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The American Cancer Society

And Now, The End Of The ESA Story (For Today)

by Dr. Len March 13, 2008

(Author's Note:

When reviewing this entry on April 11, I noted that a significant portion of this blog had not been posted in error.  I have now added that information.  It has not been edited or changed in any way from the original copy.  I suspect what happened was that in the midst of trying to get these posted in real time, I neglected to copy all the text and failed to proofread the post.  I apologize for this problem.)


Now the committee is getting into the finer details as to how ESAs should be used, and what changes may have to be made to the FDA label regarding serious risks.

The next question in front of the committee is whether or not ESAs should be limited only to patients with small cell lung cancer, which is the only cancer where there is proof that the drug doesn't have serious adverse effects.

And the vote is: No, these drugs should be available to patients with other cancers as well. 

That vote was closer: 6 yes, 8 no.

Now the committee is considering the data I wrote about earlier as to whether the drugs are NOT indicated for patients with cancer receiving potentially curative therapy, such as the pre-surgical treatment of breast cancer where it appeared that women who received ESAs had earlier and more frequent recurrence.  This question also includes the use of ESAs in patients with curable lymphomas, testicular cancer, and women who are treated with standard primary therapy, followed by adjuvant therapy.

By going into the curative group, says one panel member, we are exposing people with curative disease to greater risk than may be necessary.  If they had a serious adverse event, they could die as a result of the medication. 

The chair of the committee noted that women with curable breast cancer will accept a 1% risk of significant adverse events from their treatment, and she doesn't believe ESAs should be used in this setting.

The vote: 11 to 3.

That means the committee believes that if someone has curable cancer, they should NOT use ESAs because of the risk.

The committee is now moving on to consider whether ESAs should not be used in patients with metastatic (recurrent) breast and head/neck cancers, since data has shown that ESAs adversely influence the course of those particular diseases in different situations.  The underlying issue is whether ESAs "promote" the growth of these cancers.

But is it really because ESAs caused tumors to progress more rapidly, or do they inhibit effective therapies?  That may be a small point, but an important one since according to one panel member there is no direct evidence that ESAs cause the tumors to grow more rapidly.

The vote:  Yes 9; No 5.  That means the panel recommends that these drugs NOT be used for patients being treated for metastatic breast and head and neck cancers.

A difficult issue, based on the testimony and comments earlier today is what would be the level of red blood counts when these drugs should be used in those patients with cancer treatment related anemia in a patient without symptoms and no other serious medical problems?  That is now the question before the panel.

One of the major issues is how much discretion should a physician have in treatment a particular patient?  Should the number for the level of the red blood count be hard and fixed?  Or should the doctor have some flexibility?  The implications of this question are signficiant, both with respect to the safety and effectiveness of ESAs as well as the important question of whether or not Medicare and private insurers companies will pay for it.  This is, after all, an expensive drug.

Text added 4/11/08 (see note above):

The higher the red blood count level, the more the amount of drug would be administered, and perhaps the risks would be greater.


Ultimately, there was no vote on this question.  The FDA representatives stated that they were most interested in hearing the comments of the panel on this topic, not having a vote on the question.


The last question: Should the FDA make specific requirements for doctors who give these drugs, and patients who receive it?  An example of the options might include an approach where patients and doctors sign off on the treatment after a detailed informed consent discussion. 


One doctor objected since this is essentially “one more form” that will need to be signed by patients and not lead to improved patient awareness of the risks of ESAs.  After all, don’t oncologists already discuss the benefits and risks of the treatments they receive?


The vote: 8 to 5 with one abstention.


What about restrictive distribution systems to minimize the risk of ESAs, such as are currently in place for medications such as acne medicines that have a significant risk of birth defects?  This might require patient registries, recording who is receiving ESAs and not everyone who might want to give or receive the drugs would be able to get them, unless they met very specific criteria for treatment.


This does potentially end up becoming a significant burden for many participants in the system, from the manufacturer to the distributor to the pharmacist to the doctor and then finally to the patient.  But are the risks substantial enough to warrant this approach for ESAs?


The panel voted 1 to 10, with 2 abstentions.  So, they don’t feel such restrictions should be put into place.


