phase II trial, better disease‐specific survival was observed with consolidation chemotherapy (two, four, or six cycles of modified FOLFOX) compared with conventional nCRT [32]. After a median follow‐up of 59 months, five‐year DFS was 81% following consolidation chemotherapy compared to 50% with nCRT (p = 0.0005). There were no significant differences in survival among the experimental arms. Notably, the primary endpoint of this trial was pCR and it was not adequately powered to show differences in survival. Similarly, a North American multicenter retrospective analysis of 110 patients with cT3/4 N0–2 disease treated with short‐course radiotherapy also observed improved DFS with consolidation FOLFOX [33]. DFS at three years was 85% compared with 68% among patients treated with standard nCRT and adjuvant chemotherapy (p = 0.032). A single‐arm Chinese study of 96 patients with cT3/4 or node‐positive disease treated with consolidation XELOX (capecitabine and oxaliplatin) also reported comparable five‐year DFS of 83% [34]. Interestingly, the Polish phase III randomized trial of 515 patients with cT4 or fixed cT3 reported no significant difference in DFS between those receiving short‐course radiotherapy with three cycles of consolidation FOLFOX4 compared to traditional CRT [35]. DFS at eight years was 43 vs. 41% respectively.
The most meaningful potential advantage of early full‐dose chemotherapy is targeting subclinical micrometastases and reducing distant disease failure. In a systematic review of ten prospective studies, the overall weighted mean distant recurrence rate was 20.6% (range 5–31%). Eight studies reported distant failure rates consistent with the standard treatment paradigm (19–31%). The remaining two studies reported significantly lower rates [36, 37]. This discrepancy may be related to the shorter length of follow‐up because of differences in clinical stage, compliance, and/or the use of adjuvant therapy. It will be interesting to see if the three‐year metastasis‐free survival benefit seen in RAPIDO and PRODIGE 23 is maintained with prolonged follow‐up.
Organ Preservation
In addition to event‐free survival and local control outcomes, preservation of bowel function and quality of life continue to represent significant challenges in the management of LARC. The prevalence of low anterior resection syndrome (LARS) is 60–90% following low or ultra‐low sphincter‐sparing surgery for rectal cancer [38]. The syndrome is associated with a significant and sustained reduction in quality of life [39, 40]. A potential advantage of improved tumor regression and downstaging with TNT is the selective practice of non‐operative management and avoidance of a stoma. A multinational experience (1009 patients) of conventional nCRT and a “watch and wait” approach found two‐year local tumor regrowth was 25% [41].
A retrospective single‐center analysis of 628 patients with LARC observed more complete responders at one year with TNT compared with conventional nCRT and adjuvant chemotherapy [42]. This was the subject of a recently presented multicenter, randomized, phase II trial assessing if TNT increases the proportion of patients managed with organ preservation. Patients were randomized to induction or consolidation FOLFOX (before or after long‐course chemoradiation), followed by restaging with magnetic resonance imaging (MRI)/endoscopy 8–12 weeks later. Incomplete responders proceeded to TME, while complete clinical responders were managed non‐operatively [43]. Three‐year disease‐ and metastasis‐free survival rates were similar in the OPRA (organ preservation of rectal adenocarcinoma) trial arms, but the rate of organ preservation was improved by consolidation (58%) rather than induction (43%) chemotherapy.
In patients with early disease (cT1–2N0), the standard of care currently is surgery without neoadjuvant therapy. Systemic therapy with curative intent may be an alternative to surgery if long‐term disease‐specific outcomes were comparable. Those who achieve a clinical complete response (cCR) may be eligible for organ preservation, with salvage surgery reserved for cases of locoregional recurrence. A retrospective analysis of 81 patients with cT2N0 disease reported an increased likelihood of a cCR and avoidance of definitive surgery at five years with consolidation chemotherapy (six cycles of 5‐FU) with high‐dose radiotherapy (54 Gy) compared with standard nCRT (67 vs. 30%; p = 0.001) [44].
