Last week the New England Journal of Medicine published the most recent results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial looking at blood pressure and lipid management in patients with type 2 Diabetes.
Published guidelines for diabetes treatment suggest that diabetic patients should be treated to a blood pressure goal of <130/80 to reduce the risk of cardiovascular and renal complications. The current published blood pressure guidelines for diabetes are based on two previous large clinical trials: the United Kingdom Prospective Diabetes Study, and a post-hoc subgroup analysis of the trial Hypertension Optimal Treatment study.
In last week’s ACCORD results, diabetic patients who were randomized to intensive blood pressure control (systolic blood pressure < 120) were compared with those with those treated to a standard treatment goal for blood pressure (systolic blood pressure < 140). Patients were followed for 5 years and there was no difference found in either fatal or non-fatal cardiovascular events between groups.
In the case of lipid treatment in diabetic patients, last week’s NEJM reported on the outcome of type 2 diabetic patients treated with a statin alone (simvastatin) versus those treated with a combination of simvastatin plus fenofibrate. Although the addition of the fenofibrate did result in lower triglyceride levels and higher HDL levels, the study showed no difference in cardiovascular outcomes between these groups, except in a subgroup of patients with the most profound dyslipidemia. In this subgroup mean HDL cholesterol was 30 and mean triglyceride level was 284.
What do these findings mean? The American Diabetes Association 2010 treatment guidelines for diabetes recommend treating diabetic patients to a goal of a systolic blood pressure <130. The ACCORD study treated patients to an even more aggressive goal (sbp <120). It seems the more aggressive goal should not be recommended. Whether or not we should relax our treatment goals for diabetic patients, to the same goals as the general population with hypertension (<140) remains in question, but the study provides evidence pointing in this direction.
Perhaps the most salient point, brought out by the lipid study, is that once again physicians should be skeptical about treating to particular numerical goals without clear evidence that these targets will translate to improved outcomes for patients. Although fenofibrate is clearly effective in lowering triglycerides and raising HDL, a positive impact of this effect in terms of actual outcomes was only seen in diabetics with more profound dyslipidemia.
The other limitations of the ACCORD study worth mentioning are that:
1. Patients were only followed for 5 years, and
2. The study population was high risk type 2 diabetics (>40 and cardiovascular disease, or >55 and two additional cardiovascular risk factors).
How these results translate to healthier type 2 diabetics treated in earlier stages of illness for longer periods of time remains unknown.
Thursday, March 18, 2010
Saturday, March 13, 2010
Is Watchful Waiting too Difficult?
The rise of prophylactic double mastectomy in women with increased risk of breast cancer was recently discussed in The New York Times Health section. In particular, it noted this trend amongst women with the diagnosis of unilateral ductal carcinoma in situ (DCIS), or pre-invasive breast cancer. While it has been known that in women with genetic cancer syndromes, including BRCA1 and BRCA2, double mastectomy reduces risk, the efficacy of the approach is uncertain in women with other risk profiles, yet more women and surgeons seem to be doing it.
Knowing when to test, treat and act is part of art of medical practice. The ability to convey this information effectively is also an art. Both patients and doctors may have a hard time embracing watchful waiting with respect to many forms of cancer and pre-cancer. In the case of cancer of the cervix, it is known that infection with Human Papillomavirus (HPV) is causative in cancer development. However, only a small percentage of those infected actually go on to get cancer. Low grade dysplasia, a condition that is early in the cervical cancer development continuum, frequently spontaneously resolves without treatment. Fortunately, in the case of cervical cancer, there is now a vaccine to prevent high risk HPV infection.
"Watchful waiting" has been most discussed as a treatment strategy for prostate cancer. Treatment for prostate cancer, including radical prostatectomy, is fraught with side effects that may negatively impact quality of life. The watchful waiting approach is most commonly agreed upon for older men with medical co-morbidities, or limited life expectancy. However a recent study in the New England Journal of Medicine followed men who were screened for prostate cancer with PSAs and found no mortality benefit to early detection at 10 years, calling into question the utility of screening even younger men.
In the case of breast cancer, the United States Preventive Services Task Force recently published its revised guidelines for breast cancer screening suggesting that mammography screening be delayed in most women until age 50. These recommendations were in part based on the finding of “adverse effects” resulting from overzealous screening procedures. Although breast cancer screening in women ages 40 to 50 is known to be effective for early detection, its use is associated with the detection of a range of abnormalities of the breast, which lead to further evaluations including follow-up mammograms, MRIs and biopsies. Of course, these procedures are anxiety-provoking and costly. What's more, pre-cancerous breast disease, as is true with other precancerous conditions, may not always progress to invasive cancer.
Invasive cancer of the breast arises from pre-invasive conditions of breast tissue, the most benign of which is ductal hyperplasia, followed by atypical ductal or lobular hyperplasia, followed by ductal and lobular carcinoma in situ (DCIS). Even the carcinomas in situ (considered stage 0, cancer) vary in their genetics, histological characteristics and aggressiveness. The differentiation amongst these pre-cancerous conditions may be subtle and subject to variable interpretation depending on the pathologist. The appropriate management of these conditions, once detected, remains controversial.
