PSA: To Screen or Not to Screen

There has been much confusion/concern/media attention since the recent announcement (see the NY Times article US Panel Says No to Prostate Screening for Healthy Men) that PSA tesing was no longer recommended by the US Preventative Services Task Force. (Here's the full version of their draft recommendation.) There are many responses out there (Tara Parker Pope's Answering Questions about the PSA test is a good one), but I believe there is still more to say on the issue.

Before answering the question regarding whether we should follow the USPSTF's new recommendation, please consider...

1. The USPSTF is the same group that says

-Women shouldn't get mammograms before 50

- Recommends against teaching self-breast examination

-States that screening for testicular cancer is harmful

-Only recommends screening for diabetes in patients with high blood pressure

-Recommends against screening for depression for most primary care doctors

(I am not stating that I necessarily disagree with these recommendations.  However, it is important to understand where USPSTF is coming from when considering their PSA recommendation). 

2. Prostate cancer is still a leading cancer killer for men in the US. 

From NY Times:

One in six men in the United States will eventually be found to have prostate cancer, making it the second most common form of cancer in men after skin cancer. An estimated 32,050 men died of prostate cancer last year and 217,730 men received the diagnosis. 

The new recommendations come from findings of two large studies.  One in the US that showed no benefit in saving lives, and one in Europe that showed only some benefit.  The US study have some major limitations, including that many of the men in the placebo/no-screening group actually got screened, so I will focus on the European study.

The European Randomized Study of Screening for Prostate Cancer looked at close to 200,000 men between 50-74 for about 9 years. Not surprisingly they found almost double the rate of prostate cancer in the screened group compared to the non-screened group (8.2% vs. 4.8%).  More importantly, they reduced the rate of death by about 20%. Unfortunately, most of the men treated for prostate cancer did not benefit.  They found that for every 1410 screened, there were 48 additional cases of prostate cancer found, that if treated would only prevent one death from prostate cancer. In other words, if you are treated for prostate cancer, there's only about 1/50 chance it will save your life. Now, if the treatment were without side effects, then besides costs, there would be no reason not to screen.  (My friend Dr. Stewart Segal in his post PSA Confusion suggests covert rationing is one motivation behind the USPSTF's recommendation).  The problem is that there are side effects with treatment, and not inconsequential ones. There is about a 20-30% chance of impotence, incontinence or both. 

However, there seems to be two things not discussed in any of the reports:

1. Though the writers of the guideline seem to give value/risk of the harms of treatment, they do not address the potential benefits of the piece of mind from a negative screen.  In the European study, over 90% of men had a negative screening over the course of almost a decade.  In other words, the vast majority of men screened had the piece of mind knowing that probably didn't have to worry about prostate cancer. (There is also additional evidence that men 65 and older with a very low PSA  will likely never get prostate cancer, and screening should be stopped). 

 

2. Just because you are diagnosed with prostate cancer, doesn't mean you need to treat it.  Given the complications as a result of prostate cancer treatment, and the fact that prostate cancer tends to progress slowly, especially after the first year, watchful waiting is a reasonable approach. If in fact, if the cancer remains stable, treatment can be deferred potentially indefinitely.  However, without the diagnosis, watchful waiting can not occur. 

Bottom Line:  There is no right answer for everyone.  Patients, in consultation with their doctor, need to make a decision that's right for them.  If you are a healthy person, with no cancer risks, worry about side effects and complications of medical treatment,  and realize that there's a 98% chance that screening for prostate cancer will not save your life, you should not get a PSA test or prostate exam.  However, if you are someone that is very fearful of cancer, would have substantial piece of mind if you were one of the 90% of men that tested negative, and if you did get diagnosed with prostate cancer are willing risk treatment knowing there is only a 1/50 chance it will save your life, but about a 20-30% chance you will get side effects from treatment, then you should get tested. 

