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Keywords:

  • rectal cancer;
  • neoadjuvant therapy;
  • chemotherapy;
  • radiation therapy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND

The objective of this study was to identify predictive factors for pathologic complete response and tumor downstaging after preoperative chemoradiation for rectal cancer.

METHODS

Between 1989 and 2004, 562 patients with nonmetastatic rectal adenocarcinoma received preoperative chemoradiation and underwent mesorectal excision. The median radiation dose was 45 Gray (Gy) (range, 19.8–58.6 Gy), 77% of patients received concurrent infusional 5-fluorouracil, 20% of patients received concurrent capecitabine, and 3% of patients received other regimens.

RESULTS

Nineteen percent of patients achieved a pathologic complete response (CR), whereas 20% of patients had only microscopic residual disease at surgery, and 61% of patients had macroscopic residual disease at surgery. Downstaging of the tumor stage occurred in 57% of patients. The results from a univariate analysis indicated that tumor circumferential extent >60% (P = .033) and pretreatment carcinoembryonic antigen (CEA) level >2.5 ng/mL (P = .015) were associated significantly with lower pathologic CR rates. The univariate analysis also indicated that tumor circumferential extent >60% (P = .001), pretreatment CEA level >2.5 ng/mL (P = .006), and distance from the anal verge >5 cm (P = .035) were associated significantly with lower downstaging rates. The results from a multivariate logistic regression analysis indicated that greater circumferential extent of tumor (odds ratio [OR], 0.43; P = .033) independently predicted a lower pathologic CR rate. The multivariate logistic regression analysis also indicated that greater circumferential extent of tumor (OR, 0.49; P = .020) and greater distance from the anal verge (OR, 0.46; P = .010) independently predicted a lower downstaging rate.

CONCLUSIONS

Circumferential extent of tumor, CEA level, and distance from the anal verge predicted for the pathologic response to preoperative chemoradiation for patients with rectal cancer. Therefore, these factors may be used to predict outcomes for patients, to develop risk-adapted treatment strategies, and to target patients who participate in trials of newer therapies. Cancer 2007. © 2007 American Cancer Society.

Preoperative chemoradiation is the current standard of care for patients with rectal cancer who have stage II and III disease (tumor invading through the muscularis propria [T3], tumor invading other organs or structures [T4], and/or tumors with regional lymph node metastasis).1–6 The German Intergroup randomized trial showed that patients with rectal cancer who received preoperative chemoradiation had lower rates of local recurrence and acute and late toxicity compared with patients who received postoperative chemoradiation.1 Moreover, the German Intergroup trial demonstrated a significant pathologic response to preoperative chemoradiation. Patients who received preoperative chemoradiation had a significant shift toward earlier Tumor, Lymph Node, Metastasis (TNM) stages on pathologic staging, including a pathologic complete response (CR) in 8% of patients.1 The pathologic response to preoperative therapy also resulted in higher rates of sphincter preservation in the preoperative chemoradiation arm.1 In the recently published European Organization for Research and Treatment of Cancer (EORTC) trial, patients who received preoperative chemoradiation had smaller tumors and lower tumor and lymph node status at surgery compared with patients who received preoperative radiotherapy alone.2, 3 Moreover, in the EORTC trial, patients who received preoperative radiotherapy and either concurrent or postoperative chemotherapy had significantly lower rates of local recurrence compared with patients who received preoperative radiotherapy alone.3 Based on those trials, preoperative chemoradiation is being used increasingly used for rectal cancer.

The factors that predict response to preoperative chemoradiation in rectal cancer have not been well characterized. A knowledge of such factors may be useful to clinicians and patients for predicting treatment outcomes and, hence, for making treatment decisions. A better understanding of predictive factors eventually may lead to the development of risk-adapted treatment strategies, such as more aggressive preoperative regimens, in patients who are less likely to respond to standard preoperative therapy. A better knowledge of predictive factors also may help in the design of clinical trials for newer preoperative regimens. Hence, we performed this large, single-institution, retrospective study to identify factors that predict pathologic CR and tumor downstaging in patients with rectal cancer who received preoperative chemoradiation followed by mesorectal excision.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patient Selection

Between November 1989 and July 2004, 562 patients with newly diagnosed rectal adenocarcinoma (located ≤12 cm from the anal verge) and no evidence of distant metastasis received preoperative radiotherapy and concurrent chemotherapy followed by mesorectal excision at the University of Texas M. D. Anderson Cancer Center. The hospital and radiotherapy records of these patients were reviewed for this study. The University of Texas M. D. Anderson Institutional Review Board approved the study.