In the past several decades the diagnosis of pre-malignant breast disorders has grown, paralleling the increased use of screening mammography. DCIS is characterized by many of the same histological and genetic features as invasive breast cancer. In DCIS, however, no invasion through the duct basement membrane occurs. DCIS represents twenty percent of malignancy detected by mammography. Ninety percent of women in which this condition is detected are asymptomatic at the time of diagnosis. Longitudinal studies of the natural history of DCIS in untreated women suggest that 15 to 60 percent will develop breast cancer in the affected breast after 10 years. This is a broad range and at this point it is not well-understood what factors cause breast cancer to develop in some women with DCIS, while cancerous changes to regress in others.
DCIS is typically diagnosed after microcalcifications are detected on mammogram. by means of stereotactic needle biopsy. The current standard of care involves wider surgical excision of surrounding breast tissue. In 10 to 15 percent of cases invasive cancer is detected in the excised tissue. However, the impact of DCIS treatment on breast cancer mortality is unclear. In addition, there is not evidence to support the removal of an unaffected breast in cases where the DCIS is unilateral.
With medicine’s current focus on early detection and the abundance of information that it may provide, it becomes increasingly important to make sure that our remedies are not worse than our diseases. After all, as much as we may not like to hear it, we are all diseased, and in effect, pre-cancerous. “First do no harm,” is part of the Hippocratic Oath. It may be easier, and perceived as less risky, to do another test, or to recommend a treatment to a patient in lieu of engaging in a detailed discussion of risks and benefits. In many cases the risks of pre-cancerous conditions are not well delineated. I am very much in favor of using current medical technology and information to detect cancer and pre-cancer. However in doing this, both doctors and patients must question what will be done with the information that we discover, and develop comfort that watchful waiting can sometimes be a good option when abnormalities are detected.
Knowing when to test, treat and act is part of art of medical practice. The ability to convey this information effectively is also an art. Both patients and doctors may have a hard time embracing watchful waiting with respect to many forms of cancer and pre-cancer. In the case of cancer of the cervix, it is known that infection with Human Papillomavirus (HPV) is causative in cancer development. However, only a small percentage of those infected actually go on to get cancer. Low grade dysplasia, a condition that is early in the cervical cancer development continuum, frequently spontaneously resolves without treatment. Fortunately, in the case of cervical cancer, there is now a vaccine to prevent high risk HPV infection.
"Watchful waiting" has been most discussed as a treatment strategy for prostate cancer. Treatment for prostate cancer, including radical prostatectomy, is fraught with side effects that may negatively impact quality of life. The watchful waiting approach is most commonly agreed upon for older men with medical co-morbidities, or limited life expectancy. However a recent study in the New England Journal of Medicine followed men who were screened for prostate cancer with PSAs and found no mortality benefit to early detection at 10 years, calling into question the utility of screening even younger men.
In the case of breast cancer, the United States Preventive Services Task Force recently published its revised guidelines for breast cancer screening suggesting that mammography screening be delayed in most women until age 50. These recommendations were in part based on the finding of “adverse effects” resulting from overzealous screening procedures. Although breast cancer screening in women ages 40 to 50 is known to be effective for early detection, its use is associated with the detection of a range of abnormalities of the breast, which lead to further evaluations including follow-up mammograms, MRIs and biopsies. Of course, these procedures are anxiety-provoking and costly. What's more, pre-cancerous breast disease, as is true with other precancerous conditions, may not always progress to invasive cancer.
Invasive cancer of the breast arises from pre-invasive conditions of breast tissue, the most benign of which is ductal hyperplasia, followed by atypical ductal or lobular hyperplasia, followed by ductal and lobular carcinoma in situ (DCIS). Even the carcinomas in situ (considered stage 0, cancer) vary in their genetics, histological characteristics and aggressiveness. The differentiation amongst these pre-cancerous conditions may be subtle and subject to variable interpretation depending on the pathologist. The appropriate management of these conditions, once detected, remains controversial.
In the past several decades the diagnosis of pre-malignant breast disorders has grown, paralleling the increased use of screening mammography. DCIS is characterized by many of the same histological and genetic features as invasive breast cancer. In DCIS, however, no invasion through the duct basement membrane occurs. DCIS represents twenty percent of malignancy detected by mammography. Ninety percent of women in which this condition is detected are asymptomatic at the time of diagnosis. Longitudinal studies of the natural history of DCIS in untreated women suggest that 15 to 60 percent will develop breast cancer in the affected breast after 10 years. This is a broad range and at this point it is not well-understood what factors cause breast cancer to develop in some women with DCIS, while cancerous changes to regress in others.
DCIS is typically diagnosed after microcalcifications are detected on mammogram. by means of stereotactic needle biopsy. The current standard of care involves wider surgical excision of surrounding breast tissue. In 10 to 15 percent of cases invasive cancer is detected in the excised tissue. However, the impact of DCIS treatment on breast cancer mortality is unclear. In addition, there is not evidence to support the removal of an unaffected breast in cases where the DCIS is unilateral.
With medicine’s current focus on early detection and the abundance of information that it may provide, it becomes increasingly important to make sure that our remedies are not worse than our diseases. After all, as much as we may not like to hear it, we are all diseased, and in effect, pre-cancerous. “First do no harm,” is part of the Hippocratic Oath. It may be easier, and perceived as less risky, to do another test, or to recommend a treatment to a patient in lieu of engaging in a detailed discussion of risks and benefits. In many cases the risks of pre-cancerous conditions are not well delineated. I am very much in favor of using current medical technology and information to detect cancer and pre-cancer. However in doing this, both doctors and patients must question what will be done with the information that we discover, and develop comfort that watchful waiting can sometimes be a good option when abnormalities are detected.
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