Getting up at night to urinate   Leave a comment

Recently I visited with a patient complaining about the frequency with which he had to get up at night to go to the bathroom. The medical term for this is ‘nocturia’ derived from the latin word nox=night. While it is pretty normal for any person, man or woman, to have to get up once at night to urinate, having to do this three or more times can have a significant impact on one’s lifestyle. First there is the issue of not getting enough sleep, second, there is the issue of waking up ones partner: waking up, turning on the light, getting up, flushing the toilet, coming back to bed etc will do it. When a doctor visits with a patient about this, there are many factors to consider: when do you go to bed, when do you wake up, what time is dinner, how much fluid do you drink with dinner, and between dinner and bedtime etc.

For today I want to focus just on this fluid intake issue. Some men may drink several glasses of water or tea with dinner, or a beer or two, or one or more glasses of wine. Then, after dinner, they watch the news, read a paper or a book or pursue some other activities, during which time they drink more fluid. Lastly, there are some tablets to be taken at bedtime, requiring even more fluid. Let’s say all of this amounts to 20-30 ounces or 600-900 ml of fluid. It will take less than one hour for that fluid to be taken up from the stomach into the bloodstream, and then some time for the kidneys to filter it and convert it into urine. The urine then gets into the bladder and after a while, when the bladder has 300-500 ml in it, there will be an urge to go to the bathroom. While we lose some fluid through our skin and by sweating, in an air conditioned home this is not all that much. So most the fluid we drink will come out with the urine sooner or later. In some cases, right in the middle of your best sleep! Here is the morale of this: if you get up within a couple of hours of going to bed, think about your fluid intake between dinner and bedtime. Perhaps cutting back a bit, reducing everything you drink by 50 percent, having half a glass of tea, only one glass instead of two, that alone may reduce your nightly trips to the bathroom from three to two or even less, and you might just wake up better rested.

Posted May 12, 2012 by Claus Roehrborn in Prostate Diseases

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Radiation Therapy for Prostate Cancer: What Shall it Be?   Leave a comment

One of the most common questions I get during a discussion of treatment options for localized prostate cancer is about proton therapy when the conversation turns towards radiation therapy in general. This is not a great surprise, since a Google search for proton therapy for prostate cancer yields about twice as many hits as one for IMRT (Intensity Modulated Radiation Therapy) or conformal radiation therapy. This is quite in contrast to a search of the US National Library of Medicine (www.pubmed.org) where a similar search yields over 800 scientific citations and articles for IMRT and just over 300 for proton therapy.

On the MD Anderson website one can learn about the differences between conventional versus proton therapy (http://www.mdanderson.org/patient-and-cancer-information/proton-therapy-center/what-is-proton-therapy/index.html):

Conventional radiation therapy has evolved and improved over the years and, if given in sufficient doses, will control many cancers. However, because X-ray beams are composed of primary photons and secondary electrons, they deposit their energy along the path of the beam, to the targeted tumor and beyond, thereby delivering radiation to healthy tissues before and after the tumor site.

The advantage of proton treatment is that a physician can predict and control where the proton releases the bulk of its cancer-fighting energy. As the protons move through the body, they slow down and interact with electrons, and release energy. The point where the highest energy release occurs is the “Bragg peak.” A physician can designate the Bragg peak’s location, causing the most damage to the targeted tumor cells. A proton beam conforms to the shape of a tumor with greater precision while sparing healthy tissues and organs

However, while there are theoretical advantages to proton beam therapy from a radiation physics standpoint, no study yet has demonstrated its superiority to modern photon-based therapy in terms of either oncologic or quality of life outcomes, and at this time, there are no randomized studies to test this hypothesis (Aaronson, Odisho et al. 2012). A recent study suggests that patients may in fact be willing to participate in such randomized trials in which they would be allocated to one or the other form of radiation by a coin toss method (Shah, Efstathiou et al. 2012).

