When April with
Her showers sweet
Drives you inside to
Your window seat,
We shall excite
With landmark trials
This cruelest month
Should not deter
A nature curious
With thoughts astir.
With this week’s release
Of fine Primecuts.
Happy National Poetry Month!
Faculty Peer Reviewed
In 2006, the US Food and Drug Administration (FDA) approved the use of the Avastin (bevacizumab), a monoclonal antibody against vascular endothelial growth factor A (VEGF-A), in combination with the standard therapy of paclitaxel and carboplatin for the treatment of non-small-cell lung cancer (NSCLC). This decision was based on the results of a trial  that showed a statistically significant improvement in the median survival (12.3 months versus 10.3 months) among patients who received bevacizumab plus standard therapy when compared to patients assigned to standard therapy alone (P=0.003). This was despite a significantly greater number of deaths directly attributable to adverse effects in the treatment group including fatal pulmonary hemorrhage. Furthermore, a survival benefit was not seen in women, patients with more advanced disease and patients over the age of 65 and a subsequent meta-analysis  failed to show an improvement in mortality at one year.
In a study published this week in JAMA , a group of authors further investigated whether Avastin has any benefit in patients over the age of 65 with NSCLC. The investigators performed a retrospective analysis of a national cancer database with the primary outcome of all-cause mortality among patients who received Avastin plus standard therapy versus those who received standard therapy alone. Interestingly, the authors used two control groups to compare patients who received Avastin therapy with two standard groups diagnosed with NSCLC before and after FDA approval of Avastin, respectively. This cohort division was done out of concern that if “physicians chose bevacizumab-carboplatin-paclitaxel for their healthier patients, then a selection bias might result in better survival for those patients.”
The Avastin treatment group included 318 patients while the post and pre-FDA approval standard treatment groups had 1,182 and 2,664 patients, respectively. The Avastin treatment group had a median overall survival of 9.7 months compared to 8.9 months among patients in the post-marketing control group. The earlier control group had a median overall survival of 8.0 months. One-year survival probabilities were 39.6%, 40.1% and 35.6% between the three groups, respectively. There was no significant difference in survival between the patients treated with Avastin when compared to both the post-FDA approval group (HR, 1.01; 95% CI 0.88-1.15) and the pre-FDA approval group (HR, 0.94; 95% CI, 0.83-1.06).
The authors concluded that, “our analyses suggest that the addition of bevacizumab to carboplatin and paclitaxel is not associated with demonstrable improvement in overall survival in the Medicare population.” They also commented that finding prescription rates to be lower than one might presuppose, especially recognizing the powerful financial incentives to prescribe this expensive drug, “provides some measure of reassurance that oncologists are circumspect and judicious in their use of new agents with uncertain benefit in the Medicare population.” In a statement , the lead investigator of this study, Deborah Schrag, MD, MPH, noted, “Adoption of bevacizumab was by no mean universal. We didn’t find that all physicians rushed out to administer this drug.”
These results come on the heels of the FDA’s decision to revoke its approval of Avastin  for the treatment of breast cancer noting, “that women who take Avastin for metastatic breast cancer risk potentially life-threatening side effects without proof that the use of Avastin will provide a benefit, in terms of delay in tumor growth, that would justify those risks.” While the benefits of Avastin in certain cancers requires further elucidation, what has become evident over the past few years are the numerous adverse effects of Avastin  which include severe hypertension, fatal hemorrhage, vascular thrombosis and bowel perforation.
These well-documented adverse effects combined with the unclear benefit of Avastin leave no surprise that, following FDA approval, enthusiasm for Avastin has been muted. While the ultimate role for Avastin in the treatment of non-small-cell lung cancer has yet to be determined, these latest findings serve to emphasize the dearth of therapeutic options available to these patients and should remind physicians of the importance of palliative care  in their management.
Current classifications of breast cancer depend predominantly on a determination of the presence or absence of particular cell surface markers, specifically estrogen, progesterone and Her2 receptors, respectively. While this practice has successfully led to tailored therapies based on molecules that antagonize those receptors, the clinical response to therapy remains variable. Exciting research published this week in Nature  suggests that in the future these approaches for classifying and treating breast cancer are likely to change.
In what can truly be called a “bench to bedside” study, 997 samples of breast cancer tissue were subjected to a robust analysis of DNA mutations and their respective associations with gene transcription. This evaluation resulted in the identification of ten distinct molecular subgroups which were subsequently validated in a separate batch of 995 tissue samples. Each subgroup had a characteristic rate of clinical progression suggesting a more complex pattern of growth than what is now understood at a molecular level. Furthermore, the investigators identified novel mutations in molecles involved in oncogenic signaling pathways that may offer targets for future therapies. Addressing the clinical implications  of these findings, lead investigator Carlos Caldas, Ph.D., remarked, “We have a completely new way of looking at breast cancer…We need to carry out more research in the laboratory and in patients to confirm the most effective treatment plan for each of the 10 types of breast cancer.”
Lastly, it was announced this week  that Warren Buffett, the multi-billionaire investor and philanthropist, has been diagnosed with stage 1 prostate cancer following screening with prostate specific antigen (PSA) and that he will soon be undergoing radiotherapy. Following this announcement, shares in Berkshire Hathaway fell slightly  even though the 81-year-old chairman and CEO of the holding company is unlikely to have his life shortened by his disease. While questions are being raised regarding his ultimate successor at the company, what many want to know is why, at his age, was Mr. Buffett screened for prostate cancer in the first place. A multitude of writers and bloggers at major media outlets are asking this exact question. Writer Tara Parker-Pope  of the New York Times adeptly synthesizes the major points of the debate and correctly notes that Mr. Buffett is much more likely to suffer the adverse effects of radiation therapy than to incur any survival benefit from his treatment. The degree to which this news has sparked interest in the general media serves as a testament to how pervasive the topic of PSA testing in prostate cancer has become and one cannot help but get the feeling that well-informed participants have elevated the national debate over the past few years.
Dr. Todd Cutler is an associate editor, Clinical Correlations
Peer reviewed by Robert J. Gianotti, MD, NYU Chief Medical Resident, NYU Langone Medical
Image courtesy of Wikimedia Commons
 Sandler et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med (2006) vol. 355 (24) pp. 2542-50. Available from: http://www.nejm.org/doi/full/10.1056/NEJMoa061884
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