Active surveillance redefines paradigm for prostate cancer management

Active surveillance — in which prostate cancer is regularly monitored for signs of progression — spares men whose tumors may never progress from potential treatment-associated adverse effects, such as sexual dysfunction or incontinence.

This approach is especially common among men who are older and have limited life expectancies, as well as among younger men who want to ensure they maintain a high quality of life until treatment becomes necessary.

“Active surveillance does not mean ‘don’t treat,’” Matthew R. Cooperberg, MD, MPH, associate professor of urology and epidemiology & biostatistics at University of California, San Francisco, told HemOnc Today. “It means, ‘Don’t treat now and follow carefully with every intention of cure if there is progression.’”

The strategy has gained considerable acceptance. In community-based practices, the percentage of men with low-risk disease who underwent active surveillance climbed steadily from 6.7% in 1990 to 14.3% in 2009, a study by Cooperberg and colleagues showed. Between 2010 and 2013, the figure exceeded 40%.

Proponents contend active surveillance is a viable option because mortality rates among men whose tumors are limited to the prostate are low, and many of these men never experience symptoms from their disease.

However, some urologic oncologists question active surveillance as a standard management strategy and contend its use should be limited.

They emphasize repeat biopsies — necessary to monitor for disease progression during active surveillance — can still negatively affect quality of life. Questions also remain about whether risk stratification is an appropriate guide for active surveillance.

The debate about whether active surveillance is suitable for patients with intermediate-risk disease — who may sacrifice the chance to have their cancer treated at its most curable stage — is particularly contentious.

“By definition, the number of men who die because they went on surveillance is very low but cannot be zero — that’s the law of nature in cancer,” Cooperberg said. “If you have thousands of men on active surveillance, a few of them are going to miss the window. But, this number is likely much smaller than the number of men seriously harmed by avoidable surgery or radiation therapy.”

HemOnc Today spoke with oncologists and urologists about the benefits and risks of active surveillance, the factors that most affect risk stratification, the differences between active surveillance and “watchful waiting,” and how disparities among black patients may affect their outcomes in this setting.

An established approach

Monitoring disease rather than immediately commencing treatment is not a new concept. Active surveillance is a new way to describe — with modifications — what used to be known as watchful waiting.

Chodak and colleagues published data in 1994 in The New England Journal of Medicine that showed men with grade 1 or grade 2 prostate cancer could safely undergo conservative management and delayed hormone therapy without significantly affecting DFS.

Watchful waiting became common among men with well-differentiated and moderately well-differentiated cancers.

Today, these categories would refer to men with Gleason scores between 2 and 7. Because tumor grade can vary within a biopsy, Gleason scores are calculated by adding the most common Gleason grade in the sample with the highest grade to predict the likelihood of disease progression.

The concept of active surveillance involves more intense monitoring than watchful waiting, usually through frequent tests such as annual or biennial biopsies.

“Since we believed in watchful waiting in the past, it makes sense we can continue a more focused surveillance approach for men who are unlikely to progress,” Daniel B. Rukstalis, MD, urologic oncologist and professor of urology at Wake Forest University School of Medicine, told HemOnc Today. “Active surveillance is an evolutionary step from what we knew worked for most men — simply watchful waiting. The word ‘active’ implies that we are going to do more than simply the first biopsy. We know more about the cancer now and, therefore, we can make a better guess as to which patient is going to progress in his healthy lifetime.”

Still, some clinicians remain skeptical about this approach.

“Active surveillance has quite a few downsides for a healthy man,” William J. Catalona, MD, professor in urology at Northwestern University Feinberg School of Medicine and medical director of the Urological Research Foundation, said in an interview.

The biggest problem with active surveillance is the frequency with which patients need to undergo biopsies to monitor their disease, Catalona said. The procedures can be painful and expensive, and some lead to sepsis or other adverse effects.

“Biopsies can cause inflammation in the prostate, causing PSA levels to bounce around, which can scare the patients,” Catalona told HemOnc Today. “After biopsies, patients can get scarring around their prostate, and if they are found to need a nerve-sparing prostatectomy, it can be a lot more difficult because they had several biopsies.”

Catalona cited research that indicated men who undergo repeat biopsies may experience erectile dysfunction.

