Affiliations of authors: Division of Gastroenterology, Brigham and Women's Hospital (JJT, JRS, SS), Boston, MA; Population Sciences Division, Dana-Farber Cancer Institute (SS), Boston; Department of Health Policy and Management, Harvard School of Public Health (KMK), Boston; Harvard Medical School (JJT, JRS, SS), Boston.
Correspondence to: Sapna Syngal, MD, MPH, Smith 209, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115 (e-mail: ssyngal{at}partners.org)
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ABSTRACT |
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INTRODUCTION |
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The appropriate timing of chemoradiation for rectal cancer is controversial (4), perhaps because physicians of many specialties, including gastroenterologists, surgeons, and medical and radiation oncologists, participate in the diagnosis and treatment of rectal cancer. The participants of the National Institutes of Health Consensus Conference of 1990 (5) recommended postoperative chemoradiation for locally advanced rectal cancer (TNM stage II/III-T3 or T4 and/or lymph node-positive disease). This recommendation is supported by data from randomized trials demonstrating prolonged survival for individuals who received postoperative chemoradiation compared with individuals who received surgical resection alone (6,7) or with individuals who received surgical resection and postoperative radiation (8). Administration of chemoradiation in the preoperative period has also been advocated. Although studies have shown a decrease in the local recurrence of rectal cancer (912) and improved survival (9,12) for individuals who received preoperative radiation, the benefits of preoperative chemoradiation have not been established. Several centers have reported excellent results from uncontrolled, prospective studies evaluating preoperative chemoradiation for patients with locally advanced rectal cancer (1320). However, two multicenter North American trials that directly compared preoperative with postoperative chemoradiation were closed after several years because of insufficient accrual (21). If lack of accrual is the result of strong physician and patient beliefs regarding the appropriate management of rectal cancer, then it is unlikely that such trials will ever be successfully conducted in the United States. Moreover, future trials comparing preoperative with postoperative chemoradiation for patients with locally advanced rectal cancer may allow the patient and physician to choose which treatment arm the patient will be assigned to (22). To our knowledge, a multicenter trial from Germany (23) is the only completed randomized study of preoperative versus postoperative chemoradiation for patients with locally advanced rectal cancer. Initial results, released in abstract form, showed improved sphincter preservation and decreased recurrence for patients who received preoperative chemoradiation over patients who received postoperative chemoradiation, but a difference in survival may not be measurable for several years.
Preoperative staging determines a patient's eligibility for preoperative chemoradiation and local excision surgery. Abdominopelvic computed tomography is routinely performed after a diagnosis of rectal cancer to establish whether the disease has spread to structures adjacent to the rectum and/or established distant metastases. The depth of rectal wall invasion and involvement of regional lymph nodes can be determined by local rectal imaging using rectal endoscopic (i.e., optical) ultrasound, transrectal (i.e., non-optical) ultrasound, or rectal magnetic resonance imaging.
There are no completed studies comparing rectal cancer outcomes after preoperative staging and chemoradiation with those after postoperative chemoradiation. When clinical choices are being made under conditions of uncertainty, decision analysis techniques are helpful in comparing the benefits of two alternative strategies. A decision model explicitly demonstrates all possible consequences of each choice. The likelihood of a particular event occurring is obtained from available literature and then may be modified over a plausible range during sensitivity analysis. The purpose of this study was to use a decision analysis to compare the two management strategies for rectal cancer and to determine which strategy would yield the greatest life expectancy and quality-adjusted life expectancy.
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METHODS |
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We developed a decision model using DATA 3.5 (TreeAge Software, Williamstown, MA) to compare the two competing strategies (postoperative chemoradiation versus preoperative staging and chemoradiation) for patients aged 70 years with resectable rectal cancer (Fig. 1). The model is based on the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (24), in which both management strategies are considered acceptable for patients of this age and disease stage.
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We assumed that patients in the postoperative chemoradiation strategy would undergo a radical resection (either an abdominoperineal resection or an anterior resection) and receive postoperative chemoradiation for locally advanced disease. We assumed that patients in the preoperative staging and chemoradiation strategy would receive preoperative chemoradiation for disease determined by local imaging to be locally advanced and, if appropriate, patients with localized disease would undergo local excision surgery rather than radical resection. Tumors amenable to local excision surgery must be smaller than 40% of the circumference of the rectum, must be located within 10 cm of the anal verge, and must not involve the anal sphincter (24,25).
