February’s Paper of the Month is a systematic review and meta-analysis aiming to further investigate the uncertainty behind the outcomes of neoadjuvant chemotherapy compared to straight to surgery for T4 colon cancers.

Neoadjuvant therapy versus direct to surgery for T4 colon cancer: meta-analysis
Jung F, Lee M et al.
British Journal of Surgery, Volume 109, Issue 1, January 2022, pages 30–36

What is known about this subject?

The traditional approach to colon cancer involves surgical resection with the aim of a clear resection margin followed by adjuvant chemotherapy if certain high-risk pathological features are present. Neoadjuvant chemotherapy (NAC) has an established role in many solid tumours but its use in colon cancer has remained unclear. The FOxTROT study aimed to investigate the use of NAC in T3/T4 colon cancers. The trial found that rates of incomplete resection were halved following NAC and an improved 2-year disease control, but this was not statistically significant. In this meta-analysis by Jung et al. the authors seek to further investigate the uncertainty behind the outcomes of NAC compared to straight to surgery for T4 colon cancers.


Systematic review and meta-analysis

Study eligibility

Studies comparing one neoadjuvant therapy to straight to surgery or a second neoadjuvant therapy for T4 colon cancer.

Studies only evaluating earlier-stage (T1-T3), metastatic, or recurrent colonic cancer were excluded.

Notably, the authors excluded abstracts. However, they chose to make an exception for the phase III study abstract by the FOxTROT Collaborative Group which reported preliminary results from this study. They performed a supplementary analysis based on this data

Search Strategy

The authors searched 5 electronic databases up to 11th February 2020 including: MEDLINE (OVID); Embase (OVID); the Cochrane Central Register of Controlled Trials (CENTRALWeb of Science (Clarivate); and CINAHL; EbscoHost)


Primary – rate of R0 resection margin, major and minor 30-day morbidity, overall survival and cancer recurrence

Secondary – treatment associated adverse effects


  • The search found 11 846 unique citations of which 110 underwent full text review
  • 4 studies were included in the data synthesis (one RCT and 3 retrospective cohort studies) comprising of 43,063 patients
  • Neoadjuvant therapies included FOLFOX, 5-FU + leucovorin or radiotherapy
  • Neoadjuvant therapy was associated with an increased R0 rate compared with straight to surgery, (pooled OR 2.60, 95% CI 1.12 to 6.02)
  • Neoadjuvant treatment saw improved 3-year overall survival (pooled HR 1.92, [1.04 to 3.53]) and 5-year overall survival (pooled HR 1.42, [1.10 to 1.82])
  • 30-day rates of minor and major adverse events were no different between neoadjuvant treatment and straight to surgery
  • When data were added from the phase III abstract data of the FOxTROT trial neoadjuvant treatment was associated with decreased cancer recurrence
  • Due to the small number of studies a sensitivity analyses, subgroup analysis, and meta-regressions could not be performed.

Implications for colorectal practice?

This paper has found that neoadjuvant therapy improved the rate of complete resection and overall compared with a straight to surgery approach. This suggests that neoadjuvant treatment may help to control advanced tumours prior to surgery. However, we still do not know whether this approach might alter the extent of surgical resection required, or indeed the need for a multivisceral resection. This study is limited by the heterogeneity of neoadjuvant regimes and the small number of studies included with only one RCT. The inclusion of FOxTROT data adds strength to the findings. Importantly, the work of the FOxTROT collaborative group is ongoing with plans to investigate different neoadjuvant regimes the aim of a personalised approach to neoadjuvant treatment.