the Colorectal Service
    Departments of Surgery
    Pathology
    Biostatistics
    Medical Oncology
    Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY

    ABSTRACT

    PURPOSE: Clinical assessment of rectal cancer response to preoperative combined-modality therapy (CMT) using digital rectal examination (DRE) has been proposed as a means of assessing efficacy of therapy. However, because the accuracy of this approach has not been established, we conducted a prospective analysis to determine the operating surgeon's ability to assess response using DRE.

    PATIENTS AND METHODS: Ninety-four prospectively accrued patients with locally advanced rectal cancer (T3/4 or N1) were evaluated with DRE and sigmoidoscopy in order to determine the following tumor characteristics: size, location, mobility, morphology, and circumference. Following preoperative CMT (50.40 Gy with fluorouracil-based chemotherapy) and under general anesthesia, the same surgeon estimated tumor response based on changes in these tumor characteristics, assessed via DRE. Percent pathologic tumor response was determined prospectively by a single pathologist using whole mount sections of the resected cancer.

    RESULTS: Clinical assessment using DRE underestimated pathologic response in 73 cases (78%). In addition, DRE was able to identify only 3 of 14 cases (21%) with a pathologic complete response. There were no clinical overestimates of response. None of the clinicopathologic tumor characteristics examined had a significant impact on DRE estimation of response.

    CONCLUSION: Clinical examination underestimates the extent of rectal cancer response to preoperative CMT. Given the inaccuracy of DRE following preoperative CMT, it should not be used as a sole means of assessing efficacy of therapy nor for selecting patients following CMT for local surgical therapies.

    INTRODUCTION

    Preoperative combined-modality therapy (CMT) followed by radical surgery, according to the principles of total mesorectal excision (TME), has emerged as the preferred treatment for locally advanced (endorectal ultrasound [ERUS] T3-4 and/or N1, or clinically bulky) rectal cancer.1 This approach results in a pathologic complete response (pCR) in 7% to 31% of patients.1-8 This is of clinical significance because patients who achieve a complete or near-complete pathologic response may experience improved long-term local control and overall survival.4,7 Of equal importance is the impact that preoperative CMT, by virtue of tumor bulk reduction, may have on facilitating a sphincter-preserving resection. In addition, the apparent dramatic eradication of disease following preoperative CMT has led some surgeons to consider a local excision9-11 or observation alone12 in carefully selected, presumed clinical complete responders. The efficacy of this investigational approach is, of course, greatly dependent on accurate preoperative assessment of tumor response to CMT.

    A number of imaging modalities, including endorectal ultrasound, computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI), have been examined for their ability to assess rectal cancer response to preoperative CMT.13-18 Although the results have been promising, their definitive clinical utility has yet to be defined.

    Digital rectal examination (DRE) has also been used to assess rectal cancer response to preoperative CMT.16,19,20 Although an attractive, minimally invasive, inexpensive, office-based procedure, the accuracy of DRE in the assessment of rectal cancer response to preoperative CMT has not been adequately evaluated in a large prospective series. Our aim, therefore, was to prospectively determine the accuracy of DRE in the assessment of rectal cancer response to preoperative CMT.

    PATIENTS AND METHODS

    Patient Population

    The study group consisted of 94 prospectively accrued patients with locally advanced (ERUS T3-4 and/or N1, or clinically bulky) rectal cancer treated from 2000 to 2003 at Memorial Sloan-Kettering Cancer Center (New York, NY; Table 1). All patients had biopsy-proven rectal adenocarcinoma. Indications for preoperative CMT included transmural or lymph node involvement based on preoperative ERUS and/or a clinically bulky tumor.

    The study was approved by the Memorial Sloan-Kettering Cancer Center institutional review board, and all patients provided written informed consent before enrollment onto this study.

    Clinical Assessment Before CMT

    Before the commencement of preoperative CMT, the operating surgeon, using DRE and sigmoidoscopy comprehensively assessed the rectal cancer in terms of its size, location, mobility (fixed or tethered), morphology (exophytic, ulcerated, or sessile), and involved bowel circumference (evaluated as a percentage of the entire bowel circumference). If lymph nodes were palpable, their size and location were documented. The operating surgeon's assessment was prospectively recorded on study-specific forms.

    Preoperative CMT

    Following clinical assessment, all patients underwent a course of preoperative CMT. Patients received external-beam radiation therapy (median dose, 50.40 Gy; range, 48.60 to 54.00 Gy) according to previously published techniques.2,21 Using 15 Mv photons, a 3 or 4 field technique was used. The perineum was blocked as much as possible in the lateral fields.

    Patients received preoperative fluorouracil (FU) -based chemotherapy (bolus, 46 patients [49%]; continuous infusion, 43 patients [46%]; information not available, 5 patients [5%]). The most common regimen for bolus chemotherapy was FU (325 mg/m2/d) with leucovorin (20 mg/m2/d) given for two cycles, which consisted of 5 consecutive days in week 1 (days 1 through 5) followed by five cycles (days 29 to 33) of radiation therapy. The most common regimen for continuous infusion chemotherapy was FU (225 mg/m2/d) for a six-week continuous cycle.