After completing treatment, the hypothetical cohort was entered into a Markov model (26) grafted onto the decision tree. Incorporation of a Markov subtree allows representation of cumulative outcomes, such as mortality and quality of life. Although the decision tree is restricted to a finite time frame, the Markov model reflects events, such as death from rectal cancer, that have an ongoing risk. The Markov model in our analysis consisted of three finite health states in which a member of the cohort may exist: alive, alive with long-term surgical morbidity, or dead (Fig. 2). The model was analyzed using a cohort simulation in which a large number of hypothetical patients travel through the decision tree and then enter the Markov model (26). In the Markov model, the cohort is distributed between two health states: alive and alive with long-term surgical morbidity. Subsequent transitions to the third state (i.e., death) occur at the end of each year at a rate reflecting age-specific mortality and the ongoing risk of dying from rectal cancer. By year 11 in the Markov model, the mortality from rectal cancer was assumed to be negligible.
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The base-case probabilities, range for sensitivity analyses, and data sources are listed in Table 1. Estimates for rectal cancer stage at diagnosis, type of surgical resection, surgical mortality (death attributable to surgery), surgical complications, and long-term surgical morbidity were derived from a systematic review of the literature. Studies from 1965 through 2001 were identi- fied from MEDLINE with the following search terms: "rectal neoplasm," "surgery," "anterior resection," "low anterior resection," "abdominoperineal resection," and "local excision." For our model, we assumed that patients receiving preoperative chemoradiation would have less tumor burden at the time of surgery and that a smaller proportion of patients receiving preoperative chemoradiation than patients receiving postoperative chemoradiation would require an abdominoperineal resection (13,16,18,2729).
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The preoperative imaging modalities considered were rectal endoscopic ultrasound, transrectal ultrasound, and rectal magnetic resonance imaging. We performed a systematic review of the literature from 1965 through 2001 in MEDLINE using the following search terms: "rectal neoplasm," "endoscopic ultrasound," "ultrasound," "magnetic resonance imaging," and "staging." The following were criteria for study inclusion: 1) Tumors evaluated were rectal adenocarcinomas, 2) raw data on preoperative tumor stage, preoperative lymph node stage, and postoperative pathologic stage were reported, and 3) patients did not receive preoperative chemoradiation. We excluded studies in which patients received preoperative chemoradiation because such treatment affects the surgical pathologic stage. Imaging modalities were not further distinguished on the basis of, for example, ultrasound probe frequency or magnetic resonance imaging coil; however, any impact on staging accuracy afforded by these technical differences was accounted for in our sensitivity analysis.
The base-case conditional probabilities of disease stage on preoperative imaging, given true disease stage, are the mean values, weighted by sample size, calculated from the included studies. Our decision model was further evaluated using the best- and worst-case scenarios for preoperative staging accuracy of tumor depth. The best- and worst-case scenarios, which were obtained from the included studies, were used because a comprehensive sensitivity analysis of each of the four possible preoperative staging results for each true tumor depth (T1-T4) was not feasible. The accuracy of preoperative lymph node staging was subjected to standard sensitivity analysis.
Mortality Rates
The age-specific mortality rate for any race/ethnicity or sex was obtained from the U.S. Life Tables (30). The mortality rates from rectal cancer differ by disease stage and treatment. Patients with localized disease were assumed to have equivalent mortality rates, regardless of therapy. The 5-year disease-specific survival for patients with localized rectal cancer, which was obtained from the Surveillance, Epidemiology, and End Results1 (SEER) Program public-use database (31), was 91%.
For patients with locally advanced disease in the postoperative chemoradiation strategy, the average disease-specific survival, weighted by sample size, was calculated from prospective trials comparing different postoperative chemoradiation regimens or comparing postoperative chemoradiation with surgery alone (6,8,3234). The 5-year disease-specific survival for patients with locally advanced rectal cancer treated with postoperative chemoradiation was 70%.
Because survival following preoperative chemoradiation for patients with locally advanced disease is not yet known, and to account for the possibility of selection bias, the model was evaluated at three fixed values of 5-year disease-specific survival: equal to postoperative chemoradiation (70%), less than postoperative chemoradiation (67%), and greater than postoperative chemoradiation (73%). Although the decision to use a 3% difference in 5-year survival was arbitrary, we believed it would be a large enough difference to alter clinical practice, because this difference is similar to the 5-year survival benefit of postoperative chemoradiation over postoperative radiation (8).
