Neoadjuvant-intensified treatment for rectal cancer: time to change?

Abstract

Aim: To investigate whether neoadjuvant-intensified radiochemotherapy improved overall and disease-free survival in patients with locally advanced rectal cancer.

Methods: Between January 2007 and December 2011, 80 patients with histologically confirmed rectal adenocarcinoma were enrolled. Tumors were clinically classified as either T3 or T4 and by the N stage based on the presence or absence of positive regional lymph nodes. Patients received intensified combined modality treatment, consisting of neoadjuvant radiation therapy (50.4-54.0 Gy) and infusional chemotherapy (oxaliplatin 50 mg/m(2)) on the first day of each week, plus five daily continuous infusions of fluorouracil (200 mg/m(2) per die) from the first day of radiation therapy until radiotherapy completion. Patients received five or six cycles of oxaliplatin based on performance status, clinical lymph node involvement, and potential risk of a non-sphincter-conserving surgical procedure. Surgery was planned 7 to 9 wk after the end of radiochemotherapy treatment; adjuvant chemotherapy treatment was left to the oncologist's discretion and was recommended in patients with positive lymph nodes. After treatment, all patients were monitored every three months for the first year and every six months for the subsequent years.

Results: Of the 80 patients enrolled, 75 patients completed the programmed neoadjuvant radiochemotherapy treatment. All patients received the radiotherapy prescribed total dose; five patients suspended chemotherapy indefinitely because of chemotherapy-related toxicity. At least five cycles of oxaliplatin were administered to 73 patients. Treatment was well tolerated with high compliance and a good level of toxicity. Most of the acute toxic effects observed were classified as grades 1-2. Proctitis grade 2 was the most common symptom (63.75%) and the earliest manifestation of acute toxicity. Acute toxicity grades 3-4 was reported in 30% of patients and grade 3 or 4 diarrhoea reported in just three patients (3.75%). Seventy-seven patients underwent surgery; low anterior resection was performed in 52 patients, Miles' surgery in 11 patients and total mesorectal excision in nine patients. Fifty patients showed tumor downsizing ≥ 50% pathological downstaging in 88.00% of tumors. Out of 75 patients surviving surgery, 67 patients (89.33%) had some form of downstaging after preoperative treatment. A pathological complete response was achieved in 23.75% of patients and a nearly pathologic complete response (stage ypT1ypN0) in six patients. An involvement of the radial margin was never present. During surgery, intra-abdominal metastases were found in only one patient (1.25%). Initially, 45 patients required an abdominoperineal resection due to a tumor distal margin ≤ 5 cm from the anal verge. Of these patients, only seven of them underwent Miles' surgery and sphincter preservation was guaranteed in 84.50% of patients in this subgroup. Fourteen patients received postoperative chemotherapy. In the full analysis of enrolled cohort, eight of the 80 patients died, with seven deaths related to rectal cancer and one to unrelated causes. Local recurrences were observed in seven patients (8.75%) and distant metastases in 17 cases (21.25%). The five-year rate of overall survival rate was 90.91%. Using a median follow-up time of 28.5 mo, the cumulative incidence of local recurrences was 8.75%, and the overall survival and disease-free survival rates were 90.00% and 70.00%, respectively.

Conclusion: The results of this study suggest oxaliplatin chemotherapy has a beneficial effect on overall survival, likely due to an increase in local tumor control.

Keywords: Fluorouracil; Intensified radiochemotherapy; Neoadjuvant treatment; Oxaliplatin; Rectal cancer.

Figure 1

Neoadjuvant-intensified treatment protocol. Patients received 50.4 Gy (solid arrows) or 54.0 Gy (dashed arrows) of radiation therapy (RT), 28 d (solid arrows) or 30 d [dashed arrows of fluorouracil (5-FU) and five (solid arrows) or six (dashed arrow)] weekly cycles of oxaliplatin dependent on performance status, clinical lymph node involvement, and potential risk of a non-sphincter-conserving surgical procedure. Radiation therapy was delivered with a 3-D-conformational multiple field technique at a daily dose of 1.8 Gy/fraction. All patients received a central venous access (port-a-cath) for delivering chemotherapy. Chemotherapy consisted of a 2-h oxaliplatin infusion (50 mg/m²) on the first day of each week of radiotherapy, and five daily continuous infusions of 5-FU (200 mg/m²).

Figure 2

Absolute permanence (white column), overall survival (grey column), and disease-free survival (black column) comparisons. Patient data was stratified by year and is represented as a percentage of the total cohort of patients.