Patients with locally advanced cancer often experience disease recurrence after surgery alone; therefore, nCRT or nCT is recommended as an adjunct to surgery 9, 10, 15, 16. The neoadjuvant therapeutic strategy varies by region. In Japan, the phase III JCOG1109 NExT trial showed that the nCT-DCF regimen had a survival benefit over the nCT-CF regimen, but there was no survival benefit of nCRT over nCT-CF regimen 14. Clinical trials rigorously select patients based on specific criteria, but real-world settings include diverse patients with varying characteristics and conditions, potentially affecting treatment outcomes. Thus, the findings of clinical trials may not always be generalizable to all patients in real-world clinical settings. Despite the importance of confirming clinical feasibility and exploring clinical factors that predict treatment efficacy, recurrence, and AEs for treatment optimization, few studies have investigated these aspects in nCT-DCF regimen.
This real-world study in patients with ESCC showed that nCT-DCF treatment achieved comparable rates of R0 resection, pCR, and estimated 3-year DFS/RFS to those observed in the JCOG1109 NExT trial 14. In addition, our results were consistent with a previous observational study 22, supporting the use of nCT-DCF regimen in clinical practice. Patients achieving pCR after nCRT have better survival and lower recurrence risks than those who do not in locally advanced ESCC 23–26. However, the prognosis of pCR after nCT, especially with the DCF regimen, is not well-established 22, 27–35. Importantly, almost all previous studies on the DCF regimen used different schedules from the JCOG1109 NExT trial, including dosage and frequency of administration, or analyzed it by combining various regimens 27, 29, 30, 32–34, 36. In the present study using the standard DCF regimen, patients who achieved pCR had no recurrence and better DFS/RFS than those with pathological residual disease.
Although primary TRG grade 1a correlated with a favorable DFS/RFS and the absence of recurrence, this grading system for the primary tumor was not an independent factor for DFS/RFS. The estimated 3-year DFS/RFS rates were 100% in patients with ypStage I, including those with pCR and those with negative lymph node metastasis with ypT1-2. In addition, six patients with ypT3-4, ypN0 also had favorable outcomes, with estimated 1-year DFS/RFS rates of 100% and 3-year DFS/RFS rates of 75.0%. These findings highlight the importance of lymph node metastasis status in addition to primary TRG grade 1a. In fact, positive ypN was an independent predictor for recurrence and shorter DFS/RFS, consistent with previous studies 22, 27, 29, 30. Moreover, even in patients who did not achieve pCR, the presence of ypN was associated with worse DFR/RFS. The ypN category could also provide meaningful subclassifications for DFR/RFS, suggesting its critical role in recurrence after neoadjuvant DCF therapy followed by curative surgery. The accurate identification of patients at high risk of recurrence remains challenging, but ypN status could improve individual assessment of recurrence risk and guide further treatment decisions.
Systemic inflammatory response and nutritional status, driven by host-tumor interactions, are closely linked to tumor progression 37. Assessment tools of a systemic inflammatory response have potential as prognostic markers in both palliative and curative settings for various malignancies, including ESCC 37, 38. However, most studies on recurrence risk have focused on clinicopathological characteristics rather than systemic status of patients. In the present study, systemic inflammatory and nutritional status, including GPS 37–41, PNI 42, NLR 37, 43, and dysphagia score 44, were evaluated along with clinicopathological characteristics to assess the efficacy and toxicities of nCT-DCF treatment. GPS, combining CRP and albumin, was useful in identifying patients at higher risk of recurrence, with high GPS levels being independent predictive factors for shorter DFS/RFS. GPS showed no impact on the dose intensity of the DCF regimen or grade ≥ 3 febrile neutropenia. Only six of 75 patients had a GPS score of 1 or 2. Previous studies have shown that abnormal GPS levels can identify patients with a poor prognosis in locally advanced EC, even though low albumin or abnormal GPS levels are rare in this population 45, 46. GPS may serve as a clinically accessible predictive marker for recurrence and shorter DFS/RFS but not for AEs.
