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WHAT ARE THE PARADIGM SHIFTS IN PROSTATE CANCER?

Perinchery Narayan MD

 

Active Surveillance

The first major change that has occurred recently is the shift from radical therapy for all newly diagnosed cancers to Active surveillance or monitoring for many.

At the AUA 2015 meeting, Stacy Loeb MD from New York University told Medscape News "the era of Active Surveillance has arrived". In a study that used 2013 data from the National Prostate Cancer Register of Sweden, Dr. Loeb and her colleagues found a significant increase in the use of Active Surveillance as primary management for 70% of very-low-risk and 47% of low-risk prostate cancer patients.

 

It has been known for decades that many prostate cancers discovered with PSA testing do not pose a threat during a man’s lifetime and are non aggressive. These non-aggressive cancers do not grow and metastasize and therefore, can be monitored - This is  termed "Active Surveillance".

 

Recent studies have shown that 50 to 70% of low grade, low risk cancers discovered by PSA testing will not progress over 10 years of follow up. We are not yet at the point where we can identify with certainty the subtypes among low grade cancers that will not progress. So monitoring is required. By careful monitoring and treatment of only those cancers that progress, many men with prostate cancer can continue to enjoy good quality of life without side effects of treatment.

The American Urology Association Guidelines 2017 for treatment of localized prostate cancer  recommend Active Surveillance as the best available care option for very low-risk localized prostate cancer patients. (Strong Recommendation; Evidence Level: Grade A) and Active Surveillance as the preferable care option for most low-risk localized prostate cancer patients. (Moderate Recommendation; Evidence Level: Grade B)

 

The decision to monitor a cancer can only be made by a man who is   educated about the facts and controversies associated with prostate cancer. He also needs to have  several discussions with a urologist willing to monitor him so that he can get a clear picture of his risks and benefits. Even when cancers increase in grade and volume  in men on Active Surveillance  cure is possible in 95 %  and only 4 to 5% may develop metastatic cancer.

There are several advantages to Active Surveillance.

Men can enjoy life for many years without side effects of therapy. Fifty to 60% may never need treatment. In older patients who have  limited life expectancy due to other illnesses Active Surveillance with palliative treatment may be all that is necessary to keep cancer controlled during their lifetime.  Several  randomised clinical trials have shown that  active monitoring with treatment given only when there is progression of cancer  will confer the same survival benefit at 10  years of follow up ( 99% survival in both) as immediate radical therapy but without the side effects. REFERENCES

 

Side effects of immediate definitive treatment of  prostate cancer that are  severe, permanent and lead to poor quality of life( because they involve sexual dysfunction,bowel dysfunction and incontinence) can be avoided by many men temporarily for many years or permanently if they choose Active Surveillance or some form of partial therapy instead of radical surgery or radiation  

 

Men must also be informed of the downsides of Active Surveillance

 

Trials of Active surveillance have shown that 36 to 57% of men will be upgraded from low grade to higher grade cancer within 2 years after being on surveillance. The number of men whose cancer grows while on Active surveillance  increases to 55% by 15 years. In a recent randomized clinical trial, the ProtecT trial 6.3 % of men on Surveillance developed metastasis despite being monitored closely to prevent  metastases. Progression occurred in 22.9% in men on AS. This was more than double the number compared to men who received immediate treatment. More men on surveillance  also died  of prostate cancer  compared to active treatment although the number was small .

 

 

Men on Active surveillance or any kind of monitoring without treatment have a psychologic burden of anxiety. A third to half of them refuse AS and opt for immediate radical therapy  because of psychologic burden even though they have low grade cancer and are eligible for monitoring. In the ProtecT trial there was a 22.9% progression in the Active surveillance arm during 6 to 10 years of follow up and so treatment was required in these men.Only 44% or less than half of eligible men  actually underwent surveillance  during the study. The number that  remained on active surveillance will   decrease with further follow up as even some  low grade cancers that were misclassified  will grow with time.  If a man is on AS and cancer grows then the  treatment required at the time of progression may be more intense than if he had immediate treatment at the time of diagnosis. The side effects and costs of treatment must be weighed against the benefits of quality of life that can be enjoyed for many years if on Active Surveillance. ASCO WARNING ref

 

 

Partial or focal therapy may not be possible if progression occurs Therefore a decision to monitor should not be taken lightly. Men on active surveillance are committing to an intense surveillance program involving multiple biopsies over several years and  as well as imaging studies. Despite all this Active Surveillance is still a good option for many men.

4K Test to reduce Overdiagnosis and Detect Aggressive Cancer

The 4K test, is a new blood test that accurately identifies risk of aggressive prostate cancer. It has an important significance in deciding whether to proceed with a biopsy if a patient has an abnormal DRE or elevated PSA. It has accuracy in predicting aggressive cancer and predicting metastasis 20 years before it occurs. It also has individual predictive ability so patients can set personal thresholds for themselves along with their care provider based on their age, life expectancy, and health.

In the past, people have used age specific PSA, PSA velocity, and PSA density to improve the specificity of PSA to detect prostate cancer. However, recent studies have suggested that using PSA velocity is not of much benefit. (Review Biomarkers in prostate cancer surveillance and screen: past, present, and future) PSA density requires a rectal ultrasound and is somewhat invasive and still does not provide much more information that PSA alone

The 4K Test combines four prostate-specific kallikrein assay results with clinical information in an algorithm that calculates the individual patient’s percent risk for aggressive prostate cancer. In a prospective, blinded, multicenter US study the 4Kscore Test was shown to have greater accuracy than PSA, PHI and PCA3 in predicting aggressive prostate cancer.  In addition, a major European study has demonstrated the 4Kscore Test predicts the probability of distant metastases within 20 years.

Selective use of PSA, and Shared Decision Making for Screening with PSA

Elevated PSA (prostate specific antigen) is the single most important test that can lead a man to discover if he has prostate cancer. PSA is a protein secreted by prostate cells. A small amount of PSA is normal in the blood of all men because of physiologic cell growth and death. When prostate cells become cancerous, they divide and grow rapidly. There is more cell breakdown, and more of the PSA gets into the blood. An elevated blood level of PSA suggests that the patient may have cancer and needs to be investigated further. Studies have estimated that PSA elevations can precede symptomatic prostate cancer by 5 to 10 years or even longer.

Since the approval of PSA by the FDA in the late 1980s almost a billion PSA tests have been done. Studies have shown that this has resulted in a stage shifting of prostate cancer. Prior to widespread use of PSA most patients were diagnose with late stage prostate cancer. Presently most patients are diagnosed with very early stage prostate cancer. Studies have estimated that there has been a 50% reduction in Prostate Cancer death rates in the last 25 years and 50-70% of this is attributed to widespread use of PSA. One of the downsides of widespread PSA use has been over diagnosis and over treatment of prostate cancer. This has lead to the USPSTF and National Organizations recommending that PSA should be used judiciously and after shared discussion with patients. 

For further details see "Section PSA or no PSA"

Next Paradigm shift is image guided diagnosis with mp MRI

Finally the  era of Personalized Prostate Cancer Care has arrived

There has been a paradigm shift  in the field of  prostate cancer.

A paradigm shift, as  defined by American physicist and philosopher Thomas Kuhn, is a fundamental change in the basic concepts and experimental practices of a scientific discipline. With respect to prostate cancer it is almost as if a “scientific revolution” has occurred in the field with  simultaneous rapid advances in several pathways including  detection, staging, treatment and  followup.

The Good News