The standard approach for initial therapy of locally advanced rectal cancer (LARC) combines fluorouracil (5-FU)-based preoperative chemotherapy with radiotherapy; this treatment has been shown to reduce local recurrence rates (Gerard, et al. 2006). The use of chemoradiotherapy produces increased tumor shrinkage in comparison with radiotherapy alone. Because oxaliplatin demonstrably improves response in the treatment of patients with colon cancer and serves as an active radiosensitizing agent, there is interest in combining oxaliplatin to the 5-FU/radiotherapy regimen. The goal of therapy with oxaliplatin/5-FU and radiotherapy would be to decrease micrometastases at distant sites and produce primary tumor shrinkage before surgery (Aschele, et al. 2011). Previously published phase II data on oxaliplatin combined with capecitabine (an oral 5-FU prodrug) and concurrent radiation followed by surgery produced more favorable adherence with therapy but higher toxicities in the oxaliplatin arm (Fernandez-Martos, et al. 2010). Aschele and colleagues (2011) recently published the results of the STAR-01 randomized phase III trial which studied the effect of oxaliplatin added to the preoperative standard approach for patients with LARC.
- Patients (N= 747) with resectable, locally advanced (cP3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy) in 28 daily fractions combined with 5-FU infusion (225 mg/m2/d) either alone (control group, arm A) or combined with oxaliplatin (60 mg/m2 weekly for six weeks) (study group, arm B)
- Overall survival (OS) was the primary end point; a protocol-planned analysis of response to preoperative treatment was reported
- Grade 3-4 adverse events during the study therapy occurred more frequently in the patients receiving oxaliplatin/5-FU and radiation versus the 5-FU/radiation alone group (24% versus 8%, respectively; P < .001)
- Ninety-seven percent of patients in the control group received > 45 Gy versus 91% in the study arm (P< .001)
- The number of patients who underwent surgery was similar (96% v 95%; arm A versus arm B)
- The rate of pathologic complete responses was identical for both arms (16%) (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904)
- Twenty-six percent versus 29% of patients had positive lymph nodes (arm A versus arm B), with 46% versus 44% having tumor infiltration beyond the muscularis propria (P = .701)
- Intra-abdominal metastases were found at time of surgery in 2.9% (arm A) versus 0.5% of patients in arm B (P = .014)
The authors of the study concluded that the addition of oxaliplatin to the previous standard of care involving 5-FU-based preoperative chemoradiotherapy significantly increased toxicity without increasing primary tumor response. Toxicities included higher rates of diarrhea (15.3% versus 4.2%; P < .001), radiation dermatitis (4.5% versus 1.8%; P = .037), and asthenia (3.1% versus 0%). Fifty-three patients (15%) required a reduction of the oxaliplatin dose and 75% received at least 80% of the planned cumulative dose of the study drug. Adding oxaliplatin had no effect on primary tumor response.
The addition of oxaliplatin to the standard 5-FU/radiotherapy approach for LARC would seem to be a reasonable approach given the activity of oxaliplatin in the metastatic and adjuvant colorectal cancer setting. Therefore the negative results of the STAR-01 trial are surprising. The authors propose that oxaliplatin is not a clinically effective radiation sensitizer using the dose and schedule reported in the STAR-01 trial, despite the positive phase II data previously published by Fernandez-Martos and colleagues (2010). Subsequently reported data from the ACCORD trial demonstrate similar results and offered small benefits not reaching statistical significance (Aschele et al. 2011). The increased toxicity from the oxaliplatin/5-FU/radiotherapy combination is also problematic, particularly with grade 3-4 adverse events at 24%. There is a need for further study on the optimal approach to LARC and the potential role of novel therapies in this setting.
Aschele, C., Cionini, L., Lonardi, S., Pinto, C., Cordio, S., Rosati, G.,…Boni, L. (2011). Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: Pathologic results of the STAR-01 randomized phase III trial. Journal of Clinical Oncology, 29 (20), 2773-2780. doi:10.1200/JCO.2010.34.4911 Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed?term=aschele%2C%20cionini
Fernandez-Martos, C., Pericay, C., Aparicio, J., Salud, A., Safont, M.J., Massuti, B.,…Alonso, V. (2010). Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo Cancer de Recto 3 Study. Journal of Clinical Oncology, 28 (5), 859-865. doi:10.1200/JCO.2009.25.8541 Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed?term=fernandez-martos%2C%20pericay%2C%20aparicio
Gerard, J.P., Conroy, T., Bonnetain, F., Bouche, O., Chapet, O., Closon-Dejardin, M.T.,…Bedenne, L. (2006). Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T 3-4 rectal cancers: Results of FFCD 9203. Journal of Clinical Oncology, 24 (28), 4620-4625. doi:10.1200/JCO.2006.06.7629. Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/17008704