The Importance of Lymph Node Status After Neoadjuvant Therapy for Rectal Cancer

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In a retrospective tumor registry (SEER) analysis of outcomes for rectal-cancer patients treated over a 14-year period with either presurgical or postsurgical radiation therapy, the importance of pathological lymph node status was found to be significantly more adverse for patients who had presurgical treatment. These patients define a subgroup for whom aggressive post-surgical treatment would seem warranted.

Source: Chang GJ, et al. Lymph node status after neoadjuvant radiotherapy for rectal cancer is a biologic predictor of outcome. Cancer. 2009;115:5432-5440.

Surgical resection remains the primary treatment for localized rectal cancer. However, the preoperative use of chemoradiotherapy has become increasingly employed, based upon clinical trials that demonstrated improved local control and overall survival compared with postoperative adjuvant therapy.1, 2 However, lymph node (LN) status after surgery for rectal cancer is affected by preoperative therapy. In fact, preoperative therapy has been associated with a decrease in pathological stage of both tumor (T) and nodal (N) status in about 60% of those treated and a pathologic complete response in 8%-31% of patients.2-5 The question addressed in the current research is whether the persistence of pathologically positive lymph nodes after neoadjuvant chemoradiotherapy has significance beyond that observed in lymph node-positive patients who did not have neoadjuvant therapy.

For this, patients undergoing radical resection for rectal adenocarcinoma were identified from the Surveillance Epidemiology and End Results (SEER) registry (1991-2004). SEER, a population-based cancer registry, collects cancer incidence and survival data from 18 regional, population-based registries covering approximately 26% of the U.S. population. Included are data on patient demographics, primary tumor site, tumor morphology, disease stage, first course of treatment (surgery, radiotherapy), patient follow-up, and survival. The authors evaluated patient characteristics, overall survival, and cancer-specific survival (CSS) by pathologically determined N stage after surgery and use of preoperative or postoperative radiotherapy were compared.

Of the 23,809 patients identified, 12,513 received preoperative (n = 5367) or postoperative (n = 7146) radiotherapy and resection. Preoperative patients were more likely to be younger (p < .001) and histopathologically free of detectable nodal metastasis (pN0) than postoperative (51.8% vs. 31.7%, p < .001). Median total numbers of LNs (6 vs. 10) and positive LNs (2 vs. 3) were lower among preoperative than postoperative (p < .001 for both). OS and CSS were similar among pN0 patients. However, on proportional hazards regression, pathologic lymph node stage was associated with an increase in relative risk for death by 21% overall (HR = 1.21; 95% confidence interval [CI] 1.09-1.35, p < .001) and by 23% for cancer-specific mortality (HR = 1.23; p = .001) for patients receiving preoperative compared with postoperative chemoradiotherapy.

These high-risk patients should be targeted for studies of novel multidisciplinary approaches, including expanded chemo and biologic therapies.

Commentary

Pathologic LN status after neoadjuvant radiotherapy for rectal cancer is a biologic marker of prognosis. That is, patients who have demonstrated nodal disease after presurgical chemoradiotherapy form a subgroup of lymph node positive patients with an adverse prognosis. Although not previously demonstrated, this certainly makes sense. Persistent nodal disease after treatment suggests a more resistant disease, and it would be unlikely that responses to post-surgical treatment would be comparable to those with nodal disease for whom there was no prior experience with radiation or chemotherapy.

The question is what to do with this information. For starters, it would make sense that aggressive systemic treatment, perhaps including novel biologic agents, could be undertaken and, hopefully, this would be the subject of future clinical trials. Although local control is clearly superior for those who had received neoadjuvant therapy, the influence on overall survival has been less obvious, implying that systemic therapy is advisable for most patients after surgery. However, these patients with residual nodal disease may benefit from additional localized treatment, as they may be the patients more likely to experience local recurrence. Again, this would seem an excellent question for clinical trial.

References

1. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med. 1997;336:980-987.

2. Sauer R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351:1731-1740.

3. Bouzourene H, et al. Importance of tumor regression assessment in predicting the outcome in patients with locally advanced rectal carcinoma who are treated with preoperative radiotherapy. Cancer. 2002;94: 1121-1130.

4. Janjan NA, et al. Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer. Am J Clin Oncol. 2001;24: 107-112.

5. Wheeler JM, et al. Preoperative chemoradiotherapy and total mesorectal excision surgery for locally advanced rectal cancer: Correlation with rectal cancer regression grade. Dis Colon Rectum. 2004;47: 2025-2031.