Physician-Patient Communication Oncologist counsels patient about options for treatment of prostate cancer. Photo courtesy of Thinkstock.

Prior to ASCO’s 2016 endorsement of the Cancer Care Ontario (CCO) guideline on active surveillance in the management of localized prostate cancer,¹ most men—over 90%—diagnosed with low-risk localized disease were treated with active therapy.² Today, about 50% of American men with low-risk disease opt for active surveillance instead of therapy. In Sweden, nearly 80% of men with low-risk prostate cancer undergo surveillance rather than treatment.³

This year, approximately 165,000 men in the United States will be diagnosed with prostate cancer,⁴ and half of those men will have low-risk tumors that pathologists rate as Gleason 6 disease. Changes to the Gleason score grading system in 2014 by the International Society of Urological Pathology classified Gleason 6 as grade 1, putting the cancer in the very low–risk category.

Strong evidence suggests that Gleason 6 disease, when not associated with higher-grade cancer, almost never develops into aggressive cancer requiring treatment. Thus, many patients with Gleason 6 cancer are able to sidestep therapy, such as surgery and radiation therapy, and its attendant side effects, including sexual, urinary, and bowel dysfunction, for active surveillance, which is increasingly being adopted as the standard of care for men with a Gleason 6 score.

Defining Gleason 6 Cancer

According to the CCO guideline,⁵ active surveillance is a curative-intent strategy that involves regular monitoring for changes in a Gleason 6 classification to a higher-risk category and the potential need for therapy if the cancer is progressing. It is distinct from the observational approach of watchful waiting, which involves fewer tests and is usually reserved for patients with a life expectancy of less than 5 years.

The definition of low-risk prostate cancer used in the CCO guideline includes a Gleason score of 6 or less; a prostate-specific antigen (PSA) measurement of 10 ng/mL or less; and a stage of T2a or less. Some patients with low-volume, intermediate-risk disease (Gleason 3 + 4 = 7) may also be offered active surveillance.

The guideline includes other factors when considering active surveillance for patients with low-risk, localized disease. For example, patients who are younger and have high-volume Gleason 6 cancer and patients of African American ethnicity who may have a greater risk of disease progression over their lifetime may benefit from immediate treatment instead of active surveillance. Patient preference regarding active treatment vs active surveillance should also be considered when recommending a care management strategy.

Managing Localized Prostate Cancer

According to the CCO recommendation, active surveillance for patients with Gleason 6 cancer should include:

• PSA testing every 3 to 6 months
• Annual digital rectal exam
• A 12- to 14-core confirmatory transrectal ultrasound biopsy, including anterior-directed cores, within 6 to 12 months of starting surveillance, and then a serial biopsy every 3 to 5 years thereafter.

Optionally, a multiparametric magnetic resonance imaging scan could be performed when a patient’s clinical findings are discordant with pathologic findings and would be useful for identifying occult cancers or evidence of disease progression.

During surveillance, if a patient is reclassified to a higher-risk category—defined by a repeat biopsy showing a Gleason score of 7 or higher and/or increases in tumor volume—treatment such as prostatectomy or radiotherapy should be considered.

Weighing the Risks and Benefits of Active Surveillance

A study published in 2016 by Hamdy et al compared active monitoring, radical prostatectomy, and external-beam radiotherapy in the treatment of localized prostate cancer. These researchers found that after 10 years, death rates from the cancer were low overall—about 1%. However, more men on active monitoring had disease progression than men in either the surgery or radiotherapy group,⁶ illustrating that not every man with Gleason 6 disease may be a good candidate for active surveillance. In addition to the possibility that a nonthreatening Gleason 6 cancer may progress to Gleason 7 or higher and metastasize, a patient’s age, willingness to adhere to regular monitoring and biopsies, and acceptance of some risk to avoid aggressive treatment when it may not be necessary are all factors patients and physicians must weigh when deciding on an oncology care plan.

Recently, The ASCO Post held a roundtable with three experts in prostate cancer to discuss these issues, as well as whether Gleason 6 disease should be called cancer; how to determine which patients can safely engage in active surveillance; and what diagnostic tools may be on the horizon to accurately differentiate a nonthreatening Gleason 6 cancer from one that will progress to aggressive disease.

Brian F. Chapin, MD

Jonathan I. Epstein, MD

Maha Hussain, MD, FACP, FASCO

Our panel included Brian F. Chapin, MD, Assistant Professor in the Department of Urology, Division of Surgery, at The University of Texas MD Anderson Cancer Center, Houston; Jonathan I. Epstein, MD, Professor in the Department of Pathology, Urology, and Oncology and Reinhard Professor of Urologic Pathology at Johns Hopkins Medical Institutions, Baltimore; and Maha Hussain, MD, FACP, FASCO, Genevieve E. Teuton Professor of Medicine in the Division of Hematology/Oncology and Deputy Director of the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine, Chicago.