The American Society of Radiation Oncology (ASTRO) published an evidence based review of proton beam therapy through its emerging technology committee and summarized the state of the evidence as follows: “Proton beam therapy (PBT) is a novel method for treating malignant disease with radiotherapy. The purpose of this work was to evaluate the state of the science of PBT and arrive at a recommendation for the use of PBT. The emerging technology committee of the American Society of Radiation Oncology (ASTRO) routinely evaluates new modalities in radiotherapy and assesses the published evidence to determine recommendations for the society as a whole. In 2007, a Proton Task Force was assembled to evaluate the state of the art of PBT. This report reflects evidence collected up to November 2009. Data was reviewed for PBT in central nervous system tumors, gastrointestinal malignancies, lung, head and neck, prostate, and pediatric tumors. Current data do not provide sufficient evidence to recommend PBT in lung cancer, head and neck cancer, GI malignancies, and pediatric non-CNS malignancies. In hepatocellular carcinoma and prostate cancer there is evidence for the efficacy of PBT but no suggestion that it is superior to photon based approaches. In pediatric CNS malignancies PBT appears superior to photon approaches but more data is needed. In large ocular melanomas and chordomas, we believe that there is evidence for a benefit of PBT over photon approaches. PBT is an important new technology in radiotherapy. Current evidence provides a limited indication for PBT. More robust prospective clinical trials are needed to determine the appropriate clinical setting for PBT” (Sheets, Goldin et al. 2012)

In this context it is interesting to review a study published in this week’s Journal of the American Medical Association (JAMA), the abstract of which is reproduced below (Sheets, Goldin et al. 2012):

Intensity-Modulated Radiation Therapy, Proton Therapy, or Conformal Radiation Therapy and Morbidity and Disease Control in Localized Prostate Cancer

  1. Yang Wu, PhD;
  2. Til Stürmer, MD, PhD;
  3. Paul A. Godley, MD, PhD;
  4. Ronald C. Chen, MD, MPH

[+] Author Affiliations

  1. Author Affiliations: Department of Radiation Oncology (Drs Sheets, Goldin, and Chen and Mr Holmes), Cecil G. Sheps Center for Health Services Research (Drs Meyer, Godley, Carpenter, and Chen), School of Medicine (Mr Holmes), Lineberger Comprehensive Cancer Center (Drs Meyer, Wu, Reeve, Godley, Carpenter, and Chen), School of Nursing (Dr Chang), Department of Epidemiology (Dr Stürmer), Department of Health Policy and Management, School of Public Health (Drs Reeve and Carpenter), University of North Carolina at Chapel Hill.

Abstract

Context There has been rapid adoption of newer radiation treatments such as intensity-modulated radiation therapy (IMRT) and proton therapy despite greater cost and limited demonstrated benefit compared with previous technologies.

Objective To determine the comparative morbidity and disease control of IMRT, proton therapy, and conformal radiation therapy for primary prostate cancer treatment.

Design, Setting, and Patients Population-based study using Surveillance, Epidemiology, and End Results–Medicare-linked data from 2000 through 2009 for patients with nonmetastatic prostate cancer.

Main Outcome Measures Rates of gastrointestinal and urinary morbidity, erectile dysfunction, hip fractures, and additional cancer therapy.

Results Use of IMRT vs conformal radiation therapy increased from 0.15% in 2000 to 95.9% in 2008. In propensity score–adjusted analyses (N = 12 976), men who received IMRT vs conformal radiation therapy were less likely to receive a diagnosis of gastrointestinal morbidities (absolute risk, 13.4 vs 14.7 per 100 person-years; relative risk [RR], 0.91; 95% CI, 0.86-0.96) and hip fractures (absolute risk, 0.8 vs 1.0 per 100 person-years; RR, 0.78; 95% CI, 0.65-0.93) but more likely to receive a diagnosis of erectile dysfunction (absolute risk, 5.9 vs 5.3 per 100 person-years; RR, 1.12; 95% CI, 1.03-1.20). Intensity-modulated radiation therapy patients were less likely to receive additional cancer therapy (absolute risk, 2.5 vs 3.1 per 100 person-years; RR, 0.81; 95% CI, 0.73-0.89). In a propensity score–matched comparison between IMRT and proton therapy (n = 1368), IMRT patients had a lower rate of gastrointestinal morbidity (absolute risk, 12.2 vs 17.8 per 100 person-years; RR, 0.66; 95% CI, 0.55-0.79). There were no significant differences in rates of other morbidities or additional therapies between IMRT and proton therapy.

Conclusions Among patients with nonmetastatic prostate cancer, the use of IMRT compared with conformal radiation therapy was associated with less gastrointestinal morbidity and fewer hip fractures but more erectile dysfunction; IMRT compared with proton therapy was associated with less gastrointestinal morbidity.

Because there is no randomized study on this topic, perhaps we can learn about the relative efficacy and safety of the different forms of radiation from this type of research, called comparative effectiveness research. Since its creation in 1989, the Agency for Healthcare Research and Quality (AHRQ) of the US Government has spearheaded efforts to boost the quality of health care in the United States, including funding research on the comparative effectiveness of interventions. Part of the reason for this effort is the observation that a randomized trial might take a decade to develop, enroll, conduct and eventually analyze, while there may be data on the safety and efficacy of interventions available already that could be analyzed and provide at least some partial answer right now.