Read "The Estrogen Dilemma" With Caution

There is a piece in the New York Times called "The Estrogen Dilemma" which many women will read with great interest. I would urge women to read this with great caution before jumping to any conclusions.
The article is a well written piece by journalist Cynthia Gorney, who discusses both the controversy of hormone replacement and possible benefit with memory and mood, simultaneously with her own personal medical history. I would imagine many women readers will identify with both Ms. Gorney's depression (since it is so common) and her struggle with the decision whether or not to stay on hormone replacement (since there is so much confusion around the issue).
The article pokes many holes in the landmark Women's Health Initiative (WHI). Prior to this study, many physicians, myself included, were prescribing hormone replacement to perimenopausal and post-menopausal women like candy. We did this because the data on the purported benefits seemed robust, and the data on risks seemed minimal. The WHI proved that making routine decisions without large, randomized clinical trials was not necessarily a good idea. The WHI showed that, at least in the population studied, the risks of hormone replacement (breast cancer) outweighed the benefits (heart attacks turned out to be a risk not a benefit). More importantly, many doctors stopped prescribing hormone replacement because alternatives to protect against heart attacks (statins, aspirin) and osteoporosis (bisphosphonates, calcium, vitamin D) existed and didn't carry the same risks. However, this doesn't mean that the risks/benefit ratio for hormone replacement applies to every women equally. Women who suffer from severe symptoms of menopause, especially with a low risk of breast cancer, would certainly have a risk/benefit ratio favoring hormone replacement.
Gorney's article suggests that perimenopausal mood issues such as depression, memory/attention, as well as prevention of Alzheimer's disease can all be linked to estrogen deficiency, and estrogen replacement just might be the solution. These facts coupled with very real holes in the WHI data regarding women in their late 40's and early 50's (who weren't in the study), suggests that hormone replacement may in fact be just what many women need.
However, the key is the lack of data. Though studies are underway, we do not know whether or not estrogen can help with perimenopausal mood disorders, or even if it does, whether it is any better than other treatment such as anti-depressants. In addition, though there is reason to believe that the dangers found in women in the WHI might not apply to younger women, we do not have data to prove that it is safe. Absence of evidence is not the same thing as evidence of absence (harm).

Bottom Line: Medicine has to be individualized. Every therapy and test, including screening tests like PSA's and mammograms, have risks and benefits. Balancing those risks and benefits is important, and is not the same for every patient. Age, individual risk for disease, personal preference, and symptoms are all important factors. Estrogen may have an important role in mood disorders and memory for women, and may be safe if started in the late 40's and early 50's, but we simply don't know for sure. Estrogen, especially when given with progesterone is definitely linked to breast cancer, and given later in life, increases the risk for heart attacks. If you are a perimenopausal women that identifies with Ms. Gorney, and you think that estrogen replacement may be the miracle cure you are looking for, proceed with caution. Weigh all the available data, risks and benefits before jumping to conclusions from a very well written and emotionally impactful article. Your physician can be very helpful in guiding this decision.

The Pap Smear: A Symbol for Our Health Care System's Problems

Today the Wall Street Journal and other sources reported on a study from The Annals of Internal Medicine that showed that most US doctors don't know the guidelines of how often women should get a pap smear. More importantly, doctors were doing a lot of pap smears on women who didn't need them. In all the talk about health care reform, reducing costs by eliminating unnecessary testing has been mentioned multiple times. Thus, if we can figure out how to get rid of all of these unneeded pap smears, maybe we can find the cure for our health system's woes.

The results of the study are not surprising to me, as I have seen this in clinical practice. The more I thought about why this is occurring, the more I thought about the pap smear as a symbol of our health care system's problems. So why so many pap smears?

1. Pap smears have saved lives. Cervical cancer used to be a major killer of US women. Now it is rare to hear about a women who has died of cervical cancer. Not true in third world countries when screening is not possible. The fact that we have virtually gotten rid of a cancer with early detection is truly amazing. But the danger here is that it has set up the paradigm that this is true for all diseases and cancers. Recently, breast cancer and prostate cancer screening have come under fire for not really saving any lives. However, even with the data, patients and advocacy groups will not likely take a screen only if proven life saving approach. Breast self-examination has absolutely no data to support this practice, and in young women who are likely to find non-cancerous bumps, may actually be harmful. Yet, this practice is routinely recommended for many young women.

