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Originally published as JCO Early Release 10.1200/JCO.2004.04.198 on December 9 2003 © 2004 American Society of Clinical Oncology. Cost-Utility Analysis of Preoperative Radiotherapy in Patients With Rectal Cancer Undergoing Total Mesorectal Excision: A Study of the Dutch Colorectal Cancer GroupFrom the Department of Medical Decision Making, Department of Surgery, and Department of Radiotherapy, Leiden University Medical Center, Leiden, the Netherlands Address reprint requests to W.B. van den Hout, PhD, Department of Medical Decision Making, J10-S, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands; e-mail: W.B.van_den_Hout{at}LUMC.NL
PURPOSE: To compare the societal costs and the (quality-adjusted) life expectancy of patients with rectal cancer undergoing total mesorectal excision (TME) with or without short-term preoperative radiotherapy (5 x 5 Gy). PATIENTS AND METHODS: We used a Markov model to project the clinical and economic outcomes of preoperative radiotherapy. Data on local recurrence rates, quality of life, and costs were obtained from the patients of a multicenter randomized clinical trial. In this trial, 1,861 patients with resectable rectal cancer from 108 hospitals were randomly assigned for TME surgery with or without preoperative radiotherapy. Outcome measures of the model were life expectancy, quality-adjusted life expectancy, lifetime costs per patient, and the incremental cost-effectiveness ratio. RESULTS: The base case model estimates that the loss of quality of life due to preoperative radiotherapy is outweighed by the gain in life expectancy. Life expectancy increases by 0.67 years; quality-adjusted life expectancy, by 0.39 years; and costs, by $9,800 per patient. The corresponding cost-effectiveness ratio is $25,100 per quality-adjusted life year. Sensitivity analyses indicate that the cost-effectiveness ratio remains acceptable under a wide range of assumptions. CONCLUSION: Assuming that the reduced local recurrence rate does lead to a survival advantage, the cost-utility analysis estimates that the improved survival outweighs the impaired quality of life and the increased costs. We conclude that short-term preoperative radiotherapy in patients with rectal cancer undergoing TME is both effective and cost-effective.
In the treatment of rectal cancer, local recurrence is of major concern, as it causes severe disabling symptoms, is difficult to treat, and is often fatal [1]. The best chance for cure in patients presenting with rectal cancer is standardized total mesorectal excision (TME). Since the introduction of TME surgery, local recurrence rates have decreased to rates as low as 5% to 8% [2,3], as compared with 15% to 45% after conventional surgery [4–6]. Two recent meta-analyses have shown that adjuvant radiotherapy also reduces local recurrence rates by almost 50%, and reduces overall mortality by 2% to 10% [7,8]. Preoperative radiotherapy (PRT) with higher biologically effective doses (of at least 30 Gy) showed larger reductions than PRT with lower doses and than postoperative radiotherapy. However, the trials included in these meta-analyses all started before the broad introduction of TME surgery. The only randomized comparison of TME surgery with or without PRT is the trial conducted by the Dutch Colorectal Cancer Group [9,10]. At 2 years follow-up the estimated local recurrence rates in this trial were 2.4% with PRT, compared with 8.2% without PRT. This relative reduction of local recurrence is similar to that in the meta-analyses, but the absolute reduction is smaller, and the current follow-up does not show a difference in survival. From a health policy perspective, clinical benefits of treatments should be estimated in terms of survival benefits, and balanced against the effects on quality of life and costs. This is especially true in oncology, a field in which costs and other disadvantages of treatment can be considerable [11,12]. PRT has been associated with increased postoperative morbidity such as perineal dehiscence, wound infection, cardiovascular complications, and prolonged hospital stay [13–19]. Information on long-term complications and quality of life is scarce [20]. The objective of this study was to compare the societal costs and the (quality-adjusted) life expectancy of patients with rectal cancer undergoing TME with or without PRT.
We analyzed lifetime costs, life years (LYs) and quality-adjusted life years (QALYs) for patients undergoing TME-surgery with or without PRT, from a societal perspective following the recommendations from the Panel on Cost-Effectiveness in Health and Medicine [21]. Between January 1996 and December 1999, 1,861 patients with resectable rectal cancer from 84 hospitals in the Netherlands, 23 other European hospitals, and one hospital in Canada were included in the TME-study. They were randomized for TME-surgery with or without short-term PRT (5 x 5 Gy). The main outcome measures in this trial were local recurrence, survival, and quality of life. The trial has been described in more detail elsewhere [9,10], for a median follow-up time of 24 months. Our analyses are based on the data with a median follow-up of 38 months (range, 13 to 68 months). A state-transition Markov model was developed to integrate all available data from the TME-study, and to facilitate long-term extrapolation and sensitivity analyses, using the software package DATA 3.5 (TreeAge Software, Williamstown, MA). Future costs and QALYs were both discounted at 3%[21].
