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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2004.06.010 on January 12, 2004

Annals of Surgical Oncology 11:187-191 (2004)
© 2004 Society of Surgical Oncology
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ORIGINAL ARTICLES

Residual Mesorectal Lymph Node Involvement Following Neoadjuvant Combined-Modality Therapy: Rationale for Radical Resection?

Francesco Stipa, MD, Alma Zernecke, MD, Harvey G. Moore, MD, Bruce D. Minsky, MD, W. Douglas Wong, MD, Martin Weiser, MD, Philip B. Paty, MD, Jinru Shia, MD and Jose G. Guillem, MD, MPH

From the Colorectal Service, Department of Surgery (FS, AZ, HGM, WDW, MW, PBP, JGG), Department of Radiation Oncology (BDM), and Department of Pathology (JS), Memorial Sloan-Kettering Cancer Center, New York, New York.

Correspondence: Address correspondence and reprint requests to: Jose G. Guillem, MD, MPH, 1275 York Avenue, Room C-1077, New York, NY 10021; Fax: 646-422-2318; E-mail: guillemj{at}mskcc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: In order to evaluate the impact of preoperative radiation and chemotherapy (combined modality therapy, or CMT) on primary rectal cancer and mesorectal lymph nodes (MLNs), middle and lower third rectal cancers were resected with total mesorectal excision (TME) and assessed for frequency of MLN retrieval and residual MLN involvement.

Methods: Between 1990 and 2001, 187 consecutive patients underwent abdominoperineal resection (APR) or low anterior resection (LAR) for locally advanced (endorectal ultrasound [ERUS] stage, T3–4) mid and distal rectal cancer following preoperative CMT. Sphincter preservation was possible in 150 patients (80%). The mean number of retrieved MLNs was 10.6. Pre-CMT ERUS stage was compared with final pathologic stage.

Results: Comparison of pre-CMT ERUS stage with pathologic stage revealed a decrease in T stage in 93 patients (49%), as well as a decrease in the percentage of individuals with positive MLNs, from 54% to 27% (P < .0001). The overall incidence of positive MLN involvement was 27%, and incidence paralleled pathologic T stage (pT): pT0 = 7%, pT1 = 8%, pT2 = 22%, pT3 = 37%, and pT4 = 67%.

Conclusions: Following preoperative CMT, the incidence of residual MLN involvement remains significant and parallels increasing pT stage. Therefore, the standard of care for locally advanced distal rectal cancer should continue to include formal rectal resection (TME).

Key Words: Mesorectal lymph nodes • Radiotherapy • Rectal cancer • Staging


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Preoperative radiation and chemotherapy (combined modality therapy, or CMT) followed by local excision is a potential sphincter-preserving approach for carefully selected, distal rectal cancers. In several series managed with this approach (generally employed in cases not suitable for major abdominal surgery or patients refusing a permanent stoma), local recurrence is reported to be between 4% and 20%.1–4 However, these studies involved small sample sizes and limited follow-up.

Although the anticipated long-term efficacy of preoperative CMT and local excision is based on the assumption that mesorectal lymph nodes (MLNs) will be "downstaged," the management of these lesions, including those with an apparent complete clinical response, is controversial, in part because of our current inability to accurately identify preoperatively the complete eradication of disease in both the primary tumor site and the MLNs. Two prospective, randomized trials in which treatment with preoperative radiotherapy and surgery was compared with surgery alone for primary rectal cancer demonstrated a reduction in the percentage of involved lymph nodes in the radiotherapy group.5,6 However, neither study report described the rate of MLN involvement stratified by final T stage in the treated patients.

Our aims were therefore to assess the efficacy of preoperative CMT on advanced rectal cancer T stage; assess the incidence of lymph node metastasis in the irradiated mesorectum; and determine if the reduction in T stage is associated with a comparable reduction in MLN involvement.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between January 1990 and December 2001, 991 consecutive patients who underwent treatment for primary middle and distal third rectal adenocarcinomas (<12 cm from the anal verge) at Memorial Sloan-Kettering Cancer Center were identified through a query of the prospective Colorectal Service Data Base. Only middle and distal third lesions were included in the current analysis in order to increase the likelihood that a total (TME) or near-total mesorectal excision would be performed as part of formal rectal resection. Of these, a total of 446 patients received preoperative external beam radiation therapy ± 5-fluorouracil (5-FU)-based chemotherapy. Our study population consisted of a subset of 187 patients who had evidence of T3–4 disease on pre-CMT endorectal ultrasound (ERUS). Distance from the anal verge to the caudal tumor edge was available for all patients. Tumors were classified as middle third (>=6 but <12 cm from the anal verge) or distal third (<6 cm from the anal verge). Other clinical and pathologic features considered included the patient’s age and gender, final TNM stage, and total number/number of positive MLNs retrieved. Staging and metastatic workup for all patients included liver function tests, carcinoembryonic antigen (CEA) level determination, endoscopic examination of the rectum, chest radiography, and computed tomography (CT) scanning of the abdomen and pelvis.

