Locally Advanced Oesophageal Cancer Treatment and Surgery

Locally advanced oesophageal cancer is treated with multimodality therapy: chemotherapy, with or without radiotherapy, before surgery, followed by oesophagectomy and, in selected patients, adjuvant immunotherapy. The current evidence favours perioperative FLOT chemotherapy for adenocarcinoma. For squamous cell carcinoma, the recent Japanese JCOG1109 trial supports triplet DCF chemotherapy in patients fit enough to tolerate it, with chemoradiation as the alternative.

Dr. Preeti Vijayakumaran, Consultant, Oncology, Artemis Hospitals, Gurugram, India, whose fellowship training at Tata Memorial Hospital was in thoracic surgery, walked through the trials that built this standard, the case for and against surgery, how oesophagectomy is performed today, and the role of immunotherapy. The staging workup that defines locally advanced disease is covered in the article on how oesophageal cancer is diagnosed and staged, and the overall approach in the complete guide to oesophageal cancer diagnosis and treatment.

What locally advanced oesophageal cancer means for treatment

For treatment planning, locally advanced disease is anything beyond clinically T2 N0: a tumour that has grown through the muscle wall, involves regional lymph nodes, or both, but has not spread to distant organs. Treatment is always multimodality. Depending on the stage at presentation, it is either neoadjuvant chemoradiation or chemotherapy followed by surgery, with further adjuvant treatment where recommended, or surgery followed by adjuvant therapy.

Is there a role for upfront surgery?

Yes, in a defined group. Clinically T2 N0 disease of the mid or lower oesophagus or the gastro-oesophageal junction that is resectable on imaging can go straight to oesophagectomy, provided the preoperative staging is accurate. For all other locally advanced disease, preoperative therapy should be offered. The ongoing debate has been which preoperative therapy: chemoradiation or chemotherapy alone.

CROSS, MAGIC and FLOT4: treatment before surgery beats surgery alone

Two sets of trials established that treatment before surgery improves survival over surgery alone.

CROSS randomised patients with both squamous cell carcinoma and adenocarcinoma to neoadjuvant chemoradiotherapy followed by surgery or to surgery alone. Patients who received chemoradiotherapy first did far better than those who went straight to surgery, and the squamous cell carcinoma subgroup benefited most. After CROSS was published, the field reached a consensus around neoadjuvant chemoradiotherapy.

For adenocarcinoma, the OEO2, MAGIC and ACCORD-07 trials showed that patients given chemotherapy before surgery, or before and after it (perioperative chemotherapy), did better than those who had surgery first. The FLOT4 trial then established FLOT (docetaxel, oxaliplatin, leucovorin and fluorouracil) as the preferred perioperative regimen.

The settled position at that point was neoadjuvant chemoradiation for locally advanced squamous cell carcinoma, and perioperative chemotherapy for adenocarcinoma.

Chemoradiation versus chemotherapy: the missing comparison

The weakness of that consensus, as Dr. Vijayakumaran framed it, was that none of these trials compared the two strategies against each other. Each had a surgery-alone arm and one treatment arm. Three newer trials were designed to answer the head-to-head question.

Neo-AEGIS: no significant survival difference

Neo-AEGIS compared the CROSS chemoradiation protocol with perioperative chemotherapy in adenocarcinoma. The two strategies did not differ significantly in overall survival or disease-free survival.

ESOPEC: FLOT outperforms CROSS in adenocarcinoma

ESOPEC, also in oesophageal adenocarcinoma, compared perioperative FLOT chemotherapy with the CROSS protocol, measuring median overall survival and three-year and five-year overall survival. The survival curves separated significantly. Over a median follow-up of 55 months, the FLOT group did much better: median overall survival was 66 months with FLOT against 37 months with CROSS.

This result led to the worldwide conclusion, as Dr. Vijayakumaran put it, that FLOT is the best therapy for oesophageal adenocarcinoma.

JCOG1109 NExT: triplet chemotherapy for squamous cell carcinoma

For squamous cell carcinoma, the answer came from the Japanese JCOG1109 NExT trial. It enrolled patients with stage IB, II and III disease, excluding T4 tumours, and randomised them to three arms: doublet chemotherapy (cisplatin and fluorouracil), triplet DCF chemotherapy (docetaxel, cisplatin and fluorouracil), or neoadjuvant chemoradiation. All patients then underwent oesophagectomy with D2 lymphadenectomy (removal of the second tier of lymph nodes), and overall survival was compared.