To this end the authors used the so called SEER database of Medicare aged patients living in specific geographic regions of the country and representing some 28% of the population (http://seer.cancer.gov/). To be clear, the patients in this study – together with their doctors – chose to have either IMRT or conformal or proton therapy, they were not randomized to either treatment, and thus, several selection biases limit our ability to generalize the findings. For example, one might assume that younger patients more often do their own research on the web and find out about proton therapy, or one might assume that patients may choose one or the other treatment simply because of proximity to where they live, a hypothesis which in fact is verified in a study by Aaronson et al (Aaronson, Odisho et al. 2012). Furthermore, when patients required additional treatment for either complication or recurrent cancer, this may not always be captured in the SEER database, as they patient may receive such treatment outside a facility that reports to SEER.

The authors corrected by propensity matching for some of these differences in the groups and biases and then looked for those outcomes that are really of interest: rates of gastrointestinal and urinary tract morbidity, problems with erections and potency, hip fractures which may be the result of the radiation, and the need for additional cancer therapy. Their findings were somewhat surprising. There was no significant difference in proton therapy– vs. IMRT treated patients in urinary incontinence diagnoses or procedures, erectile dysfunction, or hip fractures. Proton therapy– treated patients were more likely to receive a diagnosis of gastrointestinal morbidity and undergo gastrointestinal procedures. Rates of additional cancer therapy were no different between the 2 groups, suggesting that cancer control was similar.

Incidentally, the patients receiving the older conformal radiation therapy, more often had to have additional cancer treatments compared to IMRT, and that difference was statistically significant:

So what are you to make of these data, imperfect as they may be? If you choose radiation therapy as treatment for your prostate cancer, it seems you can safely choose IMRT treatment expecting the best tradeoff between efficacy (better than conformal) and safety (better than proton in terms of gastrointestinal morbidity, 12.2% vs. 17.8%).

There are other advantages: in most communities an IMRT center will be relatively close to where you live, and you don’t have to travel and/or check into a hotel for the two months of treatment. Plus, you are saving the US healthcare and your insurance a significant amount of money, since proton therapy is significantly more costly than photon based IMRT.

References

Aaronson, D. S., A. Y. Odisho, et al. (2012). “Proton beam therapy and treatment for localized prostate cancer: if you build it, they will come.” Arch Intern Med
172(3): 280-283.

Shah, A., J. A. Efstathiou, et al. (2012). “Prospective preference assessment of patients’ willingness to participate in a randomized controlled trial of intensity-modulated radiotherapy versus proton therapy for localized prostate cancer.” Int J Radiat Oncol Biol Phys
83(1): e13-19.

Sheets, N. C., G. H. Goldin, et al. (2012). “Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer.” JAMA
307(15): 1611-1620.

Continence and Potency after Prostatectomy   Leave a comment

Are you a Mac or a PC person? Do you prefer the graphic capabilities of the Mac, the sometimes easier access to certain software with the PC? Is speed more important than storage? Weight more important than a built in CD Rom drive? If you have pretty clear ideas what is important to you, then you can create a table with all the characteristics which are important in decision making, fill in the boxes with ‘+’ and ‘-’ or with a rating system, then add everything up, and the decision is made and you can head out to buy the best computer for yourself.

Now let’s say you are discussing restaurant food. Are you a fish or a steak person? There are many characteristics of these food items upon which you may base your decision when you eat out: flavor, consistency, nutritional value, health benefit vs risks, price and others. So you can add all those up and make a decision for yourself what to eat tonight, and then you can head out to … but wait: what restaurant? Did we forget something even more important than the calories or how much fat is in the meal? Did we forget who cooks the meal? Are there perhaps differences in the quality of the steak from restaurant to restaurant, and even if the quality is the same, perhaps in the way the steak is prepared? Does that not influence your decision where to eat quite a bit? Probably so.

Recently a group of researchers published a paper in the Journal of Clinical Oncology about the adverse effects on continence, meaning urine control, and sexual function. The abstract of the paper is reproduced below.

Adverse Effects of Robotic-Assisted Laparoscopic Versus Open Retropubic Radical Prostatectomy Among a Nationwide Random Sample of Medicare-Age Men

Michael J. Barry, Patricia M. Gallagher, Jonathan S. Skinner, and Floyd J. Fowler Jr

 Purpose

Robotic-assisted laparoscopic radical prostatectomy is eclipsing open radical prostatectomy among men with clinically localized prostate cancer. The objective of this study was to compare  the risks of problems with continence and sexual function following these procedures among Medicare-age men.

