Of the 3194 consecutive patients who underwent surgical resection for rectal cancer at the Samsung Medical Center, Korea between October 1998 and May 2009, 544 underwent surgical resection after PCRT. For this study, the inclusion criteria included: (1) histologically confirmed rectal adenocarcinoma; (2) tumors located within 10 cm of the anal verge; (3) locally advanced (cT3-4 or N1) tumors; (4) curatively resected tumors; and (5) no evidence of distant metastatic disease. Additionally, individuals were excluded according to the following criteria: (1) history of any other malignancy or hereditary colon cancer syndrome; (2) history of rectal cancer requiring emergency surgery; and (3) multiple missing data points in the database or an inability to evaluate pathological tumor response.

Of the initial 544 patients with rectal cancer who underwent PCRT, 70 (12.9%) patients achieved a complete pathological response, whereas the remaining 474 did not. Of these 474 patients, 295 patients were excluded from the study for the following reasons: the presence of another malignancy (one patient); a history of hereditary colon cancer syndrome (three patients); transanal local excision including transanal endoscopic microsurgery (nine patients); a lack of sufficient clinical information in the database (14 patients); and an inability to evaluate tumor regression grade (TRG) after repeated pathological examinations (268 patients). Thus, 249 individuals with rectal cancer were included in the present study; all of whom had undergone PCRT and curative surgery.

All of the subjects underwent PCRT. Radiation therapy was administered using a three-field technique within 6-wk periods, delivering 40.4-50.4 Gy. Chemotherapy was also initiated on the first day of pelvic radiotherapy and was delivered concurrently using two chemotherapeutic regimens: (1) 5-fluorouracil (500 mg/m² per day) for 3 d during the first and last weeks of radiotherapy; and (2) oral capecitabine (825 mg/m²) given twice daily during radiotherapy without weekend breaks. The median interval between PCRT and surgery was 55 d (range: 26-120 d).

All of the subjects also underwent radical surgery, including total mesorectal excision, high vascular ligation and en bloc resection of any adjacent involved organ after complete PCRT. The operative techniques that were employed in this study included abdominal perineal resection and low anterior resection with colorectal or coloanal anastomosis.

Before PCRT, clinical staging was determined by CT, MRI and/or endorectal ultrasound. Clinical restaging was then conducted 6 wk after the completion of PCRT via CT, MRI and ¹⁸F-FDG-PET/CT using the protocols described in our previous study[20]. Therapeutic responses with ¹⁸F-FDG-PET/CT were evaluated via the maximal standard uptake value (SUV). In 66 patients, the SUV could not be evaluated, either because ¹⁸F-FDG-PET/CT was not ordered (50 patients) or was performed at a different hospital (16 patients).

After radical surgery, the final tumor pathological staging was evaluated by experienced pathologists. Tumors were classified according to the TNM grading system, 6th edition. Responses to treatment were evaluated according to the TRG, as described by Mandard et al[21]. Specifically, the TRG classification system was defined as follows: grade 0, no regression; grade 1, dominant tumor mass with obvious fibrosis and/or vasculopathy (minimal regression); grade 2, dominant fibrotic changes with few tumor cells or groups (moderate regression); grade 3, very few tumor cells in the fibrotic tissue with or without mucous (near total regression); grade 4, no observed tumor cells with only fibrotic masses or acellular mucin pools present (complete regression).

We evaluated several variables to estimate the relationship between gross findings and tumor response. Prior to PCRT (pre-CRT) tumor location, the movability, size, morphology and involved bowel circumference were recorded. Next, after the PCRT (post-CRT), the tumor size and morphology were reassessed at a follow-up hospital visit 6 wk after completion of PCRT. The involved bowel circumference was subdivided into “encircling” and “unidirectional” categories by digital rectal examination (DRE), wherein encircling was defined as occupying more than half of the lumen. Tumor movability was also subcategorized into “movable,”“tethered,” and “fixed.” The pre-CRT tumor size was assessed using DRE in combination with any available colonoscopic or radiologic imaging results. The post-CRT tumor size was measured according to the pathological tumor or scar size. The tumor morphology was classified as being either “benign-like” or “malignant-like” in shape. By definition, benign-like shapes were observed to only consist of scar tissue, discolored lesions, erosions and shallow ulcers, whereas, in malignant-like shapes, infiltrative, fungating and ulcerofungating lesions were present. Pre-CRT tumor morphology was assessed using DRE and colonoscopic results. The resected specimens were used to classify the post-CRT morphology. Gross changes were determined to be present if malignant-like specimens had transitioned into benign-like specimens after PCRT.

All statistical analyses were performed using either the χ² or Fisher’s exact test in addition to logistic regression modeling. Significant differences were defined as P < 0.05. To predict complete regression, we used scoring models with parameters that revealed statistical significance, wherein scoring model performance was assessed by receiver operating characteristic (ROC) curve plots for risk scoring and area under the curve (AUC) estimation. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for each variable were calculated.