ERUS was performed prior to commencement of CMT with a 10-MHz probe (Type 1850; Bruel and Kjaer Medical, Naerum, Denmark). Rectal wall penetration (uT stage) was assessed according to the criteria of Hildebrandt and Feifel.7 Circular or oval structures >5 mm were considered to be malignant lymph nodes (uN positive). Nodes <5 mm with central hyperechogenicity were considered benign. Echogenicity was assessed according to the criteria of Beynon.8

In general, 4680 cGy of pelvic radiation was delivered in 180-cGy fractions, followed by a 360-cGy boost to the primary tumor, for a total dose of 5040 cGy. A multiple-field technique was used, including a 10 x 10 cm or 12 x 12 cm field encompassing the primary tumor bed and the lateral pelvis. Surgery was generally performed 4 to 7 weeks after completion of radiation. The majority of patients (80%) were treated at Memorial Sloan-Kettering Cancer Center. All but seven patients received concomitant chemotherapy consisting of either two cycles of 5-FU (325 mg/m2) and leucovorin (20 mg/m2) bolus daily x 5 days, during weeks 1 and 5, or continuous-infusion 5-FU (225 mg/m2) given throughout the course of radiation.

All patients underwent either an abdominoperineal resection (APR) or a low anterior resection (LAR). Only patients who underwent open resection (not laparoscopic) were included in the analysis. All resections were performed with a sharp mesorectal technique (dissection in the avascular plane between the fascia propria of the rectum and parietal peritoneum). Anastomoses were performed with an intraluminal circular-stapling device or were hand-sewn (primarily for coloanal reconstruction). The level of the anastomosis ranged from 1 to 8 cm above the anal verge, with a median distance of 4 cm. Final tumor staging (pT and pN stage) was based on review of the original pathology report in all cases.

Statistical analysis was performed with the StatXact statistical software package (Cytel Software Corp., Cambridge, MA).9 Comparison of paired proportions was assessed with the McNemar test.10

This retrospective study was reviewed and approved by the Institutional Review Board at Memorial Sloan-Kettering Cancer Center.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Characteristics of the study population are shown in Table 1. There was a predominance of male patients. Eighty percent of surgical procedures were sphincter-sparing, with nearly half involving a coloanal anastomosis. The mean number of lymph nodes retrieved in the irradiated mesorectal specimens was 10.6, versus a mean of 13.8 in 562 historical, nonirradiated specimens.


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  		TABLE 1. Characteristics of patient population
 
Pre-CMT ERUS showed 177 uT3 lesions (95%) and 10 uT4 lesions (5%). Of these, 101 (54%) met the criteria for mesorectal lymph node involvement and were designated uN1. Table 2 shows the pre-CMT stage distribution based on ERUS. Pre-CMT ERUS stage was compared with final pathologic stage (Table 3). In 89 T3 and four T4 patients, a decrease of at least one T stage was observed following CMT (50% and 40%, respectively).


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  		TABLE 2. Pre-CMT staging by ERUS
 

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  		TABLE 3. Primary rectal cancer response: Comparison of pre-CMT ERUS stage (uT) with pathologic T stage (pT)
 
The finding of positive MLN on ERUS (uN1) was compared with pathologic N stage (Table 4). In 101 patients (54%), ERUS revealed findings consistent with uN1 disease according to the previously mentioned criteria. Pathological evaluation of the irradiated mesorectum revealed MLN metastases in 51 patients (27%). This difference was statistically significant (P < .0001).


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  		TABLE 4. MLN status before and after CMT
 
Residual MLN involvement following preoperative CMT was assessed according to pT stage (Table 5). In patients with a complete pathologic response of the primary tumor (pT0), a 7% incidence of positive MLN was noted. Among patients with pT1 and pT2 tumors, the percentages with positive MLN were 8% and 22%, respectively. Finally, in patients with pT3 and pT4 lesions, the incidences of positive MLN were 37% and 67%, respectively.


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  		TABLE 5. Percentage of patients with positive MLN involvement by pathologic T Stage (pT)
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Preoperative CMT is being increasingly utilized in the treatment of locally advanced rectal cancer.11–13 Up to 25% of patients have a complete or near-complete pathologic response to preoperative CMT.11 Whether these excellent responders can potentially be managed with a lesser surgical procedure (local excision) or with no surgery remains controversial. Our current data demonstrate that although a reduction in pT stage can be anticipated following preoperative CMT, as determined by ultrasound, the percentage of involved MLNs remains significant. Furthermore, the percentage of MLN involvement increases with increasing pathologic T stage.