Pretreatment Evaluation

All patients underwent digital rectal examination, chest X-ray, abdominal and pelvic computed tomography (CT) scans, and flexible endoscopy. Selected patients also underwent rigid proctoscopy based on physician preference. Tumor size was determined based on the length of the tumor, as assessed by rigid proctoscopy, flexible endoscopy, and/or digital rectal examination. The distance of the inferior aspect of the tumor from the anal verge and the percentage of rectal lumen circumference involved by tumor also were determined by rigid proctoscopy, flexible endoscopy, and/or digital rectal examination. Endoscopic ultrasound was performed in 469 patients (83%). Clinical stage was based on the findings of endoscopic ultrasound and CT scans. At the time of treatment, biopsies and operative pathologic specimens were reviewed by gastrointestinal pathologists at the University of Texas M. D. Anderson Cancer Center who determined tumor pathology, histologic grade, and pathologic stage. The 6th edition of the American Joint Committee on Cancer TNM system was used for staging.6 The clinical tumor classification was T2 (tumor invading the muscularis propria) in 31 patients (6%), T3 (tumor invading through the muscularis propria) in 474 patients (84%), T4 (tumor invading other organs or structures) in 49 patients (9%), and unknown in 8 patients (1%) (Table 1). The clinical lymph node classification was N0 (no regional lymph node metastasis) in 248 patients (44%), N1 (metastasis in 1–3 regional lymph nodes) in 301 patients (54%), N2 (metastasis in ≥4 regional lymph nodes) in 4 patients (1%), and unknown in 9 patients (2%).

Treatment

All 562 patients received preoperative radiation therapy with concurrent chemotherapy followed by mesorectal excision. The median dose of radiotherapy was 45 Gray (Gy) (range, 19.8–58.6 Gy). Among the 562 patients, 555 (99%) received a dose of at least 45 Gy, including 363 patients (65%) who received a dose of 45 Gy to the pelvis and 192 patients (34%) who received a dose of 45 Gy to the pelvis along with a sequential or concurrent boost. Radiation therapy was delivered in 1.8-Gy fractions, Monday through Friday, typically over 5 or 6 weeks, using 15-megavolt (MV) to 18-MV photons and customized blocking. A 3-field technique (1 posterior field and 2 lateral fields) and an open tabletop (belly board) device for bowel exclusion were used in 548 patients (98%).

Concurrent chemotherapy was administered with continuous infusional 5-fluorouracil (5-FU) to 430 patients (77%) at a median dose of 300 mg/m2 (range, 250–300 mg/m2) given Monday through Friday. Concurrent chemotherapy was administered with capecitabine to 114 patients (20%) at a median dose of 1650 mg/m2 per day (range, 1050–2000 mg/m2 per day) typically given Monday through Friday. Concurrent chemotherapy was administered with uracil and tegafur to 9 patients (2%) and with other fluoropyrimidine-based regimens to 9 patients (2%).

All patients underwent mesorectal excision. Two hundred thirty-four (42%) patients underwent low anterior resection, 140 (25%) patients underwent proctectomy with coloanal anastomosis, 161 (29%) patients underwent abdominoperineal resection, 22 (4%) patients underwent pelvic exenteration, and 5 (1%) patients underwent other procedures. The median number of lymph nodes removed was 8 (range, 0–40 lymph nodes removed). The median follow-up was 62 months (range, 15–170 months).

Statistical Analysis

Pathologic CR was defined as the absence of any tumor cells in the operative pathologic specimen, at the primary site, or in lymph node regions. Tumor downstaging was defined as the lowering of the tumor (T) classification from pretreatment clinical staging to postoperative pathologic staging. The following potential predictors were evaluated: age, sex, race, clinical T classification, clinical lymph node (N) classification, presence of mucinous features, grade, tumor size, distance from the anal verge, circumferential extent of tumor, anal canal involvement, pretreatment carcinoembryonic antigen (CEA) level, radiotherapy dose, and type of chemotherapy. Chi-square tests were performed to determine significant univariate predictors of pathologic CR and tumor downstaging. Then, a logistic regression analysis was used to identify the significant multivariate predictors of pathologic CR and tumor downstaging. All variables that were significant in the univariate analysis were entered into a multivariate model. In a backward, stepwise fashion, the significant univariate variable with the least significance was eliminated from the multivariate model. This was continued until only significant variables remained. Locoregional control was estimated by using the Kaplan-Meier method and was compared between different groups by using the log-rank test.7 A P value <.05 was considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Pathologic Response

Among all 562 patients, 108 patients (19%) had a pathologic CR, 114 patients (20%) had only microscopic residual disease at surgery, and 340 patients (61%) had gross residual disease at surgery. There was a significant lowering of the T classification (P<.001) and the N classification (P < .001) from pretreatment clinical staging to posttreatment pathologic staging. The T classification was downstaged in 316 patients (57%), and the N classification was downstaged in 183 patients (33%). The T classification was upstaged in 17 patients (3%), and the N classification was upstaged in 69 patients (12%). The pathologic T classification was T0 in 115 patients (20%), T1 in 36 patients (6%), T2 in 160 patients (28%), T3 in 220 patients (39%), and T4 in 30 patients (5%). The pathologic N classification was N0 in 386 patients (69%), N1 in 108 patients (19%), N2 in 41 patients (7%) and unknown in 27 patients (5%).