Tumor-related proteins produced by cancer cells can be secreted into the bloodstream and used as noninvasive tumor markers in clinical settings. The serum SCC-Ag is a widely used marker for estimating prognosis in ESCC 47, 48, but few studies have investigated its relationship with the therapeutic effect of nCT 49. The levels of serum SCC-Ag were negatively associated with pCR and primary TRG grade 1a, as only one out of 32 patients with elevated serum SCC-Ag achieved pCR, and three achieved primary TRG grade 1a. The serum SCC-Ag levels may guide the selection of patients with ESCC who may benefit from nCT. Gender differences may also influence the efficacy, outcome, and toxicities of systemic treatments. Consistent with results of the present study, an individual data network meta-analysis found that males tend to benefit more from nCT than females in EC 50. Another study suggested that males may have a better PFS with three courses of DCF compared to two courses in ESCC 51. However, there are conflicting results, with some studies suggesting that females may have a positive impact on prognosis 52–54. Of note, gender was not associated with recurrence in logistic regression analysis. Women represented only 23% of the study population, potentially affecting these findings.
Adjuvant nivolumab has become the standard of care for EC patients who undergo R0 resection after nCRT without achieving a pCR 9, based on the phase III Checkmate 577 trial 55. Although the efficacy of adjuvant nivolumab after nCT followed by surgery has not been proven, 14 out of 64 patients with pathological residual disease after R0 resection received adjuvant nivolumab in the present study, with 13 of whom had positive ypN. The recurrence pattern showed that 63.2% of patients with recurrence had distant metastases. Adjuvant nivolumab therapy did not reduce locoregional recurrence compared to placebo in the Checkmate 577 trial but did reduce distant recurrence, with a median distant metastasis-free survival of 28.3 months vs. 17.6 months 56. These results suggest that adjuvant nivolumab may reduce distant metastasis. Further research is needed to determine the benefits of adjuvant nivolumab for patients at high risk of recurrence after nCT followed by surgery.
Most patients in the present study met the eligibility criteria of the JCOG 1109 NExT trial, including age between 20 and 75 years, creatinine clearance ≥ 60 mL/min, and ECOG PS 0–1 14. However, DCF treatment was discontinued to due to toxicities in nine patients (10.5%), suggesting that not all of these patients are suitable for the DCF regimen due to its high incidence of AEs. Additionally, in a real-world study of 1,074 surgically resectable advanced ESCC patients who were propensity score-matched, no survival advantage of DCF over CF was observed in patients aged 76 years or older 57. Therefore, careful patient selection is crucial for the nCT-DCF regimen, especially when considering indications beyond the eligibility criteria in the clinical trial. Of the 86 patients who received nCT-DCF, 77 (89.5%) received prophylactic granulocyte colony-stimulating factor (G-CSF) or pegfilgrastim from the end of DCF administration at cycle 1 to prevent neutropenia. However, grade ≥ 3 neutropenia and febrile neutropenia were common. There were no clinicopathological factors associated with grade ≥ 3 neutropenia or febrile neutropenia. Administering pegfilgrastim on day 3 reduced grade 4 neutropenia to 8.7%, with no febrile neutropenia in EC patients 58, and starting G-CSF on day 3 decreased grade 3–4 neutropenia and febrile neutropenia compared to day 7 in head and neck cancer patients 59. Early administration of G-CSF or pegfilgrastim may be beneficial.
The present study had several limitations. First, it was conducted at a single institute, with treatment regimens determined by attending physicians. In addition, considering the nature of a retrospective study, there is a potential for selection bias. Second, the relatively small sample size limits definitive conclusions and additional analyses. As most patients (76.7% of all patients) received the DCF regimen after it was established as the standard regimen based on the results of the JCOG 1109 NExT trial, the follow-up period was relatively short, hampering OS analysis. An individual-patient data analysis of 3,154 ESCC patients who underwent nCT and surgery, including 1,046 with the DCF regimen, showed that RFS can serve as a surrogate endpoint for OS 60. Additionally, a meta-analysis on trials for resectable EC concluded that DFS is a valid surrogate endpoint for OS in neoadjuvant, perioperative, or adjuvant settings 61. Therefore, the findings of DFS/RFS in the present study would be crucial for treatment decisions regarding neoadjuvant DCF treatment. Third, non-hematological AEs were not fully captured in the retrospective study, possibly leading to lower incidence compared to the clinical trial. Longer-term follow-up and larger sample sizes are required for further analysis to assess the long-term efficacy of DCF treatment.
In conclusion, real-world data demonstrate the efficacy and safety of neoadjuvant DCF treatment in clinical practice. Achieving primary TRG grade 1a or pCR has favorable DFS/RFS, while elevated baseline serum SCC-Ag levels are a negative predictor of primary TRG grade 1a or pCR. Conversely, positive ypN and GPS are independent predictors for worse DFS/RFS.