An independent sample set of patients with primary rectal cancer who underwent PCRT was used to evaluate the performance of the scoring model in predicting complete regression. For this validation, 15 patients were enrolled between May 2009 and July 2009. Scores from this preliminary analysis were tested for sensitivity, specificity, PPV and NPV.

The demographics of the included patients are described in Table 1. In total, 177 men (71.1%) and 72 women (22.9%) were enrolled with a median age of 55 years (range: 24-81 years). Of these individuals, 210 presented with T3 grade tumors, whereas 39 had T4 grade disease. The demographics of subjects who were enrolled in the separate validation set are also described in Table 1.

After PCRT, the following pathological tumor staging distribution was observed: ypT0, n = 74 (including ypTis in four patients); ypT1, n = 11; ypT2, n = 51; ypT3, n = 105; and ypT4, n = 8. At this point in time, 189 patients were found to be node-negative, whereas 60 patients were node-positive, as per the pathological N staging criteria (including ypT0N1 in three patients). TRG grading was as follows: grade 0 in two patients, grade 1 in 49, grade 2 in 86, grade 3 in 42, and grade 4 in 70.

The pre-CRT size (P = 0.001), pre-CRT movability (P < 0.001), pre-CRT carcinoembryonic antigen (CEA) (P = 0.021), ycT (P < 0.001), ycN (P < 0.001), post-CRT size (P < 0.001), post-CRT morphology (P = 0.004), gross change (P < 0.001), and post-CRT SUV (P < 0.001) were all identified to be univariate predictors of complete regression (Table 2). Multivariate predictors for complete regression included pre-CRT movability (P = 0.024), post-CRT size (P = 0.018), post-CRT morphology (P = 0.023) and gross change (P = 0.009). The data from pre-CRT CEA and post-CRT SUV were incomplete, therefore, we did not include these variables in the multivariate analysis (Table 3).

Scoring models were established to predict pCR using pre-CRT CEA and post-CRT SUV, which identified four statistically significant variables: pre-CRT movability, post-CRT tumor size, post-CRT morphology, and gross change. Each parameter was scored as either 0 or 1 according to each criterion. Although the pre-CRT CEA and post-CRT SUV were not included in the multivariate analyses, they were included in the risk score calculation, due to their assumed clinical importance. The scoring model was calculated by summing these six scores, defining the minimum scoring model as 0 and the maximum as 6 (Table 4). Next, a risk score was calculated for each subject, given that no missing data points existed for that selected risk factor. After excluding for the 98 subjects for whom ¹⁸F-FDG-PET/CT and pre-CRT CEA were not measured, scoring was performed in a total of 151 individuals. The AUC of the scoring model was 80.5%, suggesting that this was a reasonable predictor of complete regression (Figure 1). When the cutoff point was set at 4.5, the sensitivity and specificity rates for predicting complete regression were 64.5% and 80%, respectively, with a PPV of 45.5%, an NPV of 89.7% and an accuracy of 76.8% (Table 5).

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Figure 1 Area under the receiver operating characteristic curve. A: Risk score in the test set was 80.5%, suggesting it was a reasonable predictor of complete regression (P < 0.001, 95% confidence interval = 0.723-0.886, n = 151); B: In the validation set, risk score was 87.5%. (P < 0.031, 95% confidence interval = 0.672-1.078, n = 151).

The ROC curve for the risk score performance that was obtained from the validation set had an AUC = 0.875, which can be seen in Figure 1. These results indicate that this scoring model performed well in an independent sample. Using a cutoff point of 4.5, the prediction of complete regression had a sensitivity of 75%, specificity of 90%, PPV of 75%, NPV of 90.91%, and accuracy of 86.7%.

Pathological complete response (pCR) has been associated with improved oncologic outcome. Although surgery is recommended after preoperative chemoradiation therapy (PCRT), regardless of tumor response, the ability to predict an individual’s chance of achieving pCR before commencing therapy would probably allow for a more tailored treatment.

Although it is important to predict therapeutic responses, there is no reliable technique to accurately predict pCR after PCRT. This study demonstrates that a combination of clinical, laboratory and metabolic information would best predict pCR.

Recent reports have highlighted the importance of tailored treatment in rectal cancer, including “wait and watch” after chemoradiation. In this study, the authors designed a scoring model using clinical and gross parameters for predicting pCR. The developed scoring model was found to be significantly predictive in both test and validation sets.

This study demonstrates that gross tumor changes and other associated morphological findings may represent important predictors of pathological tumor responses with both clinical parameters being easily estimated via physical examination.

The study aimed to evaluate a number of clinical parameters and identify a method of predicting pCR after CRT in patients with advanced rectal cancer. It is an interesting study, meticulously carried out and reported.