Selection of appropriate end-points (pCR vs 2yDFS) for tailoring treatments with prediction models in locally advanced rectal cancer.

PURPOSE: Personalized treatments based on predictions for patient outcome require early characterization of a rectal cancer patient's sensitivity to treatment. This study has two aims: (1) identify the main patterns of recurrence and response to the treatments (2) evaluate pathologic complete response (pCR) and two-year disease-free survival (2yDFS) for overall survival (OS) and their potential to be relevant intermediate endpoints to predict. METHODS: Pooled and treatment subgroup analyses were performed on five large European rectal cancer trials (2795 patients), who all received long-course radiotherapy with or without concomitant and/or adjuvant chemotherapy. The ratio of distant metastasis (DM) and local recurrence (LR) rates was used to identify patient characteristics that increase the risk of recurrences. FINDINGS: The DM/LR ratio decreased to a plateau in the first 2 years, revealing it to be a critical follow-up period. According to the patterns of recurrences, three patient groups were identified: 5-15% had pCR and were disease free after 2 years (excellent prognosis), 65-75% had no pCR but were disease free (good prognosis) and 15-30% had neither pCR nor 2yDFS (poor prognosis). INTERPRETATION: Compared with pCR, 2yDFS is a stronger predictor of OS. To adapt treatment most efficiently, accurate prediction models should be developed for pCR to select patients for organ preservation and for 2yDFS to select patients for more intensified treatment strategies.

Role of radiotherapy with surgery for T3 and resectable T4 rectal cancer: evidence from randomized trials.

PURPOSE: The main treatment for resectable rectal cancer T2-T4 N0-N2 M0 is surgery. The benefit of preoperative or postoperative radiation therapy can be analyzed in terms of improvement of local control, sphincter preservation, and survival weighted against increased toxicity. METHODS: Only randomized trials can provide strong evidence of a positive cost-benefit ratio of such combined approach. The most recent trials were reviewed. RESULTS: Three randomized trials, including the latest German CAO-ARO trial, have demonstrated the superiority of preoperative radiotherapy with or without chemotherapy (vs. postoperative) in terms of local control and toxicity. The Ducth TME trial showed that even with modern standard surgery, preoperative radiotherapy improved local control. Preoperative irradiation using a high dose in a small volume and a long interval before surgery may improve sphincter preservation (Lyon trials). Concurrent chemoradiation (FFCD 9203, EORTC 22921, did not significantly improve sphincter preservation or survival but significantly reduced the local recurrence rate. CONCLUSIONS: In 2005 examination of randomized trials provides evidence for the benefit of preoperative chemoradiation in improving local control and probably sphincter preservation in rectal cancer. Randomized trials should be designed to further demonstrate improved sphincter preservation and to increase survival using adjuvant medical treatments.