Patients and Methods

A population-based random sample was drawn from the 20% Medicare claims files for August 1, 2008, through December 31, 2008. Participants had hospital and physician claims for radical prostatectomy and diagnostic codes for prostate cancer and reported undergoing either a robotic or open surgery. They received a mail survey that included self-ratings of problems with continence and sexual function a median of 14 months postoperatively.

Results

Completed surveys were obtained from 685 (86%) of 797 eligible participants, and 406 and 220 patients reported having had robotic or open surgery, respectively. Overall, 189 (31.1%; 95% CI, 27.5% to 34.8%) of 607 men reported having a moderate or big problem with continence, and 522 (88.0%; 95% CI, 85.4% to 90.6%) of 593 men reported having a moderate or big problem with sexual function. In logistic regression models predicting the log odds of a moderate or big problem with postoperative continence and adjusting for age and educational level, robotic prostatectomy was associated with a nonsignificant trend toward greater problems with continence (odds ratio [OR] 1.41; 95% CI, 0.97 to 2.05). Robotic prostatectomy was not associated with greater problems with sexual function (OR, 0.87; 95% CI, 0.51 to 1.49).

Conclusion

Risks of problems with continence and sexual function are high after both procedures. Medicare age men should not expect fewer adverse effects following robotic prostatectomy.

J Clin Oncol 30:513-518. © 2012 by American Society of Clinical Oncology

The questions that were asked were as follows:  “Since this prostate surgery,how muchof a problem have you had with leaking or dripping urine?” and “Since this prostate surgery, how much of a problem  have you had with sexual functioning, such as problems with erections?”  Possible responses were “No problem,” “A very small problem,” “A small problem,” “A moderate problem,” and “A big problem.” . Then they tabulated the responses to these questions by the type of surgery the patients had, either open or robotic:

As can be seen, after both types of procedures a similar proportion of men have a moderate or big probleml with continence as well as a moderate or big problem with sexual function. The authors admit that they did not have any information on the status of the patients regarding continence or sexual function before the surgery:

The main weakness inherent in our study design is that we could not obtain preoperative data on patients’ health status, continence, or sexual function. 

While it probably is safe to assume that most of these men considered themselves to have good continence before the surgery, ie having no or little urine leakage, the question of sexual function is more important. All men were at least Medicare age, ie 65 years or older. Sixty percent of the patients in both groups were over the age of 70 years, about 15% were 75 or older. What do we know about sexual function in men in their 70s?

From the Massachusetts Male Aging Study (Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994. Vol 151, page 54) we know that in a sample of over 1,700 men in New England only 37% of those 65 and older had no degree of impotence, ie impaired sexual function, and  only 33% of those 70 years and older. And, 40-50% admit to having  a moderate or big problem with sexual function. Unfortunately, there is no way to sort out in the current study who had already problems with sexual function before the operation and who did not.

The bigger issue however, getting back to my initial question, is: If you have cancer, what are you going to have: open surgery or robotic? Is this a Mac vs PC or fish vs steak type question? The surgery does not come from an assemply line with quality control, assuring that one PC looks and works like the next. Rather the surgery is done by a surgeon, and, like the fish vs steak question, there are differences in experience that may make a big difference in outcomes. The authors admit that

Our results may reflect a long national learning curve to achieve optimal outcomes with RALRP, which has been introduced into clinical practice relatively recently. We did not have data on the procedure volumes of the respondents’ surgeons in this study. Patients of   surgeons who have more experience with either procedure than the average surgeon may have lower risks of adverse effects, although patients of surgeons with less experience than the average surgeon may have greater risks.

Many studies have shown that it takes literally hundreds of procedures to be really good at the procedure and achieve good outcomes time after time, which is true for both types of procedures.  A study published in the New England Journal of Medicine in 2002 suggests that of 1,000 urologic surgeons in the US,  25% perform 1 to 4, 25% 5 to 9,  25% 10 to 15, and only 25% 16 to 58 prostatectomy procedures per year. This would suggest that 75% or 3/4 of all surgeons do not have sufficient volumes to achieve the learning curve in a reasonable time (Begg, Riedel et al: Variations in morbidity after radical prostatectomy, NEJM 2002, Vol346, pages 1138-44).