Model Overview A schematic representation of the model is shown in Figure 1. For the time from random assignment until TME surgery, pretreatment and treatment costs, LYs, and QALYs were assigned by randomization group. After TME surgery, patients start in one of the initial states: R0 (microscopically negative resection margins of > 1 mm), R1 (microscopically positive resection margins at 1 mm or less), R2 (macroscopically incomplete local resection or distant metastases at surgery), or death (for all patients dying before leaving the hospital). In case of recurrence, the R0 and R1 patients move to the states local recurrence, distant recurrence, or local and distant recurrence. Recurrences were not modeled explicitly for R2 patients, because any reduction in local recurrence rates due to PRT is not expected to improve survival. From rectal cancer- or non-rectal cancer-related causes, all patients eventually die.
Initial Probabilities and Transition Rates The initial probabilities and transition rates for the Markov model were estimated for all TME patients. For the initial R0, R1, and R2 states, transition rates were estimated using Gompertz distributions to allow for rates that increase or decrease with time. For the noninitial states, constant transition rates were used. All analyses were performed for patients with specific initial age, and weighted for the age distribution in the TME study (mean age, 64 years; standard deviation, 11 years). For the recurrence rates, proportional hazards were considered for PRT, for the inferior margin (the distance from the anal verge to the tumor), and for their interaction. These variables have been shown to be significant predictors of local recurrence risk [10], and may be determined by preoperative staging procedures. For the mortality rates, proportional hazards for PRT and age were considered. For the base case analysis, all nonsignificant proportional hazards were excluded (stepwise backward-forward regression: P > .05 for removal and P < .05 for entry). Table 1 summarizes the parameter estimates. Sensitivity analyses were performed on the inclusion of all estimated proportional hazards (whether significant or not) and on the proportional hazard of PRT for the local recurrence rate after R0 and R1 resection (95% CIs, 0.15 to 0.65, and 0.10 to 0.72, respectively).
The observed non-rectal cancer mortality in the TME study was low compared with the average Dutch mortality, possibly due to the exclusion of patients with comorbidity. Therefore, long-term non-rectal cancer mortality rates were obtained from 1995 to 1999 Dutch life-tables (provided by Statistics Netherlands [http://www.cbs.nl], and weighted for the 67% male TME study population). We used the short-term non-rectal cancer mortality from the TME study (until a follow-up time of 4 years), the long-term mortality from Dutch life-tables (after a follow-up time of 8 years), with linear interpolation in between. In our base case model, a reduction in local recurrence rates by PRT will automatically lead to a gain in survival. To investigate the possibility that reduced local recurrence rates might not lead to a difference in survival, we conducted an alternative analysis in which all mortality rates after PRT were uniformly increased, to such an extent that the life expectancy for both randomization groups was identical. To investigate the impact of local recurrence risk on the estimated QALYs and cost-effectiveness (CE) ratio, the local recurrence rates were uniformly varied in both randomization groups. A plot of the QALYs and CE ratios by local recurrence risk allows the reader to assess the effect of PRT for subgroups of patients based on their 5-year local recurrence risk without PRT. This figure can be used to assess the cost-effectiveness and effectiveness of PRT in particular groups of patients that were not explicitly included in our Markov model (eg, by tumor stage or inferior margin). Note, however, that the estimates provided by the plot are subject to larger error than the other results presented in this article, because subgroups may differ by more than only their local recurrence rate.
Health-Related Quality of Life For the base case analysis, utility values from the general public were used, based on the EuroQoL questionnaire (Table 2). The time from randomization until surgery differed between the two treatment groups, and the utility values during this period were adjusted for loss of quality of life due to the PRT. For the time from TME surgery until discharge, utility values measured during hospitalization in the CUA sample were used. Utility values for the R0 and R1 states until 9 months after TME surgery differed significantly by randomization group, time, and stoma type (ie, patients with no stoma, a diverting stoma, a removed diverting stoma, and a permanent stoma, weighed by their distribution over time). After 9 months, utility values remained relatively constant over time, and no significant differences were observed between randomization groups. Therefore, for the time following 9 months after surgery, we calculated a weighted average of the 12-, 18-, and 24-month scores, and assumed that utility values within each health state were constant thereafter. Utility estimates for the R2 state and all recurrence states were calculated independent of time because of the smaller number of observations. Utility values for the R2, distant recurrence, and combined local and distant recurrence states only differed by randomization group. For the local recurrence state, utilities did not differ by randomization group.
We performed a sensitivity analysis on the utility estimate for the local recurrence state, since local recurrence is the main outcome measure of the TME study and since this utility estimate was based on the relatively small number of 15 observations available from 12 local recurrence patients without a distant recurrence (median follow-up time after local recurrence diagnosis ranged from 0.7 to 10.6 months). We also analyzed the impact of using the patients' preferences based on their VAS scores. These VAS scores were transformed to TTO scores using the power transformation TTO = 1 - (1 - VAS)1.75, estimated from the CUA sample [26,27].
