European Journal of Radiology 83 (2014) 245–249

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Clinical implication of negative conversion of predicted circumferential resection margin status after preoperative chemoradiotherapy for locally advanced rectal cancer Nam Kwon Lee a , Chul Yong Kim a,∗ , Young Je Park a , Dae Sik Yang a , Won Sup Yoon a , Seon Hahn Kim b , Jin Kim b a b

Department of Radiation Oncology, Korea University Medical Center, Korea University College of Medicine, Seoul, Republic of Korea Division of Colorectal Surgery, Department of Surgery, Korea University Medical Center, Korea University College of Medicine, Seoul, Republic of Korea

a r t i c l e

i n f o

Article history: Received 22 August 2013 Received in revised form 17 October 2013 Accepted 21 October 2013 Keywords: Rectal neoplasms Circumferential resection margin Preoperative chemoradiotherapy Magnetic resonance imaging

a b s t r a c t Objective: To evaluate the prognostic implication of the negative conversion of predicted circumferential resection margin status before surgery in patients with locally advanced rectal cancer with predicted circumferential resection margin involvement. Methods: Thirty-eight patients (28 men, 10 women; median age, 61 years; age range, 39–80 years) with locally advanced rectal cancer with predicted circumferential resection margin involvement who underwent preoperative chemoradiotherapy followed by radical surgery were analyzed. Involvement of the circumferential resection margin was predicted on the basis of pre- and post-chemoradiotherapy magnetic resonance imaging. The primary endpoints were 3-year local recurrence-free survival and overall survival. Results: The median follow-up time was 41.1 months (range, 13.9–85.2 months). The negative conversion rate of predicted circumferential resection margin status after preoperative chemoradiotherapy was 65.8%. Patients who experienced negative conversion of predicted circumferential resection margin status had a significantly higher 3-year local recurrence-free survival rate (100.0% vs. 76.9%; P = 0.013), diseasefree survival rate (91.7% vs. 59.3%; P = 0.023), and overall survival rate (96.0% vs. 73.8%; P = 0.016) than those who had persistent circumferential resection margin involvement. Conclusions: The negative conversion of the predicted circumferential resection margin status as predicted by magnetic resonance imaging will assist in individual risk stratification as a predictive factor for treatment response and survival before surgery. These findings may help physicians determine whether to administer more intense adjuvant chemotherapy or change the surgical plan for patients displaying resistance to preoperative chemoradiotherapy. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Pathological circumferential resection margin (CRM) involvement in rectal cancer is a well-established prognostic factor for local recurrence and overall survival (OS) [1–6]. However, with recent advances in magnetic resonance imaging (MRI) technology, several studies showed that MRI could accurately provide measurements of the distance from the tumor to the mesorectal fascia and have highlighted the importance of assessing clinical CRM status before preoperative chemoradiotherapy (CRT) [7,8]. In general,

∗ Corresponding author at: Department of Radiation Oncology, Korea University Medical Center, Anam Hospital, 73 Inchon-ro, Seongbuk-gu, Seoul 136-705, Republic of Korea. Tel.: +82 2 920 5516; fax: +82 2 927 1419. E-mail address: [email protected] (C.Y. Kim). 0720-048X/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejrad.2013.10.029

positive CRM was defined as a 60 years were 94.4% and 64.5%, respectively (P = 0.036). None of the other variables evaluated correlated significantly with LRFS, DMFS, DFS, or OS. In a multivariate analysis that used a stepwise backward selection procedure, predicted CRM after preoperative CRT remained a significant predictor of DFS (hazard ratio = 5.465; 95% confidence

