Consultant, Surgical Oncology, Artemis Hospitals, Gurugram
Part 6 of 10 in Diagnosis and Management of Esophageal Cancer
Managing Locally Advanced Esophageal Cancer: What the Major Trials Show
September 6, 2026
Locally advanced esophageal cancer is always treated with multimodality therapy, but exactly which combination of chemotherapy, radiation and surgery to use, and in what order, has been settled largely through a sequence of large international trials.
Multidisciplinary Planning Comes First
In any centre with a cancer programme, management should ideally start with a multidisciplinary board discussion involving the surgical oncologist, medical oncologist, radiation oncologist, a nuclear medicine expert and the radiologist together, weighing the stage and treatment options before deciding what suits the individual patient.
When Upfront Surgery Is Still an Option
Upfront esophagectomy alone still has a role in T2N0 disease, especially when the tumour sits in the mid or lower esophagus or at the gastroesophageal junction and is resectable on imaging, provided the pre-operative staging is accurate. In every other case, some form of pre-operative therapy is offered instead, and the real debate has been whether that should be chemoradiation or chemotherapy alone.
The CROSS Trial and the Case for Neoadjuvant Therapy
The CROSS trial compared surgery alone against neoadjuvant chemoradiation followed by surgery, across both squamous cell carcinoma and adenocarcinoma. Patients who received neoadjuvant chemoradiation did far better than those who went straight to surgery, irrespective of what adjuvant treatment followed, and within that group, the squamous cell carcinoma subgroup did even better than the adenocarcinoma subgroup. For adenocarcinoma specifically, a separate set of trials, OEO2, MAGIC, ACCORD and FLOT, independently showed that perioperative chemotherapy also beat upfront surgery. Together, these established a world consensus: neoadjuvant chemoradiation for locally advanced squamous cell carcinoma, and perioperative chemotherapy for adenocarcinoma.
Chemotherapy or Chemoradiation for Adenocarcinoma: The ESOPEC Trial
What none of those trials had done was compare neoadjuvant chemoradiation directly against neoadjuvant chemotherapy head to head, since each had only ever tested one of the two against surgery alone. Three trials set out to answer that directly. Neo-AEGIS, comparing the CROSS chemoradiation protocol against the FLOT perioperative chemotherapy protocol in adenocarcinoma, found no significant difference in overall or disease-free survival between the two. The ESOPEC trial, also in esophageal adenocarcinoma, then compared the same two protocols but found a real difference: over a 55-month median follow-up, the FLOT group's median overall survival reached 66 months, against 37 months for the CROSS group. That result settled the question worldwide: FLOT perioperative chemotherapy is now considered the best option for esophageal adenocarcinoma.
The Best Regimen for Squamous Cell Carcinoma: The JCOG Trial
For locally advanced squamous cell carcinoma, the JCOG trial addressed stage 1B, 2 and 3 disease, excluding T4, by randomising patients to a two-drug chemotherapy regimen, a three-drug DCF chemotherapy regimen, or neoadjuvant chemoradiation, all followed by esophagectomy with D2 lymphadenectomy. The triple-drug DCF regimen improved overall survival over the two-drug regimen, and this DCF group actually did better than the chemoradiation arm as well. The current standard, therefore, is that a fit patient able to tolerate the toxicity should receive DCF as neoadjuvant therapy for squamous cell carcinoma, while other patients are offered a chemoradiation regimen instead.
Is Surgery Always Necessary?
One further question worth asking is whether surgery can be avoided altogether if definitive chemoradiation alone matches trimodality therapy's survival, since esophagectomy is not a small operation and carries its own risk of post-operative complications. A dedicated comparison of definitive chemoradiotherapy against neoadjuvant chemoradiotherapy plus surgery for stage 2 and 3 squamous cell carcinoma found that trimodality therapy still had a clear survival advantage. Definitive chemoradiation without surgery remains a reasonable option, but specifically for patients who are unfit to undergo esophagectomy because of comorbidity, age or other factors, rather than as a routine alternative for everyone.
This article is based on a Jivo Masterclass session conducted by Dr. Preeti Vijayakumaran, Consultant, Surgical Oncology, Artemis Hospital, Gurugram. The article has been summarised with the assistance of an AI tool from the original masterclass recording. Watch the full Masterclass recording
This guide is based on a live Jivo Masterclass: Dr. Preeti Vijayakumaran taught doctors across Africa on March 16, 2025.
FROM THE LIVE Q&A
Dr. Shipamba
What is the role of imaging in the workup of esophageal cancer?
