Primecuts – This Week In The Journals

September 7, 2010

By Gopi Nayak, MD

Faculty Peer Reviewed

This week as Labor Day weekend marks the end of summer, President Obama calls for major spending on public works to jump-start the economy, while tennis stars continue to battle it out at Arthur Ashe stadium.

 In medical news, this week’s JAMA featured a prospective multicenter cohort study of women with BRCA1 and BRCA2 mutations to estimate the risk and mortality reduction following prophylactic mastectomy [1] and salpingo-oophorectomy, specifically stratifying risk reduction based on mutation status and prior history of breast cancer.

 The study confirmed the benefit of risk-reducing mastectomy (RRM) to prevent the occurrence of breast cancer with a difference of 0 new breast cancer diagnoses over a 3 year follow-up period among women who underwent RRM vs 7% in women undergoing aggressive screening alone.  In women who underwent risk-reducing salpingo-oopherectomy (RRSO), the risk of ovarian cancer decreased by 85% and 70% in BRCA1 mutation carriers with and without a history of prior breast cancer, respectively.  No primary peritoneal cancers were observed in BRCA2-positive women who underwent RRSO vs 3% observed in women who did not have RRSO.  Next the authors looked at the effect of RRSO on breast cancer risk.  RRSO was associated with a significant reduction in breast cancer risk in women without a previous diagnosis of breast cancer, more prominent in BRCA2 carriers (64% reduction) vs BRCA1 carriers (37% reduction) perhaps owing to the higher percent of ER-positive breast tumors in BRCA2 vs BRCA1. The study showed no decrease in risk of a second primary breast cancer in women who had a prior breast cancer diagnosis at the time of RRSO.  The study also showed a significant reduction in all-cause mortality, breast cancer-specific mortality and ovarian cancer mortality after risk-reducing salpingo-oopherectomy; there was also a suggestion that earlier intervention (prior to age 50) may be more beneficial than later ones.   

 Overall the risk reduction estimates afforded by RRM and RRSO are striking, however further refining the estimates based on mutation status and prior cancer history may change how physicians counsel their patients and will allow women with known BRCA mutations to make better informed decisions regarding their treatment.  Though it may make the decision to delay or not undergo RRM or RRSO even more difficult, especially for younger women who want to preserve their ovarian and breast function.   

 In other cancer-related news, The Lancet reports Trastuzumab may increase overall survival in HER2-positive advanced gastric or gastro-esophageal junction cancer [2] when used in combination with chemotherapy.  This randomized, multicenter international phase 3 trial of chemotherapy with trastuzumab vs standard chemotherapy demonstrated a median overall survival increase from 11.1 to 13.8 months and a median progression-free survival increase from 5.5 to 6.7 months, with a stronger effect seen in patients with tumors expressing high levels of HER2 protein.  Longer term survival rates in both groups were similar. There was no difference in overall rates of adverse events, however patients in the trastuzumab plus chemotherapy group had higher rates of certain side effects such as diarrhea, stomatitis and thrombocytopenia, and treatment related mortality was slightly higher (3% vs 1%).  Based on the results of this study the authors concluded that trastuzumab can be considered “a new standard option for patients with HER2-positve gastric or G-E junction cancer when combined with current chemotherapy regimens.”  However, as pointed out in a commentary by Munro and Niblick, the cost of treatment for one patient is approximately ~$21 000, equivalent to the totally yearly health spending for 3 US citizens or 500 citizens in India.  The authors question whether 2 ½ months is a large enough increase in survival time to warrant an expenditure of that size.  The authors of this study, funded by F Hoffman-La Roche, the makers of Trastuzumab, certainly suggest yes, but in the face of a potential worldwide market worth more than ₤265 ($408) million per year, it may have been hard to say no.

