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10.1245/s10434-006-9269-4
Annals of Surgical Oncology 14:455-461 (2007)
© 2007 Society of Surgical Oncology
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Original Article

The Potential of Restaging in the Prediction of Pathologic Response After Preoperative Chemoradiotherapy for Rectal Cancer

Isacco Maretto, MD1, Fabio Pomerri, MD2, Salvatore Pucciarelli, MD1, Claudia Mescoli, MD3, Enrico Belluco, MD1, Simona Burzi, MD2, Massimo Rugge, MD3, Pier Carlo Muzzio, MD2 and Donato Nitti, MD1

1 Department of Oncological and Surgical Sciences, Clinica Chirurgica II, University of Padua, Via Giustiniani, 2, 35128 Padua, Italy
2 Department of Diagnostic Sciences and Special Therapies, Radiology Unit, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), University of Padua, Via Giustiniani, 2, 35128, Padua, Italy
3 Department of Diagnostic Sciences and Special Therapies, Pathology Unit, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), University of Padua, Via Gabelli, 61, 35128, Padua, Italy

Correspondence: Address correspondence and reprint requests to: Salvatore Pucciarelli, MD, E-mail: puc{at}unipd.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: We performed this study to prospectively evaluate the postchemoradiotherapy performance of transrectal ultrasonography (TRUS), pelvic computed tomography (CT) scan and magnetic resonance imaging (MRI), and endoscopic biopsies for predicting the pathologic complete response of rectal cancer patients.

Methods: Four weeks after completion of preoperative chemoradiotherapy, 46 consecutive patients with mid to low rectal cancer were prospectively evaluated by proctoscopy, TRUS, and pelvic CT scan and MRI. On the basis of T and N status, patients were classified as T0 or T1–4 and N-negative or N-positive. For each staging modality used, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated. Findings were compared with the pathologic tumor-node-metastasis stage.

Results: On histopathologic analysis, 12 patients had pT0 and 34 had pT1–4 lesions; out of 45 assessable patients, 9 were N-positive. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in predicting T status (T0 vs. T ≥1) were 77%, 33%, 74%, 36%, and 64%, respectively, for TRUS; 100%, 0%, 74%, not assessable, and 74% for CT; and 100%, 0%, 77%, not assessable, and 77% for MRI. The corresponding figures in predicting N status (N-negative vs. N-positive) were, respectively, 37%, 67%, 21%, 81%, and 61% for TRUS; 78%, 58%, 32%, 91%, and 62% for CT; and 33%, 74%, 25%, 81%, and 65% for MRI.

Conclusions: Current rectal cancer staging modalities after chemoradiotherapy allow good prediction of node-negative cases, although none of them is able to predict the pathologic complete response on the rectal wall.

Key Words: Rectal cancer • Staging • CT scan • MRI • TRUS


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Total mesorectal excision surgery is a widely accepted treatment for mid to low rectal cancer, although for locally advanced rectal cancer, combined treatments are required.1,2 Traditionally, the pretreatment local staging for rectal cancer includes digital rectal assessment, proctoscopy, transrectal ultrasonography (TRUS), pelvic computed tomography (CT), and magnetic resonance imaging (MRI). More recently, positron emission tomography has also been considered. Unfortunately, although numerous studies and meta-analyses have been performed3–5 to compare the performance of these staging modalities overall and for specific parameters (T and N stage; circumferential margin), no general agreement has been achieved. An even more controversial issue is the performance of the same imaging modalities on restaging patients after preoperative chemoradiotherapy (CRT) and before surgery.6–8 The inflammation and fibrosis induced by the CRT both on the pelvic tissues and tumor may reduce the performance of the staging modalities.

With the preoperative CRT approach, the 5-year local recurrence rate has been reported to be 6% and the rate of pathologic complete response (pCR) to be 8%.2 For patients with a good pathologic response to preoperative CRT, the oncological outcome has been reported to be better for responders than for nonresponders.9–11 Moreover, lymph node metastases in patients with a pCR on the rectal wall after preoperative CRT have been reported in 2% to 9% of cases.12–15 On the basis of these results, both an observation approach16 and nonconventional surgery (i.e., transanal local excision) have been suggested.17–19 On considering the adoption of an organ-preserving local approach for patients with a good response to preoperative CRT, the main concern is the risk of leaving mesorectal lymph node metastases in patients with a pCR on the rectal wall. Consequently, performing restaging (postirradiation) imaging modalities to define the tumor response on both the rectal wall and the mesorectum would be crucial in the selection of candidate patients for an observation or local excision approach.