As a consequence there are several important caveats with the current study:

  • elderly patients with a mean age over 70 yrs (in my series of robotic prostatectomies the mean age is 63 and less than 10% are older than 70 yrs) lead to worse outcomes
  • no information about the continence and sexual function status prior to the procedure limits the strength of the conclusions
  • no information about the numerical experience of the surgeon limits the ability to apply the findings to individual surgeons with a known experience

What should you do when facing  the diagnosis of prostate cancer requiring treatment? By all means, make a table, list the advantages and disadvantages, make a priority list for yourself etc. And, when the answer is ‘steak’, then ask questions, listen to your friends, neighbors and colleagues, and find the best ‘steak house’ …

Claus G. Roehrborn, MD  

 

The PSA Puzzle   Leave a comment

The PSA Puzzle

In this blog we will review some of the recent controversies surrounding the use of prostate specific antigen or PSA testing, specifically in the setting of screening for prostate cancer, but also other uses of PSA in men’s health. You can click on the slides to see them larger as you go, or review the slide show at the end of the blog.

Prostate cancer makes up 29% or about one-third of all cancers in men and accounts for 9% or about 29,000 cases of all cancer-related deaths in the United States in 2012 (Siegel, Naishadham et al. 2012) Like other cancers, for example, lung and bronchial cancer, prostate cancer death rates have decreased in recent years and ironically, this decrease started a few years after the introduction of PSA-based screening in the late 1980s. In fact, between the years 1994 and 2008, the decrease in the death rate due to prostate cancer was 3.7%, and this is the largest numerical decrease of any cancer death rate including lung and breast cancer in women.

Very recently, the US Preventive Services Task Force (USPSTF) recommended against prostate specific antigen-based screening for prostate cancer and gave this recommendation a grade D (Chou, Croswell et al. 2011).  A grade D recommendation indicates moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. The US Preventive Service Task Force consists of 16 physicians, pediatricians, family physicians, geriatricians, epidemiologists, and statisticians, public health officials, obstetricians,nursing personnel, and others, while there is at the moment no medical or radiation oncologists and no urologists on its panel.

Let’s focus for a moment on the prostate. The prostate gland is situated between the bladder and the pelvic floor and through it runs the urethra transporting urine to the outside and on occasion also seminal fluid… Thus, the prostate is located at the point where the urinary tract (the kidney, ureter, bladder and urethra) meet with the genital tract consisting of penis, prostate, and the testicles in the scrotal sac.

PSA or prostate specific antigen is an enzyme produced in the glandular epithelial cells of the prostate and only there. It is specific to the prostate, but not specific to any particular prostate disease. Every man has a measureable level of PSA as long as he has a prostate; the only exception being a man who had a total prostatectomy and those who are surgically or medically castrated. Normal prostates in younger men produce a very low level of PSA. In benign prostatic hyperplasia (BPH), the PSA increases with age and with the size of the gland. There are certain inflammatory diseases of the prostate known as prostatitis and while rare, these can lead to a temporary increase in PSA. Pre-cancerous lesions in the prostate such as high-grade prostate intraepithelial neoplasia or high-grade PIN, atypia or dysplasia can cause a moderate elevation of PSA as well. The most common cause of PSA elevation however, is prostate cancer and the higher the PSA, the greater is the risk for cancer. There is however, no totally safe range.

Data from the well-known prostate cancer prevention trial (PCPT) demonstrate this very well (Thompson, Goodman et al. 2003; Etzioni, Howlader et al. 2005; Thompson, Ankerst et al. 2006; Thompson, Tangen et al. 2008; Thompson, Tangen et al. 2009). The risk of prostate cancer increases with increasing PSA and so does the risk of high-grade disease, meaning a cancer with a score of 7 or above by the Gleason grading method. However, even with a PSA of less than 1 the risk of prostate cancer is still 10%. It increases to 30 to 40% with the PSA being 4.

What is PSA testing used for? We can use it to screen for prostate diseases in a distinct population; for example, all men over 50 or all men in Dallas County or all men with a family history of prostate cancer. We also use it to diagnose or find diseases in men presenting to health care providers with symptoms or problems of the lower urinary tract, such as pain, voiding or urination problems, and other symptoms. We also use it to monitor diseases of the prostate during and after treatment or to verify the absence of the disease; i.e. an undetectable PSA after a total prostatectomy. Let’s look for a moment at the history of screening for prostate cancer.

In the middle of beautiful Austria surrounded by the Alps, is the province of Tirol and in the middle of it is located the city of Innsbruck. In this city, Dr Georg Bartsch conducted a screening study in which he screened about 85% of all men over the age of 45 over a period of 10 to 15 years (Bartsch, Horninger et al. 2008). During this time period the detection rate for prostate cancer virtually skyrocketed above and beyond what the normal incidence rate is; however, during this time period the mortality due to prostate cancer also decreased in Tirol (white circles) more so than in the rest of Austria (black circles). In this study, where there was no control group, screening resulted in a reduction in mortality compared to the rest of the Austria population.

