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Prostate Cancer

Options for Increasing Prostate-specific Antigen After Radical Prostatectomy

a report by

Per-Anders Abrahamsson

Secretary General, European Association of Urology (EAU)

When prostate-specific antigen (PSA) levels rise to a certain threshold after prostate cancer treatment, i.e. radical prostatectomy or radiation therapy, a patient experiences what is technically known as a `biochemical recurrence'. In other words, when this PSA threshold is reached, it means that prostate cancer has reappeared in some form, either locally in the prostate area or in metastatic form in other tissues and organs. In most cases, the cancer remains at a microscopic level, and many years may pass before any physical evidence is detectable on clinical exam or any abnormalities are seen on a scan. In practical terms, biochemical recurrence means that one is now faced with a chronic disease that will directly affect patient monitoring, and decisions concerning a future treatment strategy will have to be made. Unfortunately, insufficient research data are available to provide clear guidance about when salvage therapy should be considered and which type of second-line therapy is most effective in particular circumstances. How to Define Biochemical Recurrence PSA is manufactured by both normal prostate cells and prostate cancer cells. This is why PSA levels should fall to undetectable levels in men treated with radical prostatectomy, where the prostate is removed. After a prostatectomy, biochemical recurrence is now generally defined as a PSA of 0.2ng/ml following at least two tests. However, some physicians use a higher threshold of 0.4ng/ml or greater to define biochemical recurrence. A Common Challenge Studies indicate that biochemical recurrence affects roughly 15­30% of men initially thought to be curable with localised treatment for prostate cancer. For example, a study published in the Journal of Urology that followed 3,478 men who underwent radical prostatectomy for prostate cancer found that 32% were likely to suffer from biochemical recurrence within 10 years. Another study, published in the Journal of the American Medical Association, tracked 1,997 men who had undergone radical prostatectomy, for an average period of a little over five years, and found that 15% experienced biochemical recurrence within that time. It is important to note, however, that both studies selected the most favourable patients as part of their screening studies. The percentage of patients who experienced biochemical recurrence would likely have been higher if less stringent patient selection criteria had been used. The main message, however, remains unchanged: a rising PSA after initial treatment for prostate cancer is something that many men will have to deal with. Assessing the Risk on a Personal Basis Several factors contribute to a personalised risk profile. One important factor is whether a patient is found to have localised or more advanced disease at the time of biochemical recurrence. As indicated in Table 1, pre-treatment `numbers' such as Gleason score and pathological cancer

stage will provide some indication of whether the recurrence is local or metastatic. Also important is the rate of PSA increase before diagnosis (known as PSA velocity) and the time it takes for PSA to double in value following treatment, known as PSA doubling time. Similarly, posttreatment PSA doubling time may also be used to assess the likelihood that disease is local or metastatic and provide an insight into prognosis. When post-treatment PSA doubles in less than six months, for example, and certainly when it doubles within three months, it is likely that the cancer has spread and therefore requires systemic treatment. Research has also shown that the length of time it takes PSA to double can be used to estimate the likelihood of whether disease will become clinically evident as local or metastatic following biochemical recurrence. Knowing Whether and When to Act Following radical prostatectomy, if PSA indicates that biochemical recurrence has occurred, the chief concern is to determine whether to consider treatment. If the decision to treat is affirmative, what to do and when must be considered. Unfortunately, no professional agreement currently exists about when salvage treatment for recurrent prostate cancer should begin, or which salvage treatments are best. Of course, if the cancer appears aggressive ­ as indicated by the pre-treatment numbers (see Table 1) or if PSA has doubled in less than six months ­ immediate treatment seems to be the most likely recommendation, probably with hormone therapy to prevent or delay metastasis. However, a large group of patients will find themselves in a grey area, with clinical profiles and PSA doubling times that are not sufficient to trigger immediate salvage therapy. For this category, one may opt to defer treatment until PSA levels rise to a particular level. This means that more frequent PSA testing is to be initiated to monitor progression. Although many men diagnosed with biochemical recurrence will want to take immediate action to stop the cancer, going ahead with therapy for the sake of doing something may cause more harm than good. The risks and complications of salvage surgery or radiation, already high when

Per-Anders Abrahamsson is Secretary General of the European Association of Urology (EAU). He is also a Professor of Urology at Lund University, Chairman of the Department of Urology at Malmö University Hospital in Sweden and an Adjunct Professor in the Department of Urology at the University of Rochester Medical Center in Rochester, New York. Previously, he was Chairman of the Department of Urology at Lund University Hospital. Professor Abrahamsson is the author of 275 scientific publications, including book chapters and books, and is a member of the Editorial Boards of several scientific journals. He has been the main organiser of several international conferences, is a frequently invited speaker at scientific meetings and has received a number of national and international awards. Professor Abrahamsson received his MD and PhD from Lund University. E: [email protected]

© TOUCH BRIEFINGS 2007

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Prostate Cancer

Options for Men Who Have Undergone Surgery First of all, the cancer is to be restaged to determine what the likelihood

