Long-Term Outcome of Patients with Complete Pathologic Response after Neoadjuvant Chemoradiation for cT3 Rectal Cancer: Implications for Local Excision Surgical Strategies

All consecutive patients treated by neoadjuvant CRT and surgery for cT3 rectal cancer between January 1996 and September 2008 were identified from our institutional, prospectively maintained rectal cancer database. Patients with synchronous distant metastasis were excluded from the study. All patients had biopsy-proven adenocarcinoma of the rectum. The distance of the tumor from the anal verge was measured by rigid rectoscopy. Pre- and post-CRT primary tumor and nodal staging were evaluated by endorectal ultrasound and/or pelvic magnetic resonance imaging. Lymph nodes ≥ 5 mm in size were considered positive. In cases with discrepancy between the two imaging techniques the higher stage was considered. Distant metastasis was excluded by thoracoabdominal and pelvic computed tomographic scan.

A total of 188 consecutive patients with rectal adenocarcinoma treated by neoadjuvant CRT followed by surgery with TME (LAR and APR) or LE at our institution between January 1996 and September 2008 were identified. Initially considered for this study were 150 cT3 rectal cancer patients. Of these, 11 were excluded because they had synchronous distant metastasis, leaving a total of 139 patients for analysis. Complete pathologic response in the primary tumor was observed in 42 patients (30%).

In the present study, we evaluated the oncologic outcome of consecutive patients with cT3 low and mid rectal cancer with ypCR after neoadjuvant CRT, treated and prospectively followed up at a single institution during a 12-year period. At pathologic examination of the surgical specimen, ypCR was observed in 30.2% of the cases. In an updated analysis on a total of 4,732 rectal cancer patients treated by preoperative CRT in 81 prospective arms from phase II and III trials, Sanghera et al.6 have recently reported a ypCR rate of 14.8%, varying from 0 to 43% in the different arms. In their study, factors associated with ypCR were the use of two drugs, c.i. 5-FU administration, and RT dose of > 45 Gy. These findings could account for the relatively high ypCR rate observed by us because 71% of our patients received 50.4 Gy; in addition, c.i. 5-FU and two drugs regimens were provided to a large number of our patients.

Our retrospective survival analysis indicates that patients with ypCR have statistically significantly better oncologic outcomes than those without ypCR, and that in patients with ypCR, the risk of developing local recurrence and distant metastasis during follow-up is considerably lower, with 5-year DMFS and LRFS of 92.5 and 94.9%, respectively. Our results are consistent with data reported by others. Maas et al.7 in a recent pooled analysis of data from 3,105 locally advanced rectal cancer cases treated by preoperative CRT, reported that ypCR disease (n = 484) had significantly better results, with 5-year DFS and LRFS of 83.3 and 97.2%, respectively. De Campos-Lobato et al.10 have recently reported that in a series of 238 locally advanced rectal cancer cases treated by preoperative CRT during a 10-year period, 5-year OS, DFS, and LRFS were 92.7, 92.4, and 100%, respectively, in the 58 ypCR patients. Rödel et al.12 evaluated pathologic tumor response on surgical specimens of 385 locally advanced rectal cancer patients treated within the preoperative CRT arm of the CAO/ARO/AIO-94 trial and found that ypCR was an independent prognostic factor for local and distant metastasis. Capirci et al.9 in an outcome analysis on a pool of 566 patients with locally advanced rectal cancer and ypCR after preoperative RT with or without chemotherapy, reported 5-year rates of OS, DSS, and DFS of 90, 94, and 85%, respectively, with a local recurrence rate of 1.6%. Other studies have observed better long-term outcome in patients with primary tumor downstaging (ypT0–2 vs. ypT3–4).11 ^, 38 On the basis of this evidence, it has been postulated that tumoral ypCR achievement might be indicative of a prognostically favorable biological tumor profile with less propensity for local or distant recurrence and improved survival.7 Alternatively, significantly lower local recurrence rate and distant metastasis rate in the subset of tumors displaying ypCR might be explained by a higher sensitivity to both radiation and chemotherapy.