 The Archives of Internal Medicine addressed the question of biochemical recurrence (increasing PSA after radical prostatectomy or radiation therapy) [3] and its association with prostate cancer specific mortality.  This observational VA study demonstrated a biochemical recurrence (BCR) rate of 34%, 37%, and 37% at 5, 10, and 15 years after prostatectomy and a prostate cancer mortality of 3%, 11%, and 21% at 5, 10, and 15 years.  Following radiation therapy, BCR rates were 35%, 46%, and 48%, with prostate cancer mortality rates of 11%, 20%, and 42% at 5, 10, and 15 years.  As expected, biochemical recurrence is associated with an increased rate of prostate specific mortality, yet the relative risk even after BCR, remains low, with death caused by prostate cancer seen in less than half of men with BCR.  For patients this information may provide some relief or perhaps just increased uncertainty. 

 In cardiovascular news, given the discrepancy between dosing strategies among physicians, the CURRENT-OASIS 7 trial sought to identify optimal dosing regimens of clopidogrel[4]  and aspirin during the initial 7 days after acute coronary syndromes in patients referred for early invasive strategy.  The study design consisted of a 2×2 factorial design to investigate if doubling the loading and initial maintenance doses of clopidogrel (600mg followed by 150mg daily for 6 days) is superior to standard dosing (300mg followed by 75 mg daily for 6 days) and whether high dose aspirin (300-325mg) is superior to low dose aspirin (75 to 100mg) for 30 days after ACS.  Full dose aspirin was given to both groups on day one and both clopidogrel groups received 75mg of clopidogrel daily for the remainder of the 30 day treatment period.  At 30 days, results showed no difference in cardiovascular death, myocardial infarction or stroke between high and low dose clopidogrel groups, though an increased risk of major bleeding was seen in the high dose group.  During subgroup analysis, double-dose clopidogrel was associated with a significant reduction in the rate of stent thrombosis in the subset of patients who underwent PCI.  In the aspirin comparison group, no significant benefit was seen between high and low doses and no significant difference was seen with regard to risk of major bleeding events; however, a nominally significant increase in minor bleeding and a slight increase in the incidence of major GI bleeding was seen in the high dose group.  The authors concluded that treatment with either high or low dose aspirin for the first 30 days appears to be acceptable, and given the increased risk of major bleeding, this study suggests standard dosing of clopidogrel is the preferred regimen, except perhaps in patients undergoing PCI.

 A retrospective study of 100,000 Swedish patients presenting with a first acute myocardial infarction [5] (MI) demonstrated that patients presenting with STEMI were younger, had less prior cardiovascular disease and had used fewer medications prior to presentation.  Prior use of aspirin, beta-blockers, ACE inhibitors or statins were all independently associated with a lower risk of presenting with a STEMI vs an NSTEMI.  Use of one medication was associated with a decreased risk of presenting with a STEMI, with a further risk reduction of 15-25% when 2 and 3+ medications were taken.  However, 30 day mortality was not affected by the number of medications taken.  The study emphasizes the benefit of preventive medications, in this case decreasing the risk of STEMI in patients presenting with a first acute MI.

 Several articles this week featured the topic of medical education and training.

This weeks New York Times featured NYU in an article on new changes to the standard medical school curriculum.[6]  Instead of waiting for their third-year, medical students were introduced to patients on their first day of class, prior to receiving any medical knowledge.  The curriculum at NYU and at other medical schools across the country have been revised to increase clinical exposure during the first two years of school with the aim to foster more personal relationships earlier on between patients and students.  Some say these changes, taking place at NYU and at other national medical schools, is in response to a fear among medical professions that today’s young physicians lack humanity and have a “loss of idealism, empathy, and morality.”  In fact a study published by Dr. Fitzhugh Mullen of George Washington University ranked NYU fifth worst in the nation at promoting socially conscious medicine.  It is unclear from this article what his study findings were based on.  Regardless of why the changes were instituted, NYU medical students will have a chance to improve their clinical skills and see pathology as it manifests itself while they learn the fundamental sciences behind disease. 