Is Gleason 6 Cancer or Indolent Disease?

There is a debate among oncology providers about whether Gleason 6 is cancer. What is your definition of Gleason 6?

Dr. Chapin: Gleason 6 is cancer. It has all the pathologic hallmarks of cancer when viewed under the microscope. But even with this understanding, the cancer has very limited potential to metastasize, which is where active surveillance comes in when deciding treatment. You want to avoid the potential side effects of unnecessary treatments and only intervene if the cancer changes over time and/or progresses.

Dr. Epstein: Because a pure Gleason 6 score determined at radical prostatectomy—where you can examine the entire tumor—has no risk of metastasizing and no risk of leading to the patient’s death, some people question whether we should call Gleason 6 an indolent lesion of epithelial origin (or IDLE) rather than cancer. But morphologically, Gleason 6 is cancer. It looks like a higher-grade cancer under the microscope. It can invade nerves and extend outside of the prostate and has all the features of local aggressiveness that you don’t see with benign tumors.

Dr. Hussain: I agree. Morphologically, Gleason 6 is cancer, and from an oncologist’s perspective, I have had patients with “biopsy-based” Gleason 6 disease who developed metastasis.

Risk-Stratifying Patients

What is the best way to identify patients who are likely to have cancer with a low-risk potential for metastasis? Is there a molecular classifier of metastatic potential oncologists can use to risk-stratify their patients?

Dr. Chapin: There is no reliable test currently. There are genomic tests to evaluate RNA expression of the tumor, which can provide clinicians with some degree of risk stratification for upgrading/upstaging or mortality. I typically don’t use genomic-based testing for Gleason 6 cancer because the pathologic diagnosis of the tumor and the clinical information derived from examining the patient are usually enough to tell me the patient is unlikely to develop metastases or die of his disease.

I usually tell my patients, “I am going to put you on a surveillance-based approach. The risk of dying of prostate cancer if you do absolutely nothing is about 5%.” The goal then is to survey them to identify new disease or progression to a higher grade, at which time they can receive active therapy.

Dr. Epstein: I agree. Part of the determination is based on the pathology report, and part is based on a clinical exam. In terms of pathology, we split risk into two categories: low risk and very low risk. Very low risk is based on the following factors: a Gleason 6 score, one or two positive biopsy cores, and the amount of cancer per core is either under 50% or the cancer is limited to one side of the prostate.

To classify very low–risk patients, in addition to the pathologic criteria I mentioned, we also use a PSA measurement, and that varies among institutions. Some centers use a PSA of less than 10 ng/ mL. At Johns Hopkins, we use a PSA density of less than 0.15 ng/mL/cc because we have found in many studies that it is a better measurement of risk. Low-risk prostate cancer is not as restrictive, meaning you only need a Gleason 6 score, PSA of less than 10 ng/mL, and either a nonpalpable nodule or a small palpable nodule.

We feel more comfortable suggesting active surveillance for patients with very low–risk disease than for patients with low-risk Gleason 6 disease because low-risk patients have a higher likelihood of higher-grade cancer in their prostate that was not sampled, and they will need treatment.

Dr. Hussain: Clearly, we make our decision about low-risk disease based on a combination of factors, including no palpable mass on the rectal exam; low-volume cancer (for example, three or fewer positive biopsy cores); a PSA of less than 10 ng/mL; and a low PSA density (< 0.15 ng/mL/cc).

In addition to PSA levels and tumor measurements to stratify risk for disease progression, what other factors do you take into account when deciding the best treatment course for patients with Gleason 6 cancer?

Dr. Chapin: Age, specifically in relation to life expectancy, and the impact of other disease comorbidities on that life expectancy, will help determine a decision regarding active surveillance or treatment. For example, if a man has 6 to 8 positive biopsy cores of Gleason 6 cancer, a man in his 50s may be more likely to have treatment than a man in his 70s.

We feel more comfortable suggesting active surveillance for patients with very low–risk disease than for patients with low-risk Gleason 6 disease because low-risk patients have a higher likelihood of higher-grade cancer in their prostate that was not sampled, and they will need treatment.

— Jonathan I. Epstein, MD

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I also think about what factors are correlated with a patient’s risk of upgrading to a higher Gleason score cancer or what is the chance that the patient’s cancer is understaged/undergraded or that the index lesion was completely missed. Based on standard transrectal ultrasound biopsies, we know Gleason 6 is misdiagnosed in between 20% and 30% of patients.

