This study evaluated the effect of the time gap between NAC completion and radical surgery on the survival outcomes of patients with ESCC. We found that this time gap should not be too short (< 42 days) or too long (> 56 days). A period of around 42–55 days after NAC completion might be optimal for performing a radical esophagectomy.
Neoadjuvant therapy followed by esophagectomy is the standard treatment for locally advanced ESCC.[3, 16, 17] It enables downstaging of the tumor, and eliminates micro-metastases, thereby increasing the possibility of radical esophagectomy and the survival rate. Among neoadjuvant therapy approaches, chemoradiotherapy is preferred to chemotherapy because of higher response rates compared to chemotherapy.[18] Many studies have been conducted to evaluate the safety, efficacy, and optimal use of neoadjuvant chemoradiotherapy in the treatment of ESCC. However, the findings of JCOG1109 study suggested a considerable advantage of NAC with DCF followed by esophagectomy.[5] In NAC studies, esophagectomy was performed 4–8 weeks after chemotherapy.[6, 7, 19] Many studies have been conducted to assess the impact of extending the time between neoadjuvant chemoradiotherapy and esophagectomy.[8–10] However, to our knowledge, no similar study for NAC has been undertaken. Delaying surgery after NAC allows patients to recover from the side effects of the drugs and improve their nutrition. However, prolonging the time between chemotherapy and surgery raises concerns about tumor progression, which has a negative impact on the treatment. Early surgery on patients after chemotherapy, on the other hand, is preferred because chemotherapy does not cause as much fibrosis and inflammation as chemoradiotherapy.
The study found that patients with TTS from 6–8 weeks seemed to have a lower rate of severe postoperative complications (Clavien-Dindo classification ≥ grade IIIa) than those with TTS > 8 weeks or < 6 weeks. A meta-analysis on the effect of TTS after neoadjuvant chemoradiotherapy for esophageal cancer showed that a > 7–8 weeks delay in surgery significantly increased perioperative mortality.[8] Theoretically, radiation therapy causes more local edema, inflammation, and fibrosis than chemotherapy. Late toxicity of radiation also has a more severe impact on patients. Chemotherapy also causes systemic adverse effects, edema, and fibrosis to a certain extent. Wang et al.[20] found that early surgery (within 21 days) increased the incidence of lymphatic leakage in patients receiving NAC for gastric cancer. Therefore, although the results were inconclusive, we believed that surgery should be considered neither too soon nor too late after NAC.
In our study, patients in the group with TTS of 6–8 weeks had the highest OS and PFS. In a meta-analysis, Qin et al.[8] suggested that a > 7–8 weeks delay in surgery after neoadjuvant chemoradiotherapy for esophageal cancer significantly reduced OS. When studying the effect of TTS after NAC on gastric cancer patients, Wang et al.[20] found that delayed surgery after chemotherapy was an independent risk factor for decreased OS and PFS. Therefore, avoiding performing esophagectomy too soon or late after NAC is reasonable.
The study has severe limitations. First, this is an observational study which leads to some imbalances of the three groups. Although we tried to minimize these imbalances by multivariable analyses, potential bias could not be ruled out completely. Only a randomized controlled design could eliminate this limitation, but it might not be feasible in practice. Second, the sample size was relatively small, and the separation of TTS into three groups was arbitrary and based on the availability of the data.
In conclusion, time from NAC completion to radical esophagectomy should be considered in the treatment of patients with ESCC. We suggest the optimal TTS after NAC is 6–8 weeks. The surgery should not be performed too early, before six weeks after NAC. More studies are required to confirm our findings.