Phase II Trial of Preoperative High-dose-rate Endorectal Brachytherapy (BT) FOLFOX Chemotherapy for Stage II/III Rectal Cancer

Summary

Introduction and Rationale:

Over the past 30 years, major advances in adjuvant therapy and surgical techniques have markedly improved cure rates for patients with locoregionally advanced rectal cancer such that pelvic tumor control is over 90%. Preoperative chemoradiation consisting of 5 ½ weeks of external beam radiotherapy combined with radiosensitizing 5-fluorouracil followed by total mesorectal excision (TME) then adjuvant chemotherapy represents the current standard of care. Despite improved survival and locoregional control, disease-free survival have plateaued at rates of 70% because of the high incidence of distant metastasis in about 1/3 of patients.

Clearly, development of more effective systemic therapy approaches to eliminate micrometastatic disease are needed to further improve survival outcomes. The incorporation of oxaliplatin, combined with 5-fluorouracil (FOLFOX), as adjuvant treatment of resected stage II-III colon cancer has led to clinically and statistically significant improvements in disease-free and overall survival in colon cancer. In rectal cancer, FOLFOX has been used primarily after TME but with compliance rates of typically 70%.

One approach to address systemic disease and improve compliance is to treat patients with FOLFOX chemotherapy upfront prior to locoregional therapy. Moreover, incorporating an effective radiation regimen with lower incidence of short and long-term side effects may further enhance compliance to systemic therapy. External beam radiation therapy (EBRT) can increase side effects both acute and chronic toxicity by exposing normal tissue nearby the tumor such as the bladder, bowel, and sexual organs. An appealing technical alternative to EBRT is a brachytherapy (BT) approach using a rectal applicator placed intraluminally in direct contact with the tumor to deliver radiation while sparing adjacent normal organs and decreasing exposure to the pelvic bone marrow. A rectal brachytherapy approach treating over 300 patients has been reported by the McGill group showing equivalent pelvic control, higher pathologic complete response rates and lower short and long-term toxicity. The rectal brachytherapy regimen consists of 4 daily treatments over one week given without chemotherapy which significantly shortens treatment time and cost compared to a standard course of fractionated external beam pelvic radiotherapy. One concern of the rectal brachytherapy approach is that pelvic nodes typically covered in the external beam technique may result in suboptimal outcomes. However, careful patterns of failure studies from a large Dutch preoperative external beam randomized study have shown very low rates of isolated pelvic nodal relapse and minimal benefit of external beam radiotherapy to decrease such failure.