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Originally published as JCO Early Release 10.1200/JCO.2004.11.918 on December 9 2003 © 2004 American Society of Clinical Oncology.
Economics of Preoperative Radiotherapy With Total Mesorectal Excision: What Can We Learn From the Dutch Experience?Departments of Surgery, Clinical Epidemiology and Biostatistics, and Medicine, Faculty of Health Sciences, McMaster University; Juravinski Cancer Centre, Hamilton, Ontario, Canada Patients undergoing rectal cancer surgery may also receive radiation therapy to reduce local tumor recurrence and improve survival [1,2]. In parts of Europe, a 5-day course of preoperative radiotherapy (PRT) alone is recommended for most patients, while other European and North American countries utilize a 5-week course of postoperative chemoradiotherapy for patients with stage II or III tumors [3]. Total mesorectal excision (TME) stresses sharp and complete dissection of the mesorectum, the lymph node–bearing portion of the rectum [4]. Compared with traditional blunt rectal cancer surgery, TME seems to lead to superior rates of sphincter preservation, local tumor control, and survival [4]. The Dutch Colorectal Cancer Group has conducted a randomized trial that compared outcomes of TME, with and without PRT, for patients with resectable rectal cancer [5]. At a median follow-up of 2 years, local recurrence rates were 2.4% and 8.2% for radiated and nonradiated patients, respectively, with no significant difference in overall survival [5]. These results may change with further follow-up. In this issue of the Journal of Clinical Oncology, van den Brink et al [6] compare the costs and benefits (improved quality-adjusted life expectancy) between the radiotherapy and nonradiotherapy arms of the Dutch trial. This report follows recommended methodology and interpretation standards for cost-effectiveness analyses [7,8]. Data on costs and utilities were prospectively and extensively collected as part of the trial protocol. Costs included both health care and non–health care expenditures, such as lost wages or out-of-pocket expenses. Utilities, representing quality-of-life measures, were obtained by administering quality-of-life questionnaires to patients at various points, then calculating scores and inferring time-trade-off values as assigned by the general public. Appropriately and where needed, additional cost and utility data were gathered using a subsample of 112 patients. Uncertainty was explicitly dealt with by varying numerous parameters, and then by examining the impact on the corresponding cost-effectiveness ratios. The authors conclude that PRT in conjunction with TME is both effective and cost effective, with one quality-adjusted life-year (QALY) "purchased" for an acceptable $25,100 (all values of currency are in US dollars). Before the reader accepts that PRT with TME is cost-effective for life expectancy, many important issues should be considered. First, the reader must assume that PRT leads to a survival advantage. However, at a 38-month median follow-up, there is no difference in survival between PRT and TME alone (75.5% v 74.5%; P = .75). Modeled differences in survival translated to an increase in long-term life expectancy of 0.67 years for PRT, and, when quality of life (utilities) was considered, there was a 0.39-year increase in quality-adjusted life-years. But if there is truly no gain or, worse, a loss in life expectancy for PRT and increased costs, then this would be a dominant outcome or a lose-lose proposition that mitigates against the use of PRT. While performing an economic analysis prospectively within a clinical trial ensures high internal validity [7], it should also force economic and quality-of-life investigators to confront any uncertainty in the therapeutic results of the respective trial. For example, as part of their sensitivity analysis, the authors could have reported the impact of using the upper and lower bounds of the 95% CI for the survival proportional hazard ratio in their Markov models, as was done for local recurrence. The second concern is the generalizability of this cost-effectiveness analysis, which relates to the validity of the results in the economic analysis. This analysis should have considered scenarios in which surgical quality could be better or worse than that in the Dutch TME trial [7]. This is important, since the Dutch trial is likely not the final statement on the role of radiation therapy when optimal TME is practiced [9]. For example, the local recurrence rate of 8.2% in the surgery-only arm of the Dutch trial is higher than rates reported by certain groups practicing TME [4,10]. Moreover, a recent article on the quality of surgical specimens in the trial on which this analysis was performed reported that in only 57% of cases was the mesorectum completely resected, which is considered a marker of high-quality TME surgery [11]. Hence, better quality TME could have resulted in lower local recurrence rates, with subsequent lesser benefit of PRT and a less attractive cost-effectiveness ratio for PRT. Conversely, many patients undergoing surgery outside Dutch TME trial hospitals may have a lower quality of rectal cancer surgery, which might result in a more advantageous cost-effectiveness ratio for PRT. In support of this hypothesis are the results from the Swedish Rectal Cancer Trial, which compared traditional surgery with and without short-course PRT. The local recurrence rates in the radiated and nonradiated patients were 11% and 27%, respectively, and an economic analysis done in conjunction with this trial found a cost-effectiveness ratio for PRT of $3,700 per life-year [12]. Aside from surgical quality, and to their credit, the authors do consider how other factors such as patient age, completeness of dissection, or stage, influence the risk of local recurrence and the resulting PRT cost-effectiveness ratios. For example, for patients with stage I tumors, the low 1.7% risk of local recurrence leads to a less attractive cost-effectiveness ratio for PRT, of $100,000 per QALY. van den Brink et al [6] raise a third issue in the discussion, that international data differences limits the ability to generalize their results, or, put another way, that their findings might not apply to jurisdictions outside the Netherlands. Yet their conclusion that PRT treatment is cost effective with no geographic qualification, and their use of exchange rates, subordinates this important point. The authors converted Dutch costs to US dollars using the exchange rate on November 1, 2002. However, exchange rates can neither tell us how individuals in different countries value their health status, nor enable us to convert costs from one country to another. The following example illustrates this latter point: in the study, hospital costs for surgery were $429 per day, and this appears to have included surgical fees. If we use the United States as a comparison country, we can safely say that in the year 2002, hospital costs per day would have far exceeded $429. The final issue we wish to discuss is one that is generic to many health economic analyses, which is the inability of such studies to assist the policy maker. Economics is based on three fundamental concepts: scarcity (whatever resources are available, they are insufficient to support all possible activities); choices (because resources are scarce we must choose between different ways of using them); and opportunity cost (by choosing to use resources in one way, we forgo other opportunities to use the same resources). On the basis of these concepts, resources are used efficiently if, and only if, the value of what is gained from the use of these resources exceeds the value of what is forgone by not using them in any other way. The appeal of cost-effectiveness analyses to decision makers is they appear to provide guidance on how to maximize the health of the community from the use of available resources [13,14]. For example, in the current study, the authors state that the cost-effectiveness ratio for PRT of $25,100 per QALY meets an "acceptable" threshold. However, this use of cost-effectiveness ratios and the threshold (acceptable price) approach does not inform the decision maker on the amount of resources required to implement PRT nationwide, and which other intervention(s) will not be performed to free-up the required resources. Hence, this approach does not help the policy maker to decide if redirecting resources to allow the provision of PRT with TME is an efficient (cost-effective) use of the redirected resources, resulting in more health gains for the community than those lost from the necessary canceling of other intervention(s) (ie, the opportunity cost implications of the new intervention) [15-17]. Researchers should compare the costs and benefits of treatments, but should not deduce cost-effectiveness for a particular treatment unless they are willing to determine the opportunity costs of the selected treatment. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. 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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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