Fujita and colleagues published data in The Journal of Urology that showed more biopsies appeared associated with a decrease in Sexual Health Inventory for Men score (P = .04), and a history of three or more biopsies appeared to more greatly affect the score than two or fewer biopsies (P = .02).

A report by Braun and colleagues showed erectile function decreased 1 (95% CI, 0.2-1.7) point yearly on the International Index of Erectile Function-6 scale during the first 4 years of active surveillance.

“The other major problem is, 40% of men who fulfill the criteria for active surveillance and undergo radical prostatectomy have higher Gleason-grade cancer in their prostate or have cancer that has spread to the margins of the prostate or beyond,” Catalona said. “These patients who seem to be good candidates for active surveillance really are not. In studies that have good long-term follow-up, only about half of patients who enrolled in active surveillance but later had to undergo radiation or surgery had curable disease.”

Many of these men would have had better outcomes had they undergone early treatment, Catalona said.

“It’s ironic that these people who think they have a tumor that is so indolent it does not need treatment later find out they missed the opportunity to be cured,” he said.

Patient stratification

Most men have at least some sort of low-grade cancer in their prostate, according to Ian Thompson, MD, Mays Family Foundation distinguished university presidential chair and director of cancer therapy and the research center at The University of Texas Health Science Center at San Antonio. The likelihood is approximately equivalent to age.

Photo courtesy of UT Health Science Center San Antonio. Photo by Kevin Geil.

The question then becomes, who should be treated?

Low-risk prostate cancer typically is defined as a Gleason score of 6 — or 3 + 3 — or lower, whereas a Gleason score of 7 (3 + 4) or a PSA between 10 and 20 tends to be considered intermediate risk.

However, there have been secular and temporal changes to Gleason scoring over the years, Thompson said. Grade inflation over time may affect whether a patient would derive benefit from active surveillance or if they would be better suited for treatment.

“[The scoring is] based on a pathologist’s eyeballs and brains,” Thompson said. “There’s a way you can determine the reliability of score assignment. The kappa statistic, which is 0.7, means there is a substantial amount of variation in a pathologist giving a score to a pathology slide. Fundamentally, it means if you give the same slide to a pathologist every 6 weeks, there will be some variation in how it’s scored.”

Stratification is important because clinicians differ in their opinions about which patients should receive active surveillance. Although several societies — including the National Comprehensive Cancer Network and American Urological Association — recommend active surveillance as an option for low-risk disease, opinions are not unanimous.

Survey data from Kim and colleagues, published in 2014 in Medical Care, showed 71.9% of U.S. radiation oncologists and urologists reported active surveillance is effective and 80% felt it was underused. However, 71% indicated their patients are not interested in active surveillance, and more physicians recommended radical prostatectomy (44.9%) or brachytherapy (35.4%) than active surveillance (22.1%) for low-risk patients.

The decision is even less clear for intermediate-risk disease.

Klotz and colleagues reported the long-term outcomes of men with favorable- or intermediate-risk disease who underwent active surveillance. Results, published in 2014 in Journal of Clinical Oncology, indicated 94.3% of the population remained alive at 15 years, 55% of whom were still on active surveillance. These data led the researchers to conclude that active surveillance is safe and effective for select patients with intermediate-risk disease.

However, another report — presented by Andrew Loblaw, MD, radiation oncologist at Sunnybrook Health Sciences Centre in Toronto, and colleagues at the Genitourinary Cancers Symposium in February — showed patients with intermediate-risk disease who underwent active surveillance were 3.75 (95% CI, 1.37-10.28) times more likely to die of prostate cancer than patients with low-risk disease.

“Despite the [active surveillance] selection factors that we used in our clinic for intermediate-risk patients, we’re still seeing a greater risk of dying of prostate cancer,” Loblaw said during a press conference. “More research is needed to better identify the group of patients that may be watched conservatively.”

Potential for biomarkers

James Brooks, MD, professor of urology, chief of urologic oncology and vice chair of the department of urology at Stanford University School of Medicine, and colleagues involved with the Prostate Active Surveillance Study (PASS) — which has more than 1,200 patients enrolled and is led by Daniel W. Lin, MD, of University of Washington — hope to identify biomarkers of aggressive disease in patients with prostate cancer and define the proportion of patients who undergo active surveillance who progress based on those biomarkers.