In our study, when comparing pre-CRT lymph node staging and lymph node pathologic status, a trend association was observed between ypCR achievement and mesorectal lymph node downstaging. Moreover, we found metastatic lymph nodes in 12% of patients with ypCR compared to 29% in patients with no ypCR. Notably, all our three patients with ypCR and metastatic mesorectal lymph nodes were staged as having cN-positive disease before CRT. Our data are similar to the figures reported by Hughes et al.15 in a study of 143 patients in which the incidence rate of metastatic mesorectal lymph nodes was 17% in the 23 patients with ypCR versus 35% in patients with no ypCR. However, other authors have reported lower incidence rates of metastatic mesorectal lymph nodes in patients with ypCR. In a study by Coco et al.13 of 272 rectal cancer patients, the rate of positive nodes in ypCR cases was 1.8%, while it ranged between 24.1 and 52.0% in no-ypCR patients. Pucciarelli et al.17 in a study of 235 patients reported positive nodes rate of 2% in ypT0 cases versus 38% in ypT3 cases. Read et al.39 in 644 patients treated by preoperative RT or CRT, reported metastatic lymph nodes in 1 (2%) of 42 ypT0 patients and in 158 (36%) of 602 ypT1–4 patients. Similarly, Guillem et al.40 in a series of 188 cT3N rectal cancers treated by CRT and TME, found that metastatic mesorectal lymph nodes incidence increased from 3% in ypT0 to 36% in ypT3–4.

In our study, subset survival analysis in patients with ypCR demonstrated no outcome differences in the group of patients treated by LE compared to patients treated by TME. In the 17 ypCR patients treated by LE, 5-year DSS, DMFS, and LRFS were 100, 87.4, and 92.9%, respectively. These findings confirm previous data reported by Bonnen et al.23 from M. D. Anderson Cancer Center, who found no 5-year OS, DFS, and LRFS differences in cT3 rectal cancer patients comparing 26 patients treated by LE (ypCR = 54%) with 169 patients treated by TME (ypCR = 22%). Callender et al., from the same institution, have recently compared outcomes in a larger cohort of patients and reevaluated the original patients after longer follow-up: 47 patients underwent LE (ypCR = 49%) and 473 patients underwent TME (ypCR = 23%). There was no statistically significant difference between the 10-year actuarial local recurrence rate for the LE group versus the TME group (10.6 and 7.6%, respectively), and no significant difference in OS, DSS, and DFS between groups.19 Kundel et al.16 in 320 locally advanced rectal cancers, compared ypCR patients who had LE (n = 14) with those who underwent TME (n = 37). With a median follow-up of 48 months, no patients in LE group experienced recurrence, versus 4 in TME group, while OS, DFS, and LRFS were similar in both groups. Guerrieri et al.20 reported that in 61 cT3 rectal cancer treated by CRT and transanal endoscopic microsurgery, long-term local and distant metastasis failure probability were both 0% in 9 ypCR patients, compared to 5 and 4% in no-ypCR patients. Nair et al.21 in 44 cT2–3 rectal cancers treated by CRT and LE reported that local recurrence and distant metastasis rates were both 4% in the 25 ypCR patients, compared to both 16% in no-ypCR patients. Finally, Habr-Gama et al.27 reported long-term outcome results of their experience comparing operative and nonoperative treatment in 265 patients with rectal adenocarcinoma (mostly cT3) treated by CRT. Patients with incomplete clinical response were referred to TME surgery. Patients with incomplete clinical response treated by surgery resulting in ypCR were compared to patients with complete clinical response treated by nonoperative treatment. Five-year OS and DFS were 88 and 83%, respectively, in the resection group and 100 and 92% in the observation group.

In conclusion, within the limitations of retrospective analysis, our data confirm the existing evidence indicating that patients with ypCR rectal cancer after preoperative CRT have a favorable long-term outcome, with a low risk of local recurrence and distant metastasis regardless of the type of surgical treatment. Such patients appear to be good candidates for organ-preserving strategies to be explored in clinical studies. On the other hand, the poor outcome of no-ypCR patients treated by LE strongly indicates that conservative surgical treatment should be avoided in this subset of patients. In parallel, new functional imaging modalities and molecular factors that are predictive of response to treatment should be investigated because they might be used to select the best treatment and to develop strategies aimed at enhancing the effectiveness of CRT.