So that’s it folks.  The panel has recommended to the FDA that ESAs should remain on the market, with some specific restrictions based on evidence that in some cases the drugs

Filed Under:

Cancer Care | Medications | Treatment

And The Vote Is "Yes" Regarding ESAs

by Dr. Len March 13, 2008

And now we get to the meat of the matter at today’s hearings on the safety and effectiveness of ESAs: the opportunity for the committee to weigh in on the issue as to whether or not ESAs should be removed from the market for treating cancer treatment-related anemia (CTA).


It is clear the landscape has changed regarding blood transfusions since 1993, when these drugs were first approved.


Transfusions back then were more risky.  But more blood was donated and available for the support of active cancer treatment.  However, there were significant and life-threatening infections passed through blood transfusions. There were other risks as well.


Time has passed on, now we have ESAs, and transfusions are less common in no small part because of the use of the drug.  As I write this, a transfusion expert on the panel is now saying, we can actually significantly reduce the blood level at which transfusions are required compared to what we thought previously.  And, he added, there is an adequate blood supply.


The theme that does weave through the comments is the lack of clear data, despite the information on the clinical trials presented this morning.  There is also the question about the inconvenience and time required to receive a transfusion.  It is not as easy as getting a shot in the doctor’s office.


Another issue that hasn’t been addressed carefully today is whether or not ESAs improve the fatigue in patients on active chemotherapy.  A study is now being presented regarding a Cochrane meta-analysis that ESAs do improve cancer related fatigue and that the improvement is meaningful.


An FDA representative countered that there is a concern regarding missing information in many of these quality of life studies which could influence the conclusions regarding the use of these drugs in fatigue.


Could the label be revised to say that the drug should be used if transfusions are not appropriate?  That could be considered, according to the FDA, if and when they get to the labeling.


But the bottom line right now is whether or not these drugs should be kept on the market for the specific treatment of CTA.  Ultimately, that is a decision of the FDA, but the committee’s recommendation this afternoon will guide that decision.


So, now the vote:  should the products continue to be available for the indication chemotherapy induced anemia?


And the answer is: yes according to a majority of the committee (13-1) 


The next topic is going to be whether or not the label should be modified.


More to follow…

Filed Under:

Cancer Care | Medications | Treatment

ESAs: Why Didn't We Know This Earlier?

by Dr. Len March 13, 2008

Over the past number of years, medicine has tried to develop more evidence and science based rationales for the treatments we recommend.


The data currently being presented at the FDA Oncologic Drug Advisory Committee hearing today suggests that when it comes to ESAs (see previous blog), we still have a way to go in developing the evidence of their safety and risks.  The testimony currently being presented by the FDA representative shows genuine concern that when the evidence is carefully examined, the outcomes may not be what we would have expected.


In short, there are now a number of closely analyzed studies that show patients who have received ESAs as part of their treatment regimen may have actually done worse than patients who did not receive the drugs, and who instead relied on transfusions to keep their red blood counts at an adequate level.


For example, in one clinical trial called PREPARE, women with breast cancers 2 cm or larger when they were diagnosed were treated with chemotherapy in an effort to reduce the size of the cancer before they underwent surgery.


Two different chemotherapy regimens were used, and within each chemotherapy regimen ½ the women received an ESA for anemia, and the others were treated for their anemia with transfusions.


The FDA was notified in late November 2007 by the pharmaceutical company which sponsored the trial that in fact the women who received the ESA had their cancer return more frequently and earlier after their primary treatment than women who received blood transfusions.   In other words, the use of ESAs in these women with breast cancer worsened their outlook. 


In breast cancer, once the cancer recurs it can be controlled but infrequently cured with current therapies.


Other trials in other cancers showed similar outcomes.  Some of these trials were with active cancer treatment and there were a couple where the patients were anemic but not undergoing cancer treatment and who had just the anemia related to the underlying disease. 


The findings were similar: by various measures, the patients on ESAs did worse.


When it came to specific forms of cancers, the FDA representative has testified at this hearing that in small cell lung cancer, ESAs did not worsen the disease.  But in other cancers including non-small cell lung cancer, breast cancer, head and neck cancer, lymphoid cancers, cervical cancers and another study with various cancer types all showed evidence of harm with ESAs.


