ARA II y Cancer Editorial

Reection and Reaction
TES was previously on the speakers bureau for Lilly Oncology and Genentech. RG has received fees for consultancy from Genentech and AstraZeneca. 1 Bang YJ, Kwak EL, Shaw AT, et al. Clinical activity of the oral ALK inhibitor PF-02341066 in ALK-positive patients with non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2010; 28: 3 (abstr). Mitsudomi T, Morita S, Yatabe Y, et al. Getinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010; 11: 12128. Mok TS, Wu YL, Thongprasert S, et al. Getinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 94757.
Herbst RS, Sun Y, Eberhardt WEE, et al. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol 2010: 11: 61926. Heymach JV, Johnson BE, Prager D, et al. Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously treated nonsmall-cell lung cancer. J Clin Oncol 2007; 25: 427077. Rubinstein LV, Korn EL, Freidlin B, Hunsberger S, Ivy SP, Smith MA. Design issues of randomized phase II trials and a proposal for phase II screening trials. J Clin Oncol 2005; 23: 7199206.
Angiotensin-receptor blockers and cancer: urgent regulatory review needed

The meta-analysis, published today in The Lancet Oncology, by Sipahi and colleagues1 is disturbing and provocative, raising crucial drug safety questions for practitioners and the regulatory community. Are angiotensin-receptor blockers (ARBs) associated with increased risk of incident malignancies? Should we be concerned about all ARBs or a single drug, telmisartan? How can this uncertainty best be resolved? What actions should practitioners take while this concern undergoes further examination and analysis? Increasingly, independent drug-safety analyses are appearing in the medical literature,24 and there are several reasons for this greater availability of drugsafety data. Researchers in many areas of medicine are undertaking large, randomised controlled trials (RCTs) to assess clinical outcomes. When done skillfully, large RCTs oer scientic insights that can extend well beyond the original primary endpoint and main hypothesis. The richness of this expanding database of trials is both an opportunity and a risk for the scientic community. The opportunity exists to ask new hypothesis-generating questions that could substantially contribute to scientic knowledge. However, such analyses are also inherently risky. As any experienced clinical trialist or statistician can verify, the more questions that are asked, the more likely a spurious nding is to be discovered. In this context, how should we view the analysis by Sipahi and colleagues? There are clearly some important strengths. The analysis is very large, examining new onset of cancer in trials enrolling more than 60 000 patients and cancer death in trials involving more than 90 000 patients. The investigators seem to have done
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a thorough search of the literature and have applied appropriate lters to include relevant data and exclude potentially unreliable data. There are also important weaknesses, which the investigators acknowledge including the post-hoc nature of this investigation and the fact that the trials were not designed to explore cancer outcomes. Based on these limitations, the investigators are appropriately cautious in their interpretation of the results. What should be the next steps in resolving this important emerging controversy? We should recognise that additional data exist that were not available for the current meta-analysis. Despite years of active scrutiny and criticism, publication bias is still a highly prevalent problem in trials funded by pharmaceutical companies.5 Some studies with unfavourable outcomes are never published, or appear as incomplete manuscripts with selective reporting of outcomes.6 This practice was evident in the past decade, with controversies over the safety of drugs such as rofecoxib and rosiglitazone.2,4,6 35 of 42 trials of rosiglitazone were unpublished at the time the rst meta-analysis found evidence for adverse cardiovascular outcomes. In the rosiglitazone example, data were available to independent investigators only because a lawsuit by the State of New York required the manufacturer to publicly disclose all clinical trial results. How do we access additional, unpublished data on ARBs and cancer safety? Fortunately, pharmaceutical companies routinely submit data from clinical trials to regulatory agencies, including the US Food and Drug Administration and global regulatory authorities. These data are often more detailed than the results in published reports, allowing more sophisticated approaches for
Published Online June 14, 2010 DOI:10.1016/S14702045(10)70142-X See Articles page 627
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Reection and Reaction
determining hazard ratios from survival analyses. Furthermore, when important safety questions arise, regulatory authorities can order drug makers to submit a complete trial dataset. This is precisely what should happen in the case of ARBs. Regulators must review the possible association between ARB use and cancer, and promptly report their ndings. In the interim, we should use ARBs, particularly telmisartan, with greater caution. These drugs are often overprescribed, as a result of aggressive marketing and in the absence of evidence that they are better than angiotensin-converting enzyme (ACE) inhibitors. ARBs can be reserved for patients with intolerance to ACE inhibitors. More selective use of ARBs will also save money for healthcare systems, since nearly all ARBs are proprietary and ACE inhibitors are generic. Steven E Nissen
Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA nissens@ccf.org
I have received research support for clinical trials from Pzer, Astra Zeneca, Novartis, Novo Nordisk Roche, Daiichi-Sankyo, Takeda, Sano-Aventis, Resverlogix, and Eli Lilly. I consult for many pharmaceutical companies, but require them to donate all honoraria or consulting fees directly to charity so that I receive neither income nor a tax deduction. 1 Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC. Angiotensinreceptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol 2010; published online June 14. DOI:10.1016/ S1470-2045(10)70106-6. Nissen SE, Wolski K. Eect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: 245771. Colhoun HM; SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 2009; 52: 175565. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286: 95459. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its inuence on apparent ecacy. N Engl J Med 2008; 358: 25260. Ross JS, Madigan D, Hill KP, Egilman DS, Wang Y, Krumholz HM. Pooled analysis of rofecoxib placebo-controlled clinical trial data: lessons for postmarket pharmaceutical safety surveillance. Arch Intern Med 2009; 169: 197685.
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Laparoscopic total mesorectal excision

