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cT3N0 Rectal Cancer: Potential Overtreatment With Preoperative Chemoradiotherapy Is Warranted

José G. Guillem, Juan A. Díaz-González, Bruce D. Minsky, Vincenzo Valentini, Seung-Yong Jeong, Miguel A. Rodriguez-Bigas, Claudio Coco, Rebecca Leon, José L. Hernandez-Lizoain, José J. Aristu, Elyn R. Riedel, Donato Nitti, W. Douglas Wong, Salvatore Pucciarelli

From the Memorial Sloan-Kettering Cancer Center, New York, NY; Clinica Universitaria, University of Navarra, Pamplona, Spain; University of the Sacred Heart, Rome; University of Padua, Padua, Italy; National Cancer Center, Goyang, Republic of Korea; and The University of Texas M.D. Anderson Cancer Center, Houston, TX

Corresponding author: José G. Guillem, MD, MPH, Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room C-1077, New York, NY 10021; e-mail: guillemj{at}mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Purpose Although combined-modality therapy (CMT) is the preferred treatment for T3 and/or lymph node (LN)-positive rectal cancer, the German rectal cancer study published in 2004 demonstrated that 18% of patients deemed suitable for preoperative CMT by endorectal ultrasound (ERUS) may be overstaged. Because data also suggest that LN-negative rectal cancer after total mesorectal excision may not require radiotherapy, it is reasonable to consider omitting radiotherapy for the cT3N0 subset. We therefore determined the accuracy of pre-CMT ERUS or magnetic resonance imaging (MRI) staging, to explore the validity of a nonpreoperative CMT approach for cT3N0 disease.

Patients and Methods One hundred eighty-eight ERUS-/MRI-staged T3N0 rectal cancer patients received preoperative CMT (fluorouracil based and 45-50.4 Gy) followed by radical resection. Rates of pathologic complete response (pCR) and mesorectal LN involvement were determined.

Results Tumors were located a median of 5 cm from the anal verge. Sphincter-preserving surgery was performed in 143 patients (76%). Overall pCR was 20%, and 41 patients (22%) had pathologically positive mesorectal LNs. The incidence of positive LNs significantly increased with T stage: ypT0, 3%; ypT1, 7%; ypT2, 20%; ypT3-4, 36% (P = .001).

Conclusion The accuracy of preoperative ERUS/MRI for staging mid to distal cT3N0 rectal cancer is limited because 22% of patients have undetected mesorectal LN involvement despite CMT. Therefore, ERUS-/MRI-staged T3N0 rectal cancer patients should continue to receive preoperative CMT. Although 18% may be overstaged and therefore overtreated, our data suggest that an even larger number would be understaged and require postoperative CMT, which is associated with significantly inferior local control, higher toxicity, and worse functional outcome.

	INTRODUCTION

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Significant progress in the management of locally advanced rectal cancer has been achieved during the last decade. This includes the use of preoperative chemoradiotherapy, referred to as combined-modality therapy (CMT),¹ and the widespread implementation of total mesorectal excision² and autonomic nerve preservation.³ Most recently, the German Rectal Cancer Study Group established that there is significant improvement in local control, toxicity profile and sphincter preservation in patients with locally advanced rectal cancer treated with preoperative versus postoperative CMT.¹ This has led to increased utilization of preoperative CMT worldwide, resulting in greater reliance on pretherapy imaging and staging. We have also seen an increased interest in tailoring therapy to specific stages of disease, in an effort to decrease the likelihood of preoperative overtreatment.