Chemotherapy and Compliance
Chemotherapy for LARC has traditionally been fluoropyrimidine‐based. In the postoperative (adjuvant) setting, oxaliplatin improves progression‐free and disease‐free survival in colonic cancer [7]. The role of oxaliplatin in neoadjuvant treatment has been debated. Apart from the German CAO/ARO/AIO‐04 trial [45], several trials and meta‐analyses have failed to demonstrate a survival advantage with oxaliplatin added to radiosensitizing fluoropyrimidine nCRT [46–50].Furthermore, oxaliplatin was associated with significant toxicity including neurotoxicity and increased risk of infection. For TNT, the optimum regimen is unknown (e.g. capecitabine alone, CAPOX, or FOLFOX). Toxicity of treatment regimens is a concern, and poor compliance could be a major challenge if patients do not complete the intended dose‐intensity. Encouragingly, several trials evaluating induction and/or consolidation chemotherapy reported favorable compliance rates of over 90% with toxicity profiles comparable to those of standard nCRT [36, 51, 52]. In the Spanish GCR‐3 study, 91% of patients completed the study protocol in the induction chemotherapy arm compared with 54% in the nCRT/adjuvant chemotherapy arm (p <0.001) [53]. Garcia‐Aguilar et al. reported compliance rates of 77–82% depending on the number of cycles of mFOLFOX given [25]. The two most recent phase 3 TNT trials (RAPIDO and PRODIGE 23) clearly demonstrate that it is safe and efficacious to incorporate oxaliplatin into neoadjuvant chemotherapy regimens. Neither trial included oxaliplatin during radiotherapy.
Novel Chemotherapeutic Agents
Integration of targeted agents in the treatment of LARC has been the focus of several modern early phase trials [54]. Preclinical studies have demonstrated that vascular endothelial growth factor (VEGF) blockade in combination with standard chemoradiotherapy enhances tumor regression. VEGF blockade induces alterations to the vasculature of the tumor microenvironment, increasing tumor perfusion and oxygenation and improving intratumoral drug delivery [55]. A meta‐analysis reported a pooled pCR rate of 27% with neoadjuvant therapy including bevacizumab [56]. A small single‐institution prospective phase II trial evaluating induction FOLFOX with bevacizumab followed by radiotherapy reported favorable pathological, toxicity, and survival outcomes [57]. Forty‐three patients with clinical stage II–III low rectal adenocarcinoma and MRI‐defined high‐risk features (cT4, cN2, predicted positive lateral nodal involvement, threatened circumferential resection margin [CRM]) were included. The pCR rate was 37.2% and three‐year DFS was 86%. Irinotecan has no adjuvant role in colon cancer and can have significant toxicities including colitis and sepsis. It has been successfully incorporated into neoadjuvant, adjuvant, and palliative chemotherapy for pancreatic cancer in the FOLFIRINOX regimen [58]. Several French trials use it as the backbone of a TNT approach in rectal cancer, but there is hesitancy to adopt it elsewhere.
The Italian TRUST trial also observed favorable results with induction FOLFOXIRI (5‐FU, leucovorin, irinotecan, and oxaliplatin) and bevacizumab plus nCRT [59]. This phase II single‐arm study of 49 patients with predicted node‐positive or clinical T3/4 disease reported a pCR rate of 36% and two‐year DFS of 80%. The GEMCAD 1402 trial randomized patients to induction mFOLFOX with or without aflibercept (VEGF inhibitor) [60]. In per protocol analysis, a pCR was achieved in 25.2% of the experimental arm and 14.5% of the control group (p = 0.10). In the EXPERT‐C trial, patients with MRI‐defined high‐risk disease were randomized to induction CAPOX with cetuximab (epidermal growth factor receptor [EGFR] inhibitor) or CAPOX alone, followed by standard nCRT [61]. In this study, however, no significant difference in the primary endpoint of pCR was observed among groups. Capecitabine and cetuximab are no longer combined in routine practice as there is unacceptable synergistic skin toxicity. Although the addition of targeted agents has yielded some positive oncological outcomes, concerns exist surrounding their safety profile and associated toxicity. The AVACROSS phase II single‐arm study evaluating induction XELOX with bevacizumab reported a high postoperative complication rate (58%), with 24% of patients requiring surgical reintervention [62]. No agent has emerged as superior to oral or intravenous 5‐FU as a radiosensitizer. In colon cancer there has been no therapy added to systemic adjuvant therapy