Impact of time duration after neoadjuvant therapy to surgery on response and outcome in rectal cancer patients.

Until the 1970s and 1980s, surgery was often the only therapy used in the treatment of patients with rectal cancer. However, analyses of patterns of failure demonstrated that pelvic recurrence after surgery was common, resulting in significant patient morbidity and death. To reduce these high failure rates, cooperative group studies from the USA evaluated different strategies of postoperative radiation therapy and 5-fluorouracil (5-FU)-based chemotherapy. These study results showed that adjuvant radiation therapy and chemotherapy improved local control and survival versus surgery alone, leading to the routine integration of these modalities into daily practice in the USA. To address the potential merits of preversus postoperative therapy, neoadjuvant trials have been pursued in rectal cancer patients. The CAO/ARO/ AIO-94 trial from Germany directly compared preto postoperative approaches. This landmark study demonstrated that by simply altering the sequence of radiation therapy and chemotherapy with respect to surgery, there were improved rates of compliance, local control, sphincter preservation, and reduction in acute and late toxicities with preoperative radiation therapy and chemotherapy. In the preoperative therapy arm, patients received 50.4 Gy in 28 fractions over 5.5 weeks with concurrent 5-FU, followed by surgery 6 weeks later. Significant tumor downstaging was observed after preoperative combined modality treatment, leading to an 8% complete pathologic response rate. These findings led to a new standard of care for the treatment of rectal cancer in the USA. Modifications of this neoadjuvant approach have been investigated in an effort to increase the percentage of responders. Recent European trials have further evaluated the role of concurrent 5-FU-based chemotherapy with radiation therapy in the neoadjuvant treatment of rectal cancer. Trial results from the European Organization for Research and Treatment of Cancer (EORTC), Federation Francophone de la Cancerologie Digestive (FFCD), and Poland indicated improved complete pathologic response rates of 11.7–16% and local control for patients treated with concurrent 5-FU and radiation therapy versus radiation therapy alone. In these trials, patients received 45–50.4 Gy in 25–28 fractions over 5–6 weeks with concurrent 5-FU-based chemotherapy, followed by surgery performed 3–10 weeks after completion of neoadjuvant therapy. Other studies have shown the impact of radiation dose escalation on the rate of pathological complete response to neoadjuvant therapy. In a review of 134 patients at Princess Margaret Hospital who received 40, 46 or 50 Gy in 2-Gy fractions with continuous-infusion 5-FU, the pathological complete response was 18%, 23%, and 33% for the three dose levels, respectively. The 2-year actuarial local relapse-free survival was 72%, 90%, and 89%; disease-free survival was 62%, 84%, and 78% and overall survival was 72%, 94%, and 92% for the 40, 46, and 50 Gy levels, respectively. Patients receiving doses of 46 or 50 Gy had improved outcomes compared with patients receiving 40 Gy, but there was no significant difference between 46 or 50 Gy. In contemporary therapy, patients routinely receive 50 Gy of external beam irradiation with chemotherapy. Improved disease-free and overall survival rates have been observed with the addition of newer chemotherapeutic agents (oxaliplatin, irinotecan) to Published online July 29, 2008. Address correspondence and reprint requests to: Christopher G. Willett, MD; E-mail: christopher.willett@duke.edu