Hematology-Oncology 9/8/2011

Dr. Shi: Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer
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Dr. Shi presented a very recent paper from the Scandinavian Prostate Cancer Study Group documenting the results of a trial which randomized men with prostate cancer to surgery or watchful waiting.  These results mark a median of 12.8 years of follow-up (range: 3 weeks to 20.2 years).  The investigators looked at a fairly specific group: these were men under 75 with at least a ten-year life expectancy who had localized disease diagnosed by biopsy with a PSA <50 ng/ml and a negative bone scan.  The original N was 695, of whom just over half had died by 2009, and the primary endpoints were all-cause mortality, disease-specific mortality and distant metastases.  For the most part, their tumors were diagnosed by symptoms, not population-level screening.

The authors report an absolute reduction in the risk of death from any cause of 6.6 percentage points (95% CI -1.3 to 14.5), which corresponds to a number needed to treat (NNT) of 15.  The absolute risk reduction and NNT for death from prostate cancer were similar, as you would expect.  The ARR for distant metastases was 11.7 points (95% CI 4.8-18.6) corresponding to a NNT of 8.5.   

In their subgroup analysis, it appeared that all of this benefit accrued to men under 65 (there were no significant differences in any of the three endpoints for men older than 65).  They report an absolute risk reduction for disease specific mortality of 9.4 percentage points in men under 65, although their confidence interval can't exclude a reduction as small as 0.2 points or as large as 18.6 points.

One of the most important points of the discussion, and of Dr. Shi's summary, was that this is not at all about screening for prostate cancer.  As above, these men were largely diagnosed because they presented with symptoms and many of them had palpable tumors.  So as general internists, this study gives us some guidance about what we can recommend to younger men who, for whatever reason, have received a diagnosis of early prostate cancer, but it doesn't take us beyond the USPSTF's current recommendation regarding screening:

"for men younger than age 75 years, the benefits of screening for prostate cancer are uncertain and the balance of benefits and harms cannot be determined."

Another important theme of the discussion was the low emphasis on harms associated with radical prostatectomy in this article.  The procedure has very high rate of adverse effects, particularly impotence and incontinence.  While the authors reported the 1-year cumulative incidence in the radical prostatectomy group (32% for incontinence, 58% for impotence,) they didn't give a level of detail commensurate to the exploration of benefits, which makes it hard to weigh the risks and benefits even for patients very much like those in the study.


Dr. Kim Suh: A Novel Test for Colon Cancer
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Slobbery bedside manner...

Dr. Kim Suh presented a very euphemistically entitled study from Kyushu University in Japan.  The authors tested the ability of a very highly trained black labrador retriever to detect colon cancer based on breath samples and watery stool samples.  The dog's name is Marine, and she is a fixture at the oddly but accurately named St. Sugar Cancer Sniffing Dog Training Center in Chiba, Japan.  Marine  was originally trained for water rescue, but switched careers and has been learning to detect various human malignancies since 2005.


The authors collected stool and breath samples from people with known colorectal cancer and from healthy volunteers.  All subjects underwent colonoscopy with or without biopsy as indicated, which was considered to be the gold standard against which the dog's performance was judged.  Testing was conducted between November and June, because apparently the dog has trouble concentrating in hot weather. Each test consisted of four samples from individuals without cancer and one who did have cancer.  The placement of the samples in the test room was dictated by a random number table, and their identity was blinded to the dog, the handler and the lab assistants.  However, the accuracy of the dog's identification was rapidly communicated to the handler after it made its final choice so that it could be appropriately rewarded (with a tennis ball).

Future member of Tumor Board?

The dog's results were compared with the final diagnoses at colonoscopy and with conventional FOBT testing.  With respect to colonoscopy, positive identification by the dog had a sensitivity and specificity of 0.91 and 0.99 for breath samples and 0.97 and 0.99 for stool samples.  Interestingly, there was very little correlation with FOBT, demonstrating that whatever the dog is smelling, it's not a human blood product.

Following on from the first article, it seems like the obvious question is whether the Scandinavian Prostate Cancer Study Group can train a dog to tell the difference between indolent and aggressive prostate cancer.  Then the dog could tell the surgeon who is likely to enjoy a longterm survival benefit from radical prostatectomy.  Cost-effectivness would depend on the dog's number-needed-to-smell.

Joking aside, an important thing to note about studies like this is that you can't calculate positive or negative predictive values from the data they use to give sensitivity and specificity unless the prevalence in the study population mirrors the prevalence in your own population.  This is because the likelihood of a false positive depends on the prevalence of the disease; if everybody has it, there can be no false positives, and if nobody has it there can be no true positives.  In the case of this study, the incidence of colorectal cancer in the "population" was one out of every five samples, or 20% - clearly much higher than it would be in a normal screening population - so you can't generalize a PPV calculated from this study to the real world.  This is a much commoner mistake than it seems like it should be, and is worth looking out for.