According to the 1990 National Institutes of Health consensus conference, adjuvant postoperative CMT is recommended for all pT3 and/or pN+ rectal cancers.⁴ However, recent data now suggest that these criteria may be too broad. A number of studies^5-7 have demonstrated that patients undergoing resection of pT3N0 rectal cancer with favorable pathologic features experience a low rate of local failure after surgery alone, suggesting that these patients may not significantly benefit from postoperative CMT. Gunderson et al reported a retrospective analysis of pooled data demonstrating similar 5-year overall survival for pT3N0 rectal cancer patients treated with surgery and chemotherapy alone (84%) versus those treated with CMT (74% to 80%), further suggesting that trimodality therapy may be excessive for some patients in the T3N0 subset.⁸ Similar data were reported from the National Cancer Data Base.⁹ Although these data may support the omission of postoperative CMT after curative resection of T3N0 rectal cancer with favorable pathologic features, it is important to note that these data are retrospective in nature; thus, extrapolation of these data into the preoperative paradigm presumes accurate pretherapy staging. The purpose of this study was, therefore, to determine the frequency of regional lymph node (LN) involvement after preoperative CMT in patients with rectal cancer staged as cT3N0 on either endorectal ultrasound (ERUS) or magnetic resonance imaging (MRI).

	PATIENTS AND METHODS

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An international consortium of six institutions, each with a high volume of rectal cancer patients, was created, including Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY), The University of Texas M.D. Anderson Cancer Center (Houston, TX), Clinica Universitaria, University of Navarra (Pamplona, Spain), University of Padua (Padua, Italy), Catholic University of the Sacred Heart (Rome, Italy), and National Cancer Center, Korea (Goyang, Republic of Korea).

Two hundred seventy-four patients, staged preoperatively with T3N0 rectal cancer, were identified from the participating institutions. Eighty-six patients were excluded for the following reasons: lack of ERUS/MRI pretherapy staging (n = 29); history of receiving less than 45 Gy radiotherapy (n = 25); undergoing nonradical resection (n = 7); and receiving irinotecan or oxaliplatin as additional chemotherapeutic agents (n = 25).

The study population thus consisted of 188 patients. All lesions were biopsy-proven rectal adenocarcinomas located within 12 cm of the anal verge (AV). The databases of each institution were queried to identify clinicopathologic and demographic details. The study was approved by the MSKCC Institutional Review Board.

ERUS
ERUS was performed using a 7- to 10-MHz probe revealing the rectal mucosa, submucosa, and muscularis propria. On ERUS, the rectum appears in five layers, as follows: (1) interface with the mucosa; (2) mucosa; (3) submucosa; (4) muscularis propria; and (5) interface with the perirectal fat. Rectal wall penetration (uT stage) was assessed by ERUS according to the criteria established by Hildebrandt and Feifel.¹⁰ Circular hypoechoic structures of at least 3 mm in diameter were classified as malignant LNs (uN positive). Nodes less than 3 mm in diameter or nodes with central hyperechogenicity were considered benign.

MRI
MRI was performed using a high–spatial-resolution phased-array MR technique. MRI diagnosis of T3 lesions were based on the presence of tumor signal intensity extending through the muscle layers into the perirectal fat, with a broad-based bulging configuration, and in continuity with the intramural portion of the tumor.¹¹ Positive LN status was ascertained using signal intensity, border characteristics, irregular contour, or heterogeneous texture. Size morphology was not used as a significant predictor for LN positivity.

Preoperative CMT
All patients received external-beam radiation therapy (median dose, 50.40 Gy; range, 45 to 61.20 Gy) according to previously published techniques,¹² administered in conventional fractions of 1.8 Gy (1.8 daily Gy 5 days/wk). Fluorouracil (FU)-based chemotherapy was administered concurrently to all patients. Patients received chemotherapy in various treatment regimens, including: bolus FU (32%), continuous-infusion FU (44%), and oral chemotherapy (24%). Additionally, a secondary drug was administered with FU or oral chemotherapy in 48% of cases; these included cisplatin (11%), carboplatin (17%), and leucovorin (20%).

The most common regimen for bolus chemotherapy was the Mayo regimen: bolus FU (325 to 425 mg/m²/d) with leucovorin (20 mg/m²/d) administered for two cycles, in weeks 1 and 5 of radiation therapy. Continuous-infusion FU was administered (225 to 300 mg/m²/d) during the 6 weeks of radiation therapy. Oral chemotherapy included capecitabine (825 mg/m² bid, 7 days/wk, administered concurrently with radiation), or raltitrexed (3.0 mg/m² concomitantly administered with radiotherapy on days 1, 19, and 38).