For many other cancers, potential adverse effects of ESAs have not been determined according to the FDA.  These include: GI cancers, urological cancers, ovarian cancers, uterine cancers, germ cell cancers, leukemia, central nervous system cancers, kidney cancers, melanoma and sarcoma.


As a result, the FDA has recently put another warning on ESAs which says that even if the goals of increasing red blood counts are modest (under 12 grams of hemoglobin), current scientific studies do not show that there is no risk of  decreased survival and accelerated tumor growth.  The warning also says that the lowest dose of ESAs should be used. 


So while today it appears that the harms are associated with levels of hemoglobin above 12 (normal is 13-14), even targeting a lower dose doesn’t imply these drugs don’t have significant adverse effects.


The FDA has just concluded their testimony.  They recommended that ESAs should be used as supportive care agents and that they are not primary treatments for cancer.  They also acknowledged that ESAs do decrease the need for RBC transfusions.  There are numerous risks, and they do not increase survival and may increase tumor growth.

The bottom line from the FDA’s perspective is that the risk:benefit ratio of ESAs needs to be reconsidered.  However, results from adequately designed ongoing or proposed studies will not be available for several years.


So, as a doctor, my sense is that there is some information we know about these drugs, and much we do not know.  The situation is just like what we found when we looked carefully at hormone replacement therapy in post-menopausal women.  We found that many of our preconceptions about this treatment were not correct.  What we thought was a reasonably safe treatment for post-menopausal symptoms was in fact associated with significant risks.


The hearing today about ESAs is ongoing, so we can’t make any conclusions as to the outcome.  But what we can reflect on is why did it take us this many years to ask the questions we are now asking?

Filed Under:

Cancer Care | Medications | Treatment

Should Procrit and Aranesp Use Stop?

by Dr. Len March 13, 2008

As I write this I am sitting in a meeting room in a hotel in Gaithersburg, Maryland attending a hearing in front of the FDA’s Oncologic Drugs Advisory Committee.   The purpose of the meeting is to review the data about the safety and effectiveness of drugs called ESAs, or erythropoiesis-stimulating agents.  You may know the drugs by their trade names, Procrit and Aranesp.


In plain English, these are drugs that have been used since 1993 to reduce the need for transfusions in patients on active cancer chemotherapy (there are other uses in other diseases but these are not the focus of today’s meeting).


What makes today so important is that the FDA has made one of its recommendations removal of these drugs from the market in the United States.


As described in past blog entries (including a recent posting decribing increased deaths in patients receiving these drugs), these drugs have come under increased scrutiny over the past year as evidence has emerged that patients who receive ESAs may be at increased risk of premature death and thromboembolic events, such as deep vein thrombophlebitis (blood clots in the legs and other veins in the body) or pulmonary embolism (blood clots that break off from the legs or elsewhere and travel to the lungs).


The problem is that these drugs have been used for two purposes in cancer care, one of them approved by the FDA and one “off label” or not approved by the FDA.  In addition, some doctors have “pushed” the drugs in order to increase red blood counts in patients to normal levels, as opposed to more modest goals which reduce symptoms but may be less than normal.


The FDA approved indication, from 1993 until now, is to reduce the need for transfusions in patients undergoing active treatment with chemotherapy.  In today’s presentations, that indication is called “CIA,” or chemotherapy induced anemia.


The other use of these medications is for the fatigue associated with cancer, which is frequently not related to active treatment (although fatigue is certainly a prominent feature of cancer treatments).  That use was never approved by the FDA, yet doctors have been using ESAs to treat this condition as well.  The problem here is that there is insufficient scientific evidence to support the use of the medication in this situation, although its use in this circumstance has increased over the past several years.


From my perspective, the problem with the information that I am listening to as I write this is limited to the use of ESAs in CIA.  Comments regarding the other use of ESAs are minimized since this use is off label.


The FDA staff has asked the ODAC to make a recommendation by the end of the day as to how the FDA should handle the controversy surrounding these drugs.