2. Women (and many men) want/expect a yearly physical, and most women believe that a pap smear is part of this. Similar to other types of cancer screenings, there is very little evidence that a routine check up is beneficial. This is not to say that you shouldn't visit your doctor regularly. However, many of the things doctors do during a physical have limited to no value. There are some things that have tremendous value, such as checking blood pressure and weight, and talking about diet, exercise, smoking cessation, etc. However, having the doctor check your whole body every year when your feeling just fine is unlikely to be helpful. Yet, the American public expect a full exam every year. After all, their health care premiums are quite high, so they might as well get checked out. This extends to the pap smear. It saves lives (as above), is part of my regular check up, and I am paying a lot of money for this; so therefore I expect my yearly pap.

3. Physicians have little disincentive to refuse to do a pap smear. The pap smear only takes a few minutes. Trying to take the time to explain #1 and #2 above makes little sense for the primary care physician who is not paid by time spent counselling a patient, but by how many patients she can see. In other words, talking a patient out of an unneeded test actually costs the primary care doc money, because that time could be used for seeing another patient. More importantly, if the physician refuses the pap smear, and the patient goes elsewhere to get the pap smear and is found to have cervical cancer; the physician could get sued placing her entire career in jeopardy!

If pap smears save lives, patients expect/demand them, talking a patient out of an unnecessary pap smear only costs me money and not doing the pap could get me sued, why wouldn't I do a pap smear on every women that wanted one?

4. The pap smear rep reminded me to get the test. The drug companies are not really the problem any more. Every day you read about a drug company laying off employees. This is because most drugs are or will soon go generic and there is little in the pipeline. This is not the case for devices and testing. Big labs have reps that come to physician's offices to discuss the latest fancy new test. Like the drug reps, they bring lunch too. The difference: medical devices and testing though FDA approved are not nearly has heavily regulated as the drug companies when it comes to selling to physicians. Drug reps by law are restricted to saying only what is in their label to physicians. It works a little bit differently for the lab and device reps. As newer tests and devices become available, watch for more of a focus on selling these products. Don't be surprised to see direct to consumer advertisements asking patients to ask their doctors about such and such a test.

5. The experts don't agree. It is very hard to keep up with evidence based guidelines in primary care. It's even harder when there are multiple guidelines, and harder still when they don't agree. For prostate cancer, the American Cancer Society and the American Urological Society say that doctors should test for prostate cancer. The US Preventative Health Task Force guidelines say that we shouldn't. Initially, some of the groups recommended more frequent pap smears, but recently decreased the interval due to evidence that less frequent screening was better. However, with all multiple guidelines that often differ, it is not surprising that so few primary care physicians actually knew what all the experts actually did agree upon. Another issue is that reasons behind differing guidelines have to do primary with politics and money. The Urologists want primary care docs to test for prostate cancer because they make money when the test comes back positive. The government doesn't want you to test for prostate cancer, because testing leads to more testing and treatment which costs them (you the taxpayer) more money.

6. Doctor's don't follow guidelines anyway. Even if there was one clear and definitive guideline for docs to follow, they probably wouldn't. There are likely multiple reasons. Our current Continuing Medical Education system (CME) that is supposed to keep docs up to date is horrible and funded by commercial interest. The stimulus package already gave some money for comparative effectiveness research and there will likely be more money for this in any health care reform bill that passes. However, if docs don't know the results of what is best or what actually works, then the data is not all that useful. It is unlikely that a drug company is going to fund a CME program that shows their drug is not useful. So who is going to fund the dissemination of comparative effectiveness findings? There is also no real incentive to follow guidelines. Again, docs get paid for how many patients they see, not by how beneficial their advice was to patients or whether they gave guideline appropriate care.

Since pap smears don't cost a substantial amount of money, it is unlikely that getting rid of all these unnecessary pap smears is going to put a dent in health care spending. However, the underlying reasons behind the many unneeded pap smears is a symbol of what what's right and wrong about our health care system. We should give this study's findings, and more importantly the reasons behind these findings, a critical look.