Surgical Procedure
Within 4 to 12 weeks of completing CMT, all patients underwent radical resection (low anterior resection, abdominoperineal resection, exenteration, or Hartmann resection) according to the principles of sharp mesorectal technique, emphasizing dissection in the avascular plane between the rectal fascia propria and parietal peritoneum. The intervals between completion of preoperative CMT and surgery varied according to physician preference.

Pathologic Assessment
Standard pathologic analysis was performed on all radical resection specimens according to the techniques described by Quirke et al.¹³ Each post-CMT rectal cancer was staged according to guidelines established by the AJCC Cancer Staging Manual.¹⁴

Statistical Analysis
Associations between LN positivity and clinical/pathologic variables were examined using Fisher's exact test for categoric variables, an exact version of the Mantel-Haenszel test for trend for ordinal variables, and the Wilcoxon test for continuous variables. Associations between response variables and each institution were examined using Fisher's exact test. All calculations were performed using SAS version 9.1 (SAS Institute, Cary, NC)

	RESULTS

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Patient Population
One hundred eighty-eight patients (122 men and 66 women; median age at diagnosis, 61 years; range, 27 to 82 years) were identified. Median distance of the tumor from the AV was 5 cm (range, 0 to 12 cm). Staging modality therapies included ERUS (130 patients) and MRI (58 patients). Surgical procedures included low anterior resection (143 patients), abdominoperineal resection (41 patients), Hartmann procedure (one patient) and total pelvic exenteration (one patient). Median time to surgery after completion of CMT was 43 days (range, 22 to 168 days). The recommended interval between conclusion of chemoradiotherapy and surgery is 4 to 8 weeks. There is some evidence that surgery immediately after radiotherapy results in less downstaging; in our study, only 5% of patients underwent surgery earlier than 4 weeks after chemoradiotherapy. However, to the best of our knowledge, there is no published evidence that waiting more than 8 weeks results in greater downstaging.^15,16 Demographic characteristics are presented in Table 1.

Study of Potential Associations
To discard potential bias in the detection of pathologically positive LNs, we studied possible associations between patient and tumor characteristics, clinical staging method, and chemotherapy regimens (Table 2). Distance from the AV did not correlate with ypN (P = .58), because 24 (23%) of 103 patients with tumors located 0 to 5 cm from the AV had ypN compared with 17 (20%) of 85 patients with tumors located 6 to 12 cm from the AV. As seen in Table 2, the rate of ypN+ did not differ significantly between rectal cancers staged pre-CMT with ERUS (25%) or MRI (16%; P = .19).

In addition, the varying methods used to administer chemotherapy (oral agents, continuous-infusion FU, and bolus FU) were not found to be significantly associated with the incidence of ypN+ (P = .94). Furthermore, the use or absence of carboplatin, cisplatin or leucovorin as additional chemotherapeutic agents did not influence the incidence of ypN+ (ypN+ v ypN–, 22% v 22%; P = .88). Lastly, there was no significant correlation between the individual institutions and ypN+ (P = .51).

	DISCUSSION

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Our study demonstrates that 22% of rectal cancer patients staged, pre-CMT, as having cT3N0 rectal cancer on either ERUS or MRI do in fact have pathologically positive LNs. Because preoperative CMT may not only reduce the total number of LNs but also sterilize mesorectal LNs,^17-19 the true rate of unidentified pathologically involved LNs is likely to be higher. Of note, although the median number of mesorectal LNs retrieved after preoperative CMT was only nine, the rate of positive LNs was strikingly high. Our results suggest that reliance on ERUS or MRI for rectal cancer staging results in a substantial number of cT3N1 rectal cancers being understaged and therefore potentially not receiving preoperative CMT. Thus, we believe that preoperative chemoradiotherapy should remain the standard of care for patients with ERUS-/MRI-staged T3 rectal cancers. However, our data also suggest that, because of the potential for overstaging, there may be subsets of patients who will not benefit from this approach. In any case, given the significant improvement in local control, acute and long-term toxicity, and sphincter preservation associated with preoperative versus postoperative CMT,¹ our data underscore the need for improved pretherapy staging of rectal cancer.