Ten percent of the study participants have intermediate-risk disease, but some are benefitting from active surveillance, Brooks said.

“I have several patients who are now 5 years into the study and have a low, stable PSA and their biopsies are not changing considerably,” Brooks told HemOnc Today. “So, we know there are patients with intermediate-risk prostate cancer who do benefit. The problem we have is that for intermediate-risk patients, meaning those with Gleason 7 prostate cancer, we have no real good predictors of aggressive and non-aggressive disease.”

Data from long-term outcomes studies that compared watchful waiting vs. radical prostatectomy indicate there is a risk for dying of prostate cancer among untreated patients who are Gleason 7 or above.

“The risk is relatively low for someone with low-volume Gleason 3-plus-4 cancer, particularly those who are older,” Brooks said. “Those who are intermediate risk in our study tend to be around age 70 years. However, some clinicians offer relatively low-volume Gleason 3-plus-4 cancer active surveillance regardless of age. I’m just uncomfortable with that for patients in their 40s and 50s and most patients in their 60s.”

Patients with Gleason 7 disease who do not receive treatment have a 3% to 20% risk for dying of prostate cancer within 10 to 15 years, Brooks added.

“Those are real risks the patients are assuming,” he said. “I would be nervous to put a patient with a good life expectancy and low comorbidities on surveillance. What we need to do — and this is the intent of the PASS trial — is develop biomarkers and predictors to help us sort out who has aggressive disease.”

Rukstalis, however, suggested patients with intermediate-risk disease are the real beneficiaries of active surveillance.

“I am not certain we are benefitting men [with low-risk disease] by doing a series of follow-up biopsies,” he said. “The low-risk men would be excellent candidates in the past for watchful waiting. Active surveillance is useful for intermediate-risk patients because they would probably have been pushed toward treatment during the era of watchful waiting. They would have either been missed by taking a watchful waiting approach, or potentially over-treated if they chose not to wait and watch.”

An appropriate follow-up strategy that manages side effects would identify an intermediate-risk patient who is likely to progress and avoid curative therapy for those who are not.

“A biopsy is easier than a radical prostatectomy,” Rukstalis said. “For the group of people who have a biopsy and don’t progress, active surveillance is a good idea.”

Thompson disagreed.

“A microfocal Gleason 3-plus-3 in a 70-year-old and a microfocal Gleason 3-plus-3 in a 50-year-old both have a low risk over the next 15 years,” Thompson said. “Although it is correct there is a huge burden on the patient with a Gleason 3-plus-4 who has to be on surveillance for a longer period of time because they are younger, the longer you follow it, the greater the likelihood the tumor develops into a more morbid tumor.

“A younger man with a 3-plus-4 should probably be treated rather than an older man with a 3-plus-4,” he added. “The point being, you look at the tumor and patient characteristics, you can tell pretty quickly.”

The disparity for black patients

Many studies have shown disparities in prostate cancer burden between black men and white men. Black men are diagnosed with prostate cancer at a greater rate and are more likely to have high-grade disease than white patients.

Black patients also often have aggressive disease that goes unrecognized with current diagnostic approaches.

In a paper published in 2013 in Journal of Clinical Oncology, Sundi and colleagues determined black men with low-risk prostate cancer who qualify for active surveillance but undergo immediate surgery are more likely to experience disease upgrading (27.3% vs. 14.4%; P < .001), have positive surgical margins (9.8% vs. 5.9%; P = .02), and have higher Cancer of the Prostate Risk Assessment Post-Surgical scoring system scores.

There is not a disparity in care between black and white men because active surveillance is used similarly across all ethnicities, Brooks said. However, there are likely unknown genetic factors that could indicate why certain ethnicities are more prone to develop prostate cancer and experience an aggressive form of the disease.

“We have looked at ethnicity in prostate cancer diagnoses in California between 1995 and 1997 so we can look at long-term outcomes,” he said. “We found that Asian patients have less frequent prostate cancer than Caucasians, but when it shows up, it tends to be higher stage and grade, which is very similar to what African Americans present with. Yet, Asian patients have the best survival — better than Caucasians and much better than African Americans.”