Costs Costs of primary treatment were estimated conditionally on randomization group and R-status. For all Dutch patients, volume data on preoperative screening, type of TME surgery (eg, low anterior resection, abdominoperineal resection), duration of first hospital stay including reinterventions, and postoperative adjuvant radiotherapy and chemotherapy were available. For the costs of PRT, we performed a true resource cost calculation using the cost pricing analysis of the Dutch Bone Metastasis Study [29,30]. To adapt the calculation for specific features of the irradiation used in the TME study, all Dutch radiotherapy institutes participating in the TME study (n = 18, 100% response) filled out a mailed questionnaire on the use of computed tomography planning, shielding, and portal imaging. Sensitivity analysis was performed on the costs of PRT by increasing and decreasing the estimated costs by 50%. The costs of continuing care were estimated as time-dependent monthly costs, conditionally on randomization and model state. Data on hospital readmissions were available for the total Dutch sample. Volumes of outpatient visits and follow-up investigations were modeled according to the protocol of the TME study. Visits to medical specialists or general practitioners, allied health professionals, hours of home help, and district nursing were obtained from weekly (0 to 3 months after surgery) and monthly (3 to 12 months after surgery) diaries filled out by the CUA sample. Medication use and the use of stoma care products were estimated from the pharmacists' and stoma suppliers' registrations of patients in the CUA sample. The costs of treatment for recurrence were assigned as constant monthly costs, conditionally on local or distant recurrence. As local recurrence is the main outcome measure in the TME study, we evaluated the costs of diagnosis and treatment of local recurrences in detail by retrospective examination of the medical records of all 69 patients diagnosed with a local recurrence (with and without distant recurrence, median follow-up time after recurrence diagnosis was 6 months; range, 0 to 29 months). These costs included the costs of diagnostic procedures, outpatient visits, surgery, radiotherapy, chemotherapy, hospitalization, and admissions to nursing homes. For distant recurrences, total costs were estimated by multiplying the available readmission costs by a factor 2.2 (in accordance with the ratio of total and readmission costs for the 69 patients with local recurrence). The quality-of-life questionnaire, administered in the Dutch sample, included questions on paid productivity losses. Paid labor was significantly lower in the PRT + TME group, even 2 years after surgery. Unpaid productivity losses were assessed in the CUA sample using the Health and Labor Questionnaire [31] (before treatment, and at 3 and 12 months after TME surgery). There was a trend toward less unpaid labor per year in the PRT + TME group. After discharge, volumes of paid and unpaid labor were modeled time-dependently and conditionally on randomization group and model state. Paid labor was valued using the friction cost method [32]. In this method, each employee is considered replaceable, and productivity costs are calculated only for the friction period of 4 months, which is the estimated time needed to find a replacement [32]. Sensitivity analysis was performed on the exclusion of productivity costs. Hours of informal care and out-of-pocket costs (eg, clothing) were retrieved from the diaries in the CUA sample. Time and travel costs were based on average durations and travel distances for different types of health care in the Netherlands. During hospitalization, time costs were calculated based on 8 hours per day. The valuation of time was assessed in the CUA sample using the willingness-to-pay method, eliciting the amount of money that patients would be willing to pay to save the time needed for an outpatient visit to a medical specialist.
Validation of the Model Figure 2 compares the results obtained from the base case model to the results directly observed from all TME patients. The modeled local and distance recurrences meticulously follow the observed rates. Because the observed nonsignificant beneficial effect of PRT on distant recurrences was not included in the base case analysis, the modeled distant recurrence rates with or without PRT are identical. During the first 3 years, modeled survival is somewhat higher than observed survival. At the median follow-up of 38 months, the overall observed survival in the PRT + TME group was 75.5% compared with 74.5% in the TME surgery-alone group (P = .75). From 3 years on, modeled survival is lower than observed survival because Dutch life-tables were increasingly used to model long-term non-rectal cancer mortality, and thus, the observed low non-rectal cancer mortality in the TME study was of less influence.
Base Case Analysis The model estimates that the average life expectancy of patients undergoing TME surgery with or without PRT is approximately 13 years (Table 3), compared with 18 years if they had not had rectal cancer. Approximately 35% of the patients eventually die from causes related to rectal cancer, with or without diagnosed recurrence. The addition of PRT leads to an estimated decrease in the long-term probability of local recurrence by 5.2%. The model estimates that the reduction of local recurrences will translate into a survival benefit of 2.8% and 3.2% after 5 and 10 years, respectively. The mean gain in life expectancy and quality-adjusted life expectancy, respectively, are estimated at about 8 months and 5 months. The quality-adjusted gain is smaller, because of the quality adjustment during gained LYs, but also because of the short-term quality loss due to the PRT.
The addition of PRT leads to an estimated increase of the societal costs by $9,800 (Table 4). This increase is not only caused by the costs of the PRT itself, but also by a slightly longer hospitalization period after TME surgery, by considerably higher continuing care costs (hospital admissions, outpatient visits, home help, district nursing, and medication use), and by higher time costs. These higher costs are partly compensated by lower costs of postoperative adjuvant therapy, local recurrence treatment, and unpaid labor. Patients in the TME-alone group received postoperative radiotherapy more often. The lower local recurrence costs in the PRT + TME group are not only explained by the reduction of local recurrences but also by less intensive treatment after recurrence for these patients. Costs of unpaid labor are lower in the PRT + TME group because the annual unpaid productivity losses due to PRT are more than compensated by the unpaid labor performed during gained LYs.
For the base case analysis, PRT leads to a QALY gain of 0.39 and an increase in costs of $9,800. This results in a CE ratio of $25,100 per QALY.