Although results tend to be experience- and technology-dependent, the accuracy of ERUS for assessing depth of wall penetration and LN metastases ranges from 62% to 92% and 64% to 88%, respectively.^19-21 Data from pooled analyses,^20-23 as well as from recent smaller studies^24,25 reveal that the sensitivity of ERUS in detecting LN metastasis ranges from 50% to 83%, comparable with that of MRI (sensitivity, 45% to 79%).^11,26-28 Our results, based on pooled data from our international multicenter consortium, suggest that ERUS and phased-array MRI staging of LN status in cT3 rectal cancer may be less accurate than previously anticipated. Although pretreatment MRI can help identify patients who may have positive circumferential margins,²⁹ accurate identification of patients with N+ disease is more challenging.³⁰

Although previous studies have reported on the accuracy of ERUS and MRI for both T and N status, the relationship between T level and N level has not been adequately examined. Our study, which represents the largest exclusively focused on cT3N0 rectal cancers, demonstrates a high (22%) incidence of residual positive LNs after preoperative CMT. Although the accuracy of selected series of three-dimensional ERUS (88%) and endorectal MRI (91%) for LN staging are encouraging, these results are based on small sample size and are not limited to patients with cT3 disease.^31,32 Therefore, it seems that at the present time, pretherapy imaging is likely to result in understaging and thus undertreatment of a number of cT3 rectal cancers.

The omission of preoperative CMT for ERUS-/MRI-staged cT3N0 rectal cancer patients will result in at least 22% of these patients (and perhaps as many as 30% to 40%, when one accounts for the downstaging encountered with preoperative CMT) requiring postoperative CMT. As previously discussed, postoperative CMT is associated with increased toxicity and local recurrence rates,¹ decreased compliance to the chemotherapy regimen after major surgery, and diminished bowel function secondary to potential irradiation of a low anastomosis.³³ Although these facts would seem to favor recommending preoperative CMT routinely for all patients with locally advanced rectal cancer, the German study¹ demonstrated that 18% of patients staged clinically as having cT3, cT4 or node-positive rectal cancer on ERUS were overstaged; LNs were negative in patients randomly assigned to undergo surgery first. Had these patients in the German study been randomly assigned to the preoperative rather than the postoperative arm, they would have received preoperative therapy and would thus have been overtreated and subjected unnecessarily to the short- and long-term complications of pelvic radiation.¹²

In the hands of an experienced practitioner, however, ERUS is capable of discerning very superficial uT3N0 rectal cancers. Superficial uT3 rectal cancers with small LN metastases, which may be amenable to postoperative treatment with chemotherapy, can also be identified. It may be possible for some carefully selected patients who are truly LN negative, whose tumors demonstrate minimal invasion of the perirectal fat and confirmed well-differentiated histopathology, to undergo total mesorectal excision followed by chemotherapy and—in the setting of negative circumferential margins—to forgo radiotherapy. The optimal treatment for these truly superficial uT3 lesions warrants further study in the form of a randomized trial.

Given the current limitations of pretherapy imaging, clinicopathologic features of the primary rectal cancer may help identify those lesions more likely to be associated with LN metastases. Although a number of studies have demonstrated an association between clinicopathologic factors, such as extent of tumor invasion into the perirectal fat^6,7,34; regional LN metastases³⁵; lymphovascular invasion^7,34,36,37; high-grade mucin production³⁸ and signet ring features³⁹; positive distal margin and CRM^13,40; and prognosis, these results were based on analysis of the entire resected specimen rather than pretherapy biopsy. Although we recognize that pretherapy detection of these unfavorable features would lead to the delivery of preoperative CMT, because of the inherent problems of sampling error incurred when biopsying a cancer, it is unlikely that a pretherapy biopsy would reliably exclude any of the aforementioned unfavorable pathologic features.