Other considerations include family history and any germline or known genetic mutations, such as BRCA-mutated breast cancer. I believe having that history can put patients at a higher risk of developing or having a progressing cancer that will require treatment at a later time. However, I may still consider active monitoring for that patient if he consents to consistent repeat biopsies, PSA testing, and physical exams.

Once the patient is educated on the low risk of his cancer, his preference regarding active surveillance or treatment must also be taken into consideration.

Dr. Epstein: I also take life expectancy into account when determining surveillance vs treatment for patients. I am very comfortable recommending active surveillance for a very low–risk, healthy patient in his 50s or 60s with a life expectancy of over 10 years. I’m not as comfortable recommending monitoring for younger low-risk patients because they may have a higher-grade cancer in their prostate that was not sampled and may need treatment eventually. But I am comfortable recommending surveillance for low-risk patients when they have less than a 10-year life expectancy, because the chances are they are likely to die of something else before their prostate cancer becomes aggressive.

That said, my approach might be considered controversial because other physicians are comfortable suggesting active surveillance for patients with low-risk disease regardless of age. The decision also depends on the patient’s preference.

Dr. Hussain: Yes. Age, life expectancy, comorbidities, and risk of disease are all considerations in deciding whether to proceed with monitoring or treatment. Other factors that I personally think should be considered at the individual patient level are the family history with regard to prostate cancer and its outcomes in relatives if applicable and if any germline mutations that may be associated with higher-risk disease, as these factors also provide information that can help inform the decision. I also agree that it is critical to understandthe patient’s preferences. Surgery and radiation therapy carry risks, so balancing the risk/benefit ratio is critical, as are the ability and willingness of the patient to comply with needed regular clinical monitoring and biopsies.

Choosing Active Surveillance or Treatment

What is the chief dilemma for patients and physicians in deciding the best course of care in this setting?

Dr. Chapin: For physicians, there is a time constraint because explaining all of the requirements for active surveillance vs treatment takes time. I probably spend twice as much time with a patient when I’m discussing surveillance as when I’m talking about treatment with a patient who has intermediate-grade cancer. There is also a financial incentive for physicians to treat patients, which—as a community—we need to overcome.

For patients, there is a certain comfort level they have to reach with the fact that they have cancer and they are not getting rid of it through active surveillance. The reflexive answer when patients have cancer is to say, “let’s treat it,” and it’s really hard for them to accept the idea that their cancer will most likely not cause a problem if left untreated.

Gleason 6 is cancer. It has all the pathologic hallmarks of cancer when viewed under the microscope. But even with this understanding, the cancer has very limited potential to metastasize.

— Brian F. Chapin, MD

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When I talk to patients, I always ask them what their expectation is and what outcome they are hoping for. Often, for men in their 60s with significant lower urinary track symptoms, obstructive symptoms from benign prostatic hyperplasia, and poor erectile function, surgery may be preferable to surveillance because treatment would resolve their obstructive symptoms and they wouldn’t have to go through repeat biopsies and monitoring. Taking into account urinary and sexual function status is important when helping patients with newly diagnosed low-grade prostate cancer decide on their next course of action.

All patients with prostate cancer, regardless of Gleason score, should get a second opinion for another perspective on their situation before making any decision regarding active surveillance or treatment.

Dr. Epstein: For patients with very low–risk disease, active surveillance is nearly the standard of care. It becomes more of a question mark for younger patients with low-risk disease because even though they still have Gleason 6 prostate cancer, it is a higher-volume Gleason 6. In these cases, whether to offer surveillance becomes a judgment call.

I explain to patients that nothing is 100% guaranteed. Even though we may tell patients that there is an 80% to 90% chance their cancer will not progress, it’s not 100%. But I reassure them that if they are closely monitored and we do regular repeat biopsies, if their cancer starts to advance in terms of grade or tumor volume, they can elect to undergo therapy, either radiation or radical prostatectomy, and it is rare that their cancer will not be cured. It’s not 100%, but it’s rare.

Some patients are very comfortable living with the fact that they have cancer. They come for their repeat biopsy, and if the results are good, they won’t have to have another biopsy for a year or two. They can put cancer out of their mind and continue to live their life without the fear of cancer. But I agree with Dr. Chapin—other patients wake up every morning worried that they have cancer, and they just want it out. Whether to undergo active surveillance or treatment is an individual choice and depends on the patient’s comfort level with whichever decision he makes.