Dr. Tuason: Erythropoietin Stimulating Agents for Treatment of Anemia in Chronic Kidney Disease
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 Dr. Tuason presented an article reviewing the use of recombinant human erythropoietin (rHU EPO) in the management of anemia caused by chronic kidney disease (CKD).  

The use of erythropoietin stimulating agents (ESAs) such as darbepoetin alfa, epoetin alfa and epoetin beta to boost hemoglobin levels in CKD has a controversial history.  One of the main putative benefits was historically thought to be a reduction in the incidence of serious cardiovascular events related to left ventricular hypertrophy and heart failure, for which anemia is a risk factor.  Some investigators have also claimed beneficial effects of higher hemoglobin levels on various indices of quality of life, restless legs syndrome, and bleeding time.

The authors review three recent, large trials all of which were designed to assess the optimal hemoglobin level in patients with stage III-V CKD by randomizing patients to target-based therapy with ESAs.  

The CREATE trial (2006, N=603) randomized patients to a target hemoglobin of either 13-15 g/dl or 10.5-11.5 mg/dl.  The primary endpoint was a composite of cardiovascular events.  Most patients in both group received some therapy with epoietin beta, although as you might expect more patients were treated in the higher hemoglobin target group.  There was no difference in the primary endpoints between the two groups.

The CHOIR trial (also 2006, N=1432) randomized patients to a hemoglobin target of 11.3 g/dl or 13.5 g/dl, and was terminated early by its data and safety monitoring board when a higher incidence of serious cardiovascular events including deaths, MIs, strokes and hospitalizations for CHF were observed in the higher hemoglobin group. 

The TREAT trial (2009, N=4000) randomized patients to a hemoglobin goal of 13 g/dl, or a goal of >9 g/dl with darbepoietin rescue therapy for those who fell below this level.  Again, a primary end point was a composite of cardiovascular event, and once again there was no difference.  However, there was a significantly higher incidence of ischemic stroke with a number needed to harm of about 40.

So, we have three very large, well-designed trials, none of which show any benefit to targeting higher hemoglobins and two of which show clear evidence of increases in the kind of event this drug was initially hypothesized to decrease.  However, somewhat bizarrely, the authors of this review concluded that we should "avoid the knee-jerk response of underutilization of these drugs."  They cite putative benefits in ""the need for transfusions, quality of life and exercise tolerance, [regression of] LVH" and a hypothetical reduction in the progression of chronic allograft nephropathy in transplant patients.  

This conclusion deserves a little dissection.  While it is possible that ESAs are beneficial in "reducing the need for transfusions," the need for transfusions itself is defined by hemoglobin targets which, as we have seen, are not clear.  The argument about regression of LVH is equally strange, in that the whole point of treating LVH is to prevent hypertensive cardiomyopathy and associated cardiovascular events - exactly the kind of events that ESAs clearly increased the incidence of in both the CHOIR and TREAT trials.  Allograft nephropathy is, of course, a totally different condition then the anemia of chronic renal disease, and even the authors admit that there's actually not really any published data on this anyway.  

But it's their argument about "the wealth of data accumulated in the 1980s and 1990s showing improved quality of life scores and increased vitality" which deserves special attention.  In support of this claim they cite 

• A study of Arousing Periodic Limb Movements with an N of 10, no control group and a 30% drop out rate,
• An unblinded, placeboless trial of ESAs influence on subjective assessments of quality of life,
• A trial of erythropoietin to correct hemoglobin to the normal range which showed increased energy levels.  This is, of course, exactly the range of correction which the TREAT, CHOIR and CREATE trials strongly suggest is dangerous, and finally,
• A study which they say shows "improvements in exercise training" with recombinant erythropoietin, but which as far as I can tell actually shows improvements similar to exercise training.

This, Dr. Yee pointed out, is a problem with reviews as a genre; they're put together by individuals who usually have strong views on the subject under discussion which may distort their analysis.  Dr. Irwin said that further research is clearly needed to define optimal hemoglobin levels, but that in his experience ESAs can improve quality of life and that there are cases where this benefit may outweigh the risks.  He also stressed that, in such cases, the optimal hemoglobin is the one that makes the patient feel better and discouraged the inflexible use of targets.  Finally, Dr. Yee gave an interesting oncological perspective on ESAs.  Many solid tumors over-express erythropoietin receptors, and so giving ESAs to patients with active cancer can accelerate tumor progression.

To summarize, the take-home points from Dr. Tuason's presentation, were essentially that 

1. Current optimal hemoglobin levels in CKD patients are not established, 
2. The use of ESAs to raise hemoglobin to the targets used in these trials is not beneficial and probably harmful, and
3. That one has to be cautious, when reading a review article, to try to understand how the reviewer's professional opinion may distort the conclusions they draw from the evidence.