The aim of this study was, then, to prospectively evaluate the postirradiation performance of the current imaging modalities for staging rectal cancer (TRUS, pelvic CT scan, and MRI) and endoscopic biopsies on predicting a pCR in an unselected consecutive series of patients with mid to low rectal cancer.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection, Inclusion Criteria, and Study Design
Between July 2003 and April 2005, 61 consecutive patients with biopsy-proven mid to low (up to 11 cm from the anal verge) rectal adenocarcinoma underwent clinical staging, including clinical history and physical examination, laboratory studies, proctoscopy and/or colonoscopy, TRUS, pelvic and total-body CT scanning, pelvic MRI, and carcinoembryonic antigen level assessment. The poorest baseline staging for each parameter evaluated (T, N, circumferential margin, and involvement of adjacent organ) was considered the definitive pretreatment stage in cases of discordance between the different staging modalities. Patients with the following characteristics underwent preoperative CRT: preoperative stage T3 or T4 with or without node positivity, age up to 75 years, and Eastern Cooperative Oncology Group performance status 0 to 2. The remaining underwent operation without neoadjuvant CRT and were excluded from the study. The study was approved by the local institutional review committee and was performed in accordance with the precepts established by the Declaration of Helsinki.

Chemotherapy regimens and radiotherapy modalities have been reported elsewhere.15,20,21 In brief, external-beam radiotherapy was delivered in fractions of 1.8 Gy/day by using the three-fields or box technique for a total of 50.4 Gy. Patients underwent 5-fluorouracil–based chemotherapy administered by bolus (350 mg/m2/day) or by continuous venous infusion (225–300 mg/m2/day) throughout radiotherapy.

Restaging by using pelvic CT scan and MRI, TRUS and flexible rectosigmoidoscopy with at least eight biopsies of the tumor bed were planned on the fifth week after completion of CRT. The standard total mesorectal excision surgery20,22 was planned 6 to 8 weeks after completion of CRT. As a rule, the inferior mesenteric artery was divided at its origin, and standard lymphadenectomy performed. The mesorectum was completely removed by using a sharp dissection in the avascular planes between the fascia propria and parietal tissue under direct vision.

Imaging Techniques
On the morning of the day on which the CT was performed, all patients were given a rectal enema. The investigation was made by using a helical CT scanner (Somatom Emotion; Siemens Medical Systems, Erlangen, Germany) with the patient prone, after rectal insufflation of air (100–300 mL), given until the patient indicated discomfort. All patients were administered intravenous contrast medium (2 mL/kg; Omnipaque 300; Nycomed Imaging A.S., Oslo, Norway), and 3-mm cuts were made through the pelvis from the anal verge to the iliac crests.

On a different day, during the morning of the day on which MRI was performed, all patients received a rectal enema and underwent MRI at 1.0 T (Magnetom Harmony; Siemens Medical Systems, Erlangen, Germany) with a phased-array surface coil, used with the patient in the supine position after insuffation of air (100–300 mL) into the rectum. After axial and sagittal T2-weighted turbo spin echo images were obtained, axial T1-weighted spin-echo gadolinium-enhanced images (.2 mL/kg; Magnevist; Shering AG, Berlin, Germany) were obtained. After a rectal enema and a digital examination with the patient lying in the Sims’ position, TRUS was performed by using a 5- to 10-MHz frequency and a 5- to 30-mm-focal-distance 360° real-time transducer rotating inside a degassed water-filled balloon (60–120 mL) at the tip of the probe (Leopard Ultrasound Scanner; B&K Medical, Gentofte, Denmark).

Image Analysis
All CT and MRI pelvic images were analyzed and reviewed at a workstation (Sienet Magic View 1000; Siemens, Berlin, Germany) by the same radiology team. A single surgeon performed and analyzed TRUS images.