Dr. Hussain: The dilemma for the patient is the discomfort level related to the diagnosis of “cancer” and balancing that with the chronicity and potential uncertainties of active surveillance. The decision to undergo active surveillance has to be reassessed as time goes on. From the medical perspective, the critical issue is to be sure the patient really does have low-grade, low-volume disease and can safely be monitored over time. The other part of the equation is sustainability—that is, how willing is the patient to have regular follow-ups to make sure the cancer hasn’t changed?

One feature of prostate cancer, particularly low-risk disease, is that it is not imminently deadly, so patients and physicians have time for shared treatment decision-making discussions and can plan on next steps and change course when warranted.

Developing More Effective Prognostic Tools

Are there new prognostic tools on the way that may accurately predict the true biologic behavior of prostate cancer?

Dr. Chapin: Aside from magnetic resonance imaging (MRI), which is becoming the standard of care in many active surveillance protocols, there are genomic tests available. Tumor biopsy tissue analyses with the Oncotype DX, Prolaris, and Decipher tests constitute a first step toward that goal, but in my opinion this iteration isn’t the answer.

The ideal situation is to be able to more accurately identify patients with a low risk of disease progression for active surveillance and patients with higher-grade tumors, looking at which tumor types are more likely to respond to specific therapies in a more personalized approach to their care. For example, some tumors may be more suited to surgical removal vs radiation therapy, and some may be more suited to androgen-deprivation therapy vs chemotherapy.

In Gleason 6 cancer, we need to improve our current evaluation of the disease, and I hope at some point we can move beyond the Gleason score to give us that information. The Gleason score system was developed in the 1960s, and it is still probably the strongest prognostic factor for a patient’s outcome over everything else we currently have.

Whether to undergo active surveillance or treatment is an individual choice and depends on the patient’s comfort level with whichever decision he makes.

— Jonathan I. Epstein, MD

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Dr. Epstein: The best tool we currently have other than pathology is the multiparametric MRI, which is not perfect, but it relatively selectively identifies higher-grade cancer. Molecular tests, including PTEN/ERG, are unproven in predicting the risk of prostate cancer progression in the active surveillance population, and that throws into question their utility in the treatment paradigm.

In terms of using serum or urine markers to monitor prostate cancer, there is also nothing that is considered standard of care. However, the tools we have now are pretty precise, with between 85% to 90% accuracy. It’s unlikely we will ever get to 100% accuracy because of the sampling issue.

Dr. Hussain: Based on the significant progress to date, I am optimistic that the molecular tests will get even better in the future, and coupled with smarter imaging technologies, they will help to better and more accurately assess the extent and the potential biology of the cancer at an individual patient level. Hopefully, that will allow us to minimize the burdens of imaging and biopsies on patients.

Right now, PSA screening is the key test for early detection, and the question is, can we have a smarter test? We need more research to come up with better potential screening tools that might complement or give us alternatives to the current PSA test.

Age, life expectancy, comorbidities, and risk of disease are all considerations in deciding whether to proceed with monitoring or treatment, and patient preference is a critical factor.

— Maha H.S. Hussain, MD, FACP, FASCO

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Physicians need to counsel their patients about how to balance the risks of monitoring with the risks of treatment and its potential side effects, because there is a lot of stress and uncertainty surrounding these issues for patients. Next to testing, the physician-patient relationship is the most critical element in determining the best course of action for the patient. Shared decision-making between the physician and the patient should include assurance, guidance, and advice from the physician based on the patient’s medical condition, comorbidities, and age, taking into account the patient’s preference for active surveillance or treatment. A second opinion can also help finalize the patient’s decision and validate his plans. ■

DISCLOSURE: Drs. Chapin, Epstein, and Hussain reported no conflicts of interest.

REFERENCES

1. Chen RC, Rumble RB, Loblaw DA, et al: Active surveillance for the management of localized prostate cancer (Cancer Care Ontario Guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement. J Clin Oncol 32:2182-2190, 2016.

2. Cooperberg MR, Broering JM, Carroll PR: Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol 28:1117-1123, 2010.

3. Loeb S, Folkvaljon Y, Curnyn C, et al: Uptake of active surveillance for very low-risk prostate cancer in Sweden. JAMA Oncol 3:1393-1398, 2016.

4. American Cancer Society: Key statistics for prostate cancer. Available at www.cancer.org/cancer/prostate-cancer/about/key-statistics.html. Accessed June 26, 2018.

5. Morash C, Tey R, Agbassi C, et al: Active surveillance for the management of localized prostate cancer. Available at www.cancercareontario.ca/en/guidelines-advice/types-of-cancer/2286. Accessed June 26, 2018.

6. Hamdy FC, Donovan JL, Lane JA, et al: 10-Year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med 375:1415-1424, 2016.