Table 1. Patient, Tumor, and Treatment Characteristics
CharacteristicNo. of patients (%)
  1. CEA indicates carcinoembryonic antigen; Gy, Gray; 5-FU, 5-fluorouracil.

Median age [range], y57.9 [20.7–87.8]
Sex
 Men354 (63)
 Women208 (37)
Clinical tumor classification
 T231 (6)
 T3474 (84)
 T449 (9)
 Unknown8 (1)
Clinical lymph node classification
 N0248 (44)
 N1-N2305 (54)
 Unknown9 (2)
Median tumor size [range], cm5 [1–15]
Median distance from anal verge [range], cm5 [0–12]
Median circumferential extent [range], %60 [10–100]
Grade
 Well differentiated32 (6)
 Moderately differentiated413 (73)
 Poorly differentiated33 (6)
 Unknown84 (15)
Pathology
 Adenocarcinoma547 (97)
 Mucinous adenocarcinoma15 (3)
Median pretreatment CEA [range], ng/mL2.5 [0–185]
Median radiotherapy dose [range], Gy45 [19.8–58.6]
Concurrent chemotherapy
 Protracted infusional 5-FU430 (77)
 Capecitabine114 (20)
 Uracil/tegafur9 (2)
 Other9 (2)

Univariate Predictors

The univariate analysis indicated that tumor circumferential extent >60% (P = .033) and pretreatment CEA level >2.5 ng/mL (P = .015) were associated significantly with a lower pathologic CR rate (Table 2). The pathologic CR rates, based on circumferential extent of tumor and CEA level, are shown in Table 3. The univariate analysis also indicated that tumor circumferential extent >60% (P = .001), pretreatment CEA level >2.5 ng/mL (P = .006), and distance from the anal verge >5 cm (P = .035) were associated significantly with a lower tumor downstaging rate (Table 4). The rates of tumor downstaging, based on circumferential extent of tumor, CEA level, and distance from the anal verge, are shown in Table 5. The other variables that were evaluated (age, sex, race, clinical T classification, clinical N classification, presence of mucinous features, grade, tumor size, anal canal involvement, radiotherapy dose, and type of chemotherapy) were not associated significantly with rates of pathologic CR or tumor downstaging.

Table 2. Significant Predictors of Pathologic Complete Response
PredictorOR (95% CI)P
  1. OR indicates odds ratio; 95% CI, 95% confidence interval; CEA, carcinoembryonic antigen.

Univariate analysis
 Circumferential extent >60%0.53 (0.32–0.89).016
 CEA >2.5 ng/mL0.40 (0.20–0.82).010
Multivariate analysis
 Circumferential extent >60%0.31 (0.13–0.76).010
Table 3. Rates of Pathologic Complete Response
PredictorPathologic CR, %
  • CR indicates complete response; CEA, carcinoembryonic antigen.

  • *

    Either, but not both.

Circumferential extent, %
 ≤6023
 >6013
CEA, ng/mL
 ≤2.524
 >2.511
Circumferential extent ≤60% and CEA ≤2.5 ng/mL27
Circumferential extent >60% or CEA >2.5 ng/mL*16
Circumferential extent >60% and CEA >2.5 ng/mL6
Table 4. Significant Predictors of Tumor Downstaging
PredictorOR (95% CI)P
  1. OR indicates odds ratio; 95% CI, 95% confidence interval; CEA, carcinoembryonic antigen.

Univariate analysis
 Circumferential extent >60%0.51 (0.35–0.76).001
 CEA >2.5 ng/mL0.48 (0.29–0.81).006
 Distance from anal verge >5 cm0.70 (0.50–0.98).035
Multivariate analysis
 Circumferential extent >60%0.49 (0.27–0.89).020
 Distance from anal verge >5 cm0.46 (0.25–0.83).010
Table 5. Rates of Tumor Downstaging
PredictorTumor downstaging, %
  1. CEA indicates carcinoembryonic antigen.

Circumferential extent, %
 ≤6065
 >6049
CEA, ng/mL
 ≤2.564
 >2.546
Distance from anal verge, cm
 ≤561
 >552

Multivariate Predictors

The multivariate logistic regression analysis indicatedthat greater circumferential extent of tumor (P = .033) was the only factor associated significantly with a lower pathologic CR rate (Table 2). The multivariate logistic regression analysis also indicated that greater circumferential extent of tumor (P = .020) and greater distance from the anal verge (P = .010) independently predicted lower tumor downstaging rates (Table 4).