The CT, MRI, and TRUS images were assessed for depth of tumor infiltration and metastatic lymph nodes after tumor-node-metastasis classification.23 An absence of residual abnormalities in the rectal wall was considered to be T0, a tumor judged to be confined to the rectal wall was defined as T1 or T2, and full-thickness involvement of the rectal wall with nodular or grossly spiculated tumor infiltration of the perirectal fat was defined as T3. Cases with evident invasion of surrounding organs or structures other than perirectal fat were defined as T4. Lymph nodes ≥ 5 mm were considered to be positive for metastases.3,24–26 For each patient, the largest lymph node size was considered independently of the number of lymph nodes.

Histopathology
Pretreatment and posttreatment biopsy samples and surgical specimens were evaluated by the same team of pathologists by using the Quirke protocol.27 As concerns the surgical specimen, the following data were recorded: tumor location, depth of invasion on the rectal wall, and presence of lymph node or distant metastases. The cancer staging was assessed by following the American Joint Committee on Cancer tumor-node-metastasis classification.23 A pCR was defined as the absence of viable tumor cells at histological analysis of the surgical specimen, and pure acellular mucin was considered to be "no residual tumor."

Statistical Analysis
Post-CRT clinical T and N stages by using pelvic CT and MRI and TRUS were compared with the corresponding pathologic T and N stages as assessed on the surgical specimen. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy rates were calculated for each imaging modality by following the formulas listed in Table 1Go. A comparison was also made between post-CRT endoscopic biopsy samples of the tumor bed and the presence or absence of the tumor at histopathologic analysis of the surgical specimen.


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  		TABLE 1. Definitions of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy
 

   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients and Treatments
Out of 61 patients with mid to low rectal adenocarcinoma observed in the study period, 15 underwent surgery-alone treatment because they were staged as clinical tumor-node-metastasis stage I (n = 9) or IV (n = 2) or had a Eastern Cooperative Oncology Group performance status >2 (n = 3) or refused preoperative CRT (n = 1). The remaining 46 patients who received preoperative CRT form the study population. The demographic characteristics of patients, tumor locations, and the surgical procedures performed are summarized in Table 2Go.


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  		TABLE 2. Demographic characteristics, tumor locations, and surgical procedures of the 46 patients considered for the study
 
Imaging Modalities Findings
At baseline (before CRT) clinical staging, 4 patients were staged as clinical tumor-node-metastasis stage II and 42 as clinical tumor-node-metastasis stage III. Post-CRT staging was performed with the following modalities: pelvic CT scan (n = 46), MRI (n = 43), and TRUS (n = 42). Patient refusal and pain experienced during the examination were the main reasons for patients not undergoing MRI (n = 3) or TRUS (n = 4), respectively.

With pelvic CT and MRI, none of the patients was staged as T0 or T1. T and N staging after pelvic CT scan was as follows: T2, n = 13 (28%); T3, n = 23 (50%); T4, n = 10 (22%); N-negative, n = 24 (52%); and N-positive, n = 22 (48%). T and N staging after pelvic MRI (43 cases) was as follows: T2, n = 23 (53%); T3, n = 14 (33%); T4, n = 6 (14%); N-negative, n = 31 (72%); and N-positive, n = 12 (28%). T and N staging after TRUS (n = 42) was as follows: T0, n = 11 (26%); T1, n = 4 (9.5%); T2, n = 5 (12%); T3, n = 18 (43%); T4, n = 4 (9.5%); N-negative, n = 28 (67%); and N-positive, n = 12 (33%).

Histopathology
T staging was available in all patients, with the following distribution: T0, n = 12 (26%); T1, n = 6 (13%); T2, n = 10 (22%); T3, n = 14 (30%), and T4, n = 4 (9%). Because 1 patient with pT0 underwent local excision, N staging was available in 45 patients, 36 (80%) of whom were N-negative and 9 (20%) N-positive. One patient with a complete response on the rectal wall (pT0) had metastatic disease in the mesorectum. Previously undetected liver metastases were found at operation in four patients.

Post-CRT Endoscopic Biopsies
Post-CRT biopsies, performed in the first 22 cases, were negative in all pCR cases (n = 6), although they were also negative in 11 of 16 cases with residual cancer. The overall concordance rate between post-CRT biopsies and histopathology findings on the surgical specimen was 50%. On the basis of these disappointing preliminary results, this part of the study was discontinued, and no further biopsies were performed in the last 24 patients.

