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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.