J Thorac Cardiovasc Surg 2005;129:1205-1206
© 2005 The American Association for Thoracic Surgery
Reply to the Editor
Artyom Sedrakyan, MD, PhDa,
Ken O’Byrne, MDb
a Department of Public Health and Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom, Cardiothoracic Surgery, Yale University School of Medicine, New Haven, CT 06520, Department of Health Policy and Management, Johns Hopkins School of Public Health, Baltimore, MD 21205
b Consultant Oncologist, Department of Oncology, St James’s Hospital, Dublin, Ireland
We support and applaud the efforts of Ms Burdett and her team in conducting an individual patient data-based (IPD) meta-analysis of postoperative chemotherapy trials. Although there are controversies regarding the conduct of IPD meta-analyses, such as the inclusion of data from unpublished studies and potential investigator bias in terms of data submitted,1,2 such studies may be particularly useful in conducting subgroup analyses to identify those patients most likely to benefit from therapy and the optimal treatment regimen to be used.
The non-IPD nature of our meta-analysis does not, however, take away from the validity of the findings that clearly demonstrate a survival advantage for patients treated with adjuvant chemotherapy over those treated with surgery alone.3 This is also underpinned by a recent presentation on adjuvant UFT (uracil and tegafur), the oral 5-fluorouracil derivative, at the 2004 annual meeting of the American Society of Clinical Oncology. In this work, individual patient data from 2003 patients recruited to 6 randomized controlled trials were systematically reviewed. The overall survival benefit for treated patients is 5.3% (hazard ratio = 0.77; P = .011) at 5 years and 7.7% (hazard ratio = 0.74; P = .001) at 7 years. This is similar to our reported survival benefit for UFT. In addition, continued divergence of the survival curves over time is similar to those commonly seen in breast cancer adjuvant trials.4
The authors are correct that since our publication, further randomized controlled trials have been presented. The 2 largest and principal new studies presented at the 2004 meeting of the American Society of Clinical Oncology for platinum-based chemotherapy, however, reported substantial benefits associated with adjuvant chemotherapy.5,6 Combining the results of these trials with the previous randomized controlled trials evaluating platinum-based regimens has demonstrated a further overall benefit for platinum-based postoperative chemotherapy (relative risk, 0.86; 95% confidence interval, 0.80–0.93). Moreover, sensitivity analyses determined that even if there were unreported or future studies enrolling more than 2000 patients that showed a statistically significant 20% higher risk of mortality for platinum-based chemotherapy (the very unlikely scenario), the overall estimate would still significantly favor chemotherapy.
In the past there have been many instances in which the failure to adapt significant advances in treatment has led to delays in passing on the benefits to the patient in the clinic. Examples include thrombolytic therapy or beta-blocker therapy after myocardial infarctions.7,8 These non–IPD-based systematic reviews highlighted that each year of delay may cost thousands of lives worldwide and were influential for the development of evidence-based medicine. We believe that delay in the case of postoperative chemotherapy may have the same consequences and be interpreted as reflecting clinician uncertainty and potentially lead to the design and conduct of further clinical trials in which the question has been clearly answered.9,10 As Sir Austin Bradford Hill pointed out in his presidential address at the Royal Society of Medicine (January 14, 1965), "All scientific work is incomplete—whether it be observational or experimental. It is liable to be upset or modified by advancing knowledge. That does not confer upon us a freedom to ignore the knowledge we already have, or to postpone the action that appears to demand at a given time." In this regard the evidence is very strong that adjuvant chemotherapy improves patient survival postresection. Optimizing therapy and targeting those patients most likely to benefit from treatment are clinically important questions that the IPD study may address. Further trials in the already studied population randomizing patients to a "no chemotherapy" arm are, however, unlikely to contribute to existing knowledge and are ethically questionable.
References
- Clarke MJ, Stewart LA. Obtaining individual patient data from randomized controlled trials. In: Egger M, Smith GD, Altman D, editors. Systematic reviews in health care, meta analysis in context. London, UK: BMJ Publishing Group; 2001. pp. 109-121.
- Cook DJ, Guyatt GH, Ryan G, et al. Should unpublished data be included in meta-analyses?. Current convictions and controversies. JAMA 1993;269:2749-2753.
- Sedrakyan A, Van Der Meulen J, O’Byrne K, Prendiville J, Hill J, Treasure T. Postoperative chemotherapy for non-small cell lung cancer. a systematic review and meta-analysis. J Thorac Cardiovasc Surg 2004;128:414-419.[Abstract/Free Full Text]
- Hamada C, Ohta M, Wada H, et al. Survival benefit of oral UFT for adjuvant chemotherapy after completely resected non-small cell lung cancer. Proc Am Soc Clin Oncol. 2004;22abstract 70023..
- Winton TL, Livingston R, Johnson D, et al. A prospective randomised trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage 1B and II non small cell lung cancer (NSCLC) intergroup JBR.10. J Clin Oncol 2004;22(14S):7018.
- Strauss GM, Herndon J, Maddaus MA, et al. Randomised clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer (NSCLC). report of cancer and leukemia group B (CALGB) protocol 9633. J Clin Oncol 2004;22(14S):7019.
- Antman EM, Lau J, Kupelnick B, Mosteller F, Chalmers TC. A comparison of results of meta-analyses of randomized controlled trials and recommendations of clinical experts. JAMA 1992;268:240-248.[Abstract]
- Lau J, Antman EM, Jimenez-Silva J, Kupelnick B, Mosteller F, Chalmers TC. Cumulative meta-analysis of therapeutic trials for myocardial infarction. N Engl J Med 1992;327:248-254.[Abstract]
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