PrimeCuts: This Week in the Journals

October 26, 2009

mtredoubtTodd Cutler MD

Faculty peer reviewed

It’s a tired cliché, but this week the flies on the wall at the American Cancer Society were undoubtedly privy to some fascinating conversation. The dialogue began, in the popular press at least, with a special communication published in JAMA, in which the authors sounded a clarion call for a nationwide overhaul of the current breast and prostate cancer screening guidelines. In a strongly-worded argument, the authors synthesized the results of multiple studies at the levels of epidemiology, clinical practice, and molecular biology to support their stance that mammograms and PSA testing have the same general failing: they are large screening programs that contribute to minimal, at best, reductions in mortality, but create massive physical and emotional burden to patients.  The likely explanation for this phenomenon, the authors suggested, is that cancers discovered when they are localized rarely progress to life-threatening disease, while aggressive cancers, or interval cancers, metastasize rapidly and therefore are infrequently detected at stages where diagnosis via screening tests and subsequent interventions improve clinical outcomes. Modest decreases in mortality were difficult to attribute to early detection considering the changing landscape of general breast and prostate cancer treatment over the past 20 years.

The authors sketched a broad, if not purposefully nebulous, outline to guide the medical community moving forward. Their recommendations include the development of biomarkers that delineate between aggressive and indolent tumors  as well as systematically reducing treatment for patients with low-risk lesions. The authors, perhaps recognizing the political and social consequences of these implementations, suggest a moratorium on the use of the word “cancer” to describe minimal-risk lesions and instead advise implementing use of the term “indolent lesions of epithelial origin” (IDLE). They also asserted that physicians require more accurate stratification tools to comprehensively educate patients in regards to the risks and benefits of cancer screening.

While deficiencies of mammograms and PSA tests have been widely discussed for many years, their entrenched status in the medical community’s screening armamentarium and their popularity with the general public, make any near-future supplantation seem unlikely. On the same day the article was released, however, the New York Times reported that the American Cancer Society (ACS) was planning to modify its stance on the benefits of breast and prostate cancer screening – partially in response to the JAMA publication. Dr. Otis Brawley, the ACS chief medical officer, was quoted as saying, “We don’t want people to panic…but I’m admitting that American medicine has over-promised when it comes to screening. The advantages to screening have been exaggerated.” Dr. Brawley tepidly continued, “If a woman says, ‘I don’t want [a mammogram],’ I would not think badly of her, but I would like her to get it.”

In order to quash any suggestion of short-term indecision, the next day Dr. Brawley released a statement on the ACS website reaffirming the Society’s stance that women above the age of 40 should receive annual mammograms and that men should discuss the risks and benefits of prostate screening with their physician. He acknowledged, however, that, “Simple messages are not always possible, and over-simplifying them can in fact do a disservice to the very people we serve.” That same day, the New York Times ran a follow-up piece in which Dr. Barnett S. Kramer, associate director for disease prevention at the NIH, charged, “The health professions have played a role in oversimplifying and creating the stage for confusion. It’s important to be clear to the public about what we know and be honest about what we don’t know.” Two days later, the CEO of ACS, Dr. John Seffrin, reiterated the statement of Dr. Brawley, while acknowledging the imperfections of breast and prostate cancer screening.

So, what to make of all of this? The evidence is mounting against the effectiveness of mammograms in preventing metastatic breast cancer. The authors of the JAMA article cleverly strengthened their argument against mammograms by paralleling their inadequacies with PSAs – a test many practicing physicians have already dropped in light of its clinical shortcomings. The paradigm shift called for, however, requires technologic and infrastructural advances that appear to be out of reach considering modern capabilities. While these statements from ACS and other societies will undoubtedly spark a move towards change, for the time being it appears that the status quo will be maintained so as to prevent any conception that physicians are lurching from one recommendation to another a politically dangerous notion when considering the exquisitely sensitive emotions evoked by the topic of breast cancer. This may be the beginning of a reform movement in the medical community that will end up affecting millions of Americans.