Lantus and Cancer- A Closer Look Is Not Reassuring

Kevin MD brought up the issue of Lantus and cancer on his blog, linking to both my original post which stated that patients should be concerned, as well as a post from Amy Tenerich at Diabets Mine who takes a more conservative approach, like the ADA and AACE. ( I do question the motivations of these groups in my recent post on this matter: Lantus Causes Cancer! Why Doesn't Anyone Seem Care? ). Some responders to my inital post felt that I had not read the studies correctly. Therefore, below is my detailed interpretation of the four studies recently presented which caused the controversy.

The first study was a German study of 127,000 patients, which 20,000 were treated with Lantus. Most of these patients had Type 2 diabetes. Overall, this study found a correlation with all insulins and cancer, but no difference between the analogue insulins. However, because patients on combination analogue and human insulin were excluded in the study, the dose of lantus was much lower than the other analogues. The researchers then adjusted for insulin dose, and they found a dose dependent relationship of cancer and Lantus. The magnitude of this effect was such that 1 cancer might be caused for every 100 patients taking Lantus for a year. One of the limitations of the study was that it was not possible to break the analysis down by types of cancers caused. Given this and other possible limitations, the editors of the journal decided not to publish this study until these results could be replicated in other studies/countries, especially considering the importance of the findings if corroborated.


Since then 3 other studies were performed, and subsequently all four were published together.



The second study was a Swedish study matched a national cancer database and a national diabetes database looking for a connection. This study included over 120,000 patients of which about 6000 were on Lantus. They found no increase in risk for cancer with Lantus when taken with other kinds of insulin. These patients were younger, and more likely to have type 1 diabetes. However, analysis of patients who took Lantus alone, most of whom had type 2 diabetes, showed a doubling of breast cancer, which was highly statistically significant (though no increase in other types of cancers).


A third Scottish study used national database registeries similar to the Swedish study and they found exactly the same thing. The patients who took Lantus with other insulins, who were generally younger type 1 diabetics had no increased risk of cancer with Lantus compared to human insulin (actually had lower rates) but the patients on Lantus without other insulins, mostly older type 2 diabetics had a higher risk of cancer. There was also similarly an increased risk of breast cancer in women taking Lantus alone, which was about the same magnitude as the Swedish study.



The fourth study looked at cancer risks associated with a range of insulins. This retrospective UK study looked at over 62,000 adults that were started on oral agents and/or insulin. Diabetes developed in adulthood, so these were mostly type 2 diabetics. In general, the study found no difference between human insulin and analogue insulins like glargine (Lantus). However, the study did find that metformin use is associated with a lower risk of cancer, and seemed to abolish cancer risk. Also, only 10,000 patients in the study were on insulin, and only 2000 on Lantus. Plus, it was not clear who was taking meformin plus Lantus. Thus, given the very small number of patients on Lantus, some of who may have been taking metformin, this negative finding is not all that reassuring.

Taken together, in my opinion, these 4 studies strongly suggest a link between new cancers in adult type 2 diabetics who are taking Lantus alone. Now, we can't say that Lantus actually causes cancer. In fact, it is unlikely that Lantus actually causes cancer alone, because it takes years to develop most cancers. However, it is more likely that Lantus causes existing cells to grow and divide more rapidly. Usually, the body's own natural cancer fighting abilities take care of these cells. In other words, though Lantus may not cause cancer, adult type 2 diabetics taking Lantus seem to develop clinically apparent cancers at much higher rates (double for breast cancer) then those not on Lantus. Though whether or not Lantus is causative of cancer is an interesting academic discussion. However, from the patient's standpoint if taking Lantus increases the likelihood they will develop cancer, that's all they need to know.



Large observational studies are far from perfect. The can detect differences (i.e. adult type 2 diabetics taking Lantus were more likely to get cancer), but can detect the reasons for these differences. The only way to show actually causation would be a very large, randomized control trial conducted over years. However, this will take years to complete. The Europeans are suggesting meta-analysis of even larger databases to find out sooner.

Until we know for sure, given a possible risk for Lantus increasing the rate of cancer development, I would suggest it would be prudent to stop taking Lantus if you are a type 2 diabetic, especially if you are not taking other kinds of insulin. Detemir insulin (Levemir) is a reasonable alternative. Though it has not been studies as extensively, its effect on the IGF-1 receptor (the purported mechanism of the cancer association) if much, much less than Lantus.