Several large randomised trials comparing laparoscopic versus open resection for colon cancer have shown that the laparoscopic method can provide an equivalent oncological outcome, a similar rate of complications, and a more rapid short-term recovery. However, as with open surgery, the safety and benets of laparoscopy still lies with the surgeon, who must develop competency along a personal learning curve that assures proper patient selection, technical performance, and a low conversion rate. Because of the greater technical demands of rectal resection, many surgeons have doubted the wisdom of attempting laparoscopic total mesorectal excision (TME) for rectal cancer. Data from randomised trials of laparoscopic TME have thus far shown an unacceptably high incidence of conversion and positive radial margin and suggested more autonomic nerve dysfunction in laparoscopic cases.14 In this issue of The Lancet Oncology, Kang and colleagues5 have shown in a multicentre, randomised study that laparoscopic rectal resection can be done with a high rate of technical success after neoadjuvant chemoradiation for locally advanced rectal cancer. In the laparoscopic group the incidence of positive radial margin or incomplete total mesorectal excision was low (29% and 47%, respectively), the lymph node yield was high (median 17), and the rates of conversions to open surgery and complications were low (12% and 212%, respectively). These excellent results were achieved by seven high-volume surgeons who were experienced in minimally invasive surgical techniques. No unusual operative techniques or instruments were required. The pelvic dissection was done by monopolar cautery or harmonic scalpel, and transection of the rectum was achieved by laparoscopic staplers guided by digital rectal exam. The rates of abdominoperineal resection (141% and 112%) and coloanal anastomosis (194% and 194%) were equivalent. The message to surgeons from the authors seems to be that achieving a high quality laparoscopic TME with adequate retraction, precise control of dissection plane, and accurate division of rectum below the tumour is simply a matter of good patient selection, meticulous technique, and experience. The authors report that the recovery benets of minimally invasive surgery are similar to prior studies: the patients who received laparoscopic TME had fewer wound complications, less pain and narcotic use, and
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Published Online June 17, 2010 DOI:10.1016/S14702045(10)70150-9 See Articles page 637
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Reection and Reaction

Angiotensin-receptor blockers and cancer: urgent regulatory review needed

Custom Medical Stock Photo/Science Photo Library

Reection and Reaction

Laparoscopic total mesorectal excision

Life in view/Science Photo Library

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