Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

Federica Papaccio, Susana Roselló, Marisol Huerta, Valentina Gambardella, Noelia Tarazona, Tania Fleitas, Desamparados Roda, Andres Cervantes, Federica Papaccio, Susana Roselló, Marisol Huerta, Valentina Gambardella, Noelia Tarazona, Tania Fleitas, Desamparados Roda, Andres Cervantes

Abstract

Most clinical practice guidelines recommend a selective approach for rectal cancer after clinical staging. In low-risk patients, upfront surgery may be an appropriate option. However, in patients with MRI-defined high-risk features such as extramural vascular invasion, multiple nodal involvement or T4 and/or tumors close to or invading the mesorectal fascia, a more intensive preoperative approach is recommended, which may include neoadjuvant or preoperative chemotherapy. The potential benefits include better compliance than postoperative chemotherapy, a higher pathological complete remission rate, which facilitates a non-surgical approach, and earlier treatment of micrometastatic disease with improved disease-free survival compared to standard preoperative chemoradiation or short-course radiation. Two recently reported phase III randomized trials, RAPIDO and PRODIGE 23, show that adding neoadjuvant chemotherapy to either standard short-course radiation or standard long-course chemoradiation in locally advanced rectal cancer patients reduces the risk of metastasis and significantly prolongs disease-related treatment failure and disease-free survival. This review discusses these potentially practice-changing trials and how they may affect our current understanding of treating locally advanced rectal cancers.

Keywords: high-risk locally advanced rectal cancer; total neoadjuvant treatment; watch and wait strategy.

Conflict of interest statement

A.C. declares institutional research funding from Genentech, Merck Serono, BMS, MSD, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Natera, Astellas and Fibrogen and its advisory board and speaker fees from Merck Serono, Roche, Servier, Takeda and Astellas during the last five years.

Figures

Figure 1
Figure 1
Evolution of rectal cancer treatment in the last decades. Randomized phase III trials that have improved outcomes are shown in red, and diagnostic tools and surgical/non-surgical approaches established with observational studies are in bold. TME: total mesorectal excision; SCRT: short-course radiotherapy; CRT: chemoradiotherapy; MRI: magnetic resonance imaging.
Figure 2
Figure 2
MRI from patients showing locally advanced rectal cancer with high-risk features. (A) Upper third rectal cancer with peritoneal reflection invasion (cT4a). (B) Same patient showing extra-mural vascular invasion. (C) Lower third rectal cancer in a male with invasion of the anterior part of the mesorectal fascia (cT3d) and multiple large size peritumoral lymph nodes (N2) (D).
Figure 3
Figure 3
Comparison of RAPIDO and PRODIGE 23 trial designs. MRI: magnetic resonance imaging; EMVI: extra-mural vascular invasion; lat LN+: lateral lymph nodes involved; DrTF: disease-related treatment failure; MRF: mesorectal fascia; DFS: disease-free survival; CRT: chemoradiotherapy; TME: total mesorectal excision; SCRT: short-course radiotherapy.
Figure 4
Figure 4
(A) Flow chart for assessment, selection and implementation of a watch and wait strategy. (B) Follow-up time table during watch and wait strategy. TNT: total neoadjuvant treatment; CRT: chemoradiotherapy; DRE: digital rectal examination; MRI: magnetic resonance imaging; cCR: clinical complete response; Mo: months. * colonoscopy is to be performed one year after diagnosis and thereafter as per guidelines.

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