Original Study
Disease Control, Survival, and Toxicity Outcome After Intensified Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: A Single-Institution Experience

https://doi.org/10.1016/j.clcc.2016.02.006Get rights and content

Abstract

Purpose

To report the long-term follow-up data and determine the toxicity rate concerning patients with locally advanced rectal cancer (LARC) treated with an intensified neoadjuvant treatment regimen.

Patients and Methods

Patients with histologically proven stage II to III adenocarcinoma of the rectum were included and treated with a trimodal approach. Intensified neoadjuvant treatment (chemoradiotherapy [CRT]) consisted of radiotherapy (total dose 50.4/54 Gy) and concomitant oxaliplatin (50 mg/m2/week) and 5-fluorouracil (200 mg/m2/5 daily continuous infusion). Surgery was planned 7 to 9 weeks after the end of CRT. Adjuvant chemotherapy was recommended in those patients with lymph node metastasis at diagnosis.

Results

One hundred patients (median age, 64 years) were eligible. Overall, the 5-year overall survival and disease-free survival (DFS) were 76.4% and 74.5%, respectively. CRT was well tolerated, with only 17% grade 3/4 acute toxicity. Twenty-four patients (24%) had a pathologic complete response (pCR), and only 1 patient had perioperative metastasis. The 5-year DFS were 95.7% and 66.7% for pCR and no-pCR tumor histology, respectively (P = .0275).

Conclusion

Although oxaliplatin is not considered to be a standard treatment, the high 5-year rate of overall survival and DFS, the low severe toxicity rates, and the effective benefit on pCR and perioperative metastasis support an intensified treatment regimen for LARC.

Introduction

Rectal cancer comprises approximately 2.4% of all human malignancies. More than 39,000 new cases of rectum cancer are estimated to have occurred in 2015 in the United States, and when combined with colon cancer, 132,700 individuals will be diagnosed, resulting in 49,700 deaths.1

In the past 40 years, survival rates have improved, and today in locally advanced rectal cancer (LARC) the standard of care is a trimodal approach combining surgery, radiotherapy (RT), and chemotherapy.2 Frequent distant metastasis (30-40%) in this patient population has stimulated researchers to test more effective systemic cytotoxic therapy that could be provided in a neoadjuvant setting.3

Historically, 5-fluorouracil (5-FU) has represented the main radiation sensitizer, resulting in a pathologic complete response (pCR) rate of 5% to 20%, but it is not effective on distant metastasis.4 Thus, the goal of further research was to intensify the therapy at the primary tumor site, regional pelvic lymph nodes, and distant sites while minimizing the treatment and limiting toxic adverse effects.

There are several large phase 3 studies, including ACCORD 12/0405, CAO/ARO/AIO-04, NSABP R-04, and STAR-01, that have been completed and have evaluated the role of oxaliplatin (OXP) as novel radiation-sensitizing agent.5, 6, 7, 8 These trials showed more grade 3/4 toxicity when adding OXP to 5-FU concomitant treatment, but no significant difference was observed in surgical complications or the incidence of postoperative death within 60 days.9 The best result was the large (1236 patients) German CAO/ARO/AIO-04 randomized trial, which convincingly showed an improved pCR rate, from 13% to 17% (P = .038), at the cost of higher grade 3/4 toxicity (23% vs. 20%).6 Generally this significant effect on pCR was modestly confirmed in the meta-analysis of these studies (odds ratio, 1.20; 95% confidence interval [CI], 1.01-142; P = .04). Moreover, the OXP-5-FU regimen reduced the incidence of perioperative metastasis, supporting the hypothesis that it could improve systemic control.9 But long-term results are currently maturing, and thus whether OXP in addition to 5-FU can improve treatment outcome and patient survival remains unknown.

While waiting for longer follow-up data from these trials, we here present our intensified neoadjuvant setting experience with OXP used as a radiosensitizer in addition to standard 5-FU in patients with LARC. The aim of the study was to report the toxicity rate, oncologic outcomes, and main prognostic factors that could influence treatment response and survival by adding OXP to a standard chemoradiotherapy (CRT) regimen.

Section snippets

Patient Selection

Patients originated from the Department of Radiotherapy, Policlinico Umberto I, “Sapienza” University of Rome. The investigational protocol was reviewed and approved by the institutional review board and the scientific review committee. Written informed consent was obtained from all patients before the initiation of therapy. All patients underwent complete physical examination, transrectal ultrasound, and total-body contrast-enhanced computed tomography (CT). Magnetic resonance imaging (MRI) of

Patient Characteristics

Between January 2007 and December 2014, a total of 100 patients received intensified neoadjuvant CRT. Table 1 lists the demographics of the study population, which included 67 men (67%) and 33 women (33%). Ages ranged from 38 to 76 years, with a median of 64 years. Most patients (n = 81, 81%) had regional lymph node involvement at diagnosis.

Treatment Compliance

Overall, 92 patients (92%) completed the programmed CRT. All patients received the RT prescribed total dose. RT was interrupted for a mean period of 8 days

Discussion

The intensification regimen with OXP resulted in excellent disease control rates and long-term survival in this patients population. We demonstrated impressive 5-year OS and DFS (76.4% and 74.5%, respectively). The combination of OXP and 5-FU was associated with a high pCR rate (24%) and a low incidence of perioperative metastasis (1%) without a substantial increase in adverse effects (17% of grade 3/4 acute toxicity).

Rödel et al6 also supported these findings in a phase 3 randomized study,

Conclusion

The combination of OXP and 5-FU is an intensive but tolerable treatment regimen. It resulted in excellent OS and DFS rates and had a valid effect on pCR and perioperative metastasis.

Disclosure

The authors have stated that they have no conflict of interest.

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