Surgical Outcomes in Total Neoadjuvant Therapy for Rectal Cancer versus Standard Long Course Chemoradiation

Abstract

Objective: This systematic review and meta-analysis seeks to evaluate the impact of total neoadjuvant therapy (TNT) for rectal cancers on surgical complications and surgical pathology when compared to standard long course chemoradiotherapy (LCRT). Background: The oncological benefits of TNT are well published in previous meta-analyses, but there is little synthesized information on how it affects surgical outcomes. A recent study has suggested an increase in local recurrence and higher rates of breached total mesorectal excision (TME) plane in TNT patients. Methods: This study conformed to the PRISMA guidelines. A search was performed in Medline (via PubMed), Cochrane databases, EMBASE and CINAHL to identify relevant randomized controlled trials (RCTs) comparing outcomes between TNT and LCRT. Meta-analyses of pooled proportions between TNT and LCRT were performed, comparing primary outcomes of surgical mortality, morbidity and all reported complications; surgical-pathology differences, namely mesorectal quality, R0 resection rates, circumferential resection margin (CRM) positive rates and sphincter preservation rates. Death and progression of disease during neoadjuvant treatment period was also compared. Risk of bias of RCTs was performed using the Cochrane risk-of-bias tool by 2 independent reviewers. Results: A total of 3185 patients with rectal cancer from 11 RCTs were included in the analysis: 1607 received TNT and 1578 received LCRT, of which 1422 (TNT arm) and 1391 (LCRT arm) underwent surgical resection with curative intent. There was no significant difference in mortality (RR 0.86, 95% CI 0.13 – 5.52, P=0.88, I2=52%)) or major complications (RR 1.04, 95% CI 0.86-1.26, P=0.70, I2=0%) between TNT and LCRT. There was a significantly higher risk of breached TME in TNT group on pooled analysis (RR 1.49, 95% CI 1.03-12.16, P=0.03, I2=0%), and on subgroup analysis there is higher risk of breached TME in those receiving extended duration of neoadjuvant treatment (>17 wk from start of treatment to surgery) when compared to LCRT (RR 1.61, 95% CI 1.06-2.44, P=0.03). No difference in R0 resection rates (RR 0.85, 95% CI 0.66-1.10, P=0.21, I2=15%), CRM positive rates (RR 0.87, 95% CI 0.65-1.16, P=0.35, I2=10%) or sphincter preservation rates (RR 1.02, 95% CI 0.83-1.25, P=0.88, I2=57%) were observed. There was a significantly lower risk of progression of disease to an unresectable stage during the neoadjuvant treatment period in TNT patients (RR 0.60, 95% CI 0.39-0.92, P=0.03, I2=18%). On subgroup analysis it appears to favour those receiving extended duration of neoadjuvant treatment (RR 0.44, 95% CI 0.26-0.80, P=0.002), and those receiving induction-type chemotherapy in TNT (RR 0.25, 95% CI 0.07-0.88, P=0.03). Conclusion: TNT increases rates of breached TME which can contribute to higher local recurrence rates. TNT, however, improves systemic control by reducing early progression of disease during neoadjuvant treatment period. Further research is warranted to identify patients that will benefit from this strategy.

Methyltransferase DNMT3B promotes colorectal cancer cell proliferation by inhibiting PLCG2

“…Colorectal cancer (CRC) is the third most common and deadly tumor type worldwide, although great progress has been made in CRC treatment over the past few years [1]. While there have been some advancements in early diagnosis rates, the current surgical and chemoradiotherapy treatments are not optimal [2]. This is attributed to the pathological stage, invasion, and metastasis of colorectal cancer cells, which compromise the effectiveness of the treatment [3].…”

Non-operative management of rectal cancer: Highlighting the controversies

“…Patients with locally advanced rectal cancers should be treated upfront with neoadjuvant chemoradiation therapy to help downstage the tumor and clear lateral lymph node involvement. As neoadjuvant treatments evolved to include the new concept of total neoadjuvant therapy (TNT)[ 2 ], an increasing number of patients were found to exhibit complete response to neoadjuvant therapy with no residual tumor cells in the rectum or the lymph nodes after radical resection, known as pathologic complete response. The complete response of rectal cancers to neoadjuvant treatment inspired one of the colorectal surgery leaders, Dr Angelita Habr-Gama, the concept of non-operative management (NOM) of rectal cancer in patients with a complete response to treatment.…”