Subgroup and Sensitivity Analyses
Because the objective of PRT is to prevent local recurrences, the local recurrence rate is also the main determinant of the QALY gain and of the cost-effectiveness ratio. Figure 3 shows the effect of variations in the baseline 5-year local recurrence risk without PRT on these outcomes. For our base case analysis, the 5-year local recurrence risk without PRT was 8.6%. Figure 3 shows the estimated QALY gain of 0.39 and the CE ratio of $25,100 per QALY. For subgroups with different local recurrence risks, the figure predicts different outcome estimates. As an illustration, consider patients with tumor node metastases (tumor-node-metastasis system) stage I tumors with a 5-year local recurrence risk of 1.7% [10]. Figure 3 predicts that for these patients, PRT still provides a QALY gain of 0.08, but with a cost-effectiveness ratio of more than $100,000 per QALY. In this way, Figure 3 can be used as a method to assess the cost-effectiveness and effectiveness of PRT for other subgroups of patients, based on their 5-year local recurrence risk without PRT. For older ages, the cost-effectiveness ratio is less favorable, but still in favor of PRT (Table 5). Although the incremental costs are higher for younger ages, due to lifelong higher costs of continuing care, the CE ratio is more favorable for younger patients because they benefit more from PRT than older patients as a result of a longer life expectancy. The base case proportional hazards of PRT for local recurrences are 0.31 after an R0-resection and 0.27 after an R1-resection. As shown in Table 5, the CE ratio ranges from $19,400 to $51,800 per QALY if we vary these proportional hazards over the 95% CIs. Inclusion of all estimated significant as well as nonsignificant proportional hazards decreases the effectiveness of PRT, resulting in a CE ratio of $43,000 per QALY. Increasing the mortality rates in the PRT group to balance the life expectancy in both groups still leads to a QALY difference in favor of PRT, but the CE ratio is far less favorable, at $135,700 per QALY. In this analysis, the short-term loss in quality of life is 0.002 QALYs, and the long-term gain in quality of life because of prevented local recurrences by PRT is 0.074. The valuation of quality of life after local recurrence was estimated at 0.67, which is more favorable than we had expected. Assuming worse utilities for local recurrence leads to more favorable CE ratios, down to $20,000 per QALY. Using patients' valuations of quality of life instead of valuations from the general public also resulted in a more favorable CE ratio of $22,800 per QALY. The difference between the base case analysis and the analysis excluding productivity costs is mostly explained by the difference in unpaid labor. The analysis excluding productivity costs leads to less favorable CE ratios, because of the unpaid labor that irradiated patients provide during their improved survival. The base case analysis was performed from the societal perspective, including both health care and nonhealth care costs. The analysis from the health care perspective, excluding nonhealth care costs, results in a slightly more favorable CE ratio of $24,400 per QALY. This can be explained by higher informal care costs, travel costs, time costs and out-of-pocket expenses in irradiated patients that outweigh the long-term gain in unpaid labor by PRT. Because late effects of radiotherapy cannot be excluded [20], the base case analysis assumed that estimated differences in costs and transition rates continued to exist indefinitely. If these differences were assumed to end after 10 or 5 years, then the CE ratio would markedly improve to $14,500 and $9,500 per QALY, respectively. This improvement is mainly caused by the fact that all costs of continuing care were higher after radiotherapy. Decreasing and increasing the medical costs of PRT by 50%, resulted in CE ratios of $21,700 and $28,200, respectively, per QALY. Because the differences in costs mostly precede the difference in survival, giving the future more weight (0% discount rate) or less weight (5% discount rate) renders, respectively, the more favorable CE ratio of $21,300 per QALY and the less favorable CE ratio of $27,800 per QALY. Table 5 largely presents the results of one-way sensitivity analyses. Multivariate sensitivity analyses were performed, but are not reported because there was very little interaction. Combined effects can thus be estimated by adding up the univariate QALY and cost differences compared with the baseline analysis. For example, assuming higher costs of PRT and lower utility for local recurrence would result in incremental costs and QALYs of $11,000 ($9,800 + $1,200) and 0.49 (0.39 + 0.10), respectively, resulting in a CE ratio of $22,400 per QALY.