Dr. Preeti Vijayakumaran
Essentially, whole-body axial imaging: a PET-CT if it is available, and if not, a contrast-enhanced scan covering the neck, thorax, abdomen and pelvis for staging. In addition, endoscopic ultrasound is used in early-stage disease for more accurate T and N staging, and bronchoscopy and laparoscopy may be used in locally advanced disease, laparoscopy specifically to rule out peritoneal metastasis in cases of adenocarcinoma.
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Frequently Asked Questions
What are the methods of preventing esophageal cancer?▼
Prevention starts with understanding the risk factors, which depend on the histological subtype. For adenocarcinoma, the drivers can be obesity, reflux disease, and smoking and alcohol, so limiting smoking and alcohol matters, and an existing reflux disease needs to be managed medically. Patients with an already existing condition should also be started early on more stringent endoscopic surveillance. For squamous cell carcinoma, the pathology is more related to smoking and diet habits, and regulating those can make a difference.
Based on your experience, what do you recommend to junior doctors about such an annoying disease of our patients?▼
There is a lot of ignorance in our community, especially in our country, about a complex disease like esophageal cancer. Patients have early, subtle symptoms of difficulty swallowing, but they are often ignored and mistaken for some other common ailment. The need for awareness is foremost. As doctors, we should involve ourselves in educating more and more of the public about the disease, its diagnosis and the treatments available, so that if it is detected early, we can offer patients the maximum curative options.
In routine practice we frequently encounter cases of PPD poisoning due to suicide attempts, which lead to caustic esophageal injury resulting in chronic esophagitis. In such cases, can chronic esophagitis be considered a precancerous lesion?▼
That is a very valid question. Even in our community we see a lot of cases of caustic esophageal injury, and this chronic esophagitis can eventually lead to stricturous disease and become a predisposing cause for esophageal cancer. Patients who survive such an injury and go on to develop stricturous disease should be kept on a very stringent surveillance protocol.
Is there any specific age at which to start screening by endoscopy or another modality?▼
In our practice, screening is recommended after the age of 35 to 40 years, particularly for patients with reflux symptoms or a risk of Barrett's esophagus, though this is a variable number depending on institutional protocol. In practice, we take these patients up for endoscopic mapping: any area showing dysplastic change is biopsied. If there is no evidence of dysplasia after multiple biopsies, the patient is kept on surveillance. Low-grade dysplasia is followed up. High-grade dysplasia in a flat lesion under 2 cm is ablated, and high-grade dysplasia over 2 cm, or with a nodular appearance, is taken for endoscopic resection with histopathology follow-up on the specimen.
In this case of caustic injury from PPD poisoning, what preventive measures should be taken?▼
Most of these patients go on to develop stricturous disease, leading to significant dysphagia and a chronic inability to take oral nutrition. In such patients, an esophagectomy with a neo-esophagus is offered. In patients who do not develop stricturous disease, six-monthly endoscopic evaluation with biopsy of any suspicious area is done instead, and further imaging is not required unless a biopsy proves malignancy.
What did the CROSS trial establish?▼
That neoadjuvant chemoradiation followed by surgery gives better outcomes than surgery alone, for both squamous cell carcinoma and adenocarcinoma.
What is the standard of care for locally advanced esophageal adenocarcinoma?▼
Perioperative chemotherapy under the FLOT protocol, which the ESOPEC trial showed gives a median overall survival of 66 months versus 37 months for chemoradiation.
What is the standard of care for locally advanced squamous cell carcinoma?▼
A triple-drug DCF perioperative chemotherapy regimen in fit patients, per the JCOG trial, or a chemoradiation regimen in patients unable to tolerate it.
Can esophageal cancer be cured without surgery?▼
Definitive chemoradiation without surgery is an option, mainly for patients unfit for esophagectomy, though trimodality therapy with surgery has shown better survival for stage 2 and 3 squamous cell carcinoma.
In This Series: Diagnosis and Management of Esophageal Cancer
- 1.Diagnosis and Management of Esophageal Cancer
- 2.Early Warning Signs and Symptoms of Esophageal Cancer
- 3.How Esophageal Cancer Is Diagnosed and Staged
- 4.Telling Gastroesophageal Junction Cancer Apart From Lower Esophageal Cancer
- 5.Treating Early-Stage Esophageal Cancer: When Endoscopy Can Replace Surgery
- 6.Managing Locally Advanced Esophageal Cancer: What the Major Trials Show
- 7.Esophagectomy: How the Surgery Is Performed, and the Shift Toward Robotic Techniques
- 8.Immunotherapy in Esophageal Cancer: Where the Evidence Stands Today
- 9.Screening, Prevention and Risk Factors for Esophageal Cancer
- 10.Life After Treatment: Surveillance for Esophageal Cancer and Managing Recurrence