Health-Related Quality of Life
To assess the effect of quality-of-life outcomes on decisions regarding rectal cancer management, we incorporated utilitiesestimates of patient preferenceinto each Markov health state. A utility is a value between 0 (equal to death) and 1 (alive without long-term treatment-related morbidity). Multiplying the time spent in each health state by the utility associated with that health state results in a single outcome measure, quality-adjusted life expectancy. A decrease in utility (i.e., disutility) can be assigned to events that affect quality of life for a short period of time (i.e., initial disutility), such as surgical complications or the acute toxicity of chemoradiation, or for a long period of time (i.e., incremental disutility), such as the long-term effects of chemoradiation.
Patients who underwent abdominoperineal resection with colostomy were assigned a utility of 0.92 on the basis of the results of a published standard gamble conducted in patients with rectal cancer with colostomies (35). (The standard gamble estimates the expected utility of a health state by having patients choose the risk of death that would be acceptable in a gamble for perfect health.) Patients with persistent bowel, bladder, or sexual dysfunction after anterior resection were considered to have long-term surgical morbidity. The proportion of patients with long-term morbidity after anterior resection was the mean, weighted by sample size, of the proportion from nine cohort studies identified by systematic review of the literature (3644). Because there are no published utilities for the health states following sphincter-preserving rectal cancer surgery, the estimates used in our model were derived from patients with prostate cancer who had undergone radical prostatectomy and had sexual and/or urinary dysfunction (45). Patients with long-term surgical morbidity after anterior resection were assumed to have a utility of 0.86. The base-case utilities and disutilities were subjected to sensitivity analysis.
Sensitivity Analysis
For each model variable, a plausible range of values was determined from the available literature or, if such a range was unavailable, it was assumed to be ±30% of the base-case value. One-way sensitivity analysis was conducted on each variable sequentially. In one-way sensitivity analysis, a single variable is varied over the predetermined range of values while the other model variables are held constant. If the preferred decision changes when a model parameter is varied, the model is considered to be sensitive to this variable. The value of the variable at which the strategy preference changes is the threshold value.
Variables to which our model was sensitive in one-way sensitivity analysis underwent two-way sensitivity analysis. Two-way sensitivity analysis examines simultaneous variation of two variables while the remainder of the model variables are held constant. Two regions are formed, each denoting which strategy is preferred, given any value of the two variables being analyzed.
Clinical Outcome at 5 Years
Using the model structure, hypothetical cohorts of patients were entered into the preoperative staging and chemoradiation branch (n = 1000) and into the postoperative chemoradiation branch (n = 1000). We calculated the 5-year clinical outcome of these patients relative to the time of entry into the model.
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RESULTS |
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The results of this analysis were strongly influenced by the efficacy of preoperative chemoradiation in locally advanced rectal cancer. However, the available data comparing the benefits and risks of preoperative versus postoperative chemoradiation are controversial. Therefore, for our analysis, we considered three possible scenarios: 1) that the disease-specific survival for locally advanced rectal cancer after preoperative chemoradiation is less than the disease-specific survival after postoperative chemoradiation, 2) that the disease-specific survival for locally advanced rectal cancer after preoperative chemoradiation is equal to the disease-specific survival after postoperative chemoradiation, and 3) that the disease-specific survival for locally advanced rectal cancer after preoperative chemoradiation is greater than the disease-specific survival after postoperative chemoradiation.
Disease-Specific Survival After Preoperative Chemoradiation Is Less Than That After Postoperative Chemoradiation
We first assumed that the 5-year disease-specific survival for patients with locally advanced rectal cancer after preoperative chemoradiation was less than that after postoperative chemoradiation. With this assumption, the model analysis showed that the postoperative chemoradiation strategy was preferred. The life expectancy and quality-adjusted life expectancy gains of the postoperative chemoradiation strategy, relative to the preoperative staging and chemoradiation strategy, were 4.25 and 0.12 months, respectively (Table 2).
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Disease-Specific Survival After Preoperative Chemoradiation Is Equal to That After Postoperative Chemoradiation
We next assumed that the 5-year disease-specific survival for locally advanced rectal cancer after preoperative chemoradiation was equal to that after postoperative chemoradiation. This analysis showed that the preoperative staging and chemoradiation strategy was preferred to the postoperative chemoradiation strategy, with a life expectancy gain of 0.04 months and a quality-adjusted life expectancy gain of 3.84 months (Table 2).