This suggests clinicians need to take ethnicity into account when offering active surveillance, Brooks said.

“It might suggest that Asian patients with intermediate-risk prostate cancer might be better candidates for active surveillance than other ethnicities,” Brooks said. “This might have to do with underlying overall genetics or the genetics within the prostate cancer. This is going to blossom into a very complicated topic, and we just have to keep getting smarter on how we deploy it.”

Studies are ongoing to identify biomarkers to predict disease progression, but until then, there are a lot of conflicting data.

“[Sundi and colleagues] saw a lot of missed anterior tumors,” Cooperberg said. “More recently, there were a few studies — one we did from the CaPSURE and UCSF databases — that have not replicated these findings. We need to figure out how much of this racial variation is genetic and how much is environmental.”

Catalona also suggested that some black patients may not trust programs that call for surveillance because of historically unethical practices, such as the Tuskegee syphilis experiment conducted by the U.S. Public Health Service for 40 years.

“It’s a delicate issue, but there is a certain amount of distrust among the African American community to participate in programs where they may not be treated for a serious disease,” Catalona said. “But there are some recent papers that show that the African American communities are now starting to accept active surveillance because it avoids surgery and radiation.”

Another confounding situation that may be prejudicial is that the U.S. Preventive Services Task Force has recommended against PSA screening in asymptomatic men.

“That [guidance] ignores the fact that there were virtually no African Americans in any of the screening trials that they used to base their recommendation, and it ignores the fact that these patients have much higher burden of disease and that we should think about screening differently in this population,” Cooperberg said. “Fortunately, most of the screening guidelines outside of the task force do still recognize that African Americans should be screened earlier.”

Death due to surveillance

Cooperberg has repeatedly said there are men who choose active surveillance who will die, although the percentage — approximately 2% — is far lower than the percentage of patients who will be harmed by treatment.

However, the increasing popularity of active surveillance may prompt more clinicians to question the effect this approach has on mortality.

“The first part is true — there are going to be men who suffer and who die of prostate cancer because they picked active surveillance and they delayed treatment of a curable cancer,” Catalona said. “But to compare metastatic prostate cancer or dying of prostate cancer with incontinence or erectile dysfunction, I don’t think that’s a fair comparison.

“If somebody is incontinent or has erectile dysfunction after a radical prostatectomy, he can be treated for those conditions and can live a pretty normal life,” he added. “But if you have metastatic prostate cancer or die of prostate cancer, that’s a pretty terrible outcome.”

However, complications can occur beyond incontinence and erectile dysfunction, which are not outcomes that are comparable to metastatic prostate cancer, Cooperberg said.

“The harms I’m referring to are the truly devastating — and sometimes lethal — complications that occur all too often given the high proportion of men still treated by low-volume providers who do not achieve outcomes comparable to those reported from high-volume referral centers,” Cooperberg said.

Rukstalis acknowledged the issue is incredibly complicated.

“I disagree with [Cooperberg], but I’m not sure he’s wrong,” Rukstalis said. “The trouble with managing prostate cancer is the death from intercurrent medical illness. If a man has a high-risk prostate cancer, undergoes a radical prostatectomy and then dies from a stroke 2 years later, he didn’t benefit from his radical prostatectomy. My answer to that is we as the field, in partnership with our primary care colleagues, have not done enough work on building the predictive metrics about the man as much as we have about the cancer.

“Cooperberg’s quote says the majority of men are not healthy enough to benefit from treatment, so therefore treatment is worse than active surveillance, and I would agree with it if he phrased it that way,” Rukstalis added. “The way he phrased it allows a healthy man to plug into that, and that’s where I begin to have troubles. If the healthy man is aged 60 years and has low-risk cancer, I feel he is at the same risk of being harmed by active surveillance as if he’s a healthy 72-year-old with intermediate cancer.”

Still, due to the ongoing research and positive momentum of active surveillance, the approach may be at the forefront of the prostate cancer conversation for a long time to come.

“I remember a decade ago at a Society of Urologic Oncology meeting, there was a presentation on active surveillance and there were questions from the audience that suggested the concept was heresy,” Thompson said. “We have gone from a concept that you should never, ever consider to a point now where colleagues and I teach a post-graduate course on active surveillance for the American Urologic Association meeting.