Our analysis estimates that PRT improves life expectancy and quality-adjusted life expectancy, but also increases costs. Since cost-effectiveness is never the only decision criterion, no strict thresholds exist for acceptability of costs. Nevertheless, there is some consensus on the rule-of-thumb that less than $20,000 per QALY is definitely acceptable, less than $50,000 per QALY is acceptable, and less than $100,000 per QALY is possibly acceptable [12,33]. According to this classification, the estimated base case costs of $25,100 per QALY for adding preoperative radiotherapy to TME surgery are considered acceptable. In our analysis an extensive amount of data was collected prospectively alongside a large randomized clinical trial. This largely guarantees the internal validity of the results. Although the large number of participating hospitals improves the external validity, generalizability may still be hampered by international differences and also by the fact that effectiveness was measured within a clinical trial. The benefits may be smaller if PRT is implemented under routine care. However, sensitivity analyses on the reduction of local recurrences by PRT maintained the acceptable cost-effectiveness. The cost-effectiveness could improve if it were possible to identify R2 patients preoperatively. For these patients, the model estimates that PRT increases costs and decreases effectiveness. A recent publication [34] suggests that accurate preoperative staging with specialized magnetic resonance imaging techniques is possible. However, preliminary results based on the analysis of such subgroups should be confirmed prospectively before definite conclusions can be drawn. Although QALYs are the preferred outcome measure for cost-effectiveness analyses, they may not accurately reflect the preferences of individuals. Clinicians emphasize the importance of preventing local recurrence for its severe disabling impact [1,8,35]. This was not reflected in the estimated utility, possibly due to the relatively small number of patients and selective nonresponse. In a sensitivity analysis, we examined the effect of a considerably worse valuation for local recurrence, which, as expected, improved the CE ratio in favor of radiotherapy. The model predicts that the reduction of local recurrences by PRT will lead to a long-term survival benefit. The current follow-up in the TME study does not show a significant difference in survival. This discrepancy between estimated and observed survival is attributable to the combined nonsignificant adverse or less favorable effects of PRT on some of the observed mortality and recurrence rates. We have chosen not to include nonsignificant proportional hazards in the base case analysis, to avoid type I errors (ie, erroneously include group differences in the model), possibly at the cost of type II errors (ie, erroneously exclude group differences from the model). Moreover, the cost-effectiveness ratio including all observed proportional hazards remains within acceptable limits.
We believe that the most probable scenario is that a reduction in local recurrence rates does result in a survival benefit. This has recently been confirmed in meta-analyses of preoperative radiotherapy [7,8]. Trials that found no or only small benefits in survival [8,17,36] studied different treatment regimens (eg, postoperative radiotherapy, long-term preoperative schedules, or wider irradiation fields) and used small sample sizes. The Swedish Rectal Cancer Trial [37] is the only other study that has investigated the same 5 x 5 Gy PRT. In combination with conventional surgery, PRT reduced local recurrence rates by 16% (from 27% to 11%) and increased survival at 5 years of follow-up by 10% (from 48% to 58%), with a mean survival benefit of 21 months. In our study, the reduction of local recurrences at 5 years of follow-up by approximately 5% (from 8.6% to 3.6%) corresponds to an estimated increase in 5-year survival of approximately 3% (from 67% to 70%), with a mean survival benefit of 8 months. Our results are generally in line with the results from the Swedish study, but the absolute benefits of PRT on local recurrence rates and survival are smaller due to the introduction of standardized TME surgery. The TME trial was designed and powered to detect a reduction of local recurrences from 10% to 5% by PRT. To detect the estimated 2.8% and 3.2% survival benefits at 5 and 10 years, respectively, sample sizes of 5,700 and 5,100 analyzable patients per arm would have been required ( Recently, the cost-effectiveness for the Swedish trial was estimated at $3,700 per LY saved [39]. Our cost-effectiveness ratio of $25,100 per QALY is less favorable. This can be explained not only by smaller benefits of PRT on local recurrence rates and survival, but from differences in the assessment of costs and quality of life as well. In the Swedish trial, the assessment of costs was limited to direct inpatient and outpatient hospital costs. Also, life years were not adjusted for loss in quality of life, hence overestimating the value of an increase in survival. Although PRT has a beneficial effect on local recurrences, the disadvantages of PRT cannot be neglected. Several model parameters were in favor of no radiotherapy, eg, utilities, health care consumption, continuing care costs, and several other costs. For the patient population as a whole, these disadvantages were too small to outweigh the improved local recurrence rate with the associated survival benefit. For an individual patient, the advantages may not outweigh the disadvantages, which may turn the scales toward a preference for no radiotherapy. As a result, any guideline should be cautiously applied to individual patients. Assuming that the reduced local recurrence rate does lead to a survival advantage, the cost-utility analysis estimates that the improved survival outweighs the impaired quality of life and the increased costs. Sensitivity analyses indicate that the cost-effectiveness ratio remains acceptable under a wide range of assumptions. We conclude that short-term preoperative radiotherapy in patients with rectal cancer undergoing TME is both effective and cost-effective.