In the United States, a very large trial (Prostate, Lung, Colorectal and Ovarian=PLCO trial) was conducted from 1993 to 2001 in which nearly 80,000 men at 10 USA study centers were randomized to either be screened or to receive usual care. Men in the screening group were offered an annual PSA for 6 years and digital rectal examination for 4 years (Andriole, Crawford et al. 2009) The result of the PSA was made available to the subject’s health care providers who then decided on the biopsy and/or subsequent treatment. While there was an increase in the detection rate of prostate cancer (black line) over the control group (red line) at the top panel of the slide, there was no difference in death due to prostate cancer over a 10 year period (bottom of the panel). Amongst other pieces of evidence this trial and its conclusions led the US Preventive Services Task Force to recommend against prostate specific antigen-based screening using a grade D recommendation.

What are screening studies? In typical screening studies such as the PLCO, one-half of all participants are allocated to receive an annual PSA testing and biopsies and treatment if indicated by the results. The other half is allocated to not have an annual PSA at all for the duration of the study except if they have an abnormal digital finder examination or symptoms, in which case they would be tested, biopsied and treated. The end point is the death from prostate cancer.

The hypothesis is straightforward. If the PSA elevation indicates prostate cancer, a TRUS biopsy will find the cancer if it is there; if the cancer is found, the patient will have treatment; if the treatment is effective in curing the cancer, then patients diagnosed with elevated PSA and a cancer on biopsy will less likely die from prostate cancer over the course of the study compared to those who are not screened with PSA.

Let’s transfer this to some more practical setting. Let’s say we have another hypothesis. Our hypothesis is that better sleep leads to greater productivity. We know that certain mattresses allow for better and deeper sleep and a deeper sleep causes a person to be better rested, a better rested person will be more productive and this translates into greater efficiency and thus, a better financial bottom line of the factory.

So, we allocate one-half of all workers to sleep on a new mattress that we specifically buy for them. To the other half of the workers we say, please sleep on your old mattress, don’t buy a new mattress and don’t change it. After a certain number of years we measure the productivity and the financial bottom line comparing the two groups of workers.

In the PLCO trial, the allocation was done in a similar way, except that of the patients who were told “we will screen you every year”, 15% did not have that screening, but only 85% were compliant with the screening or attended the screening. 15% had nonattendance with the screening protocol. In the control group, 40 to 50% actually had a PSA testing even when we told them not to have a PSA testing done at all (contamination)!

So, the patients did not follow the rules of the study very well at all. What might our factory workers do? Let’s assume the same number, to 38,000 factory workers we give the new mattresses, but 15% say: we did not like it, and we did not use it (nonattendance). We give 38,000 workers instructions to use their old mattress and not to buy any new mattress, but 45% or so bought a new mattress anyway (contamination). At the end of the study, more workers who slept on a new mattress said they felt they actually slept better (more patients in the screening group were diagnosed with cancer), but there was no demonstrable difference in productivity measures between the two groups.

On the left-hand side, we have the old mattress group. Of 38,000 total, 17,000 or 45% bought themselves the new mattress. On the right-hand side, we have the new mattress group. Of those workers, 6,000 did not use the new mattress, they used the old mattress. How does this answer our question?

You may say to yourself: why don’t we compare the workers who actually did sleep on the old mattress, the 21,000 we told to do so and the 6,000 who did it anyway even though they had a new mattress, and then compare them with those workers who slept on the new mattress, the 32,000 of the group we gave the new mattress and the 17,000 of the group that we told to sleep on the old mattress who got themselves the new one despite of that. Now, we compare 27,000 old mattress users with 49,000 new mattress users, but at least we compare groups who slept on the old versus the new mattress.

This logical suggestion for a different analysis of the data, however, cannot be made. This analysis would be an analysis per protocol, i.e. analyzing by what the workers actually did and not what they were told to do. The analysis has to be done as an intention to treat, i.e.: you were told to sleep on the old mattress and whatever you actually did, this is how we analyze the data. You are an old mattress user and you did not like the new mattress? Too bad! We analyze you as a new mattress user even if you did use the old mattress. This is how the PLCO study was analyzed, by intention to treat rather than by what the patients did.

Did we answer our question? What do you think? Is the answer to buy everybody a new mattress, no new mattress for anybody? Did this study answer the question regarding the connection between new mattress use, quality of sleep and productivity, or, did the PLCO study answer our question regarding the connection between PSA testing and cancer diagnosis and mortality?  At least there are considerable questions that the study brings up in terms of non-attendance with PSA based screening, and contamination in those randomized not to be screened.

