Faculty Peer Reviewed
Good morning. As the snow melts away from New York City and the sun can once again shine on the city streets that we take for granted, the US Medical Community is too re-examining practice standards that we take for granted. This purposeful reflection seems to be an attempt to expand evidence-based practice, improve patient outcomes and reduce health-care expenditures. This week several groups provided new perspective on old issues including the treatment of pancreatic neuroendocrine tumors and breast cancer, anticoagulation in atrial fibrillation and back pain. No corner was left covered as new light was shed even on old standards: tuberculosis and smoking.
First in this week’s New England Journal of Medicine, two examples of medications with accepted indications in advanced renal cell carcinoma (RCC) were studied in pancreatic neuroendocrine tumors. These phase three trials were built on data obtained in phase 1 and 2 trials. Raymond and colleagues, in a study sponsored by Pfizer, the manufacturers of the study drug, carried out a multinational, randomized, double blind, placebo controlled trial between 2007 and 2009. They studied a total of 171 patients with pancreatic neuroendocrine tumors, half of whom received sunitinib (sutent), a tyrosine kinase inhibitor used to treat advanced RCC and refractory gastrointestinal stromal tumors, and the other half received a placebo. Patients with well-differentiated, but advanced or metastatic pancreatic endocrine tumors and evidence of disease progression were included if they had a measureable lesion and a good performance status. The study was ended early due to the disparity in results of the primary endpoint: the mean progression-free survival was 11.4 months in the sunitinib group versus 5.5 months in the placebo group (a hazard ratio of 0.42). [1,2,3,5]
In the same New England Journal issue, Yao and colleagues published results of their randomized, placebo controlled trial on everolimus for treatment of advanced pancreatic neuroendocrine tumors. Using an intention to treat analysis, researchers funded by Novartis looked at this drug, which is a mammalian target of rapamycin inhibitor (mTOR inhibitor). Like the prior study, these researchers also found a positive result in the primary endpoint of median progression –free survival. In 410 patients with evidence of radiologic progression of advanced low grade or intermediate grade pancreatic neuroendocrine tumors, the everolimus group had an 11 month median progression free survival versus 4.6 in the placebo group (hazard ratio of 0.35) [3,5]. Outcomes for patients with advanced pancreatic neuroendocrine tumors have been stagnant for many years and therefore this study and the report on sunitinib in this issue of NEJM may prove to be a modest break for this population.
Next up in cancer news, a new look at management of breast cancer that may have a major impact on women with breast cancer. JAMA published a study by Giulinano and colleagues who set out to assess the effect of complete axillary lymph node dissection on survival of patients with clinical stage T1-T2 invasive breast cancer, with no palpable nodes who have one to two SLNs that are positive for metastasis. They designed a non-inferiority trial and employed intention-to-treat as well as treatment-received analyses. All patients underwent lumpectomy, tangential whole-breast radiation and SLN detection. Patients with one to two positive SLNs were randomized to either no further axillary lymph node dissection or further axillary lymph node dissection. Supplemental systemic therapy as determined by patients’ physicians were allowed and patients were followed for a mean of 6.3 years. With regard to the primary end-point of 5 year survival as well as the secondary end-point of disease free survival, sentinel lymph node dissection alone was not inferior to a complete axillary lymph node diessection. The stats for further axillary lymph node dissection versus no further dissection were 91% vs. 92.52 % five year survival (hazard ratio 0.79), respectively and 82% versus 83% disease free survival (hazard ratio 0.87), respectively. I am excited to see how this may impact clinical practice. Perhaps clinicians will be able to use this study’s findings to counsel patients when offering a treatment plan.
In internal medicine atrial fibrillation and back pain are like bread and butter. Anticoagulation research however is certainly not allowed to get stale. To keep the metaphor going, this week’s batch of research included Conolly and colleagues’ report on apixaban. This relatively new factor Xa inhibitor dosed twice daily held up well compared to aspirin alone for the prevention of stroke or any systemic embolism in patients at high risk for stroke, but in whom a vitamin K antagonist (i.e. Warfarin) was contraindicated. The study was a randomized, double blind head-to-head comparison of apixaban dosed at 5 mg by mouth twice daily with aspirin from 81 to 324 mg by mouth once daily. Analysis was done by intention-to-treat method. Approximately 5600 patients were followed for a mean of 1.1 years and the study was stopped early due to the apparent benefits and limited adverse effects of the study drug compared to aspirin. The authors found that 51 patients experienced a primary outcome (1.6% per year) taking apixaban compared to 113 (3.7% per year) in the aspirin group (hazard ratio of 0.45). The researchers found no significant difference in bleeding and death outcomes between the two groups . On first review these results are exciting for patients with atrial fibrillation, but before putting this drug in the bottle, more long-term follow up and careful examination of adverse side effects will be necessary.