The strategy preference was sensitive to surgical mortality, probability of undergoing an abdominoperineal resection versus an anterior resection, probability of positive lymph nodes in stage T1 or T2 disease, lymph node staging accuracy, and probability of local excision surgery when lymph node staging was imperfect (Table 3). In the base-case analysis, an increased proportion of patients underwent abdominoperineal resection in the postoperative chemoradiation strategy, which has a higher surgical mortality than anterior resection or local excision surgery. The increase in the number of abdominoperineal resections in the postoperative chemoradiation strategy accounts for the slight gain in life expectancy in the preoperative staging and chemoradiation strategy. Therefore, if the surgical mortality or the probability of undergoing an abdominoperineal resection versus an anterior resection is different between the two strategies, then the strategy preference changes.
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Disease-Specific Survival After Preoperative Chemoradiation Is Greater Than That After Postoperative Chemoradiation
We next assumed that the 5-year disease-specific survival for locally advanced rectal cancer after preoperative chemoradiation is greater than that after postoperative chemoradiation. In this analysis, the preoperative staging and chemoradiation strategy was the preferred strategy, with a life expectancy gain of 4.43 months and a quality-adjusted life expectancy gain of 7.80 months (Table 2). In sensitivity analyses, the preferred strategy was preoperative staging and chemoradiation in all scenarios in which life expectancy or quality-adjusted life expectancy was the outcome.
Clinical Outcome at 5 Years
The outcome for a hypothetical cohort of 1000 patients 5 years after their initial treatment with each strategy is shown in Table 4. More patients would die from their surgery or have a colostomy in the postoperative chemoradiation strategy than in the preoperative staging and chemoradiation strategy. In the preoperative staging and chemoradiation strategy, three patients would have residual lymph node disease after undergoing local excision surgery and 72 patients with localized cancer would be incorrectly staged as having advanced disease and would receive chemoradiation unnecessarily. The number of patients who would die of rectal cancer in the preoperative staging and chemoradiation strategy, relative to that in the postoperative chemoradiation strategy, would depend on the efficacy of preoperative chemoradiation in locally advanced cancer.
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DISCUSSION |
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A decision analysis comparing abdominoperineal resection to preoperative staging followed by local excision surgery for a cohort of patients with localized disease of the distal rectum has been previously reported (46). In that analysis, the local excision strategy was always preferred, provided that the preoperative assessment of tumor depth was adequate, lymph node disease occurred in less than 25% of tumors confined to the rectal wall, local recurrence occurred in less than 28% of patients, and the utility for a colostomy was less than 0.97. However, less than 25% of patients presenting with rectal cancer have localized disease, and only 30% of those will have tumors amenable to local excision surgery. Therefore, in our analysis of patients with localized and locally advanced rectal cancer, the life expectancy gain in the preoperative staging and chemoradiation strategy due to the decreased surgical mortality of local excision would be less than 10 days, even with perfect lymph node staging accuracy. The quality-adjusted life expectancy gain would be approximately 2 months. Although the clinical decision to obtain preoperative staging may be driven by an assumption of benefit from local excision surgery, when the entire cohort of patients with resectable rectal cancer is considered, our analysis indicates that the potential survival gain from preoperative chemoradiation is a much more influential factor than local excision surgery.
The potential benefits of preoperative versus postoperative chemoradiation have not been fully elucidated. Possible advantages of preoperative chemoradiation include increased number of sphincter-sparing operations (23,27), increased ease of resection, excision of the irradiated large bowel, and less small bowel irradiation, which may reduce late complications such as small bowel obstruction (47), diarrhea, and bleeding. Furthermore, trials comparing preoperative and postoperative radiation (without chemotherapy) have demonstrated a statistically significant reduction in the rate of local recurrence using the preoperative regimen (9,11,47). However, administering chemoradiation preoperatively prevents pathologic staging of the tumor, and physicians must rely on local rectal imaging techniques to determine the extent of the disease and the appropriate management. Chemoradiation before surgery may also have greater toxicity (21) than postoperative chemoradiation, although this is controversial (23). Concern that preoperative chemoradiation is associated with a higher rate of surgical complications, specifically anastomotic leaks, than postoperative chemoradiation has not been supported by recent trials (21,48).