Dutch Colorectal Cancer Group: The following investigators participated in the study: the Netherlands —Surgeons: A.B. Bijnen and P. de Ruiter, Medisch Centrum Alkmaar; B. van Ooijen, Algemeen Christelijk Ziekenhuis Eemland, Amersfoort; D. van Geldere and R.P.A. Boom, Ziekenhuis Amstelveen, Amstelveen; R.P. Bleichrodt and S. Meyer, Academisch Ziekenhuis Vrije Universiteit, Amsterdam; R.M.J.M. Butzelaar, E.P. Steller, W.F. van Tets, and A.C.H. Boissevain, Sint Lucas Andreas Ziekenhuis, Amsterdam; F.J. Sjardin, Bovenij Ziekenhuis, Amsterdam; J.F.M. Slors, Academisch Medisch Centrum, Amsterdam; W.H. Bouma and J.G.J. Roussel, Gelre Ziekenhuizen, Apeldoorn; J.H.G. Klinkenbijl and E.J. Spillenaar Bilgen, Ziekenhuis Rijnstate, Arnhem; P.M. Kruyt and W.K. de Roos, Stichting Ziekenhuisvoorzieningen Gelderse Vallei, Bennekom; E.J.R. Slingenberg and P.D. de Rooij, Sint Ziekenhuis Lievensberg, Bergen op Zoom; M.A.J.M. Hunfeld, Rode Kruis Ziekenhuis, Beverwijk; A.L.A. Meersman, Maasziekenhuis, Boxmeer; J.K.S. Nuytinck, Ignatius Ziekenhuis, Breda; R.M.P.H. Crolla, Ziekenhuis de Baronie, Breda; J. van der Bijl, Atrium Brunssum, Brunssum, and Atrium Heerlen, Heerlen; G.W.M. Tetteroo, Ijsselland Ziekenhuis, Capelle aan de Ijssel; L.P.S. Stassen and P.W. de Graaf, Reinier de Graaf Groep, Delft; W.A.H. Gelderman and F.G.J. Willekens, Bosch Medicentrum, den Bosch; I.P.T. van Bebber and E.J. Carol, Stichting Carolus-Liduina-Lindelust Ziekenhuis, den Bosch; G.W. Kastelein and H. Boutkan, Stichting Juliana Kinderziekenhuis-Rode Kruis Ziekenhuis, Den Haag; C. Ulrich and B.C. de Vries, Medisch Centrum Haaglanden, Den Haag; H.J. Smeets and J.M. Heslinga, Stichting Bronovo-Nebo, Ziekenhuis Bronovo, Den Haag; P.V.M. Pahlplatz, Ziekenhuis Leyenburg, Den Haag; P. Heres and J.A. van Oijen, Stichting het van Weel-Bethesda Ziekenhuis, Dirksland; M. van Hillo, Stichting Talma Sionsberg, Dokkum; R.J. Oostenbroek and K.G. Tan, Albert Schweitzer Ziekenhuis, Dordrecht; H.C.J. van der Mijle and R. Looijen, Christelijk Ziekenhuis Nij Smellinghe, Drachten; J.J. Jakimowicz, Catharina Ziekenhuis, Eindhoven; O.J. Repelaer van Driel and P.H.M. Reemst, Diaconessenhuis Eindhoven; E.J.T. Luiten and R.F.T.A. Assmann, Sint Annaziekenhuis, Geldrop; C.M. Dijkhuis, Oosterscheldeziekenhuis, Goes; R.T. Ottow, Het Groene Hart Ziekenhuis, Gouda; J.T.M. Plukker, Academisch Ziekenhuis Groningen; E.J. Boerma and R. Silvis, Kennemer Gasthuis, Haarlem; J.H. Tomee, Stichting Streekziekenhuis Coevorden-Hardenberg, Hardenberg; G.J.M. Akkersdijk, Spaarne Ziekenhuis, Heemstede; C.G.B.M. Rupert, de Tjongerschans Ziekenhuis, Heerenveen; G.J.C.M. Niessen and G. Verspui, Elkerliek Ziekenhuis, Helmond; J.H. Kroesen and J.W. Juttmann, Ziekenhuis Hilversum, Hilversum; J.W.D. de Waard and M.W.C. de Jonge, Westfries Gasthuis, Hoorn; D.B.W. de Roy van Zuidewijn and W. Dahmen, Medisch Centrum Leeuwarden; R. Vree, J.A. Zonnevylle, Diaconessenhuis, Leiden; E. Klein Kranenbarg and R.A.E.M. Tollenaar, Leids Universitair Medisch Centrum, Leiden; P.A. Neijenhuis, S.A. da Costa, and S.K. Adhin, Rijnland Ziekenhuis, Leiderdorp; F.J. Idenburg, Medisch Centrum Haaglanden, Leidschendam; H. van der Veen and C.E.A.M. Hoynck van Papendrecht, IJsselmeerziekenhuizen, Lelystad; C.G.M.I. Baeten, M.F. von Meyenfeldt, and G.L. Beets, Academisch Ziekenhuis Maastricht; T. Wobbes, Academisch Ziekenhuis, Nijmegen Sint Radboud, Nijmegen; E.D.M. Bruggink and L.J.A. Strobbe, Canisius-Wilhelmina Ziekenhuis, Nijmegen; O.J. van West and R.A.J. Dörr, Pasteurziekenhuis, Oosterhout; C.D. van Duyn, Ziekenhuis Bernhoven, Oss; J.W.M. Bol and T.A.A. van den Broek, Waterlandziekenhuis, Purmerend; J.M.H. Debets and R.J.A. Estourgie, Laurentius Ziekenhuis, Roermond; H.W.P.M. Kemperman, Ziekenhuis Franciscus, Roosendaal; H.F. Veen, W.F. Weidema, and C.J. van Steensel, Ikazia