Neoadjuvant therapy versus direct to surgery for T4 colon cancer

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.
https://doi.org/10.1093/bjs/znab382
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.

Design

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)

Outcomes

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

Secondary – treatment associated adverse effects

Results

  • 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.

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Lifestyle factors and complications after surgery for colorectal cancer

December’s Paper of the Month’ aimed to assess associations between modifiable preoperative lifestyle factors and postoperative complications in patients undergoing elective surgery for colorectal cancer.

The Association Between Modifiable Lifestyle Factors and Postoperative Complications of Elective Surgery in Patients with Colorectal Cancer
doi: 10.1097/DCR.0000000000001976
Diseases of the Colon & Rectum: November 2021 – Volume 64 – Issue 11 – p 1342-1353

What is known about this subject?

The use of ‘prehabilitation’ is gaining traction as a means to preoperatively increase a patient’s functional capacity before elective colorectal cancer surgery. The aim of this intervention is to reduce postoperative morbidity and accelerate postsurgical recovery. Through prehabilitation, modifiable risk factors for an individual patient are addressed. These factors may include smoking status, nutrition, alcohol consumption and physical exercise.

Design

Retrospective analysis of data from a prospectively maintained database. The study was undertaken as part of the Colorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that influence colorectal tumour recurrence, survival and quality of life” (COLON) study

Population

Patients with newly diagnosed colorectal cancer undergoing elective surgery at 11 Dutch hospitals from August 2010 and December 2018

Those who had a history of previous CRC, other bowel resection, chronic IBD, a hereditary CRC syndrome, dementia, undergoing transanal surgery or hyperthermic intraperitoneal chemotherapy were excluded.

Methods and outcomes

Patients completed self-administered questionnaires shortly after diagnosis regarding their smoking status, alcohol consumption, BMI and physical activity.

Data on postoperative outcomes were collected from the Dutch Colorectal Audit.

The authors used multivariable logistic regression to identify which preoperative lifestyle factors were associated with postoperative complications.

Primary outcome

Occurrence of postoperative complications after elective CRC surgery. Complications were recorded up to 30 days (pre-2018) or 90 days (post-2018).

Secondary outcome

The secondary outcome was length of stay.

Results

  • 1564 patients were studied (68.9% colon cancer, 31.1% rectal cancer)
  • 87.2% were classified as ASA I or II
  • 446 patients (28.5%) experienced 1 or more postoperative complication.
  • Complication increased length of stay (12 vs 5 days, p < 0.001)
  • Current smoking (vs never smoking) was associated with postoperative complications (OR, 1.62; 95% CI, 1.02–2.56; p = 0.04)
  • BMI, alcohol consumption, and physical activity were not independently associated with postoperative complications in general
  • Among ASA class III to IV physical activity >1000 min/wk was independently associated with a reduced risk of postoperative complications (OR, 0.17; 95% CI, 0.03–0.87; p = 0.04) compared with <150 min/wk

Implications for colorectal practice?

This paper highlights the effect of smoking status on the risk of postoperative complication in elective CRC surgery. This finding serves to reinforce the need to encourage smoking cessation among newly diagnosed CRC patient. Interestingly, despite the authors hypothesis other factors such as increasing BMI and alcohol consumption showed no association.

The study was observational and did not measure the effect of modifying these named risk factors on patient outcome. It must also be acknowledged that risk factors were self-reported by patients and are reliant on the accuracy of this.

Given the results, it would be interesting to measure the effect of preoperative smoking cessation in this cohort, particularly when factoring the pressures of cancer waiting targets.

Early detection of anastomotic leakage after colorectal resection

October’s Paper of the Month is a multicentric, prospective study looking at detection one of the most feared complications of colorectal surgery: anastomotic leakage.

Diagnostic accuracy of C-reactive protein, procalcitonin and neutrophils for the early detection of anastomotic leakage after colorectal resection: a multicentric, prospective study. DOI: 10.1111/codi.15845. Colorectal Disease 2021;00:1–8.

What is known about this subject?

Anastomotic leak (AL) is one of the most feared complications of colorectal surgery. The consequences of AL include chronic sepsis, permanent stoma, delays in oncological treatment alongside substantial healthcare costs. Early diagnosis of AL can limit such sequelae and may reduce its associated morbidity and mortality. Therefore, the potential to identify patients with AL, through use of a biomarker, could be of significant value to the treating clinician. Biomarkers of interest include C-reactive protein (CRP), neutrophils and procalcitonin

Design

Observational, prospective, multicentre cohort study

Population

  • Consecutive patients ≥18yrs undergoing elective or emergency surgery requiring colonic or rectal resection with a single anastomosis without a stoma.
  • Patients receiving intraoperative intra-peritoneal chemotherapy were excluded.

Method and outcomes

  • All participants were tested for CRP, procalcitonin and neutrophil levels on the 4th postoperative day.
  • AL was defined as occurring up to 60 days postoperatively diagnosed either radiologically or clinically.
  • The authors used receiver operating characteristic curves to analyse the reliability of each biomarker as a predictor for AL. They used the area under the curve (AUC) and Youdens statistic (a statistic that captures the performance of a dichotomous diagnostic test) to determine the cut-off of each biomarker at 90% sensitivity.

Primary outcome

Reliability of CRP, procalcitonin and neutrophils to predict AL on the 4th postoperative day

Secondary outcomes

  • To determine the cut-off for each biomarker to detect the presence of AL
  • To determine whether combining these biomarkers offered additional accuracy in the detection of AL
  • To assess whether surgical access (open vs laparoscopic) affected the reliability of these biomarkers in detecting AL

Results

  • Data from 2501 patients was analysed across 34 centres.
  • The anastomotic leak rate was 8.6% (n=216)
  • 60 day morbidity and mortality were 30.1% and 1.6% respectively.
  • CRP was found to be the most reliable biomarker with an AUC of 0.84.
  • Procalcitonin and neutrophils had an AUC of 0.75 and 0.64 respectively.
  • All 3 biomarkers saw their AUC increase when patients undergoing laparoscopic surgery were analysed.
  • A CRP cut-off of 119.5mg/L had a sensitivity of 70%, a specificity of 81%, a negative predictive value of 97% and a positive predictive value of 26% for AL
  • The minimum cut-off for CRP for a sensitivity of 90% was 66.5mg/L
  • Regression modelling showed that combining all 3 biomarkers did not increase diagnostic accuracy.

Implications for colorectal practice?

This paper reports the largest prospective multicentre study examining the accuracy of 3 biomarkers for predicting AL. The data suggest that interpretation of CRP measurement on the 4th postoperative day may be the optimal timing for this. Specifically, a level of 119.5mg/L in this cohort had a high negative predictive value of 97% (the probability that individuals with a CRP <119.5mg/L don’t have AL). The authors argue that this CRP threshold may help guide the safe discharge of patients. Furthermore, additional investigation may be prompted if such levels are exceed, perhaps with the benefit of identifying AL earlier in the clinical course. All blood indices should be interpreted within the clinical context.

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