Comparison With Histopathology
T Staging
Comparisons between post-CRT imaging modalities and histopathology of surgical specimens were performed in all 46 cases for CT scan, in 43 for MRI, and in 42 for TRUS.

N Staging
Pathologic N stage was not available in the patient who underwent local excision, so comparisons were performed in 45 cases for pelvic CT scan, in 43 for MRI (the patient who underwent local excision also refused to be restaged by MRI), and in 41 for TRUS. Sensitivity, specificity, PPV, NPV, and accuracy for each imaging modality were calculated, and the data are summarized in Table 3Go.


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  		TABLE 3. Sensitivity, specificity, PPV, NPV, and accuracy of restaging after preoperative CRT for 46 mid to low rectal cancer patients
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This prospective study investigated the performance of the current imaging modalities on predicting the pCR after preoperative CRT for locally advanced mid to low rectal cancer. The predictive value of postirradiation endoscopic biopsies was also evaluated. The main findings of the study were a good prediction of N-negative cases obtained with all the imaging modalities used; the NPV was 91%, 81%, and 81% for pelvic CT scan, MRI, and TRUS, respectively. In contrast, a disappointing performance was found on predicting the pCR of the rectal wall by using pelvic CT scan and MRI, TRUS, and post-CRT endoscopic biopsy.

Regarding the prediction of pathologic T stage, none of the 46 patients enrolled on the study was restaged as T0 by pelvic CT scan or MRI. Poor results were also found with TRUS, with an acceptable 77% and 74% sensitivity and PPV, respectively, but with a poor 33% and 36% specificity and NPV, respectively, and an accuracy of 64%. The overall concordance rate of post-CRT endoscopic biopsies with histopathology findings of the surgical specimen was 50%.

The findings of this study may have clinical relevance in light of new perspectives arising from the preoperative CRT approach. The better oncological outcome9–11 and the low rates of mesorectal residual disease12–15 observed in patients with pCR after CRT prompted some authors to recommend for these patients either observation16 or an organ-sparing approach (local excision)17–19 instead of conventional surgery. On considering the use of local excision, a false-negative diagnosis for nodal metastases is more cause for concern (because of the risk of leaving mesorectal nodal metastases when performing local excision surgery) than a false-positive one (because of the risk of performing a total mesorectal excision in patients without mesorectal metastases). Therefore, the performance of imaging modalities related to the rate of false-negative results for N status (NPV) might be crucial for planning a tailored surgical procedure after CRT. The disappointing results related to the prediction of pCR on the rectal wall merely confirm the fact that a full-thickness transanal local excision is the only relatively reliable method for confirming the clinical judgment of a complete response on the rectal wall.

Unlike other studies on the same issue, the aim of this study was to compare post-CRT clinical staging with pathologic staging considering the use of organ-sparing surgery. On the basis of this consideration, and unlike other studies,7,8,28–32 T staging was categorized as T0 versus T ≥ 1. Other than the T categories used, comparisons between this study and others were also made difficult by differences in sample size, the prospective or retrospective nature of the study, treatment schedules, the definition of metastatic lymph nodes, and the timing of restaging. Most studies in this field are retrospective, with small sample sizes and an unclear definition of metastatic lymph nodes, and rarely include all imaging modalities together. Using endorectal ultrasonography or TRUS, the overall accuracy on predicting pathologic T stage after preoperative CRT has been reported to be between 48% and 66%.7,28,32 Because the most relevant cause of inaccuracy is overstaging, it is not surprising that high percentages of accuracy (>90%) have been obtained by excluding pathologic T0 and T1 cases from the comparison.29 The 64% accuracy of predicting T stage by TRUS reported in this study seems to fall in line with the above-mentioned studies.7,28,32 The overall accuracy on predicting pathologic T stage by using pelvic CT scan and MRI is also poor, ranging between 51% and 54%.30–32 The 74% and 77% accuracy found in this study for post-CRT pelvic CT scan and MRI, respectively, may be related to the differences in T categories used in our study (T0 vs. T ≥ 1 instead of the more numerous T categories used by others). Once again, as for ultrasound assessment, most of the inaccuracy was caused by overstaging. Misinterpretations observed with all imaging modalities seem to be related to the inability to distinguish tumor tissue from peritumoral vasculopathy and desmoplastic radiation-induced reactions.

