread beyond the prostate," said coauthor Mitchell C. Benson, MD, PhD, George F. Cahill Professor of Urology and chair of urology at CUMC.

In their search for a biomarker for slow-growing prostate cancer, Dr. Abate-Shen and her colleagues, including, coauthor Michael Shen, PhD, professor of medicine and of genetics and development, focused on genes related to aging, particularly those affected by cellular senescence, a natural phenomenon in which older cells cease to divide but remain metabolically active. Cellular senescence is known to play a critical role in tumor suppression in general and has been associated with benign prostate lesions in mouse models and in humans.

Using a technique called gene set enrichment analysis, the CUMC team, led by coauthor Andrea Califano, PhD, Clyde and Helen Wu Professor of Chemical Systems Biology and chair of systems biology, identified 19 genes that are enriched in a mouse model of prostate cancer in which the cancers are invariably indolent. They then used a decision-tree learning model, a type of computer algorithm, to identify three genes -- FGFR1, PMP22, and CDKN1A -- that together can accurately predict the outcome of seemingly low-risk tumors. Tumors that test negative for the biomarker are deemed aggressive.

In a blinded retrospective study, the researchers tested the prognostic accuracy of the three-gene panel on initial biopsy specimens from 43 patients who had been monitored for at least 10 years with active surveillance at CUMC. All the patients had first been diagnosed with low-risk prostate cancer (as defined by several measures, including a Gleason score of 6 or less). Of the 43 patients, 14 ultimately developed advanced prostate cancer. All 14 were correctly identified by the test.

"The bottom line is that, at least in our preliminary trial, we were able to accurately predict which patients with low-risk prostate cancer would develop advanced prostate cancer and which ones would not," said Dr. Abate-Shen.

The researchers plan to evaluate the test in a larger, prospective clinical trial, led by Dr. Benson and coauthor Sven Wenske, MD, assistant professor of urology at CUMC.

Physicians currently use several tests to diagnose prostate cancer and stage its aggressiveness. The process begins with a prostate-specific antigen (PSA) test, a digital rectal exam, or both. If these tests raise concerns, the patient is typically advised to undergo a biopsy, in which samples of prostate tissue are examined for the presence of cancer cells. If malignant cells are detected, the patient is given a Gleason score (ranging from 2 to 10), a measure of the severity of the cancer based on the cells' appearance. Patients with high Gleason scores (8 or above) are usually advised to undergo immediate treatment, while those with very low Gleason scores (5 or below) are usually advised to undergo active surveillance. "But it's not so clear what to do for patients with low (Gleason 6) or even intermediate (Gleason 7) scores," said Dr. Abate-Shen.

Men with seemingly low-risk prostate cancer currently have two basic choices. One is regular testing and monitoring, also known as active surveillance, which risks missing the window when the disease is localized and potentially curable. The other is aggressive treatment, which risks serious side effects such as urinary incontinence and impotence.

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NCI clinician-scientists at the forefront of new prostate cancer diagnostics and treatment

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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.

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.

What was the genesis of UroNav?

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.

Does this biopsy method have any implications for prostate cancer treatment?

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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