    Intraoperative Assessment of Rectal Cancer Response to Preoperative CMT

    After a median interval of 48 days (range, 19 to 155 days) from completion of radiation therapy, all patients were administered radical rectal cancer resection. Two patients in our series had an interval of 19 days between completion of radiation therapy and surgery, which was due to a scheduling preference of the patient. Three patients in our series had an interval of greater than 70 days between completion of radiation therapy and surgery, due to a variety of medical and nonmedical reasons.

    While under general anesthesia, a comprehensive DRE of the residual rectal cancer was performed by the same surgeon who performed the initial office-based assessment. During the performance of the DRE under anesthesia, the extent of tumor response was estimated by comparison with the prospectively recorded office-based DRE assessment, made available to the surgeon at that time by the study coordinator. For tumors located in the upper rectum and beyond the examining finger, an adequate DRE could not be performed, and rigid endoscopy was used to evaluate extent of response. The extent of response, based on changes in multiple tumor features (size, morphology, mobility, circumference), was categorized into five categories: 1, progression; 2, 0% to 29% response (minimal regression); 3, 30% to 59% response (moderate regression); 4, 60% to 89% response (significant regression); and 5, greater than or equal to 90% response (near complete or complete) response. In addition, on the final 32 patients, the surgeon was asked to estimate the percent response as a continuous variable (0% to 100%). The surgeon then proceeded with radical rectal cancer resection according to the principles of TME.

    Pathologic Assessment

    Whole mount sections of the surgical specimen were prepared according to the technique described by Quirke et al.22 The TME specimen was stained with Hematoxylin and Eosin and comprehensively evaluated by a single pathologist (J.S.), who was blinded to the preoperative and intraoperative assessments of clinical response. Areas of tumor response were characterized by the replacement of neoplastic glands with loosely collagenized fibrous tissue and scattered chronic inflammatory cells.

    Rectal cancer response was recorded as the estimated percentage of histologic response, ranging from no evidence of treatment effect (0% response) to a pCR, which was defined as no viable tumor identified (100% response). This pathologic grading system was developed at Memorial Sloan-Kettering Cancer Center and has been used to measure treatment response in patients with non–small-cell lung cancer receiving chemotherapy, as well as rectal cancer patients receiving preoperative CMT.13,23

    Percent pathologic response was classified into the same categories used in the clinical evaluation. The post-CMT rectal cancer was staged according to the AJCC Cancer Staging Manual, 5th Edition.24

    Statistical Analysis

    For each individual specimen, percent clinical response and percent pathologic response was established and categorized as previously described. Concordance status between DRE and pathologically based extent of response was then determined. Association of the concordance status with distance from anal verge, preoperative tumor stage, procedure, and pathologic stage was assessed for statistical significance using Fisher's exact test.25 For the 32 cases with available DRE assessment of response using a continuous variable, the Spearman's rank correlation coefficient was used to detect an association with pathologic response.26 S-Plus software (Version 3.3, Statistical Sciences, Seattle, WA) was used for all analyses.

    RESULTS

    Patient Population

    Ninety-four patients with rectal adenocarcinoma located at a median distance of 6.75 cm from the anal verge (range, 0 to 13 cm) were evaluated in this study. The median age at surgery was 60.4 years (range, 27.1 to 80.4 years). There were 38 female patients (40%) and 56 male patients (60%). Sphincter salvage with a low anterior resection was achieved in 74 patients (79%). Of the patients who were unable to undergo sphincter salvage, 19 patients (20%) underwent an abdominoperineal resection, and one patient (1%) underwent a total proctocolectomy. Fourteen patients (15%) achieved a pCR (ypT0N0; Table 2).

    Clinical Assessment of Pathologic Response

    Clinical evaluation of tumor response by DRE underestimated response in 73 patients (78%). In addition, DRE was able to identify only 3 (21%) of 14 patients with a pCR. There were no clinical overestimates of response. The overall concordance between clinical evaluation of tumor response with DRE and actual pathologic response was only 22%. Concordance between DRE and post-CMT pathologic assessment of response remained consistently poor, regardless of pathologic tumor stage (P = .2; Table 2). In addition, distance from the anal verge (P = .8), preoperative ERUS tumor stage (P = .9), and procedure performed (P = .2) did not have a significant impact on clinical estimation of tumor response.

    The specificity of clinical exam in determining complete or near-complete pathologic response ( 90% tumor regression) was 56%, the sensitivity was 24%, the positive predictive value was 19%, the negative predictive value was 61%, and the accuracy was 49%.

    Subgroup Analysis of Patients With Continuous Variable for DRE Assessment

    Similar to the results obtained using categoric data, there was no correlation between DRE assessment of response using a continuous variable and pathologic assessment of response (Spearman's rank correlation coefficient = 0.27; P = .13).

    Impact of Individual Surgeon

    Six experienced colorectal surgeons performed DRE for this study, though 78 DREs (83%) were performed by two surgeons. There was no significant difference among individual surgeons in terms of concordance rate of DRE and pathologic response assessment (P = .8).

