Long-Term Survival Highlights
The management of locally advanced esophageal squamous cell carcinoma (ESCC) has long been a subject of intense debate among thoracic oncologists and surgeons. Traditionally, neoadjuvant chemoradiotherapy (NCRT) followed by surgery has been considered a standard of care, largely influenced by landmark studies like the CROSS trial. However, a recent single-center prospective phase 3 randomized clinical trial conducted at Sichuan Cancer Hospital provides a nuanced perspective on this paradigm. The study, which followed patients for over five years, revealed that there were no statistically significant differences in overall survival (OS) or disease-free survival (DFS) between patients receiving NCRT followed by surgery and those undergoing surgery followed by adjuvant therapy (AT).
Key findings from the trial include a 5-year OS rate of 59.2% for the NCRT group compared to 59.6% for the AT group. Similarly, the 5-year DFS rates were 53.1% and 56.5%, respectively. While the aggregate data suggests equivalence, a critical subgroup emerged: patients who achieved a pathological complete response (pCR) following NCRT experienced significantly superior outcomes, with a 5-year OS rate reaching 76.5%. This suggests that while NCRT is highly effective for a specific subset of responders, it may not offer a universal advantage over surgery with postoperative adjuvant therapy for all patients.
The Evolution of ESCC Management: Neoadjuvant vs. Adjuvant
Esophageal cancer remains a global health challenge, with ESCC being the predominant histological subtype in Asian populations. Unlike esophageal adenocarcinoma, which is more common in Western countries and often associated with gastroesophageal reflux, ESCC has distinct biological drivers and response patterns to therapy. For years, the ‘neoadjuvant-first’ approach has been favored to downstage tumors and improve resectability. However, this approach exposes all patients to the toxicities of chemoradiotherapy before surgery, including those who might not derive a significant pathological benefit.
The alternative strategy—upfront surgery followed by adjuvant therapy—allows for precise pathological staging before deciding on the necessity of further treatment. This ‘surgery-first’ approach has remained popular in many centers, particularly when the tumor is deemed resectable at the outset. Until now, high-quality, long-term randomized data comparing these two specific sequences (NCRT vs. Surgery + AT) in the modern era of intensity-modulated radiotherapy (IMRT) and contemporary chemotherapy has been limited.
Study Design and Methodology
Conducted between January 2018 and April 2020 at Sichuan Cancer Hospital in China, this prospective, randomized, open-label phase 3 trial enrolled 254 patients. After rigorous screening and exclusions, 118 patients were assigned to the NCRT group and 112 to the AT group. The study population consisted of patients aged 18 to 75 with histologically confirmed, resectable, locally advanced thoracic ESCC (staged as cT1N+M0 or cT2-4aNxM0).
Intervention Protocols
Patients in the NCRT arm received a total dose of 40 Gy of IMRT delivered in 20 fractions. Concurrent chemotherapy consisted of paclitaxel and carboplatin. Surgery was typically performed 6 to 8 weeks after the completion of chemoradiotherapy. In contrast, patients in the AT arm underwent upfront surgery followed by an adjuvant chemoradiotherapy regimen tailored by a multidisciplinary team (MDT). This design reflects real-world clinical practice where postoperative decisions are often individualized based on surgical findings and nodal status.
Key Findings: Survival and Safety Analysis
The trial’s primary endpoint was overall survival, with a median follow-up period of 59.1 months. The results provide a robust look at the long-term durability of these treatment strategies.
Overall and Disease-Free Survival
The analysis showed that the hazard ratio (HR) for OS was 1.01 (95% CI, 0.67-1.51; P = .97), indicating almost identical survival probabilities between the two groups. For DFS, the HR was 1.13 (95% CI, 0.77-1.68; P = .53). These findings suggest that for the broad population of patients with resectable ESCC, the sequence of therapy—whether chemoradiotherapy comes before or after surgery—may not fundamentally alter the five-year survival trajectory.
The Prognostic Power of Pathological Complete Response (pCR)
One of the most clinically significant aspects of this trial was the evaluation of pCR within the NCRT group. Approximately one-third of patients receiving NCRT achieve pCR, meaning no viable tumor cells are found in the resected specimen. In this study, those achieving pCR had a 5-year OS of 76.5%, compared to only 52.1% for those who did not achieve pCR (HR, 0.39; P = .01). This stark contrast highlights that the benefit of NCRT is heavily front-loaded into the ‘responder’ group. For non-responders, the NCRT phase may represent a delay in surgery without a corresponding survival benefit.
Safety and Perioperative Outcomes
The study also addressed concerns regarding treatment-related toxic effects and surgical complications. Historically, neoadjuvant therapy has been associated with increased perioperative morbidity, such as pulmonary complications and anastomotic leaks. However, this trial reported manageable safety profiles in both arms. The use of IMRT likely contributed to minimizing radiation-induced damage to surrounding lung and heart tissues, which is a critical factor in maintaining post-surgical recovery and long-term quality of life.
Clinical Interpretation and Expert Commentary
The results of this trial challenge the notion that neoadjuvant chemoradiotherapy should be the mandatory starting point for all locally advanced ESCC. While NCRT remains a powerful tool, particularly for its ability to induce pCR, the equivalence of the AT arm suggests that ‘surgery-first’ remains a valid and oncologically sound pathway.
From a clinical decision-making perspective, these findings advocate for a more personalized approach. If we could accurately predict which patients are likely to achieve a pCR, NCRT would be the clear choice. Conversely, for patients predicted to be poor responders to chemoradiotherapy, moving directly to surgery avoids neoadjuvant toxicity and allows for adjuvant therapy to be tailored to the actual pathological stage. Future research should focus on identifying biomarkers—such as PET-CT response, circulating tumor DNA (ctDNA), or genomic signatures—that can guide this selection process.
Furthermore, the trial underscores the importance of the Multidisciplinary Team (MDT). In the AT arm, the adjuvant regimen was not a ‘one-size-fits-all’ approach but was designed by experts to address the specific risks of each patient. This flexibility in the adjuvant setting may be why the AT group performed as well as the NCRT group.
Conclusion
The Sichuan Cancer Hospital trial provides essential evidence that for locally advanced ESCC, both NCRT followed by surgery and surgery followed by adjuvant therapy offer comparable 5-year survival outcomes. The hallmark of success in the neoadjuvant setting remains the achievement of a pathological complete response. However, for the general patient population, neoadjuvant therapy did not demonstrate a superior survival advantage over postoperative adjuvant strategies. These findings support a more flexible treatment landscape where clinical decisions are based on tumor resectability, patient fitness, and the potential for response, rather than a universal neoadjuvant mandate.
Funding and ClinicalTrials.gov
This study was supported by grants from the National Natural Science Foundation of China and local health bureaus. The trial is registered with ClinicalTrials.gov, identifier: NCT06775652.
References
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2. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074-2084.
3. Yang H, Liu H, Chen Y, et al. Neoadjuvant Chemoradiotherapy Plus Surgery Versus Surgery Alone for Esophageal Squamous Cell Carcinoma (NEOCRTEC5010): A Phase III Multicenter Randomized Controlled Trial. J Clin Oncol. 2018;36(27):2773-2781.