Ziekenhuis, Rotterdam; F. Logeman and A.A.E.A. de Smet, Sint Clara Ziekenhuis, Rotterdam; A.W.K.S. Marinelli, Daniel den Hoed Kliniek, Rotterdam; J.H. Driebeek-van Dam, Havenziekenhuis, Rotterdam; W.R. Schouten and P.P.L.O. Coene, Academisch Ziekenhuis Rotterdam, Dijkzigt; M.A. Paul, Zuiderziekenhuis, Rotterdam; J.J. van Bruggen, Schieland Ziekenhuis, Schiedam; E.J. Mulder, Antonius Ziekenhuis, Sneek; R. den Toom and A.J. van Beek, Ruwaard van Putten Ziekenhuis, Spijkenisse; S.J. Brenninkmeyer and G.P. Gerritsen, Tweesteden Ziekenhuis, Tilburg; H.J.M. Oostvogel and J.A. Roukema, Sint Elisabeth Ziekenhuis, Tilburg; E.B.M. Theunissen, Mesos, Utrecht; L.W.M. Janssen and A. Hennipman, Universitair Medisch Centrum, Utrecht; A.J.M. van Wieringen, Mesos, Utrecht; A. Pronk and P. Leguit, Diakonessenhuis, Utrecht; F.A.A.M. Croiset van Uchelen and R.M.H. Roumen, Sint Joseph Ziekenhuis, Veldhoven; C.L.H. van Berlo and J.F.M. Reinders, Sint Maartens Gasthuis, Venlo; C.D.G.W. Verheij, Sint Elisabeth Ziekenhuis, Venray; J.H. ten Thije, Ziekenhuis Walcheren, Vlissingen; W. van Overhagen and I.H. Oei, Reinier de Graaf Groep, Voorburg; E.M.G. Leerkotte and J.W.A. van Luijt, Tweesteden Ziekenhuis, Waalwijk; H.C.M. Verkooyen and J.A.L. Jansen, Sint Jans-Gasthuis, Weert; J. Merkx and J.P. Vente, Hofpoort Ziekenhuis, Woerden; H. de Morree, Stichting Oosterscheldeziekenhuizen, Zierikzee; P.J.J. van Rijn, 't Lange Land Ziekenhuis, Zoetermeer; and W.F. Blom, Albert Schweitzer Ziekenhuis, Zwijndrecht; Pathologists: J.P.A. Baak, Medisch Centrum Alkmaar; H. Barrowclough, Algemeen Christelijk Ziekenhuis Eemland, Amersfoort; G.J.A. Offerhaus, Academisch Medisch Centrum, Amsterdam; G. Brutel de la Riviere, M.L.F. van Velthuysen, Antoni van Leeuwenhoekziekenhuis, Amsterdam; B.A. van de Wiel, Sint Lucas Andreas Ziekenhuis, Amsterdam; H.H. Oushoorn, Bovenij Ziekenhuis, Amsterdam; E. Bloemena, Vrije Universiteit, Amsterdam; T.A.J.M. Manschot, Gelre Ziekenhuizen, Apeldoorn; J.M. Wiersma-van Tilburg, Ziekenhuis Rijnstate, Arnhem; V. Potters, Stichting Ziekenhuis Lievensberg, Bergen op Zoom; H.V. Stel, Ziekenhuis Gooi-Noord, Blaricum; J. Los, Ignatius Ziekenhuis, Breda; G.W. Verdonk, Atrium Brunssum; C. van Krimpen, S.H. Sastrowijoto, and E.M. van der Loo, Stichting Diagnostisch Centrum Stichting Samenwerkende Delftse Ziekenhuizen, Delft; H.A. Meijer, Bosch Medicentrum, den Bosch; P. Blok, Ziekenhuis Leyenburg, Den Haag; C.J. Tinga, Stichting Bronovo-Nebo, Ziekenhuis Bronovo, Den Haag; E.C.M. Ooms, Medisch Centrum Haaglanden, Den Haag; C.M. Bruijn-van Duinen, Ziekenhuis Leyenburg, Den Haag; J.W. Steffelaar, Stichting Juliana Kinderziekenhuis-Rode Kruis Ziekenhuis, Den Haag; P.J. Westenend, Pathologisch Laboratorium voor Dordrecht en Omstreken, Dordrecht; I.W.N. Tan-Go and H.M. Peters, Stichting Pathologische Anatomie en Medische Microbiologie, Eindhoven; E.J.M. Ahsmann, Stichting Laboratoria Goudse Ziekenhuizen, Gouda; J.F. Keuning, Stichting Pathologisch Anatomisch Laboratorium Kennemerland, Haarlem; K. van Groningen, Spaarne Ziekenhuis, Heemstede; P.H.M.H. Theunissen, Atrium Heerlen, Heerlen; F.J.J.M. van Merrienboer, Elkerliek Ziekenhuis, Helmond; G. Freling, Ziekenhuis Bethesda, Hoogeveen; A.J.K. Grond, Laboratorium voor de Volksgezondheid in Friesland, Leeuwarden; M.C.B. Gorsira, Diaconessenhuis, Leiden; J.J. Calame, Rijnland Ziekenhuis, Leiderdorp; E.A. Neefjes-Borst, IJsselmeerziekenhuizen, Lelystad; J.W. Arends, Academisch Ziekenhuis, Maastricht; A.P. Runsink, Streeklaboratorium Zeeland, Middelburg; C.A. Seldenrijk, Stichting Sint Antonius Ziekenhuis, Nieuwegein; M. Mravunac, Canisius-Wilhelmina Ziekenhuis, Nijmegen; W.S. Kwee, Laurentius Ziekenhuis, Roermond; H. van Dekken, Daniel den Hoed Kliniek, Rotterdam; J.C. Verhaar and N.A.L. van Kaam, Stichting Pathan, Rotterdam; H. van