Although several uncontrolled studies (1320) have evaluated preoperative chemoradiation in locally advanced rectal cancer, a comparison of preoperative versus postoperative chemoradiation has not been completed in North America. Two multicenter trials aimed at addressing this questionIntergroup 0147 and National Surgical Adjuvant Breast and Bowel Protocol R-03were closed early because of slow patient accrual. The latter group has presented preliminary results on those patients enrolled (21). Although survival was equivalent between the groups, the preoperative group had more sphincter-sparing operations and had a higher proportion of disease-free patients at 1 year. The postoperative complication rate was similar in the two groups, but patients in the preoperative group had a higher rate of chemoradiation toxicity (20). A multicenter trial from Germany (Protocol CAO/ARO/AIO-94) (48) randomly assigned 823 patients with locally advanced rectal cancer undergoing radical resection with total mesorectal excision to preoperative or postoperative chemoradiation arms. Initial results from 797 patients at a median follow-up of 43 months show no difference in chemoradiation toxicity or postoperative complications between the two groups (23). However, sphincter preservation in patients with distal tumors and local and distant recurrence were improved in patients assigned to the preoperative chemoradiation arm. A statistically significant difference in survival was not detected but may become apparent with a longer follow-up interval. Thus, the North American and German trials both demonstrated increased sphincter preservation and decreased disease recurrence in those patients receiving preoperative chemoradiation.
In designing the present model, we assessed the available survival data from prospective uncontrolled trials evaluating preoperative chemoradiation in patients with locally advanced rectal cancer. This approach has the potential for selection bias, which would have occurred if patients with localized disease, incorrectly staged preoperatively as locally advanced cancer, were included in the studies. Moreover, although the trials evaluating postoperative chemoradiation contained a high percentage of patients with lymph node involvement, it is possible that the trials evaluating preoperative chemoradiation had a disproportionate number of patients without lymph node involvement and therefore yielded a longer survival time. To account for potential bias, we evaluated our model under three different assumptions: that the efficacy of preoperative chemoradiation is less than, more than, and equal to the efficacy of postoperative chemoradiation in treating patients with locally advanced rectal cancer.
The major factor affecting strategy preference was the potential survival difference between patients who received preoperative chemoradiation and those who received postoperative chemoradiation. Unlike the option of performing local excision surgery, the difference in the timing of chemoradiation affected a substantial portion of the cohort. More than 75% of patients have locally advanced disease at the time of diagnosis, and all should receive chemoradiation. Although the 5-year disease-specific survival of patients after preoperative chemoradiation is unknown, our analysis indicated that, should it be equal to or better than that for patients after postoperative chemoradiation, the preoperative staging and chemoradiation strategy would be preferred. Incorporating quality-of-life estimates into the model strengthened the preference for preoperative staging and chemoradiation. Although the short-term toxicity of chemoradiation did not affect strategy preference, differences between the long-term effects of preoperative and postoperative chemoradiation need to be assessed before determining the optimal management strategy.
When survival after pre- or postoperative chemoradiation was set as equal, the strategy preference became sensitive to surgical mortality and the probability of residual lymph node disease after local excision surgery. Variables affecting surgical mortality included the probability of undergoing an abdominoperineal resection rather than an anterior resection or local excision surgery and the probability of dying during these procedures. The probability of residual lymph node disease was affected by the probability of lymph node metastases in patient with stage T1 or T2 disease, the accuracy of lymph node staging, and the probability of having a tumor amenable to local excision. Thus, assuming that the efficacy of preoperative and postoperative chemoradiation for patients with locally advanced disease is equivalent, patients must consider whether the risks associated with the postoperative chemoradiation strategya 6% increase in absolute risk of colostomy plus a 0.2% increase in absolute risk of surgical mortalityoutweigh the risks associated with the preoperative staging and chemoradiation strategya 0.3% risk of residual lymph node disease plus a 7.2% risk of receiving unnecessary chemoradiation.
In conclusion, our analysis suggests two approaches to determine whether local preoperative staging and preoperative chemoradiation should be incorporated into the routine management of patients with rectal cancer. If there is sufficient concern that preoperative chemoradiation has either less efficacy or greater toxicity than postoperative chemoradiation, then either a substantial effort must be made to resurrect the North American clinical trials closed prematurely due to insufficient accrual or we must await the final results of the German study (23). If, however, there is consensus that the efficacy of preoperative chemoradiation is at least equivalent to the efficacy of postoperative chemoradiation, then preoperative staging and preoperative chemoradiation are beneficial for patients with locally advanced rectal cancer. Future efforts should focus on developing and evaluating imaging techniques to improve the accuracy of preoperative rectal cancer staging.
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NOTES |
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Manuscript received July 16, 2003; revised November 28, 2003; accepted December 8, 2003.
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