“The room is packed,” Thompson added. “The skeptics are still there, and nothing in this world can assure that patients with prostate cancer will never have a problem from their disease, whether it be with surveillance, surgery or radiation. But, we are now at the point where we can offer a predicted low-risk patient a less morbid option that is associated with very similar disease-specific survival as treatment.” – by Anthony SanFilippo

References:

Braun K, et al. J Urol. 2014:doi:10.1016/j.juro.2013.08.054.

Chodak GW, et al. N Eng J Med. 1994;330:242-248.

Cooperberg MR and Carroll PR. JAMA. 2015;doi:10.1001/jama.2015.6036.

Fujita K, et al. J Urol. 2009;doi:10.1016/j.juro.2009.08.044.

Kim SP, et al. Med Care. 2014;doi:10.097/MLR.0000000000000155.

Klotz L. J Clin Oncol. 2014;doi:10.1200/JCO.2014.55.1192.

Lichtensztajn DY, et al. J Urol. 2014:doi:10.1016/j.juro.2013.10.075.

Musunuru HB, et al. Abstract 163. Presented at: Genitourinary Cancer Symposium; Feb. 26-28. 2015; Orlando, Florida.

Raldow AC, et al. JAMA Oncol. 2015;doi:10.1001/jamaoncol.2014.284.

Saad F. JAMA Oncol. 2015;doi:10.1001/jamaoncol.2014.103.

Sundi D, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2012.47.0302.

Yamoah K, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.59.8912.

For more information:

James Brooks, MD, can be reached at Stanford University Hospital, 875 Blake Wilbur Drive, Palo Alto, CA 94305; email: jdbrooks@stanford.edu.

William J. Catalona, MD, can be reached at Northwestern Memorial Hospital, 675 N. Clair St. #20, Chicago, IL 60611; email: wcatalona@nm.org.

Matthew Cooperberg, MD, can be reached at UCSF Medical Center, 1825 Fourth St., San Francisco, CA 94158; email: matthew.cooperberg@ucsf.edu.

Daniel B. Rukstalis, MD, can be reached at Wake Forest Baptist Medical Center, 1 Medical Center Blvd., Winston-Salem, NC 27157; email: drukstal@wakehealth.edu.

Ian Thompson, MD, can be reached at The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229; email: thompsoni@uthscsa.edu.

Disclosure: Brooks, Catalona, Cooperberg, Rukstalis and Thompson report no relevant financial disclosures.

 

 

Is MRI-guided biopsy the ideal biopsy method for patients undergoing active surveillance for prostate cancer?

Yes.

Traditional ultrasound-guided prostate biopsy has been limited for decades by the poor sensitivity and specificity of ultrasound to detect tumors within the prostate gland. As a result, physicians have been forced to perform a systematic extended sextant 12 core transrectal ultrasound (TRUS) prostate biopsy that is blind to the location of the tumor(s) in the hopes of hitting the tumor accidentally. Prostate cancer is the only solid tumor diagnosed without imaging guiding the physician’s needle into the suspected cancer. This is problematic for men undergoing PSA screening because the patient and physician are never certain after a negative TRUS biopsy if the cancer was missed by the blind nature of the biopsy or if he truly does not have prostate cancer. Also, in men considering active surveillance, the traditional TRUS prostate biopsy may have detected a small-volume low-grade cancer but missed a more aggressive higher-grade cancer, thus making active surveillance a poor choice for management of his cancer.

Recent advances in multiparametric prostate MRI have been shown to detect clinically significant cancer within the prostate. The improved sensitivity and specificity of cancer detection by multiparametric MRI over ultrasound has been a true game changer. At the same time, new prostate biopsy devices have been developed that allow the MRI to be “fused” with ultrasound for a tumor-targeted biopsy in a physician’s office. This has allowed for the first time a true “tumor-directed” prostate biopsy and improved detection of the clinically relevant cancer(s) compared with ultrasound-directed alone. In a recent publication in JAMA reporting our 1,000-patient trial, utilizing MRI/ultrasound fusion-guided biopsy compared with traditional ultrasound alone resulted in the detection of more high-grade cancers. Not only does this allow for better selection for active surveillance but also may decrease the need or frequency for annual TRUS prostate biopsies to detect tumor progression. With the recent advances in prostate MRI and development of MRI/ultrasound fusion-guided biopsy systems, physicians now have a better way of detecting and following men with prostate cancer who are on active surveillance.