The options include:


  • Remove the indications for using these drugs to treat CIA


  • Restrict the use only in patients who will not be cured by treatment and contraindicate use in patients surgically resected for cure (such as an adjunct to adjuvant therapy)


  • Restrict use to specific cancer subtypes where safety has been adequately assessed (small cell lung cancer)


  • Contraindicate use in clinical settings where harmful effects have been demonstrated, e.g., breast and head and neck cancers


  • Risk management strategies to optimally communicate safety information to both health care providers and patients.  Such changes may include informed consent by patients, voluntary restriction of promotional activities, and limited distribution programs.



As you can imagine, there is a lot riding on the committee’s recommendation (FDA advisory committees are exactly that: they make recommendations to the FDA, but ultimately the FDA staff makes the decision).


There are many patients who have received these medications, and there are many who will be impacted by the results of this hearing.


Some interesting information has come out of the discussion so far.


For example, according to the information being presented by the pharmaceutical companies, ESAs reduce the need for transfusions in patients receiving chemotherapy by 50%.


In 2007, since the potential risks of ESAs have become known, the use of these drugs has dropped by 50%.


It has taken years for the science regarding the use of these drugs to treat the fatigue of cancer to catch up with the use of these drugs for this indication.  Bottom line, it hasn’t been until recently until the research has been completed for the off-label indication.  It showed an increase in mortality as reported previously.  Unfortunately, the science lagged significantly behind the use of these medications for this indication in the cancer community.


Now, years later, we find out that maybe what we thought worked in fact resulted in harms.  We don’t know how many patients were impacted. 


But what the discussants are saying is that we now know that if patients don’t respond to ESAs, they should be stopped.  And, they agree that the top limit goal for treating patients should be 12 grams of hemoglobin (a measure of red blood counts), not the 13 or 14 that some doctors are trying to achieve.


Another concern has been that these drugs may in fact stimulate some cancers to grow faster.  The pharmaceutical scientists have just stated that there is no solid evidence to support that concept, and they claim that the FDA makes a similar statement.


The word of the day so far is “pharmacovigilance.”  That means that the pharmaceutical companies believe now that we need to pay more attention to the problems associated with these drugs.


They have recommended much tighter control on the distribution and use of these drugs.  Some of their recommended plans include making certain that patients and doctors have informed discussion on the benefits and risks of these drugs, and that consent forms be signed.  Doctors would have to agree to participate in this program in order to receive supplies of the drug, and this program would have external oversight and auditing to assure compliance with the requirements.


There certainly will be much more discussion as this meeting continues, but it is clear that at the least the use of these ESAs is going to be substantially controlled which means decreased use.  And that is only if the FDA allows these drugs to remain on the market.


As I have said previously, stay tuned.




Please note:  Because of the circumstances, I am not able to provide the usual links at this time

Filed Under:

Cancer Care | Medications | Treatment

New Guidelines To Prevent And Detect Colon Cancer

by Dr. Len March 05, 2008

Today, the American Cancer Society released its latest recommendations for the prevention and early detection of colorectal cancer. 


The published guidelines offer a detailed roadmap on what works in colorectal cancer screening.  They include the same approaches that have been recommended in the past—including testing the stool for blood, sigmoidoscopy, colonoscopy and barium enema—and add two new approaches to the “recommended list” with the addition of CT colonography and stool DNA testing.


The experts who analyzed the data and made these recommendations made an important new distinction about tests used to screen for CRC by sorting the available screening tests into two categories: tests that are primarily used to detect colorectal cancer (CRC), and tests that have the potential to prevent colorectal cancer. 


They also indicated their preference was for tests that prevent this disease.


Here is what the authors say about what you should do: “It is the strong opinion that colon cancer prevention should be the primary goal of CRC screening.  Tests that are designed to detect both early cancer and adenomatous polyps should be encouraged if resources are available and patients are willing to undergo an invasive test.”


What many people don’t realize is that if we followed these guidelines, we could save thousands of lives every year.


The guidelines themselves are available online, along with a report that goes into great detail about which tests are recommended and why, as well as the strengths, limitations and possible harms of each test. 


These are guideline recommendations for screening people age 50 and older at average risk of developing CRC.  They are not for people at high risk because of other diseases, genetic abnormalities or family history of CRC.  In those circumstances, you need to check out the high risk screening recommendations found on our web site.


