Effect of time interval between Neoadjuvant Chemoradiation and Esophagectomy surgery on pathological complete response of patients with Esophageal Cancer

Technical Summary: Effect of Time Interval between Neoadjuvant Chemoradiation and Esophagectomy on Pathological Complete Response

Problem Statement
Esophageal cancer remains a malignancy with a poor prognosis, where 5-year survival rates have seen minimal improvement despite the widespread adoption of trimodality therapy (neoadjuvant chemoradiation [nCRT] followed by esophagectomy). A critical unresolved clinical question is the optimal timing for surgery following the completion of nCRT. While a longer interval might theoretically allow for full tumor regression maturation, leading to a higher Pathological Complete Response (pCR)—defined as the absence of viable tumor cells in the resection specimen—the evidence regarding the correlation between the "Time to Surgery" (TTS) and pCR is conflicting. Some literature suggests extended intervals improve pCR, while others indicate no benefit or even increased surgical risks. This study aims to clarify whether delaying surgery enhances pCR rates in esophageal cancer patients.

Methodology
This was a retrospective cohort study conducted at the Tehran Cancer Institute involving 147 patients with esophageal cancer treated between 2016 and 2022.

• Population: Patients with definitive diagnoses of esophageal squamous cell carcinoma (ESCC) or adenocarcinoma (EAC) involving the trunk and distal esophagus, who underwent nCRT followed by esophagectomy at least 28 days post-nCRT. Patients with metastasis, gastric involvement, or those requiring emergency/salvage surgery were excluded.
• Data Collection: Demographic and clinical variables (age, sex, tumor stage, histology, operative time, hospitalization duration) were extracted from medical records. pCR was determined using the AJCC 8th edition TNM staging system (T0N0M0).
• Statistical Analysis: Patients were stratified by TTS into three interval classifications:
  1. 4–8 weeks, 9–12 weeks, and >12 weeks.
  2. ≤8 weeks vs. >8 weeks.
  3. ≤12 weeks vs. >12 weeks.
     Logistic regression was used to analyze the relationship between TTS and pCR, adjusting for confounders such as age, sex, tumor type, and stage. Subgroup analysis was performed specifically for ESCC patients due to their high prevalence in the cohort.

Key Results

• Overall Cohort: The overall pCR rate was 49.6% (73 out of 147 patients).

  • Demographics: No significant association was found between pCR and gender, age, operative time, hospitalization duration, or tumor stage. Tumor type (SCC vs. Adenocarcinoma) showed a significant difference, with SCC patients having a higher pCR rate (53.8%) compared to Adenocarcinoma (17.6%).
  • Time to Surgery (TTS): A consistent directional trend was observed where longer intervals correlated with higher pCR rates.
    • In the 4–8 week vs. >12 weeks comparison, the 4–8 week group had an Odds Ratio (OR) of 0.43 (CI: 0.20–0.97) for achieving pCR, with a P-value of 0.064 (marginally non-significant).
    • In the ≤8 weeks vs. >8 weeks comparison, the shorter interval group had an OR of 0.56 (P=0.098).
    • In the ≤12 weeks vs. >12 weeks comparison, the shorter interval group had an OR of 0.55 (P=0.101).
  • Conclusion: Despite the trend favoring delayed surgery, no statistically significant relationship was found between TTS and pCR in the overall cohort or in the mean days analysis (P=0.465).

• Subgroup Analysis (ESCC):

  • Among the 130 ESCC patients, the trend of higher pCR with longer intervals persisted but remained statistically insignificant across all interval classifications (e.g., OR 0.47 for 4–8 weeks vs. >12 weeks, P=0.090).
  • The mean TTS for pCR-positive ESCC patients was 60.02 days versus 58.31 days for pCR-negative patients (P=0.371).

Key Contributions

1. Refinement of Evidence: The study contributes to the ongoing debate by providing data from a cohort dominated by ESCC (88.4%), a histological subtype often underrepresented in studies showing conflicting results (which frequently focus on Adenocarcinoma).
2. Granular Interval Analysis: Unlike studies using binary cutoffs, this research analyzed TTS using multiple interval classifications (4-week increments and 8/12-week cutoffs) to minimize selection bias and detect subtle trends.
3. Clarification of Non-Significance: The paper explicitly demonstrates that while a trend toward improved pCR with delayed surgery exists, it does not reach statistical significance in this specific population, challenging the assumption that longer intervals universally guarantee better pathological outcomes.

Significance and Claims
The authors modestly claim that their results neither confirm nor refute the strategy of delaying esophagectomy.

• The study acknowledges that the consistent directional trend (higher pCR with longer waits) warrants further investigation but emphasizes that the current data is insufficient to establish a definitive optimal timing strategy.
• The authors highlight that the lack of statistical significance may be due to the retrospective nature of the study, sample size limitations, and the heterogeneity of chemoradiation regimens which could not be standardized in the analysis.
• The paper concludes that the interval between nCRT and surgery, based on this dataset, cannot predict pCR in patients with esophageal cancer. It calls for prospective trials with larger, more heterogeneous cohorts and the inclusion of biopathological tumor features to better understand the relationship between tumor biology, treatment response, and surgical timing.