Although a number of clinical factors contribute to the risk of relapse after treatment, the parameters below provide a simple assessment of what the chances of biochemical recurrence are, based on clinical profile at the time of diagnosis. Low risk (33% chance of biochemical recurrence Gleason score 6 within 5 years) and PSA <10ng/ml and cancer stage T1c or T2a Intermediate risk (50% chance of biochemical Gleason score >6 relapse within 5 years) and/or PSA 10­20ng/ml and/or cancer stage T2b High risk (85% chance of biochemical relapse Gleason score 8 within 5 years) and/or PSA >20ng/ml and/or cancer stage T2c or more

Table 1: Predictors of Biochemical Recurrence at Time of Diagnosis

is that it is localised or metastatic. However, a second important clue is provided by how long after the initial treatment it took for the PSA to rise and how quickly it rose. Generally speaking, the prognosis is worse for men whose PSA never becomes undetectable after surgery, or whose PSA rises quickly after treatment. Prognosis is better for men whose PSA rises slowly a long time after treatment. A few scenarios will help show what the options are in each situation. Salvage Options After Radical Prostatectomy Most men who experience biochemical recurrence after prostatectomy and decide to undergo treatment have three options. The best strategy depends on the risk profile and a patient's comfort with side effects. Radiation Therapy Many men opt to undergo salvage radiation therapy, delivered either as external beam radiation or as brachytherapy. This may be enough to eradicate the disease in the small group of men who have a capsular incision, but for most men radiation therapy extends life but does not cure the disease. However, there are side effects to this treatment. Radiation therapy delivered after prostatectomy markedly increases the likelihood of impotence and incontinence. If a patient is already incontinent after surgery, subjecting him to radiation therapy is likely to make the problem permanent. For this reason, most men who become incontinent after surgery will wait until they regain control over their bladder or rectum before undergoing post-operative radiation therapy. Additionally, external beam radiation therapy carries an increased risk of developing rectal cancer. Radiation with Hormonal Therapy Another option is hormone therapy, or combining a short course of hormonal therapy with salvage radiation therapy.The latter option should contribute to the effectiveness of the radiation therapy. Hormonal Therapy

Table 2: Prostate-specific Antigen Velocity Before Diagnosis and Estimated Chances of Survival

An analysis of PSA velocity in the year preceding diagnosis reveals that it can predict the likelihood of survival seven years after external beam radiation therapy. Similar findings have been reported based on an analysis of men who underwent radical prostatectomy. Overall risk profile Chances of survival at Chances of survival at (based on PSA, seven years if PSA velocity seven years if PSA velocity Gleason score, 2ng/ml in the year >2ng/ml in the year cancer stage) preceding diagnosis preceding diagnosis Low risk 100% 81% High risk 96% 76%

*Source: Journal of the American Medical Association, July 2005.

Table 3: Using Prostate-specific Antigen Doubling Time to Estimate Likelihood of Outcomes Five Years After Biochemical Recurrence 1

PSA doubling time Percentage of men who showed no clinical signs of prostate cancer, in spite of biochemical recurrence* 38% 46% 62% 87% Percentage of men who showed no clinical evidence of metastatic disease, in spite of biochemical recurrence** 64% 93% 95% 99%

If the PSA doubling time is less than six months, indicating that the cancer is aggressive, radiation therapy may not be adequate as it is likely that the cancer has already spread. In such cases, a better option is hormone therapy, which can delay the time of onset to bone metastasis. However, this is where other considerations also come into play. If the patient is sexually active and wishes to remain so, hormone therapy may not be the most appropriate option. The alternative would be `erectile-sparing hormone therapy', which involves a single agent such as bicalutamide. Another option is to go on intermittent hormone therapy, allowing men to recover some quality of life while at the same time cutting off testosterone. Cryotherapy

< 6 months 6­11 months 12 months ­ 9 years, 11 months 10 years

* No clinical indication of local or systemic disease, based on digital rectal examination, transrectal ultrasonography, biopsy or bone scan. ** No clinical indication of metastasis, based on bone scan. 1: Source: Mayo Clinical Proceedings, June 2001.

delivered after the initial diagnosis of prostate cancer, may become even more significant when these therapies are delivered as salvage treatment after biochemical recurrence. Data are sparse on side effects caused by salvage therapy, simply because not that many studies have been preformed on the topic. For example, some research indicates that the likelihood of developing urinary incontinence is greater after salvage prostatectomy (where it may affect 20­60% of men) than when this operation is chosen as the first mode of treatment (where it may affect anywhere from 2 to 15% of men). It is also important to remember that average survival times are based on studies of men treated in the past, sometimes as long as 10 or 20 years ago.

Another option, also appropriate only when a localised area of cancer is found, is cryotherapy. This freezes the prostate gland to kill any remaining cancer cells. Conclusions Overall, when it comes to a personalised treatment plan for patients diagnosed with biochemical recurrence after initial treatment for prostate cancer, there are numerous factors coming into play. Besides directly medical considerations, many of which still lack sufficiently conclusive data to provide clear guidance for clinicians, quality of life issues are another aspect the doctors will have to consider.

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EUROPEAN GENITO-URINARY DISEASE 2007

23rd Annual EAU Congress

www.eaumilan2008.org

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