Another important point is that—just like the previous guidelines—the best test for you is the one you get and the one you are most comfortable with.  Making a decision may be easier for some people than others, but you need to make the decision in consultation with your health care professional.


Now on to the tests themselves.


Testing a series of stool specimens at home with the tried and true approach using guaiac cards (fecal occult blood test, or FOBT) remains an option, but only if the “sensitive” cards are used (your doctor will understand what that means).  These tests are inexpensive and widely available. 


Using a more patient friendly stool test called fecal immunochemical testing (or FIT) is also an option for screening.  This test is also more specific for finding colon cancer, and doesn’t require the limits on your diet before you do the test, as is the recommendation for FOBT.


There are important cautions with these tests, namely that you must follow the instructions carefully regarding dietary restrictions for the FOBT, and making certain you get samples from consecutive bowel movements.  Doing the test in your doctor’s office after a rectal exam (for men, it’s usually with a prostate exam and for women as part of their routine annual checkup) is not screening for CRC and should be discouraged!!!


Also, both of these tests only work effectively to find CRC and some large polyps if you do the test every year.


Which brings us to another new wrinkle in these guidelines.


In order to be considered effective in either detecting or preventing CRC, each test when done once must be able to find CRC at least 50% of the time when the disease is present.


It would be reasonable to ask if that is acceptable.  After all, don’t you want a test that will find cancer 100% of the time?


The answer from the report is that it may not be ideal, but at least it’s a standard to consider when evaluating a particular test.  More importantly, it also points out why it is so important with the FOBT and FIT tests that you repeat whichever one you use every year.  That repetition is what makes these tests work and gives you the best chance of finding CRC when it can be cured.


A new test recommended for the detection of cancer (and not prevention) is a stool DNA test.  This test is much more expensive than the others, and requires collecting an entire bowel movement and sending it to the lab for analysis.  The lab then processes the sample and looks for gene markers in the stool sample that are consistent with cancer in the bowel.


Research shows that—perhaps contrary to what you would think—patients seem to accept this test.  It meets the “50%” criteria noted above, however no one knows how often it should be repeated.  As noted in the guidelines report, the company recommends repeating this every 5 years.  However, there is no scientific evidence to back that recommendation. The bottom line is we don’t know how often it should be done to be maximally effective in detecting CRC.


Another problem with this test—as with FOBT and FIT—is that it detects cancer, not polyps (except in occasional situations).  Consequently, it is not a test that prevents cancer, but rather it is one that may find a cancer that is already present.


The next category of tests—which is the preferred approach—includes sigmoidoscopy, barium enema, colonoscopy and CT colonography.


Barium enema is infrequently performed today as a screening test. 


Similarly, the use of sigmoidoscopy is declining as a screening test for a variety of reasons including discomfort, the assumption that colonoscopy is more effective since it looks at the entire colon, and because few physicians are trained to do it well.  In addition, the new guidelines say that if your doctor does a screening sigmoidoscopy, she/he should be able to remove any polyps they see.  Few primary care physicians are capable of doing that properly.


Colonoscopy has developed a reputation as the “gold standard” for CRC screening, since the doctor can evaluate the entire colon and remove most polyps that are seen.  But not everyone can get a colonoscopy for any number of reasons, and some people don’t want to have a colonoscopy primarily because of the prep and the fact that they need to take time off from work.  Others can’t afford it, don’t have insurance, or have insurance that doesn’t cover colonoscopy as a screening test.


The report also points out that, despite the designation of this test as “the best test” by many doctors and patients, it is still not a perfect test. 


There is concern about the time the doctor takes to do the test: the longer she/he takes, the better the results.  But many doctors pride themselves on how quickly they can do the test. 


In addition, what many people don’t know is that colonoscopy is not 100% perfect at finding all polyps and all cancers.


Yes, studies do show that screening colonoscopy and removing pre-cancerous polyps reduce the incidence of CRC, but not 100% according to the guidelines report.  In fact, in one study the incidence of CRC within 5 years after colonoscopy was down about 50%, and over 10 years about 72%.  That’s pretty good, but a far cry from 100% that many doctors and patients assume to be the case.


