[16]. Alternative approaches are required to optimize delivery. Total neoadjuvant therapy (TNT) has emerged as an attractive alternative strategy—systemic chemotherapy given before nCRT (i.e. induction chemotherapy) or after it (consolidation chemotherapy) in the preoperative setting.
Potential Advantages of TNT
1 Targeting of subclinical micrometastases: Early administration of full‐dose systemic chemotherapy has the potential of eradicating occult micrometastases, reducing distant disease failure, and prolonging long‐term survival.
2 Assessment of tumor biology: TNT provides an opportunity to evaluate the innate biomolecular profile of the tumor. Disease progression during full‐dose systemic chemotherapy suggests aggressive tumor biology. Patients with unfavorable treatment‐resistant disease may receive little or no benefit from subsequent resection.
3 Increased tumor downstaging: Additional full‐dose systemic chemotherapy may improve resectability by inducing tumor downsizing. This may be related to the direct effects of the chemotherapy and/or indirectly due to the prolonged interval to resection. Patients who experience marked tumor regression may become suitable for less radical or sphincter‐preserving surgery, although this is controversial. As a general principle, adjacent structures directly invaded by the tumor (including sphincters) should be considered for en‐bloc resection unless sure they are not involved. Deviation from the initial planned surgical approach requires excellent imaging, endoscopy, and multidisciplinary input in addition to judicious intraoperative decision‐making.
4 Increased pathological complete response (pCR): A pCR represents a strong positive prognostic indicator, associated with improved local control and disease‐specific survival [17].
5 Potential for organ preservation: The clinical implication of improved tumor regression is the selective practice of surgery and potential for non‐operative management. An expectant “watch and wait” approach may be appropriate in patients who demonstrate a good response to neoadjuvant therapy.
6 Superior compliance: Surgical morbidity and postoperative complications may limit compliance to adjuvant chemotherapy. Delivery in the preoperative period may improve compliance by avoiding such limitations.
Potential Disadvantages of TNT
1 Disease progression: Delay to definitive surgery may allow local disease progression, resulting in more technically challenging resection and increased perioperative morbidity, or even unresectability. However, progression on full‐dose chemotherapy indicates an unfavorable disease profile that suggests disease course and outcome would not be altered by surgery.
2 Negative effect on performance status: Full‐dose systemic chemotherapy may negatively impact fitness, thereby delaying or preventing surgery. Reduced physiological reserve due to treatment‐related toxicity could increase the risk of perioperative morbidity (or even mortality). In practice this should not be the case with reasonable assessment of performance status, comprehensive geriatric assessment, adequate organ function parameters, and general well‐being [18]. It is better to wait for full recovery than to compromise outcome for timing.
Short‐Term Outcomes
Pathological Response
Neoadjuvant therapy has the potential to eradicate tumors entirely. A pCR, defined as an absence of tumor cells in the resected specimen, represents an important predictor of favorable oncological outcome [15, 19]. In a meta‐analysis of 16 studies involving 3363 patients with LARC treated with nCRT, those who achieved a pCR had less local recurrence (odds ratio [OR] 0.25, 95% CI 0.10–0.59, p = 0.002) and better five‐year DFS (OR 4.33, 95% CI 2.31–8.09, p < 0.001) [17].
Pathological outcomes following TNT are limited, available data are conflicting, and whether TNT improves pCR rates is unclear. Furthermore, pCR rates are influenced by interval to surgery as radiation‐induced tumor necrosis is time‐dependent. Several large series and meta‐analyses have demonstrated increased pCR rates with intervals of > 6–8 weeks following completion of nCRT [20–22]. The GRECCAR6 phase III multicenter randomized control trial of 265 patients found no significant difference in pCR rates after an interval of 7 weeks compared to 11 weeks between nCRT and surgery, with standard practice now an interval of 8–10 weeks [23]. Whether pathological response observed with TNT is due to the direct effect of chemotherapy or prolonged interval to surgery or both is unclear.
