Total neoadjuvant therapy

Data support giving all radiation therapy and chemotherapy neoadjuvantly.

The RAPIDO trial (NCT01558921) randomly assigned 920 patients to receive either short-course radiation therapy followed by six cycles of CAPOX (capecitabine and oxaliplatin) or nine cycles of FOLFOX (LV, 5-FU, and oxaliplatin) followed by surgery, or long-course chemoradiation therapy followed by surgery with the option to add adjuvant chemotherapy. The primary end point was 3-year disease-related treatment failure (defined as first occurrence of locoregional failure, distant metastasis, new primary colorectal tumor, or treatment-related death). The 3-year disease-related treatment failure rate was 23.7% (95% CI, 19.8%–27.6%) in the short-course radiation therapy group and 30.4% (95% CI, 26.1%–34.6%) in the long-course chemoradiation therapy group (hazard ratio [HR], 0.75; 95% CI, 0.60–0.95; P = .019).[35][Level of evidence B1]

In the randomized, phase III, French UNICANCER-PRODIGE 23 study (NCT01804790), 461 patients were randomly assigned to receive either six cycles of FOLFIRINOX (LV, 5-FU, irinotecan, and oxaliplatin) followed by chemoradiation therapy (experimental group) or chemoradiation therapy (standard-of-care group). Patients in both groups underwent total mesorectal excision. This was not fully a total neoadjuvant therapy trial as both groups also received adjuvant chemotherapy with modified FOLFOX or capecitabine for 3 months (experimental group) or 6 months (standard-of-care group). The 3-year DFS rate was 76% (95% CI, 69%–81%) in the experimental group and 69% (95% CI, 62%–74%) in the standard-of-care group (stratified HR, 0.69; 95% CI, 0.49–0.97; P = .034).[36][Level of evidence B1]

The total neoadjuvant approach was studied in clinical trials because data showed that many patients do not receive all of the recommended chemotherapy when given after surgery. For example, in the OPRA trial (NCT02008656), which used a total neoadjuvant therapy approach, approximately 85% of patients received all of the recommended chemotherapy, an improvement in adherence over trials that used adjuvant chemotherapy. Another potential benefit of this approach is that it allows more patients to receive nonoperative management (also known as the watch-and-wait approach), which is described in more detail below. This approach may interest patients who would otherwise require an abdominoperineal resection, which results in the need for lifelong stoma.[37,38][Level of evidence B1]

Select patients with locally advanced rectal cancer may omit radiation therapy if they receive escalated chemotherapy, but they would still need a total mesorectal excision. In the PROSPECT trial (NCT01515787), 1,194 patients were randomly assigned to receive either neoadjuvant FOLFOX chemotherapy (with chemoradiation therapy only given if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) or standard neoadjuvant chemoradiation therapy. All patients then underwent surgery and had the option to receive adjuvant FOLFOX (four or six cycles for the neoadjuvant chemotherapy group and eight cycles for the neoadjuvant chemoradiation therapy group). The study population included patients with T2, node-positive; T3, N0; or T3, node-positive disease who were eligible for sphincter-sparing surgery (thus, excluding most patients with low-rectal tumors). This study found that the omission of radiation therapy was possible in select patients without compromising oncologic outcomes based on a noninferiority study design. It should be noted that in Europe, many patients with T3, N0 disease do not undergo any neoadjuvant therapy prior to resection. Omission of radiation is beneficial for patients desiring to preserve fertility.[39]

Total neoadjuvant therapy is currently the preferred approach for most patients with locally advanced rectal cancer without distant metastases.