In the city of Goteborg in Sweden a 20,000 patients screening study was done under slightly different conditions (Hugosson, Carlsson et al. 2010); in this study there was less contamination due to the fact that PSA based testing ‘on the side’ is not readily available. In the screening group (red line) more men were diagnosed with prostate cancer than in control group (blue line). Since in Sweden there is not much PSA screening outside of the study and very little contamination, the result of the per protocol versus intention to treat analyses are quite similar. In the screening group, the death rate due to prostate cancer is statistically significantly lower by more than 40%. Two hundred and ninety-three men needed to be invited for screening, and twelve needed to be diagnosed with prostate cancer to prevent one prostate cancer death. But, it was a statistically significant reduction in death from prostate cancer.

Fritz Schroeder and others published a very large European study in 160,000 men in seven countries in which they randomized men to screening versus non-screening and also showed a reduction in mortality from prostate cancer over 14 years by about 20% (Schroder, Hugosson et al. 2009). They had some contamination although it was not as much as in the PLCO study, and when they corrected for the non-attendance with screening and the contamination with the PSA use in the non-screening group, they showed a reduction in mortality by 30%.

So, reductions of 20 to 30% in the European study, over 40% in the Swedish study, versus no effect in the per protocol analysis of the PLCO study. In fact, the European study was just extended and in the New England Journal of Medicine an update was published showing again a 21% reduction in prostate cancer mortality.  The number of cancers that would need to be detected to prevent one prostate cancer death was about 37.As one can see different trials come to different conclusions, and this is at least partially due to the way the trials are conducted, how the patients behaved in the trial, and how the trials are statistically analyzed.

Here you are with your PSA, this piece of the puzzle that is so hard to sort out, and so hard to base decisions on. I suggest to you that you don’t need to do this alone. You have a partner. You have your health care provider and the decisions that you have to make in this puzzle should be made in a joined process.

Nothing about this process is inevitable and all decisions are shared: the decision to go to a physician or health care provider; whether to get a PSA; how to interpret the PSA result; whether to do a biopsy and if the biopsy is positive whether to treat; and if so, how to treat cancer if it is found.

Remember, prostate cancer treatment over the last 20 years seems to have led to a reduction in the overall mortality as we have discussed before. Over the last 10 years several studies have been published showing a reduction in mortality from prostate cancer in men who undergo surgery versus those randomized not to be treated.

For example, a study from Sweden published in the New England Journal of Medicine shows a significant reduction in death from prostate cancer and metastases due to prostate cancer in men stratified by age and different risk groups (Bill-Axelson, Holmberg et al. 2011).  

In the US, a trial was done called the PIVOT or Primary Intervention versus Observation trial. In this trial, at least those with moderate or higher risk for prostate cancer also showed a significant reduction in mortality from prostate cancer over a period of 10 to 15 years (Wilt, Brawer et al. 2009).

Although there is benefit in treating prostate cancer, it is important to find the right doctor and surgeon. Just how important is the surgeon’s experience? The graph shows the 5 year recurrence free survival after surgery, and what one can see is that independent of the risk group – from a low to an intermediate to a high risk group of prostate cancer – surgeon’s experience was very important and it took not just 10 or 20 cases, but about 200 or more cases to achieve sufficient expertise to have the best possible recurrence free survival (Klein, Bianco et al. 2008). The 5 year recurrence rates for low risk cancer may vary by experience from 2 up to 10% for intermediate risk cancer from 10 up to 27% and for high risk cancer from 20 to almost 50%. It is important that you do find a partner and health care provider with sufficient experience.

A lot is being said about PSA testing and age, when to start and when to stop it. Perhaps it is important to visualize life expectancy in the US in the year 2012!  A 60-year-old patient according to social security data has an average life expectancy of nearly 21 years. A 70-year-old one of 13.6 years, and the old statement that at age 70 life expectancy is 10 years or less, is not true any longer. A 10 year life expectancy is realized by a 75-year-old man, as one can see on the graph.

The PSA is not only useful in prostate cancer risk assessment, but also in other prostate diseases. For example, I order PSA testing in men with voiding symptoms and BPH. I use it to roughly estimate prostate size, to determine the risk for symptomatic worsening, the risk for requiring surgery or the inability to urinate, to monitor the disease process and the response to certain types of drugs such as 5alpha-reductase inhibitors (dutasteride or finasteride).