In the Annals of Internal Medicine the latest installment of Best Practice Advice is a reminder on the judicious use of imaging in the evaluation of low back pain in adults. The American College of Physicians (ACP) issues a dressed-up version of what is already standard of care, but not necessarily standard practice. Based on data from a systematic review and a meta-analysis the ACP makes several recommendations that since their initial release in 2007 have been somewhat ignored. Why does this matter? Well from 1997 to 2005 the cost of back pain in America went up by 65% after controlling for inflation. Unfortunately measures of patient satisfaction, well-being and productivity specific to back pain have not improved significantly. Among their recommendations, they suggest that if a patient has an initial “red flag” for malignancy, infection, spinal cord or cauda equina compromise on presentation or fails to improve significantly after 1 month of appropriate therapy in the lower risk population, then and nearly only then imaging is useful. This report also stressed the need to counsel patients to improve their satisfaction and their acceptance of treatment without tests.  This article will certainly add to the internists’ tool set for managing low back pain.
Newsflash not needed that smoking is bad for us, but the impact of smoking cigarettes on breast cancer remains controversial. Xue and colleagues in the Archives of Internal Medicine published a new analysis on the data from the Nurse’s Health Study, a prospective cohort of married female nurses with data from 1976 to 2006. Xue and colleagues found that the hazard ratio of breast cancer for smokers versus never smokers was 1.06, considered a modest association. They found no association with breast cancer and those women exposed to passive or second-hand smoke. Despite the obvious issues with this analysis- it was a post-hoc analysis on a prospective cohort and that the data was obtained by voluntary questionnaire- it is strengthened by the large number of study participants and the long duration of follow up .
Last, but not least, Aagaand and colleagues are working on tackling the ancient disease of tuberculosis. Highlighted in the latest edition of Nature Medicine, Aagand and colleagues present a potentially significant and certainly innovative vaccine target. Whereas other anti-mycobacterium tuberculosis vaccines aim to prevent new infection, this vaccine named H56 was found to have effect on preventing novel infection and on reactivation in latent tuberculosis infection. 
Thanks for reading. Don’t put away your snow boots yet, but it’s time to break out your sunglasses as you peruse this week’s journals.
Dr. Greenwald is a 3rd year resident, Internal Medicine at NYU Langone Medical Center
Peer reviewed by Michael Poles, section editor, Clinical Correlations
Image courtesy of Wikimedia Commons
1. Raymond, E. et al. Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors. NEJM [Internet]. 2011 Feb 10 [cited 2011 Feb 13];364(6) 501-513. Available from http://www.nejm.org/
2. American Society of Health-System Pharmacists. “Sunitinib” [Internet]. National Center for Biotechnology Information (NCBI); 2008 Sept 1 [cited 2011 Feb 13]. Available from: www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000402.
3. American Society of Health-System Pharmacists. “Everolimus” [Internet]. National Center for Biotechnology Information (NCBI); 2009 Nov 1 [cited 2011 Feb 13]. Available from: www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000510.
4. Connolly, S. et al. Apixaban in Patients with Atrial Fibrillation. NEJM. [Internet]. 2001 Feb 10 [cited 2011 Feb 12]; Available from: http://www.nejm.org/
5. Yao, J et al. Everolimus for Advanced Pancreatic Neuroendocrine Tumors. NEJM [Internet]. 2001 Feb 11 [cited 2011 Feb 13]; 364 (6): 514-523. Available from: http://www.nejm.org/
6. Chou, R. et al. Diagnostic Imaging for Low Back Pain: Advice for High-Value Health Care from the American College of Physicians. Ann Internal Medicine. [Internet] 2011 Feb 1 [Cited 2011 Feb 12]; 154 (3): 181-189.
7. Guilinano, K et al. Axillary Dissection versus No Axillary Dissection in Women with Invasive Breast Cancer and Sentinel Node Metastasis: a randomized clinical trial. JAMA. [Internet].2011 Feb 9 [Cited 2011 Feb 12]; 305 (6):569-575. Available from http://jama.ama-assn.org/content/305/6/569.full.
8. Xue, F. et al. Cigarette Smoking and the Incidence of Breast Cancer. Arch Internal Medicine [Internet] 2011 Jan 24 [cited 2011 Feb 12];171(2):125-133. Available from: http://archinte.ama-assn.org/
9. Aagard, C et al. A Multistage Tuberculosis Vaccine that Confers Efficient Protection Before and After Exposure. Nature Medicine [Internet] 2011 Feb 1 [cited 2011 Feb 13]; 17(2): 189-195.