Thursday, January 21, 2010

Prostate Cancer, CCE, and Testing

The British Journal of Cancer has just published an interesting article regarding Prostate Cancer. They state:

There is evidence that prostate cancer (PC) screening with prostate-specific antigen (PSA) serum test decreases PC mortality, but screening has adverse effects, such as a high false-positive (FP) rate. We investigated the proportion of FPs in a population-based randomised screening trial in Finland...An FP result is a common adverse effect of PC screening and affects at least every eighth man screened repeatedly, even when using a relatively high cutoff level. False-positive men constitute a special group that receives unnecessary interventions but may harbour missed cancers. New strategies are needed for risk stratification in PC screening to minimise the proportion of FP men.

The last statement is the most powerful. It states that despite the false positive, namely a man is told that an increased PSA may be an indicator for Prostate Cancer, and then after a biopsy there does not appear to be any, then shortly thereafter they do come down with PCa. Namely false positives may not truly be false positives but early true positives. Specifically the histological test of looking at cells may not be the correct early assessment method.

The Cancer Research UK states in their assessment of the article the following:

The study, a clinical trial of the controversial PSA test for prostate cancer, tells us that false-positives are common. It also shows that men who get a false alarm:
  • are likely to get another one the next time they go for a PSA test
  • are likely to refuse future invitations to screening, and
  • are likely to actually be diagnosed with prostate cancer the next time round
The third result, in particular, is a fascinating one. It suggests that men who get a false-positive result through PSA testing, in the words of the researchers, “constitute a special group”. They could well go through unwarranted tests, but they could also harbour missed cancers that only turn up later.... As we mentioned above, there’s a large prostate screening trial running across Europe, called ESPRC. The new results, published in the British Journal of Cancer, (which Cancer Research UK owns) come from the Finnish part of this trial – its largest component.

It involves more than 80,000 men, some of whom were randomly invited to three rounds of PSA testing, with four-year gaps between each round. Roughly 30,000 men attended their first round of screening and more than 10,000 of these men went on to attend all three rounds.

The study showed that false-positives are a common part of PSA testing. In any individual round of testing, the majority of positive results are false alarms (between 60 and 70 per cent), while just over a quarter lead to an actual cancer diagnosis. Among the men who attended at least one round of screening, 1 in 8 had at least one false-positive result.

It’s worth noting that the researchers were using a fairly high cut-off level of PSA (4 ng/ml) – i.e. the level above which they were thought to have suspected prostate cancer. This sets a pretty high bar for a positive result and should minimise the number of false positives. Nonetheless, many still crept through.

Among the men who get a false alarm in one round, more than half will get another false alarm in the next one. Many men without tumours have persistently high PSA levels for some other reason, so they keep on testing positive. That’s a lot of extra worry and more potential for unneeded tests.

Indeed, in this trial, every third man who got a false alarm went through two biopsies within 4 years of their result. That’s probably an underestimate too, as it doesn’t account for any visits to private doctors.

However, the study also shows that false-positives aren’t entirely meaningless. If men had a false alarm during one round of screening, they were 3-9 times more likely to be diagnosed with prostate cancer during the next round...."

The analysis of the poor trials mentioned above is what we had commented on a year ago when the results were issued. Namely they used the 4.0 PSA level which we now know to be wrong, especially for men under 65. In addition we also now know that the better measure is PSA velocity, namely the change in PSA in a years time. If the change is 0.75 or greater then there is a 90% chance of Prostate Cancer. That is a fairly good metric. Thus is you have a PSA of 1.5 in one year and the next year it is 2,25, you have a 90% chance of incipient PC.

The 2003 NEJM article by Nelson et al on Prostate Cancer lays out the genetic progression of Prostate Cancer and it is that progression which PSA somewhat follows. Yet it is that progression that most histological exams, using say a Gleason framework, do not follow. It is worth a simple review to see what we mean. Let us go through 4 simple steps:

1. Cancer is simply a breaking down of the normal cell cycle as shown below. Cells duplicate themselves via mitosis and it is that mitotic process wherein say old cells "die" and new cells are created. In fact the old cell just repairs itself and then duplicates itself. The classic process is as below.

Most of the time the cell is resting in G0. The cell when in G1 is getting ready to reproduce. For it is in S that the DNA copies itself and then goes on to M for separation into new cells. The skin, blood, and many other cells are doing this all the time. However there may be problems. The cell DNA may be hist by radiation, some chemical which damages the DNA, or the like. Cell DNA is quite fragile.

2.The cell begins its change to reproduce and there are many internal control mechanisms. They take the cell almost through G1 up to an R point, at which if the cell DNA has any problems the corrective mechanism will kill the cell. However if the genes controlling this protective mechanism are not working due to same attack, then the cell goes past this R point and does it again and again. That is the beginning of cancer.

3. Now there are many chemical pathways that try to stop errors from propagating. We show some of them below.

The most important for Prostate Cancer is the PTEN pathway. This gene and its protein if in any way damaged result in loss of control of cell growth. Many environmental factors control the breakdown of PTEN. Once it goes the PSA starts to explode. The cancer then also becomes unmanageable. It is this final assault that will often result in death.

4. Cancer is a progressive disease of steps. The ones from Nelson, and there are updated version of it now seven years later, but this is quite reasonable are shown as follows:

A simple health cell starts on the left and spends its whole life happy and well. Then all we need is one cell which gets attacked and the process starts. But it takes many attacks, one after the other to take the cell from a slight problem to a deadly mass. Understanding these steps and being able to determine what is in the "bad" cells will be a much better path to take than what we have now with PSA but PSA is good. It works, and it does save lives.

Thus we argue three facts:

1. The clan of Comparative Clinical Effectiveness users is really a backward looking clan. In fact the PSA testing controversy shows how backward looking they can be. Yes a 4.0 PSA will result in little improvement. For by the time it gets there especially in young men it is too late. We need a forward looking clan of researchers on the clinical side. That however may be an oxymoron since the clinical researchers most often look backward.

2. The genetic markers are truly the best measures of what the problem may be. Yet we need better means and methods to measure them We need to have say nanothechnology which will scrub through the prostate and scape up telltales of the presence of the genetic markers. Are there any PTEN negative cells, and if so then they are the clones which will be reproducing and kill the patient. They are the ones which should be eliminated.

3. Genetic medicine is as we have argued recently the PC of medicine. It will be the sea change necessary to finally attain scale in the practice of medicine.