Clinical Investigation
Prognostic Value of Pathologic Complete Response After Neoadjuvant Therapy in Locally Advanced Rectal Cancer: Long-Term Analysis of 566 ypCR Patients

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Purpose

In the literature, a favorable prognosis was observed for complete pathologic response after preoperative therapy (ypCR) in patients with locally advanced rectal cancer. The aim of this study is to verify whether ypCR predicts a favorable outcome in a large series of patients.

Methods and Materials

The Gastro-Intestinal Working Group of the Italian Association of Radiation Oncology collected clinical data for 566 patients with ypCR (ypT0N0) after neoadjuvant therapy. Eligibility criteria included locally advanced rectal cancer with no evidence of metastases at the time of diagnosis, evidence of ypCR after preoperative radiotherapy ± chemotherapy (CT).

Results

Median radiation dose was 50 Gy. A total of 527 patients (93%) received one of 12 different neoadjuvant CT schedules. Sphincter preservation, anteroposterior resection, and endoscopic surgery were performed in 73%, 22%, and 5% of patients, respectively. Adjuvant CT was administered to 22% of patients. Median follow-up was 46.4 months. Locoregional recurrence occurred in 7 patients (1.6%). Distant metastases occurred in 49 patients (8.9%). Overall, 5-year rates of disease-free survival, overall survival, and cancer-specific survival were 85%, 90%, and 94%, respectively. In multivariate analysis, only age and clinical stage statistically correlated with survival outcome. Adjuvant CT was still of borderline significance (worse for adjuvant CT). No relation was found between survival and neoadjuvant CT schedules.

Conclusion

A ypCR after neoadjuvant therapy identified a favorable group of patients, even in this large series of 566 patients collected in 61 centers. Locoregional recurrence occurred only in 1.6% patients.

Introduction

Recent European randomized trials of patients with locally advanced rectal cancer (RC) showed a lower risk of local recurrence when neoadjuvant 5-fluorouracil (5-FU)–based chemoradiation (CRT) was compared with neoadjuvant radiotherapy (RT) alone 1, 2 or postoperative CRT 3, 4. Moreover, a significant greater rate of complete pathologic response after preoperative therapy (ypCR), defined as the complete absence of intact tumor cells in the resected specimen, was observed in the preoperative CRT arms of these studies. However, this did not translate into improvements in disease-free (DFS) or overall survival (OS). Conversely, several nonrandomized studies suggested that ypCR was associated with improvement in DFS 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19. The attempt to attribute prognostic value to ypCR is subject to multiple confounding factors related to interstudy variability 20, 21. In a recent systematic review, Hartley et al.(22) collected information for 3,157 patients enrolled in seven randomized trials and 45 Phase II trials. A total of 428 patients had a documented ypCR, resulting in a 13.5% ypCR rate; no survival information was referred to this group. To date, the prognostic value of ypCR after neoadjuvant therapy for patients with locally advanced RC remains uncertain.

Some recent reports addressed the role of local excision in patients who achieved a complete response in the primary tumor, opening the question of whether it is safe to perform organ preservation if ypCR is observed 23, 24, 25.

A survey was proposed by the Gastro-Intestinal Working Group of the Italian Association of Radiation Oncology (AIRO-GI) to Italian centers that treated patients preoperatively, aimed to explore whether patients who achieve ypCR represent a favorable population within patients with RC.

Section snippets

Eligibility

Eligibility criteria included locally advanced RC with no evidence of metastases at the time of diagnosis; evidence of ypCR response, defined as no viable tumor cells at both the T and N levels; any combination of neoadjuvant treatment, at least including RT; any surgical procedure; and adequate information for treatment and subsequent outcome. A group of 30 patients assigned ypT0 and no clinical evidence of lymph node metastases treated by local excision, either as a result of patient choice

Patients and clinical tumor characteristic

A total of 566 patients who received neoadjuvant RT ± concomitant CT from 1990–2004 were analyzed. Median follow-up was 45.6 months. The man-woman ratio was 1.9. Mean and median ages for all patients were 61.8 ± 10.1 (SD) and 63 years, respectively (range, 26–85 years). Median ages of 372 male and 194 female patients were 62 and 61 years, respectively. Clinical staging showed 6% UICC Stage I, 44% Stage II, and 45% Stage III. The UICC stage was unknown in 5% of patients (Table 2).

Treatment plan

The RT dose

Discussion

In the European randomized trials of neoadjuvant CRT, the rate of ypCR ranged from 11–16% 1, 2, 3 and was significantly greater than that for neoadjuvant RT alone. More recently, some Phase IIb randomized studies showed ypCR rates ranging from 24–36% 26, 27, 28, 29, 30, 31. In the European randomized studies, achievement of a greater ypCR rate did not translate into better survival for patients undergoing neoadjuvant CRT. A correlation between ypCR after neoadjuvant CRT or RT alone and clinical

Conclusion

This retrospective study includes a very large number of patients achieving ypCR after neoadjuvant treatment for RC. This favorable group of patients had a very low risk of PR and a favorable clinical outcome independent of the neoadjuvant CT schedule used. In such a group of patients, use of postoperative CT could be very debatable.

Conversely, the subset of patients older than 60 years, those with cStage III, and patients who received radiation dose of 45 Gy or less experienced a relatively

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    • Cited by (0)

    Other Italian centers and AIRO investigators: Arezzo: P. Ponticelli, R. Bagnoli; Belluno: T. Jannone; Bologna: H. Bellaria, O. Martelli, G.P. Frezza; Bologna, S. Orsola Hospital: S. Neri; Cuneo: A. Melano; Ivrea: P. Sciacero, G.F. Girelli; L'Aquila University: V. Tombolini; Lecco: F. Placa; Mestre: G.B. Pizzi; Milano National Tumor Institute: F. Valvo; Modena: A.M. Falchi; Monza: G.S. Gardani, R.M. Niespolo; Pisa University: A. Sainato; Roma Catholic University of the Sacred Heart: A. Crucitti, G.B. Doglietto; S. Giovanni Rotondo: S. Parisi; Taranto: G. Silvano, A.R. Marsella; Terni: E. Maranzano, F. Trippa; Torino University: U. Ricardi; Trento: G. Pani, S. Mussari; Udine: G. Chiaulon; Vicenza: G. Bolzicco; Viterbo: M.E. Rosetto.

    Conflict of interest: none.

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