Pathologic Response and Locoregional Control

Pathologic response was associated significantly with pelvic locoregional control (P = .049). The estimated 5-year locoregional control rate was 93% for all patients, 98% for patients who had a pathologic CR, and 91% for patients who did not have a pathologic CR.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

To our knowledge, we report the largest study to date of predictive factors for response to preoperative chemoradiation in patients with rectal cancer. Our results indicated that circumferential extent of tumor significantly predicted for pathologic CR on multivariate analysis, whereas circumferential extent of tumor and distance from the anal verge independently predicted for tumor downstaging on multivariate analysis. In addition, the CEA level significantly predicted for both pathologic CR and tumor downstaging on univariate analysis, but not on multivariate analysis.

Some recent studies also have investigated potential predictors of tumor response in rectal cancer. A recent retrospective study of 141 patients demonstrated that pretreatment CEA levels >5 ng/mL were associated with a poor response to preoperative chemoradiation.8 Another recently published study of 33 patients demonstrated that a decrease in standardized uptake values of 18F-fluorodeoxyglucose-positron emission tomography predicted a pathologic response to preoperative chemoradiation in patients with rectal cancer.9 A number of studies have explored biologic predictors of pathologic response. Some demonstrated that expression of the epidermal growth factor receptor (EGFR) predicts decreased pathologic response to preoperative radiotherapy or chemoradiation.10–12 Overexpression of cyclooxygenase-2 has been associated with a poor response to preoperative chemoradiation.13 Studies also have demonstrated that gene expression profiling may be used to predict response to preoperative chemoradiation.14 A gene polymorphism in the EGFR promoter region has been associated with response to chemoradiation.15 Although we did not evaluate biologic markers in the current study, our study is distinguished by its large size and the incorporation of multiple potential clinical predictors. Furthermore, to our knowledge, this is the first study to demonstrate that circumferential extent of tumor can serve as an important predictor of pathologic tumor response.

Because preoperative chemoradiation currently is being used widely for the treatment of stage II and III rectal cancer, knowledge of predictive factors carries increasing importance and relevance. Such factors may be used to predict treatment outcomes and to guide decision-making by both physicians and patients. An understanding of predictors of tumor response is particularly important for rectal cancer, because the response to preoperative chemoradiation, in turn, predicts long-term outcome.16–19

Predictive factors can be useful in the design of clinical trials on new therapies. Patients can be stratified on the basis of known predictive factors in clinical trials. Moreover, predictive factors may be used to investigate newer, more aggressive preoperative regimens in specific subgroups of patients that are less likely to respond to standard preoperative chemoradiation. Investigations of nonoperative treatments and local excision could be pursued in patients who are highly likely to respond to preoperative chemoradiation.20–27 A better knowledge of predictive factors eventually may lead to the development of individualized, risk-adapted treatment strategies for patients.

Although molecular markers and gene expression profiling are likely to play increasing roles in predicting treatment response in the future, the importance of clinical predictive factors, such as circumferential extent of tumor and CEA level, should not be overlooked. Indeed, studies of molecular markers and gene expression profiles should incorporate and account for known clinical predictors to obtain better prediction models. Moreover, we need to evaluate carefully how much additional information molecular markers provide compared with cheap, easily measurable clinical predictors.

Our study was retrospective and, thus, had certain inherent limitations. Pathologic response was determined based on pathology reports, and a dedicated pathology review was not performed for this study. Because the study included patients who were treated over 15 years, there may have been variations in pretreatment evaluation and pathologic assessment over time. There also may have been interobserver differences in clinical and pathologic evaluation and in the assessment of certain predictors; most noteworthy, there may have been interobserver variations in the subjective assessment of the circumferential extent of tumor. Information on certain variables, such as CEA level, was not available for all patients, which may have limited our ability to evaluate the predictive role of such variables. Tumor size, as determined by rigid proctoscopy, flexible endoscopy, and/or digital rectal examination, was not identified as a significant predictor of pathologic response. However, it is possible that tumor size may prove to be a significant predictor if it is assessed by other methods, such as CT scans. Finally, our results were based on a single-institution experience and need to be validated in other studies.

In conclusion, this large retrospective study demonstrated that circumferential extent of tumor independently predicts for pathologic complete response and tumor downstaging in patients with rectal cancer who receive preoperative chemoradiation. Moreover, distance from the anal verge independently predicted for tumor downstaging on multivariate analysis, and the pretreatment CEA level predicted for pathologic complete response and tumor downstaging on univariate analysis. These predictive factors may help predict outcomes for patients and also may be used for stratifying and targeting patients who participate in trials of newer therapies for rectal cancer.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Supported in part by Grant CA06294 from the National Cancer Institute, Department of Health and Human Services.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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