Clinical investigation
Rectum
Can histopathologic assessment of circumferential margin after preoperative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for 3-year disease-free survival?

https://doi.org/10.1016/j.ijrobp.2005.03.003Get rights and content

Purpose: This study set out to determine the impact of a positive circumferential resection margin (CRM) (R1-R2) and pathologic downstaging on local recurrence and survival in patients with borderline resectable or unresectable rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy (CRT).

Methods and Materials: A total of 150 patients with locally advanced rectal cancer were treated with long-course neoadjuvant CRT using low-dose folinic acid and 5-fluorouracil. CRT was followed 6–12 weeks later by surgical excision. The CRM rate and incidence, site, and pattern of local and systemic recurrences were recorded. The median follow-up was 25 months.

Results: The overall median survival was 37 months, with a 5-year overall survival rate of 34%. Of the 150 patients, 122 underwent curative resection; 12% had a complete pathologic response, and downstaging to pT1-T2 occurred in an additional 16%. A negative CRM (R0) was achieved in 65% overall (98 of 150). Local recurrence occurred in 10% of those with R0 resection and 62% of those with R1-R2 resections. Distant metastases occurred in 29% of those with R0 resections and 75% of those with R1-R2 resections. The 3-year disease-free and 3-year overall survival rate was 9% and 25% and 52% and 64%, respectively, for patients with and without a histologically positive CRM.

Conclusion: After 5-fluorouracil–based CRT, a positive CRM predicted for a high risk of subsequent local recurrence and a 3-year disease-free survival rate of only 9%. For this reason, the CRM should be considered a major prognostic factor and should be validated in future trials as an early alternative clinical endpoint.

Introduction

The optimal management of Stage II and III rectal cancer continues to be an increasing challenge for oncologists. Although surgery remains the mainstay of treatment, historically a high risk of local recurrence and poor survival has been reported for these patients. Randomized studies in the era before total mesorectal excision (TME) demonstrated local recurrence rates of 15–35% and a 5-year overall survival (OS) rate of approximately 60% for Dukes B2 and only 25% for Dukes C after surgery (1). The 5-year survival rate remains in the region of 40–55% in most modern series (2, 3), even when patients have undergone curative resection. Recent advances in surgical technique have resulted in a significant reduction in the risk of local recurrence; however, these improvements do not appear to have had an affect on OS (4, 5).

One-third of rectal cancer patients will present with locally advanced tumors (T3 and T4), and in up to 20% of cases, curative (histologically confirmed) R0 resection will not be achieved (6, 7). Approximately 40–50% of patients who undergo potentially curative surgery for rectal cancer will ultimately relapse and die of subsequent metastatic disease (8). TME alone is, therefore, insufficient for more locally advanced rectal cancer, and further improvements in survival are only likely to be gained with the use of better chemotherapy and radiotherapy (RT) combinations.

The main prognostic factors remain the extent of the primary tumor (T stage), regional lymph node status (N stage), and whether the circumferential resection margin (CRM) is sufficient. Previous studies (9) have confirmed that the greatest relapse rates were found in patients with nodal involvement and tumor extension beyond the rectal wall. Data from the Norwegian Rectal Cancer Project showed that at a median follow-up of 29 months, 40% of patients who had a positive CRM developed metastatic disease compared with 12% in whom the margin was >1 mm (10).

Methods of identifying and selecting which patients may benefit from preoperative chemoradiotherapy (CRT) have focused on digital rectal examination (DRE) and cross-sectional imaging using CT or MRI. DRE by an experienced coloproctologist can identify fixity as an indicator of locally advanced disease. Pelvic MRI using a surface phased array coil can demonstrate the relationship of the primary tumor to the mesorectum and the surrounding mesorectal fascia and appears to be able to predict the circumferential margin preoperatively and achieve good correlation with pathologic measurements (11, 12, 13, 14). Thus, preoperative CRT is increasingly offered to patients with rectal cancer who are expected on the basis of MRI criteria to have a close or involved resection margin with current surgical techniques.

Neoadjuvant CRT has been shown to downstage tumors, with more cases of Dukes A staging, a better surgical resection (R0) rate, and more sphincter-sparing procedures (15, 16). Controversy exists as to whether this correlates with improved survival (17, 18). In a recent large study of resectable rectal cancer cases (19), preoperative CRT was associated with a significantly improved local control rate compared with postoperative CRT, but OS was not improved. Downstaging after preoperative CRT also appears to be a significant prognostic factor, and patients with pT0, T1, or T2 disease appear to have a better prognosis (20, 21).

The aim of this study was to determine the rates of pathologic downstaging and negative circumferential margins and to define their relationship to local recurrence and disease-free survival (DFS) and OS.

Section snippets

Methods and materials

The Mount Vernon Cancer Centre serves a population of 1.8 million. A prospective database confirmed that 150 consecutive patients with primary, locally advanced rectal cancer received synchronous 5-fluorouracil (5-FU)–based CRT between January 1995 and December 2002. All patients were considered to have borderline resectable or unresectable disease by the referring surgeons.

Tumors were defined as rectal if the lower limit was located within 12 cm of the anal verge on rigid sigmoidoscopy.

Results

A total of 150 patients underwent CRT and 122 subsequently underwent surgery (81%). Five patients who had had a complete clinical response refused surgery, 4 patients died before surgery, 11 patients’ disease remained unresectable, and 4 patients had widespread peritoneal metastases at exploration and, therefore, did not undergo radical resection. One patient did not undergo surgery because of comorbidity, and three were lost to follow-up (Fig. 1).

Of the 122 patients who underwent surgery, 75

Discussion

Chemoradiotherapy before surgery is now a common approach in the treatment of locally advanced rectal cancers (15, 16, 18), which has focused on the potential for downstaging to enable a curative surgical resection or a sphincter-sparing procedure. Standard surgical resection, even with TME, in cancers that are partially or totally fixed is usually associated with very high rates of incomplete excision and almost universal local recurrence at a later date. For this reason, most surgeons accept

Conclusion

The results of this study have suggested that preoperative 5-FU–based CRT can produce effective downstaging and improve the R0 resection rates with a negative CRM in patients with locally advanced rectal carcinoma. A positive CRM is associated with very poor OS and DFS. However, of all the currently recognized risk factors for local recurrence and metastatic disease, the circumferential margin is the only one that could potentially be influenced by all forms of treatment (surgery, chemotherapy,

Acknowledgments

We acknowledge the help and cooperation of the following surgeons who also contributed to this study: J. Nicholls, R. Phillips, D. Cairns, R. Hallan, J. Gilbert, and J. McCue.

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