Dekken, Academisch Ziekenhuis Rotterdam, Dijkzigt; R.W.M. Giard, Sint Clara Ziekenhuis, Rotterdam; H. Beerman, Zuiderziekenhuis, Rotterdam; A.A.M. van der Wurff, Sint Elisabeth Ziekenhuis, Tilburg; M.E.I. Schipper, Universitair Medisch Centrum, Utrecht; H.M. Ruitenberg, Diakonessenhuis, Utrecht; R.F.M. Schapers, Stichting Pathologisch Laboratorium, Venlo; A.P. Willig, Sint Jans-Gasthuis, Weert; and A.G. Balk, Stichting Ziekenhuis De Heel, Zaandam; Radiotherapists: E.H.J.M. Rutten, Medisch Centrum Alkmaar; D. Gonzalez Gonzalez and G. van Tienhoven, Academisch Medisch Centrum, Amsterdam; B.J. Slotman and J.A. Langendijk, Academisch Ziekenhuis Vrije Universiteit, Amsterdam; G.M.M. Bartelink and B.M.P. Aleman, Antoni van Leeuwenhoekziekenhuis, Amsterdam; A.H. Westenberg, Arnhems Radiotherapeutisch Instituut, Arnhem; J. Pomp, Reinier de Graaf Gasthuis, Delft; C.C.E. Koning and R.G.J. Wiggenraad, Medisch Centrum Haaglanden, Den Haag; F.M. Gescher, Ziekenhuis Leyenburg, Den Haag; J.J.F.M. Immerzeel and A.C.A. Mak, Radiotherapeutisch Instituut Stedendriehoek en Omstreken, Deventer; J.G. Ribot and H. Martijn, Catharina Ziekenhuis, Eindhoven; D.F.M. de Haas-Kock, Stichting Radiotherapeutisch Instituut Limburg, Heerlen; G. Botke and A. Slot, Radiotherapeutisch Instituut Friesland, Leeuwarden; E.M. Noordijk, Leids Universitair Medisch Centrum, Leiden; P. Lambin, Academisch Ziekenhuis Maastricht; J. Hoogenhout, Academisch Ziekenhuis Nijmegen Sint Radboud, Nijmegen; P.C. Levendag and P.E.J. Hanssens, Daniel den Hoed Kliniek, Rotterdam; G.S.J. Bunnik and K.A.J. de Winter, Dokter Bernard Verbeeten Instituut, Tilburg; J.J. Batterman and H.K. Wijrdeman, Universitair Medisch Centrum, Utrecht; and J.M. Tabak and M.F.H. Dielwart, Zeeuws Radiotherapeutisch Instituut, Vlissingen. Other countries —J.C. Pector, Institut Jules Bordet, Belgium; J. van de Stadt, Université Libre de Bruxelles, Hospital Erasme, Belgium; P.T. Phang and J.K. MacFarlane, St. Paul's Hospital, Canada; P. Teniere, Hôpital Charles Nicolle, France; J.R. Delpero, Institut J. Paoli et I. Calmettes, France; B. Sastre, Hôpital Sainte-Marguerite, France; B. Nordlinger and C. Penna, Centre Hospitalier Universitaire Ambroise Pare, France; B. Gerdes and B. Stinner, Klinikum der Philips-Universität, Germany; P. Delrio and V. Parisi, Istituto Nazionale per lo Studio e la Cura dei Tumori, Italy; S. Pucciarelli, Universita di Padova, Italy; J. Guimaraes dos Santos, Instituto Portugues de Ontologica do Porto, Portugal; A. Nihlberg and O. Bendtsen, Falu Lasarett, Sweden; G. Lindmark, Helsingborgs Lasarett, Sweden; A. Törnqvist and T. Hallgren, Centralsjukhuset, Sweden; R. Sjödahl and O. Hallbook, University of Linköping, Sweden; M. Bohe and H. Jiborn, Allmäna Sjukhuset, Sweden; E. Nilsson, Lasarettet i Motala, Sweden; H. Krook and G. Arbman, Landstinget i Östergötland, Sweden; J. Rutegård, Örnsköldsvik Hospital, Sweden; B. Sandzén, Umeå University Hospital, Sweden; W. Graf, Akademiska Sjukhuset, Sweden; K. Smedh, Centralhospital, Sweden; K. Johansson, Västerviks Sjukhus, Sweden; and R.J. Heald and B.J. Moran, North Hampshire Hospital, United Kingdom.
The authors indicated no potential conflicts of interest.
This study was supported by grant 97-026 from the Health Care Insurance Board, the Hague, the Netherlands, and by grant CKVO 95-04 from the Dutch Cancer Society, Amsterdam, the Netherlands. Presented in part at the 1st Multidisciplinary Colorectal Cancer Congress, Noordwijk, the Netherlands, April 17–20, 2001. Participating investigators are listed in the Appendix. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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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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ABSTRACT
INTRODUCTION
= .05, two-sided, power 0.90) [