The CONTRE (Complete Neoadjuvant Treatment for Rectal Cancer) study reported a pCR rate of 33% following eight cycles of induction‐modified FOLFOX6 [24]. Surgery was performed 6–10 weeks following completion of nCRT. Another North American study reported a rate of up to 38%, with the longest regimen (six cycles of induction FOLFOX with an interval of up to 19 weeks) but only 18% in patients treated with standard nCRT [25]. Interestingly, the Spanish GCR‐3 phase II trial reported no significant difference in pCR rate between induction capecitabine plus oxaliplatin (CAPOX) and conventional nCRT (14.3 vs. 13.5%) [26]. In this study, the interval to surgery was considerably shorter (five to six weeks). A large registry‐based study of 36 268 patients with clinical stage II or III disease, 3421 of whom received induction chemotherapy, also reported no difference in pCR rates between the TNT and conventional groups [27]. These registry‐based data must be interpreted with caution as exact chemotherapeutic regimens are unknown. Furthermore, selection criteria for TNT were unavailable, and thus a significant proportion of the TNT group may have included patients with advanced disease with unfavorable biology (cT4, significant nodal burden, threatened mesorectal margin).
In a systematic review of 10 prospective studies involving 648 patients treated with TNT, the overall pCR rate was 21.8% (range 10–40%) [28]. In the 10 comparative studies included, the overall pCR rate following TNT was 19% and TNT increased the odds of pCR by 39% (OR 1.39, 95% CI 1.08–1.81, p = 0.01). Similar findings were reported in a meta‐analysis of 28 studies (retrospective and prospective) of 3579 patients receiving TNT (n = 2688) or conventional nCRT (n = 891) [29]. The pooled pCR rate with TNT was 22.4% (95% CI 19.4–25.7, p < 0.001). Interpretation and application of these data are difficult and hampered by the heterogeneity of systemic agents used, timing of chemotherapy, and interval to surgery.
The Dutch–Swedish RAPIDO trial compared three‐year DFS following short‐course radiotherapy (5×5 Gy), full‐dose preoperative CAPOX and interval TME, with conventional nCRT, TME, and selective adjuvant chemotherapy (CAPOX or FOLFOX) [30]. The RAPIDO trial found that, compared to traditional neoadjuvant CRT and surgery, short‐course radiotherapy followed by neoadjuvant chemotherapy prior to surgery reduced distant metastatic events at three years (20% vs. 26.8%). It increased pCR from 14% to 28%, with a putative survival advantage, but without altering quality of life or overall surgical morbidity. The PRODIGE 23 trial, another prospective randomized trial examining TNT, compared induction triplet neoadjuvant chemotherapy (six cycles of modified FOLFIRINOX; 5‐FU, leucovorin, irinotecan, and oxaliplatin) followed by neoadjuvant CRT, surgery, and a further three months of chemotherapy (either FOLFOX or capecitabine) with conventional nCRT, surgery, and six months of adjuvant chemotherapy [31]. It found pCR improved from 11.7% to 27.5% and three‐year metastasis‐free survival from 71.7% to 78.8% with TNT over the control arm. Metastatic disease on restaging prior to surgery was also lower with TNT (1% vs. 4.7%).
Long‐Term Oncological Outcomes
The key clinical question is whether delivery of up‐front full‐dose systemic chemotherapy and increased compliance improves disease‐specific outcomes. Long‐term survival data following TNT are lacking and predominantly limited to small case series. A systematic review of oncological outcomes following TNT, including seven prospective studies reporting five‐year survival data, found similar long‐term survival outcomes when compared with standard nCR. The overall weighted mean five‐year OS and DFS were 74.4 and 65.4% respectively. Comparative analysis of seven studies by Petrelli et al., however, demonstrated that patients who received TNT had better DFS (HR 0.75, 95% CI 0.52–1.07,