Other studies show that colonoscopy misses large adenomas (precancerous benign growths) in the bowel 6 to 12% of the time, and misses actual cancers about 5% of time.


So, although colonoscopy is certainly an excellent test for CRC screening, it doesn’t find every polyp before it becomes cancerous.  Still, it is a very effective test in preventing CRC.


The other “new kid on the block” in these recommendations is CT colonography (CTC). 


In this test, using new up-to-date technology, you can get a CT scan which has an excellent chance of finding pre-cancerous polyps and actual cancers.  The test is done on a CT machine after the same prep used for regular colonoscopy.  It is quick, and does not require sedation.  There may be pain or discomfort from the air they have to pump into your colon at the time of the test. 


The problem is what to do about polyps that are found during the study.


If you are fortunate to have access to a radiology and GI practice that work together, you may be able to get a same day colonoscopy if the radiologist sees something on the scan. 


If you are not so fortunate, you have to come back another day to get your regular colonoscopy—after going through another full bowel prep.


Research studies performed by radiologists who were very experienced in doing CTC show that this procedure is about as effective as regular colonoscopy when it comes to finding larger polyps and cancers. 


Given the fact that we don’t know as much as we would like to about the effectiveness of CTC, the guidelines recommend repeating the study every 5 years if the initial CTC is negative.


As I mentioned earlier, the test you get is the one that is best for you.


The guidelines’ authors recommend that your first-line choice should be a test that both prevents and detects colorectal cancer.  These include barium enema, sigmoidoscopy, regular colonoscopy and CT colonography.


Tests that are primary designed to detect cancer but not prevent it are acceptable, but not the first choice of the guidelines.  These include annual FOBT, annual FIT, and stool DNA (but we don’t know how often this new test should be done).


But—as recently pointed out in the Presidential campaign—these are “just words.”


The words in this report do have meaning, but they only exist on paper.  To make them do something for you, you need to do something for yourself. 


You need to make the decision to get screened for colorectal cancer, and you need to do it now.


I hope I live to see the day when everyone who needs to be screened for this disease takes advantage of that opportunity.  We will never be able to prevent every colorectal cancer, or catch every colorectal cancer early when it has a very high chance of being cured.


What we can do is save thousands of lives every year, year after year if we only do what we already know works.


Now, I ask you: Is that asking too much?


I don’t think so.


Hormones And Breast Cancer, Again

by Dr. Len March 04, 2008

An article in today’s Journal of the American Medical Association (JAMA) is bound to add more confusion to the questions surrounding the impact of hormone replacement therapy (HRT) on the risk and incidence of breast cancer in post-menopausal women.


I have written several blogs previously on this topic, most of them discussing the reasoning behind the sudden and immediate drop in the incidence of breast cancer that was noted when the Women’s Health Initiative (WHI) study was discontinued in 2002.


Unlike previously published studies which showed a dramatic reduction in breast cancer incidence after the study was stopped and the use of post-menopausal HRT declined, the evidence in this report doesn't come to the same conclusion.  But, unfortunately, it also doesn't clarify the situation.


Today’s JAMA report is a follow-up on what happened to the 16,600 women who were part of a study evaluating the benefits and risks of post-menopausal women who received combined hormonal therapy with estrogen and progesterone for their post-menopausal symptoms.  Half of these women received HRT with the combination, and the other half took a placebo.  (There was a companion study of women who had had a hysterectomy and were treated only with estrogen, but that was not part of today’s report.)


The study was stopped abruptly and unexpectedly in July 2002 when it was found that a combination of factors suggested that the HRT treatment group fared worse than the placebo “non-treatment” group based on an analysis of study measures.


Among those factors was the observation that women taking combination HRT had a higher and growing risk of developing breast cancer.


In April 2007, there was an article in the New England Journal of Medicine (NEJM) which showed that there had been a dramatic decrease in the incidence of breast cancer beginning in 2002.  This decline began almost immediately after the WHI study was discontinued. 


Those authors showed that HRT prescriptions had dropped dramatically at the same time, and concluded that the decline was directly related to fewer women taking combined HRT.


So far so good, but I wasn’t convinced.  There were other factors—either known at the time of the New England Journal report or reported shortly thereafter—which had to be considered. 


