Neoadjuvant Chemoradiotherapy and Surgery for Esophageal Squamous Cell Carcinoma Versus Definitive Chemoradiotherapy With Salvage Surgery as Needed: The Study Protocol for the Randomized Controlled NEEDS Trial

Abstract

BackgroundThe globally dominant treatment with curative intent for locally advanced esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemoradiotherapy (nCRT) with subsequent esophagectomy. This multimodal treatment leads to around 60% overall 5-year survival, yet with impaired post-surgical quality of life. Observational studies indicate that curatively intended chemoradiotherapy, so-called definitive chemoradiotherapy (dCRT) followed by surveillance of the primary tumor site and regional lymph node stations and surgery only when needed to ensure local tumor control, may lead to similar survival as nCRT with surgery, but with considerably less impairment of quality of life. This trial aims to demonstrate that dCRT, with selectively performed salvage esophagectomy only when needed to achieve locoregional tumor control, is non-inferior regarding overall survival, and superior regarding health-related quality of life (HRQOL), compared to nCRT followed by mandatory surgery, in patients with operable, locally advanced ESCC.MethodsThis is a pragmatic open-label, randomized controlled phase III, multicenter trial with non-inferiority design with regard to the primary endpoint overall survival and a superiority hypothesis for the experimental intervention dCRT with regard to the main secondary endpoint global HRQOL one year after randomization. The control intervention is nCRT followed by preplanned surgery and the experimental intervention is dCRT followed by surveillance and salvage esophagectomy only when needed to secure local tumor control. A target sample size of 1200 randomized patients is planned in order to reach 462 events (deaths) during follow-up.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier: NCT04460352.

Pathologic complete response in patients with esophageal cancer receiving neoadjuvant chemotherapy or chemoradiation: A systematic review and meta‐analysis

“…However, this requires surgical resection to assess and does not address the increasing desire to devise strategies that may allow avoidance of surgery in some patients. In fact, this approach is being tested in the currently recruiting Neoadjuvant Chemoradiotherapy and Surgery versus Definitive Chemoradiotherapy with Salvage Surgery as Needed (NEEDS) randomized trial, with final results expected in the coming years 110 . The Surgery As Needed for Oesophageal (SANO) cancer trial is also exploring this approach, with early results suggesting that, amongst those displaying clinical complete response to chemoradiation, active surveillance is noninferior to surgery 111,112 …”

“…In fact, this approach is being tested in the currently recruiting Neoadjuvant Chemoradiotherapy and Surgery versus Definitive Chemoradiotherapy with Salvage Surgery as Needed (NEEDS) randomized trial, with final results expected in the coming years. 110 The Surgery As Needed for Oesophageal (SANO) cancer trial is also exploring this approach, with early results suggesting that, amongst those displaying clinical complete response to chemoradiation, active surveillance is noninferior to surgery. 111,112 Of equal importance to identifying responder patients is the need to understand the larger nonresponder group.…”

Trimodality Therapy vs Definitive Chemoradiation in Older Adults With Locally Advanced Esophageal Cancer

“…Ultimately, such bias would best be handled in a RCT. This comparison of therapies is the subject of the Neoadjuvant Chemoradiotherapy for Esophageal Squamous Cell Carcinoma Versus Definitive Chemoradiotherapy With Salvage Surgery as Needed trial, which has an expected completion date of 2031 ( 61 ). Additionally, individuals receiving definitive chemoradiation who did not have an esophagectomy within 6 months of chemoradiation but did shortly after (eg, 6 months and 1 day) were misclassified as definitive chemoradiation.…”

Advances in diagnosis and management of cancer of the esophagus

“…This approach is under evaluation for ESCC within the international NEEDS trial, in which the non-inferiority of definitive chemoradiotherapy with surgery as needed is compared with neoadjuvant chemoradiotherapy and surgery. 225 The SANO trial is also seeking to compare active surveillance with planned esophagectomy, but in patients with both EACs and ESCCs, using overall survival as the primary endpoint. 226 Preliminary data indicate no overall survival difference when patients who achieved a complete clinical response were either operated on quickly or delayed until persistence/recurrence of disease was documented.…”