 In other education news, medical educators gathered at a forum entitled “Innovating and Updating the Medical School Curriculum.”  An article in Nature Medicine suggested that traditional cadaver dissection, a rite of passage for first-year medical students, and a staple of the traditional curriculum may become a thing of the past [7] as computer assisted simulations and three dimensional anatomical models or robotic patients take over in classrooms.  The shortage is attributed in part to the lack of cadavers as fewer people donate their bodies to medicine.

 What about that C+ in Organic Chemistry?

The Lancet featured a perspective article on the dangers of using performance in undergraduate science courses as a criteria for acceptance into medical school.[8]  The author states that instead of being a marker of future excellence as a physician, undergraduate grades have no correlation with the qualities that make a great physician: the ability to connect, communicate and empathize with patients.  His research showed that while performance in the premedical sciences does correlate with success in the preclinical years, it does not correlate with faculty evaluations of clinical performance and is “inversely associated with many of the personal, non-cognitive qualities so central to the art of medicine.”  He cites a series of psychological tests performed in the 1950s and ‘60s that states what many of us have experienced firsthand, that students who do better in science are “narrower in interests, less adaptable, less articulate, and less comfortable in interpersonal relationships.” 

 Lastly, JAMA features an article on new proposed rules on resident duty hours set forth by the ACGME.[9]  Some of the proposed rules include setting a 16 hour limit on first-year shifts, and requirements that interns are directly supervised by a physician, or the supervising physician remain on-site. 

Dr. Nayak is a first year resident at NYU Langone Medical Center

Peer reviewed by Cara Litvin, Executive Editor, Clinical Correlations

Image of  Caroline Wozniacki courtesy of Wikimedia Commons.

References:

 [1] Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, Garber JE, Neuhausen SL, Matloff E, Eeles R, Pichert G, Van t’veer L, Tung N, Weitzel JN, Couch FJ, Rubinstein WS, Ganz PA, Daly MB, Olopade OI, Tomlinson F, Schildkraut J, Blum JL, Rebbeck TR.  Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010 Sept 1; 304(9): 967-975.  http://jama.ama-assn.org/cgi/content/full/304/9/967

 [2] Bang Y-J, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang Y-K.  Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.  Lancet. 2010 Aug 28; 376:687-97.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61121-X/abstract

 [3]  Uchio EM, Aslan M, Wells CK, Calderone J, Concato J.  Impact of Biochemical recurrence in prostate cancer among US veterans.  Archiv of Intern Med.  2010 Aug 23; 170 (15): 1390-1395.  http://archinte.ama-assn.org/cgi/content/abstract/170/15/1390

 [4]  Mehta SR, Bassand J-P, Chrolvicius S, Diaz R, Eikelboom JW, Fox KA, Granger CB, Jolly S, Joyner CD, Rupprecht HJ, Widimsky P, Pogue J, Yusuf S.  Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Eng J of Med.  2010 Sept 2; 363 (10): 930-942.  http://www.nejm.org/doi/pdf/10.1056/NEJMoa0909475

[5]  Bjorck L, Wallentin L, Stenestrand U, Lapas G, Rosengren A.  Medication in relation to ST-segment elevation myocardial infarction in patients with a first myocardial infarction.  Arch Intern Med. 2010 Aug 23; 170(15): 1375-1381.   http://archinte.ama-assn.org/cgi/content/short/170/15/1375

 [6]  http://www.nytimes.com/2010/09/03/nyregion/03medschool.html?src=me&ref=general

 [7]  Palmer R.  Educators dissect the future of medical training.  Nature Medicine.  2010 Aug; 16(8): 836-837.  http://www.nature.com/nm/journal/v16/n8/full/nm0810-836a.html

 [8]  Barr DA. The art of medicine.  Science as superstition: selecting medical students.  Lancet.  2010 Aug 28; 376: 678-679.   http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61325-6/fulltext

 [9]  Kuehn BM. New rules call for more oversight, fewer hours for first-year residents.  JAMA. 2010 Sept 1; 304(9): 950-951.  http://jama.ama-assn.org/cgi/content/short/304/9/950

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