It was shown year ago that there is a relationship between age and PSA (left side) and between age and prostate volume (right side), and because of these close relationships, there is also a relationship between PSA and prostate size. It is different from age group to age group, but the higher the PSA the larger the prostate volume and the larger the prostate volume. 

The higher the PSA, the greater is the risk that a person may not be able to urinate or go into urinary retention (AUR) or require surgery for BPH. As one can see, that risk increases linearly over time with increasing values of PSA (Roehrborn 2008).

PSA is also useful if men have been treated for prostate cancer. For example, after radiation the PSA usually decreases to a level of 1.0 or less, but monitoring is important. If the PSA increases from the lowest measured level and if that increase is confirmed, the cancer has recurred and additional treatment may be needed. During hormone therapy, the PSA usually drops precipitously and any increase is indicative of the cancer not responding to the treatment any longer.

After a total or radical prostatectomy, the PSA should be undetectable (reported usually as <0.1 or <0.05), and if it becomes detectable, it indicates persistent or recurrent cancer. The rate of increase over time indicates just how aggressive this cancer is and whether or not additional treatment might be necessary.

Is the PSA the answer to all questions, is it the key that unlocks the secret to your health? Of course it is not! It is just one of many tests that your health care provider may decide to order in a shared decision making process, to help with the management of your prostate health or prostate diseases.

Let’s not throw out the baby with the bathwater by saying: PSA mass screening of the population is not useful, and therefore, PSA testing is altogether bad! That would be throwing out the baby with the bathwater. PSA may not be best used in mass screening of a large population, but it can serve a very meaningful and useful role in many situations. It is the shared decision making between you and your provider that will help to find the correct placement for this piece of the puzzle, to determine how PSA testing fits into your health care plan.

References

Andriole, G. L., E. D. Crawford, et al. (2009). “Mortality results from a randomized prostate-cancer screening trial.” N Engl J Med 360(13): 1310-1319.

Bartsch, G., W. Horninger, et al. (2008). “Tyrol Prostate Cancer Demonstration Project: early detection, treatment, outcome, incidence and mortality.” BJU Int 101(7): 809-816.

Bill-Axelson, A., L. Holmberg, et al. (2011). “Radical prostatectomy versus watchful waiting in early prostate cancer.” N Engl J Med 364(18): 1708-1717.

Chou, R., J. M. Croswell, et al. (2011). “Screening for prostate cancer: a review of the evidence for the U.S. Preventive Services Task Force.” Ann Intern Med 155(11): 762-771.

Etzioni, R. D., N. Howlader, et al. (2005). “Long-term effects of finasteride on prostate specific antigen levels: results from the prostate cancer prevention trial.” J Urol 174(3): 877-881.

Hugosson, J., S. Carlsson, et al. (2010). “Mortality results from the Goteborg randomised population-based prostate-cancer screening trial.” Lancet Oncol 11(8): 725-732.

Klein, E. A., F. J. Bianco, et al. (2008). “Surgeon experience is strongly associated with biochemical recurrence after radical prostatectomy for all preoperative risk categories.” J Urol 179(6): 2212-2216; discussion 2216-2217.

Roehrborn, C. G. (2008). “The utility of serum prostatic-specific antigen in the management of men with benign prostatic hyperplasia.” Int J Impot Res 20 Suppl 3: S19-26.

Schroder, F. H., J. Hugosson, et al. (2009). “Screening and prostate-cancer mortality in a randomized European study.” N Engl J Med 360(13): 1320-1328.

Siegel, R., D. Naishadham, et al. (2012). “Cancer statistics, 2012.” CA Cancer J Clin 62(1): 10-29.

Thompson, I. M., D. P. Ankerst, et al. (2006). “Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial.” J Natl Cancer Inst 98(8): 529-534.

Thompson, I. M., P. J. Goodman, et al. (2003). “The influence of finasteride on the development of prostate cancer.” N Engl J Med 349(3): 215-224.

Thompson, I. M., C. M. Tangen, et al. (2009). “Chemoprevention of prostate cancer.” J Urol 182(2): 499-507; discussion 508.

Thompson, I. M., C. M. Tangen, et al. (2008). “The Prostate Cancer Prevention Trial and the future of chemoprevention.” BJU Int 101(8): 933-934.

Wilt, T. J., M. K. Brawer, et al. (2009). “The Prostate cancer Intervention Versus Observation Trial:VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): design and baseline results of a randomized controlled trial comparing radical prostatectomy to watchful waiting for men with clinically localized prostate cancer.” Contemp Clin Trials 30(1): 81-8

PSA puzzle for slideshow on blog

Posted April 10, 2012 by Claus Roehrborn in Prostate Diseases

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