The prediction of N stage has also turned out to be poor with using endorectal ultrasonography, pelvic CT scan, and MRI. Endoscopic ultrasonography or TRUS accurately predicts N pathologic stage in 57% to 77% of cases,7,28,29,32 and once more our findings fall within this range. The accuracy of pelvic CT scan and MRI for predicting N stage was 62% and 65%, respectively, in this study and varies between 54% and 76% in the literature.30–32 In contrast with the disappointing findings related to the accuracy of the imaging modalities, the high NPV found in this study has also been reported by Denecke et al.8 On comparing post-CRT pelvic CT and MRI findings with pathologic stage in 23 (pelvic CT scan) and 13 (pelvic MRI) patients, these authors found an NPV of 80% and 100% for pelvic CT scan and MRI, respectively.

The weaknesses and limitations of this study may be related to the size of the study population and to the definition of metastatic lymph node used. As concerns the sample size of the study group, we are aware that our findings require confirmation in larger series, even though the prospective nature of the study, the standardization of radiology and histopathology reports, and the concordance of our findings with those reported in the literature make us confident about the results obtained.

An open question still remains as to the definition of metastatic lymph node. It has been claimed that the size of the lymph node precludes an accurate identification of metastases in patients operated on without preoperative adjuvant therapy and in those undergoing short-course preoperative radiotherapy followed by surgery some days later.33–36 An even more difficult evaluation of T and N staging can be expected on restaging patients who received long-course preoperative CRT,37 and different definitions of metastatic lymph node may also be considered. All patients in this study completed a long course of CRT 6 to 8 weeks before surgery. This treatment has the potential to modify lymph node size, shape, and texture. The prediction of nodal involvement in such cases could be also based on the contour and imaging characteristics of the lymph nodes (texture).38,39 Even if we are aware of the limitations of the size criterion and that the size cutoff of 5 mm for nodal positivity comes from series of patients who did not receive preoperative CRT, the lymph node size still remains the most frequent and reliably used criterion for defining node positivity. An ongoing study at our unit is now comparing the best size cutoff at pelvic CT scan in patients with and without preoperative CRT. However, the correlation found with histopathology findings and preliminary data from the literature suggest that the size cutoff used in this study is adequate and produces acceptable diagnostic data.3,24–26

A further limitation of the studies using current imaging modalities is their resolution power. In fact, metastases have also been found in very small lymph nodes40 and in nonnodal microscopic foci in the mesorectum.41

Whether more advanced MRI technology and 18F-2-deoxy-D-glucose positron emission tomography have the potential to improve the accuracy for distinguishing responders from nonresponders and to detect metastatic lymph nodes after preoperative CRT is a matter of debate. These technologies should still be considered to be at an experimental level and not yet available worldwide.

In conclusion, the current imaging modalities (CT scan, MRI, and TRUS) and post-CRT endoscopic biopsies have a poor performance when predicting a pCR on the rectal wall. As a consequence, the full-thickness local excision still remains the best method of accurately determining pT0 cases. As concerns the N staging, the good prediction of N-negative cases, especially by using pelvic CT scan, may be helpful when planning post-CRT surgical treatment. A potential organ-sparing approach could be considered for patients receiving preoperative CRT and having a pCR on the rectal wall as assessed by full-thickness transanal excision and an N-negative finding at pelvic CT scan. Confirmation studies on a larger series and an evaluation of different size cutoffs for the definition of metastatic lymph nodes are required.


   ACKNOWLEDGMENTS
 
Supported by the Italian Ministry of Health (Special Programme ex section 12/12 bis) and the Associazione Italiana Ricerca sul Cancro (Italian Association of Cancer Research) Veneto (progetto finalizzato 2005). The authors thank Marina Canapero for her assistance with the English language.


   FOOTNOTES
 
Presented in part at the 59th Annual Cancer Symposium of the Society of Surgical Oncology, San Diego, California, March 22–28, 2006.

Received for publication August 22, 2006. Accepted for publication October 18, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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