Triplet DCF improved overall survival over the doublet for locally advanced squamous cell carcinoma, and in Dr. Vijayakumaran's reading this arm did better than even the chemoradiation arm. Her conclusion: for a fit patient who can tolerate the toxicity, DCF should be the standard neoadjuvant therapy in squamous cell carcinoma, and for other patients chemoradiation can be used. The trial's formal comparisons were of each arm against the doublet, and outside Japan neoadjuvant chemoradiation on the CROSS protocol remains a widely used standard for squamous cell carcinoma.

Bimodality versus trimodality: can surgery be avoided?

Oesophagectomy is a major operation with significant postoperative complications. If definitive chemoradiation alone (bimodality treatment) gave the same survival as chemoradiation plus surgery (trimodality treatment), many patients could be spared the operation.

The study Dr. Vijayakumaran presented, comparing definitive chemoradiotherapy with neoadjuvant chemoradiotherapy followed by surgery in stage II and III squamous cell carcinoma, showed better survival with trimodality treatment. In her view, surgery therefore remains part of the standard for patients who can undergo it. Earlier randomised trials in squamous cell carcinoma found that adding surgery improved local control without a clear overall survival advantage, which is why definitive chemoradiation remains an accepted alternative.

For patients who are unfit for surgery because of other illnesses, age or other factors, definitive chemoradiation is a legitimate option in squamous cell carcinoma. It is also the treatment for unresectable disease. Patients treated this way need endoscopic as well as imaging surveillance, and salvage surgery should be offered if the disease recurs and the patient can tolerate it.

How oesophagectomy is performed

Oesophagectomy for cancer removes the entire length of the oesophagus, from the thoracic inlet (the opening at the top of the chest) down to the gastro-oesophageal junction. The stomach is then fashioned into a tube, the gastric conduit, which is brought up through the posterior mediastinal route (the bed of the removed oesophagus) to reconstruct a new oesophagus.

Open, laparoscopic or robotic

The operation can be done open or by minimally invasive surgery. Today, Dr. Vijayakumaran's team performs most oesophagectomies by a minimally invasive route, either laparoscopic or robotic.

In her assessment, the robotic approach gives significantly better outcomes on several counts:

• Circumferential tumour dissection, clearing tissue all the way around the tumour.
• Oncological quality of the specimen, meaning the radicality of the dissection.
• Early postoperative recovery.

Trials have not shown a clear advantage of robotic surgery over conventional minimally invasive oesophagectomy.

Transhiatal oesophagectomy for frail patients

For a very frail patient with borderline fitness, especially when the tumour is at the gastro-oesophageal junction and not bulky, she offers a transhiatal oesophagectomy, performed through the abdomen and the neck without opening the chest. It is better tolerated than a transthoracic oesophagectomy in such patients.

Rehabilitation is part of treatment

Nutritional rehabilitation and chest physiotherapy are essential components of oesophageal cancer management. Because most patients are older and many have several other illnesses, building up nutrition and lung function supports recovery from an operation of this size.

Adjuvant immunotherapy with nivolumab after surgery

What happens after surgery depends on the pathology. When neoadjuvant chemoradiation or chemotherapy has left no residual disease, no further treatment is usually needed. When residual disease remains after neoadjuvant chemoradiation, adjuvant immunotherapy with nivolumab should be offered to reduce the chance of recurrence. The supporting evidence is the CheckMate 577 trial, which tested adjuvant nivolumab in patients with residual disease after neoadjuvant chemoradiation and surgery.

Dr. Vijayakumaran noted that the effect was seen more strongly in squamous cell carcinoma, but that it also applies to adenocarcinoma. In curative treatment of oesophageal cancer, immunotherapy's role is established mainly in this adjuvant setting; it is also standard with chemotherapy in advanced disease. Before surgery, perioperative durvalumab with FLOT has been approved since 2025 for gastro-oesophageal junction adenocarcinoma on the strength of the MATTERHORN trial; for other oesophageal cancers it remains investigational, one of the questions she expects the field to answer soon.

Metastatic oesophageal cancer: what chemotherapy can offer

When the disease has spread widely, chemotherapy combined with immunotherapy or targeted therapy offers a possible benefit. Dr. Vijayakumaran was candid about its scale: the statistical survival gain is perhaps a couple of months, but treatment definitely improves the patient's quality of life during that time.

The road ahead: organ preservation

Organ preservation, avoiding oesophagectomy in patients who respond completely to chemoradiation, is still debated, because no test yet proves a complete response without removing the oesophagus; the complete guide sets out why.

Early tumours that can be treated without major surgery are covered in the article on endoscopic treatment of early oesophageal cancer. Doctors' questions on immunotherapy and metastatic disease are answered in the Live Discussion from this masterclass.