 

References:

Siddiqui MM, et al. JAMA. 2015;doi:10.1001/jama.2014.17942.

Turkey B, et al. J Urol. 2011; doi: 10.1016/j.juro.2011.07.013.

Peter A. Pinto, MD, is head of the prostate cancer section and director of the fellowship program of the urologic oncology branch at the NCI. He can be reached at pintop@mail.nih.gov. Disclosure: Pinto holds a patent related to the MRI/ultrasound fusion biopsy platform.

The majority of patients undergoing initial biopsy for the suspicion of prostate cancer do not need MRI-guided biopsy.

Such patients currently undergo transrectal ultrasound (TRUS) of the prostate with a systematic 12-core biopsy protocol (TRUS-SB). This strategy yields a positive biopsy rate of 40% to 60% based on current series, one of the most productive biopsy strategies for any solid cancer.

Multiparametric MRI has been shown to identify prostate cancers of at least 0.5 cm³ with good sensitivity. The specificity of MRI-detected lesions is highly controversial because it depends on the subjective identification of “index lesions” by a radiologist using the Prostate Imaging Reporting and Data System rating system, which is not yet fully validated.

Some studies have claimed that MRI images when fused to real-time TRUS-directed biopsy (TRUS-BX) to produce MRI-targeted biopsies (MRI-TB) can diagnose more “significant” cancers and fewer “insignificant” cancers than TRUS systematic biopsy alone. However, several recent studies have found that the overall detection rate between the two approaches is not significantly different even when the MRI demonstrates an “index lesion.” A randomized prospective study by Tonttila and colleagues demonstrated that MRI-TB plus TRUS-SB did not diagnose significantly more overall cancers (64% vs. 57%; P = .5) or more “significant” cancers (55% vs. 45%; P = .8) than TRUS-BX alone. Most investigators have concluded that TRUS-SB biopsies must be done in addition to MRI-TB. The argument that MRI-TB “may” avoid biopsies is not yet realized.

TRUS-SB is an artificial construct in which 12 to 14 cores of tissue are taken in pre-determined anatomic sections of the gland independent of the ultrasound findings. This approach was adopted based on older studies which showed that detection rates were directly correlated with the number of cores obtained.

These outdated studies have promoted a prejudice that ”nothing significant” can be seen on ultrasound. There are multiple sonographic indications of possible prostate cancer including echogenicity, asymmetry, deformation of internal prostatic anatomy, increased blood flow (Doppler) and decreased tissue compressibility (elastography). These multiple parameters (multiparametric TRUS) could be used to identify areas of increased risk for cancer with a sensitivity and specificity approaching that of MRI. In fact, a recent study by Ukimura and colleagues has shown that 78% of all lesions identified as highly suspicious on MRI were also visible on TRUS. These areas should be consciously included during TRUS-SB.

There is no doubt that MRI is superior to TRUS for identifying anterior lesions or those in a large heterogeneous transition zone. However, the existential angst over the management of prostate cancer is not based on the failure to detect a few additional lesions. The problems are overdiagnosis, overtreatment and cost. What is needed is better patient selection, improved utilization of existing imaging technology (ie, TRUS), more selective biopsy strategies and more selective treatment. Another layer of expensive imaging — however elegant — and fusion platforms, however precise, do not address these issues.

 

References:

Kapoor D, et al. Rev Urol. 2013;doi:10.3909/riu600.

Schoots IG, et al. Eur Urol. 2015;doi:10.1016/j.eururo.2014.11.037.

Tonttila PP, et al. Eur Urol. 2015;doi:10.1016/j.eururo.2015.05.024.

Ukimura O et al. Eur Urol. 2013;doi:10.1016/j.eururo.2012.09.033.

Pat Fox Fulgham, MD, is surgical director of oncology services and chair of the department of urology at Texas Health Presbyterian Hospital of Dallas. He can be reached at pfulgham@airmail.net. Disclosure: Fulgham reports no relevant financial disclosures.