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What Is the Best Way to Predict Disease-Free Survival After Preoperative Radiochemotherapy for Rectal Cancer Patients: Tumor Regression Grading, Nodal Status, or Circumferential Resection Margin Invasion?

Clinique des Pathologies Tumorales du Colon et du Rectum, Centre du Cancer, Université Catholique de Louvain, Brussels, Beligium

To the Editor:

The clinical signification of pathological response after preoperative radiochemotherapy (RCT) for rectal cancer is an important issue. The excellent article by Rödel et al¹ suggested that patients with complete (tumor regression grading [TRG] 4) and intermediate pathologic response (TRG 2 + 3) had an improved disease-free survival (DFS) after preoperative RCT. We would like to make a few comments regarding this interesting analysis.

In this series, although TRG seemed promising in the univariate analysis, the most important independent prognostic factor for DFS was the pathological (T) category and the nodal (N) status in the multivariate model. So, it is possible that, in the clinical routine, the only relevant practical parameter for DFS remains the postoperative TN stadification. It could be also speculated that pathologic TN staging after surgery not only reflects the initial staging of the tumor, but also the tumor response to the preoperative treatment as suggested by some correlations in the Rödel article.¹

It could also be interesting to clarify if clearance of the circumferential resection margin (defined according to standard guidelines as > 1 or 2 mm between the tumor and the surgical margin^2,3) was also a significant predictor of DFS or local relapse in the presented series. Indeed, it is unclear if Rödel et al took into account this important parameter since they included R0 patients—R0 being defined as "histologically tumor-free resection margins regardless of the distance between tumor and resection margins." Recently, we reviewed our own series of rectal cancer patients treated with preoperative RCT (unpublished observation). All included patients received preoperative RCT (45 Gy in 5 weeks) followed by six weeks of rest and by macroscopic complete mesorectal excision. Sixty-six patients were identified (35 were treated with oxaliplatin-based RCT and 31 with fluorouracil-based RCT).⁴ The prognostic value of clinical and pathological characteristics to predict disease-free survival was assessed: (1) In the univariate analysis using Kaplan and Meier probability (significance by log-rank test); and (2) in the multivariate analysis using Cox proportional hazards regression. The following parameters were studied: age, sex, endorectal ultrasound staging (before RCT), pathologic staging (T and N) after surgery, circumferential resection margin (CRM) invasion defined by 2 mm or less between the tumor and the surgical margin, TRG according to Dworak,⁵ TRG according to Wheeler,⁶ tumor size after RCT, assigned treatment (fluorouracil v oxaliplatin-based RCT) and the number of lymph nodes retrieved at surgery. In the univariate analysis, the only parameters statistically, significantly predictive of a decreased DFS probability were metastasis in four or more lymph nodes (P = .0003) and CRM (P = .016). Probably due to the low number of patients included, only a trend in favor of better TRG according to Dworak (P = .11) and Wheeler (P = .12) was observed. In the multivariate analysis, ypN2 (P = .03) and CRM (P = .048) remained independent predictors of DFS (P = .9 for TRG according to Dworak or Wheeler). These data confirm the findings of Rödel et al and support CRM as a possible important factor. The value of CRM as predictive of relapse has also be suggested previously by other groups.^2,7

Another factor that could be of importance is the reproductibility of the pathologic evaluation of TRG between different pathologists. In the Rödel study, a central pathology review was not performed. In our series, after training, two different pathologists reviewed all the slides independently. Accordance between pathologists for TRG was found in 97% of cases, suggesting that this technique could be easily implemented in the clinical practice after training.

It is unknown whether some rectal cancer patients will benefit from adjuvant chemotherapy after RCT. Prospective validation of the Rödel data could help to design important clinical trials with good risk stratification in this setting.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Rödel C, Martus P, Papadoupolos T, et al: Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 23:8688-8696, 2005[Abstract/Free Full Text]

2. Nagtegaal ID, Marijnen CA, Kranenbarg EK, et al: Circumferential margin involvement is still an important predictor of local recurrence in rectal carcinoma. Am J Surg Pathol 26:350-357, 2002[CrossRef][Medline]

3. Quirke P, Durdey P, Dixon MF, et al: Local recurrence of rectal adenocarcinoma due to inadequate surgical resection: Histopathological study of lateral tumour spread and surgical excision. Lancet 2:996-999, 1986[CrossRef][Medline]

4. Machiels JP, Duck L, Honhon B, et al: Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: The RadiOxCape study. Ann Oncol 16:1898-1905, 2005[Abstract/Free Full Text]

5. Dworak O, Keilholz L, Hoffmann A: Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 12:19-23, 1997[CrossRef][Medline]

6. Wheeler JMD, Warren BF, McC Mortensen NJ, et al: Quantification of histologic regression of rectal cancer after irradiation. Dis Colon Rectum 45:1051-1056, 2002[CrossRef][Medline]

7. Bouzourene H, Bosman FT, Matter M, et al: Predictive factors in locally advanced rectal cancer treated with preoperative hyperfractionated and accelerated radiotherapy. Hum Pathol 34:541-548, 2003[CrossRef][Medline]

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  Claus Rödel and Rolf Sauer
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