Total Neoadjuvant Therapy Versus Standard Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer

Overview

The National Comprehensive Cancer Network (NCCN) guidelines recommend trimodality treatment for patients with middle and low LARC with neoadjuvant chemoradiotherapy (NA-CRT), surgical resection with TME, plus additional chemotherapy (CT), in the adjuvant setting. This has markedly reduced pelvic local recurrence from historically about 25% to about 5-10%. However, the 5-year distant relapse is approximately 30% and continues to be the major cause of rectal cancer death. One strategy to address this issue is to deliver induction chemotherapy before surgery. Induction chemotherapy may be associated with better treatment compliance and may enable full systemic doses of chemotherapy to be delivered. The above cited considerations, plus favorable data from preliminary reports exploring this strategy, provides a solid rationale for shifting systemic treatment earlier into the treatment paradigm. The current study will evaluate the efficacy and the safety of total neoadjuvant therapy with standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer patients as regards effects on tumor downstaging, pathological complete response, surgical difficulty and early functional outcome.

Colorectal cancer is the third most commonly diagnosed cancer and the third leading cause of cancer death in men and women in the USA. Surgery using the total mesorectal excision (TME) remains the cornerstone of curative therapy for patients with nonmetastatic, locally advanced middle and low rectal cancer (LARC). The National Comprehensive Cancer Network (NCCN) guidelines recommend trimodality treatment for patients with middle and low LARC with neoadjuvant chemoradiotherapy (NA-CRT), surgical resection with TME, plus additional chemotherapy (CT), in the adjuvant setting. This has markedly reduced pelvic local recurrence from historically about 25% to about 5-10%. However, the 5-year distant relapse is approximately 30% and continues to be the major cause of rectal cancer death. Several other trials have attempted to demonstrate the benefits of postoperative chemotherapy as an adjunct to preoperative radiation and surgery. These trials either failed to demonstrate an advantage, or were closed early due to poor accrual. One common theme among these trials is poor compliance with adjuvant chemotherapy. Completion rates for planned chemotherapy ranged from 43 to 74% in these trials. The current rectal cancer treatment might lead to delay in the initiation of adjuvant chemotherapy especially in patients with postoperative complications, and this delay is theoretically disadvantageous in that it allows a window for growth of distant micrometastases which may already exist. One strategy to address this issue is to deliver induction chemotherapy before surgery. Induction chemotherapy may be associated with better treatment compliance and may enable full systemic doses of chemotherapy to be delivered. Other theoretical advantage of induction chemotherapy includes the possibility of shrinking or downstaging a locally advanced tumor, thereby facilitating more effective local treatment. Initial chemotherapy also permits delivery of chemotherapy agents directly to the primary tumor while it has a fully intact vasculature, undisrupted by radiation or surgery. It was supposed that increased chemoradiation-to-surgery interval would result in increased fibrosis and surgical difficulty.However, previous studies showed no increase in the technical difficulty of the operation with total neoadjuvant therapy. The above cited considerations, plus favorable data from preliminary reports exploring this strategy, provides a solid rationale for shifting systemic treatment earlier into the treatment paradigm. The current study will evaluate the efficacy and the safety of total neoadjuvant therapy with standard neoadjuvant chemoradiotherapy for locally advanced rectal cancer patients as regards effects on tumor downstaging, pathological complete response, surgical difficulty and early functional outcome.