interval, 1.060–28.190; P = 0.042) and OS (hazard ratio = 8.943; 95% confidence interval, 1.042–76.733; P = 0.046). A Cox proportional hazard model for LRFS was not feasible because the coefficients did not converge. 4. Discussion We assessed the results of preoperative CRT in patients who had locally advanced rectal cancer with CRM involvement, and evaluated whether negative conversion of CRM status correlated with survival outcomes. We found that the prognosis of patients who achieved a negative conversion of the predicted CRM status after preoperative CRT was better than that of patients who failed to achieve a negative conversion of the predicted CRM status. Presently, MRI is a highly accurate imaging modality for predicting the CRM status before and after preoperative CRT. A review of recently published studies shows that the specificity and sensitivity of MRI for predicting CRM status was 92–94% and 77–85%, respectively [12–14]. However, there is no standard criterion for predicted CRM involvement assessed by MRI. The definition of predicted CRM involvement varies from 0 mm to 5 mm, and the correlation between predicted CRM on MRI and pathologic CRM are still not fully understood [7,15–17]. Beets-Tan et al. concluded that a histological distance of at least 1 mm can be predicted with high confidence when the measured distance by MRI is at least 5 mm [7]. However, Taylor et al. have reported that predicted CRM involvement of more than 1 mm on MRI could be used to predict clear margins [17]. As mentioned in Section 1, several studies have suggested the correlation between MRI-based prediction of CRM status and survival outcomes in patients with rectal cancer. Martling

N.K. Lee et al. / European Journal of Radiology 83 (2014) 245–249

et al. reported that 5-year recurrence-free survival (70% vs. 38%; P = 0.016) and corresponding 5-year OS (77% vs. 43%; P = 0.012) were better in patients with negative CRM than in those with positive CRM predicted by MRI [9]. In a subgroup analysis of MERCURY trial, 73% of all patients were considered to have potential CRM involvement; this was reduced to 42% after treatment. They reported that prediction of CRM after preoperative CRT was significant for LR on multivariate analysis (hazard ratio of 4.25) and 5-year LR rates for patients with positive CRM after preoperative CRT was higher than those with negative CRM after preoperative CRT (28% vs. 12%; P = 0.013). Although these results were similar to those of the present study, direct comparison was not possible because patient selection was different from our study. Tumor response to preoperative CRT can be assessed by prognostic indicators such as histopathological tumor regression grade, tumor volume reduction rate, ypCR rate, or tumor downstaging. In this study, downstaging occurred in 78.9% of patients. Whereas 44.7% of patients had downclassified ypT, 89.5% had downclassified ypN and 76.3% were classified as having ypN0. Therefore, it seems logical to conclude that downstaging is mainly due to sterilization of lymph node metastasis. The ypCR rate in this study was 5.3%, lower than rates reported in previous studies [18–20]. The ypCR rates reported vary widely from 8% to 28%, presumably because the clinical tumor stages and predicted CRM status of the patients differ for each study. In addition, the T3 classification currently defined by the American Joint Committee on Cancer Staging Manual is ambiguous. Several studies have demonstrated a prognostic inhomogeneity according to the extent of mesorectal spread among T3 rectal cancers [21,22]. This study only included patients with cT4 or cT3 disease with predicted CRM involvement; therefore, a lower ypCR rate may be an obvious consequence. This study analyzed the clinical significance of the negative conversion of CRM status instead of pathologic CRM status. It may be argued that preoperative assessment of CRM status after CRT is of little benefit and have no bearing on treatment decision because patients with locally advanced rectal cancer will ultimately undergo resection following preoperative CRT, unless there is widespread distant metastatic disease, or in rare cases, highly locally advanced pelvic disease in which operation is obviously fruitless. However, from the results of our study, positive CRM following preoperative CRT indicates that the tumor is resistant to treatment and that the risk of recurrence is high, even if a clear resection margin is achieved after surgery. This study has some limitations. First, this is a retrospective study, and all retrospective studies have inherent limitations. Second, this study has a limitation stemming from its small sample size, which may weaken the statistical power. Third, the relatively short follow-up period may have caused an underestimation of true recurrence rates. In conclusion, this study is the first report that demonstrated the relevance of negative conversion of CRM status in predicting survival outcomes. The negative conversion of the predicted CRM status as predicted by MRI will assist in individual risk stratification as a predictive factor for treatment response and survival before surgery. These findings may help physicians determine whether to administer more intense adjuvant chemotherapy or change the surgical plan for patients displaying resistance to preoperative CRT. Conflict of interest None.

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