The current standard of care for locally advanced rectal cancer includes rectal resection with sharp mesorectal technique. However, carefully selected patients with early stage, distal rectal cancers may be candidates for local excision, with or without adjuvant chemoradiation.14 Patients with T1N0 adenocarcinomas with favorable histopathologic features may be suitable for local excision without adjuvant therapy. One study demonstrated no difference in outcome between local excision and anterior resection for these early stage, favorable lesions.15 However, even in T1 cancers with no adverse pathologic features, the risk of lymph node metastases may be as high as 7%.16 Furthermore, recent studies suggest that the long-term outcome for patients with T1 rectal cancer managed with local excision alone may not be as good as previously thought, with 10-year overall recurrence as high as 17%.17 Nevertheless, patients with locally advanced rectal cancers downstaged with preoperative CMT to a stage appropriate for local excision (pT0–1N0) might reasonably be expected to have a good outcome with local excision alone. However, this approach relies upon accurate restaging following preoperative CMT, especially MLN status, which at present appears to be limited.

Evaluation of response to preoperative CMT on the basis of preoperative digital rectal examination, examination under anesthesia, and proctoscopy appears to be of limited value.18,19 Current imaging modalities such as CT, MRI, and ERUS also appear to be suboptimal for restaging rectal cancer following preoperative CMT. The accuracy of ERUS for determining T and N stage has been reported to be 47% to 93% and 57% to 84%, respectively, following preoperative CMT, presumably because of radiation-related inflammation and intramural fibrosis.13,20–23 Furthermore, ERUS performed before and after CMT also appears to underestimate the degree of downstaging in comparison with analysis of the pathologic specimen.23 These results, as well as our current data, need to be interpreted with caution, given the recognized limitations of endorectal ultrasound staging. Fluorodeoxyglucose positron emission tomography (FDG-PET) may be accurate for estimating the degree of local tumor response to preoperative CMT.24 However, the accuracy of FDG-PET for identifying patients with a complete pathologic response, including MLN status, is currently under investigation.

Results of several small series of patients treated with local excision following preoperative radiation with or without chemotherapy have been encouraging. Mohiuddin2 reported an overall recurrence rate of 10% among selected patients with T3 rectal cancers treated with radiation followed by full-thickness local excision. Patients who had a complete or partial response to radiation had a recurrence rate of 0% and 13%, respectively, in comparison with 67% for patients with no response. Similarly, Schell et al.3 reported an overall recurrence rate of 9% (median follow-up, 48 months) following local excision in 11 patients with T3 rectal cancers and significant downstaging in response to preoperative CMT. In a report from our institution, 10 patients with T2 and T3 rectal cancer were selectively treated with local excision following radiation with or without chemotherapy. Two patients had recurrence after 23 and 26 months. Actuarial 2-year survival was 78%.4

Observation alone is another potential option for patients with a complete pathologic response to preoperative CMT. As discussed above, however, reliable noninvasive determination of complete response is currently unavailable, and patients treated nonoperatively are also at risk for recurrence due to undetected residual disease in the rectal wall and MLNs. In one study, 30 patients with complete clinical response to preoperative CMT were treated nonoperatively; in 8, recurrent tumor was clinically evident within 14 months after surgery, and the other 22 were free of recurrence at a median follow-up of 36 months.25 Less encouraging results, however, were noted in another study. Of 10 patients with complete clinical response to preoperative CMT, local recurrence occurred in eight within 9 months.26

Should we modify our current treatment strategies for locally advanced rectal cancer on the basis of primary tumor downstaging? In order to do so, we would have to assume that in cases of complete response of the primary tumor, a similar response has occurred in the mesorectal lymph nodes. In the current study, two patients with complete response of the primary tumor (pT0) had MLN involvement on pathologic analysis (7%). Other studies have revealed MLN involvement in up to 11% of patients with completely responding primary tumors.1,27

In conclusion, our results demonstrate that in patients with locally advanced mid and distal rectal cancer, the risk of residual MLN involvement following preoperative CMT is substantial (27%). This information is important when local excision is being considered after preoperative CMT for locally advanced rectal cancer. Because of the current inability of existing imaging modalities to reliably confirm the eradication of mesorectal nodal metastases, patients undergoing local excision alone following CMT are at risk for local failure due to residual nodal disease left in situ. We conclude, therefore, that for patients with locally advanced rectal cancer receiving preoperative CMT, definitive treatment should continue to include formal rectal resection with sharp mesorectal technique.


   ACKNOWLEDGMENTS
 
This work was supported in part by the National Cancer Institute, Award R01 CA 82534–01 for JGG.


   FOOTNOTES
 
Presented in part, at the 56th Annual Cancer Symposium, Society of Surgical Oncology, March 5–9, 2003, Los Angeles, CA.

Although a reduction in pathologic T (pT) stage can be expected following preoperative chemoradiation for locally advanced rectal cancer, the incidence of positive mesorectal lymph nodes remains significant. Furthermore, the rate of nodal positivity increases with increasing pT stage.

Received for publication June 18, 2003. Accepted for publication October 7, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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