In other exciting news, an endothelin type A receptor antagonist was effective in reducing blood pressure in patients who were refractory to at least three anti-hypertensive agents according to a report published this week in the Lancet. Endothelin acts on vascular endothelial cells to induce vasoconstriction. The randomized double-blind placebo-controlled study compares darusentan with placebo and found that blood pressure was equally reduced (p<0.0001) with escalating doses of the drug. The most common side effect in the treatment group was lower extremity edema. The addition of a new class of drug to the battery of anti-hypertensive agents at our disposal is an exciting prospect, especially in patients who are poorly managed on currently available agents. This trial, however, was small (n=329), so future studies will hopefully be powered to assess any impact on clinical outcomes.

Lastly, platelets stored at cool temperatures are rapidly cleared from circulation, which necessitates storage at room temperature, and essentially creating an ideal broth for bacterial growth. For this reason, platelet transfusions are associated with greater risk of sepsis compared to other blood products, limiting their shelf life to five days. A study in Nature Medicine illustrated this process of rapid platelet clearance.  The chilling of platelets results in the upregulation of galactose moieties on their surface that, upon transfusion in mice, are subsequently recognized by the Ashwell-Morell asialoglycoprotein receptor on the surface of hepatocytes. Inhibitors of this receptor improve the survival of refrigerated platelets to a level comparable to those stored at room temperature, a phenomenon that was replicated in Ashwell-Morell knockout mice. Binding by the Ashwell-Morell receptor was also partially dependent on the GPIb-α receptor on platelets. Additionally, this report generates interest because macrophages, and not hepatocytes, are typically considered to be the primary cell type responsible for clearing circulating platelets. While this report did show that macrophages were responsible for the clearance of rapidly chilled platelets in the short term, hepatocytes appear to be more important than previously recognized. In summary, this study raises the tantalizing proposition that modulation of sugar residues or treatment with inhibitors of the Ashwell-Morell receptor may allow for the storage of platelets at refrigerated temperatures, simultaneously decreasing the risk for transfusion-associated infections while alleviating the chronic platelet shortages that plague all hospitals.

Dr. Cutler is a 1st year internal medicine resident at NYU Medical Center.

Faculty peer reviewed by Barbara Porter MD MPH,  Clinical Assistant Professor of Medicine, NYU Medical Center

Esserman L, Shieh Y, Thompson I. Rethinking screening for breast cancer and prostate cancer. JAMA. 2009 Oct 21; 302(15):1685-92.
Kolata G. Cancer Society, in Shift, Has Concerns on Screenings [Internet]. The New York Times; 2009 Oct 20. Available from: http://www.nytimes.com/2009/10/21/health/21cancer.html?_r=1&ref=health
Brawley O. American Cancer Society Stands by Its Screening Guidelines; Women Encouraged to Continue Getting Mammograms [Internet]. The American Cancer Society; 2009 Oct 21. Available from: http://www.cancer.org/docroot/MED/content/MED_2_1x_American_Cancer_Society_Stands_by_Its_Screening_Guidelines_Women_Encouraged_to_Continue_Getting_Mammograms.asp
Parker-Pope T. Benefits and Risks of Cancer Screening Are Not Always Clear, Experts Say [Internet]. The New York Times; 2009 Oct 21. Available from: http://www.nytimes.com/2009/10/22/health/22screen.html
Seffrin J. A Special Message from CEO John Seffrin, Ph.D. on Cancer Screening [Internet]. The American Cancer Society; 2009 Oct 23. Available from: http://www.cancer.org/docroot/MED/content/MED_2_1x_A_Special_Message_from_CEO_John_Seffrin_PhD_on_Cancer_Screening.asp
Weber M, Black H, Bakris G. A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial. The Lancet. 2009 Oct 24; 374(9699):1423-1431.
7)Rumjantseva V, Grewal PK, Wandall HH. Dual roles for hepatic lectin receptors in the clearance of chilled platelets. Nat Med. 2009 Sep 27. [Epub ahead of print] Available from: http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2030.html

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