An alternative method for identifying positive nodes would be the analysis of molecular markers. Analyses of biopsies examining selected molecular markers such as c-K-ras, 4 thymidylate synthase, p27kip1, p53, apoptosis, deleted in colorectal cancer, epidermal growth factor receptor, TP53 and Ki-67 have had varying success in helping to select patients who may best respond to preoperative therapy.¹² The ability to identify patients with positive nodes pretreatment is even more limited. Furthermore, all of the studies are limited retrospective trials, and most do not examine multiple markers.

Our study has several limitations that deserve mention. First, it is a retrospective analysis and was therefore limited by the bias inherent in this type of analysis. However, given that the study patients were consecutive, offering a nonselected series of T3N0 staged rectal cancers, we believe that our results do not reflect a bias toward patients with more advanced disease, but rather reflect the average cT3N0 rectal cancer. Second, although the ERUS and MRI imaging studies utilized similar equipment and followed standardized protocols, we recognize that the expertise varied among the individuals performing and interpreting these studies among the six institutions. It should be emphasized, however, that the results were not significantly different when examined by the institutions.

The accuracy of MRI may be further enhanced with the use of superparamagnetic iron oxide particles in patients with prostate cancer.⁴¹ The accuracy of ERUS for the detection of involved perirectal LNs may be augmented if combined with fine needle aspiration⁴²; however, because this often necessitates going through tissue to biopsy the nodes, it is not favored at our institution. Neither of these techniques was used in our study.

In conclusion, our study demonstrates that the accuracy of preoperative ERUS/MRI for staging mid to distal T3N0 rectal cancer is limited because 22% of patients will have undetected mesorectal LN involvement after preoperative CMT. Therefore, patients with cT3N0 disease staged by ERUS/MRI should continue to receive preoperative CMT. Although 18% may be overstaged and therefore overtreated, our data suggest that an even larger number would otherwise be understaged and require postoperative CMT, which is associated with inferior local control, higher toxicity, and worse functional outcome. Our study also clearly emphasizes the need for continued efforts to improve our pretherapy staging of rectal cancer.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Conception and design: José G. Guillem, Juan A. Díaz-González, Vincenzo Valentini, Seung-Yong Jeong, Rebecca Leon, Elyn R. Riedel, Salvatore Pucciarelli

Administrative support: José G. Guillem, W. Douglas Wong

Provision of study materials or patients: Donato Nitti

Collection and assembly of data: Juan A. Díaz-González, Vincenzo Valentini, Seung-Yong Jeong, Miguel A. Rodriguez-Bigas, Claudio Coco, José L. Hernandez-Lizoain, José J. Aristu, Elyn R. Riedel, Salvatore Pucciarelli

Data analysis and interpretation: José G. Guillem, Juan A. Díaz-González, Bruce D. Minsky, Vincenzo Valentini, Seung-Yong Jeong, Miguel A. Rodriguez-Bigas, Claudio Coco, Rebecca Leon, Elyn R. Riedel, Donato Nitti, W. Douglas Wong, Salvatore Pucciarelli

Manuscript writing: José G. Guillem, Juan A. Diaz-González, Bruce D. Minsky, Rebecca Leon

Final approval of manuscript: José G. Guillem, Juan A. Díaz-González, Bruce D. Minsky, Vincenzo Valentini, Claudio Coco, José L. Hernandez-Lizoain, José J. Aristu, Elyn R. Riedel, W. Douglas Wong, Salvatore Pucciarelli

	NOTES

 
J.G.G. and J.A.D.-G. contributed equally to this work.

Presented in poster format at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted July 18, 2007; accepted October 19, 2007.

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