    DISCUSSION

    Our study demonstrates that clinical examination with DRE, even when performed by experienced colorectal surgeons, is an inaccurate method of determining rectal cancer response to preoperative CMT. In addition, DRE was unable to reliably identify tumors that were downstaged to a pCR. This observation was consistent, regardless of the distance of the tumor from the anal verge, preoperative ERUS stage, post-CMT pathologic stage, or whether response was assessed as a continuous or categoric variable. The inability of DRE to determine rectal cancer response is likely related, at least in part, to local inflammation and fibrosis elicited by preoperative CMT.

    Our study is unique in that it is the first to prospectively document the inaccuracy of DRE in the assessment of rectal cancer response to preoperative CMT. It is important to note that previous retrospective studies have been limited by either small sample size16,27 or uncontrolled methods of determining complete clinical response.19 In addition, the majority of prior studies have simply restaged tumors after CMT, and have not specifically assessed tumor response. Our findings are timely, because they caution against the routine use of DRE-based assessment of rectal cancer response for guiding subsequent therapy.

    There are currently several scenarios where clinical assessment of rectal cancer response to preoperative CMT is being used. First, following completion of preoperative CMT, some surgeons have advocated local excision of residual rectal cancer9-11 or observation of presumed complete responders.12 The validity of this approach is, of course, dependent on accurate identification of involved mesorectal lymph nodes. Our results suggest that DRE is not only an inaccurate means of assessing primary rectal cancer response to preoperative CMT, but is also unable to detect residual involved mesorectal lymph nodes, which may be seen in a significant number of cases.28-30 In our current series, 34 patients were noted to have pathologically positive mesorectal lymph nodes, and none of those nodes were detected by DRE. This included three patients (9%) in whom a 90% or greater response in the primary tumor was noted. Therefore, had these patients been managed with local excision of the residual primary tumor, mesorectal lymph node disease would have been left behind. However, DRE following completion of CMT remains an important component of the surgical assessment, because it allows for optimal preoperative planning and identification of lesions that remain fixed and adherent to pelvic structures.

    Another potential use of clinical assessment of rectal cancer response to preoperative CMT is as a surrogate marker of efficacy of therapy. A recent report from the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-03 trial31 that compared preoperative to postoperative CMT for rectal cancer used complete clinical response as a variable to stratify patients into subgroups for evaluation of oncologic outcome. The results of studies using clinical assessment of rectal cancer response to preoperative CMT must be interpreted carefully, as our data suggest that this method of response assessment is inaccurate. We caution against using the imprecise variable of complete clinical response to stratify patients into subgroups or as an end point in clinical studies. Our findings underscore the need for the development and evaluation of novel approaches to accurately assess rectal cancer response to preoperative CMT that may guide subsequent therapy.

    Various imaging modalities, including ERUS, MRI, CT, and most recently PET, have been used to stage patients with rectal cancer, and in a few studies to determine response following preoperative CMT. According to published reports, ERUS-based staging of rectal cancer following CMT has limited accuracy (48% to 72%).14,17,32 In addition, MRI accuracy has been reported to be as low as 54% for T stage and 54% for N stage following preoperative CMT.15 The literature on CT assessment of rectal cancer response to preoperative CMT is limited, but a recent prospective report from our institution13 suggested that CT is a poor method of determining response.

    One imaging modality that shows promise in this assessment is the PET scan.13,33 In a pilot study,13 we reported that [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) was able to confirm rectal cancer response to preoperative CMT in 100% of cases, and can accurately estimate extent of response in 60% of cases. In addition, we have also demonstrated that estimation of rectal cancer response to preoperative CMT by FDG-PET could predict long-term oncologic outcome, a finding that has recently been corroborated by others.33,34 An ongoing prospective trial at our institution has been designed to further define the role of PET-based assessment of rectal cancer response to preoperative CMT.

    In summary, clinical examination underestimates locally advanced rectal cancer response to preoperative CMT in 78% of patients. Given the inaccuracy of DRE following preoperative CMT, it should not be relied upon to select patients with rectal cancer for local therapies. In addition, its usage as a surrogate marker of prognosis or an end point in clinical trials should be discouraged. However, accurate assessment of rectal cancer response to preoperative CMT remains an important end point, as it may provide valuable prognostic information, guide the timing and type of surgical intervention, and identify refractory cases in which preoperative therapy may be altered in an attempt to improve tumor response.4,7,35

    We believe that the need to develop more accurate methods for determining rectal cancer response to CMT before surgical resection is clear and particularly timely, given the recently published results from the German Rectal Cancer Study Group,1 which established the superiority of preoperative over postoperative CMT, and are likely to result in an increased number of patients with rectal cancer receiving preoperative CMT.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    NOTES

    Supported in part by grant R01 82534-01 from the National Cancer Institute (J.G.G.).

    Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.

    Authors' disclosures of potential conflicts of interest are found at the end of this article.

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《临床肿瘤学医学期刊》2005年5月第23卷第5期