Other researchers attributed some of the decline in breast cancer incidence to a decrease in mammography rates. If you don’t look for breast cancer, you won’t find it.


There was another report from my colleagues at the American Cancer Society which suggested that the decrease in breast cancer had actually started in the late 1990s, well before the WHI study was reported.  The theory was that perhaps the incidence of breast cancer had “leveled off” after many years of screening, since many non-invasive cancers had been detected and never progressed to invasive cancer.


Then there was the concern that since women had stopped taking their hormones and stopped seeing their doctors.  If they weren’t seeing their doctors, so the reasoning went, they weren’t getting recommendations for mammograms.


Other more recent studies (also reported in this blog) suggested that in the Medicare population—which is the group at highest risk of breast cancer and the group studied in the WHI—HMO insurers discouraged women from getting mammograms if they increased their co-pay requirements.


One particular concern that I expressed in my blogs was that breast cancer takes a long time to develop.  It didn’t make sense that these cancers would suddenly disappear when HRT was stopped.  Grow more slowly?  Yes.  Disappear completely? No.


In any event, my concern—which is not widely held, to be honest—was that over time we would inevitably see an increase in breast cancer incidence and deaths.


In today’s JAMA study, the researchers looked at what happened to the health of the two groups of women—those who received combined HRT and those who received the placebo—after the WHI study was halted in July 2002.  They examined their status through March, 2005.


They concentrated specifically on some of the problems found while the WHI study was active, and which led to its discontinuation prior to the planned date.  One of those problems was the increased risk of breast cancer in the treatment group.


When it came to cancer, they found that the overall cancer risk of death increased in the treatment group after the study was halted.


Regarding breast cancer, the researchers did see a slight decrease in the risk of breast cancer, but it wasn’t the dramatic decline which would have been predicted by the other study in the New England Journal.


The researchers in the current study did note that much of the increased risk of death in the post-treatment follow-up actually came from cancers others than those studied in the original trial.  They specifically commented on the increased risk of death from lung cancer in the group that had received HRT in the past.


The researchers wrote that during the WHI study there had been a growing increased risk of breast cancer in the women who took the combined HRT.  The increased risk of breast cancer remained after HRT was discontinued, but the rate of the increase did not keep growing larger.  At the same time, and acknowledging the fact that these women kept on getting mammograms, they did not see a fall off in the incidence of breast cancer as would have been expected based on the other research I discussed above.


Although that did not jibe with what would have been expected based on the New England Journal report, according to the authors the current study simply was not big enough or long enough to confirm or deny the prior report that the decrease in breast cancer incidence was directly related to women stopping their hormones.   They concluded that their study could neither support or be used to deny any theory that had been advanced to explain the drop in breast cancer incidence reported in the NEJM.


Confused?  You probably are, and so am I.


Here we have the most carefully followed group of women who took HRT whose follow-up was continued by the researchers after the women stopped HRT.  And, despite what would have been predicted by the NEJM research, the breast cancer incidence rates did not fall off a cliff when they stopped HRT.


There certainly is a substantial amount of expert opinion that believes that the decrease in breast cancer over the past several years is related to less frequent use of HRT, over shorter durations.


But there are also other possible explanations which also have an impact on breast cancer rates, as outlined above.


So, when everything is considered, we still have uncertainty (and perhaps a bit more uncertainty at that) as to what has caused the decrease in breast cancer rates over the past several years and how much of that decrease was directly related to women stopping combination HRT.


It is inevitable that as time goes on we will be able to get a better handle on this complex question.


I will emphasize that there is nothing in this report which does anything other than support our current approach to the use of HRT in post-menopausal women, which is the lowest dose needed to control symptoms for the shortest time.  Today's report does not suggest that we should abandon those recommendations, and I certainly agree with that conclusion.


In the meantime, if we don’t do something about the flagging rates of mammography, I remain concerned that we may inevitably see an increase in the number of breast cancers diagnosed at later stages, which will inevitably lead to more deaths from this disease.


I suspect that almost all experts agree that would be a tragedy.











About Dr. Len

Dr. Len

J. Leonard Lichtenfeld, MD, MACP - Dr. Lichtenfeld is Deputy Chief Medical Officer for the national office of the American Cancer Society.