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Neoadjuvant chemoradiotherapy followed by esophagectomy.

Radiotherapy: 1.8 Gy fractions 5 days per week in 23 fractions to a total dose of 41.4 Gy.

Chemotherapy: Carboplatin AUC 2 + Paclitaxel 50mg/m2 weekly x 5 (day 1, 8, 15, 22, 29), starting on the first day of radiotherapy.

Esophagectomy: Within 8 weeks of termination of chemoradiotherapy,

Definitive chemoradiotherapy followed by surveillance, and esophagectomy only in case of residual or recurrent locoregional cancer.

Radiotherapy: Two alternative schemes:

1. 1.8 Gy fractions five days per week in 28 fractions to a total dose of 50.4 Gy.
2. 2.0 Gy fractions five days per week in 25 fractions to a total dose of 50 Gy.

Chemotherapy: Three alternative regimens:

1. Platin-Taxane Regimen: Carboplatin AUC 2 + Paclitaxel 50mg/m2 on day 1 weekly during the full course of radiotherapy.

2a. Platinum-Fluoropyrimidine Regimen: Cisplatin 75mg/m2 weeks 1 and 5 + 5-fluorouracil 1000 mg/m2/day by continuous infusion weeks 1 and 5.

2b. FOLFOX: Oxaliplatin 85 mg/m2, calcium folinate 200 mg/m2 and 5-fluorouracil 400 mg/m2 weeks 1, 3 and 5 + 5-fluorouracil 800 mg/m2 by continuous infusion weeks 1, 3 and 5.

1.8 Gy fractions 5 days per week in 23 fractions to a total dose of 41.4 Gy.

Neoadjuvant radiotherapy (arm A)

Carboplatin AUC 2 + Paclitaxel 50mg/m2 weekly x 5 (day 1, 8, 15, 22, 29), starting same day as radiotherapy

Carboplatin, paclitaxel

Esophagectomy performed within 8 weeks after termination of chemoradiotherapy

Esophagectomy

Two alternative schemes:

1. 1.8 Gy fractions five days per week in 28 fractions to a total dose of 50.4 Gy.
2. 2.0 Gy fractions five days per week in 25 fractions to a total dose of 50 Gy.

Neoadjuvant radiotherapy (arm B)

Carboplatin AUC 2 + Paclitaxel 50mg/m2 on day 1 weekly during the full course of radiotherapy (5 weeks or 6 weeks, depending on the radiotherapy regimen used).

Cisplatin 75mg/m2 on the first day of weeks 1 and 5 + 5-fluorouracil 1000 mg/m2/day by continuous infusion on the first four days of weeks 1 and 5.

Cisplatin, paclitaxel

FOLFOX: Oxaliplatin 85 mg/m2, calcium folinate 200 mg/m2 and 5-fluorouracil 400 mg/m2 on the first days of weeks 1, 3 and 5 + 5-fluorouracil 800 mg/m2 by continuous infusion on the first two days of weeks 1, 3 and 5.

Oxaliplatin, calcium folinate, 5-fluorouracil

Esophagectomy only in case of residual or recurrent locoregional cancer.

Magnus Nilsson, MD, PhD

Mats Hellström

Mehrnoush Dehgani, PhD

Lorenzo Ferri, MD, PhD

Ingrid Kiernan

John Reynolds, Prof

Grainne O'Kane, Dr

Moya Cunningham, Dr

Janne Christoffersen, RN

Ghazwan Al-Haidari, MD, PhD

Eirik Kjus Aahlin, MD, PhD

Kristin Woll, RN

Marte Romundstad, RN

Lars Cato Rekstad, MD, PhD

David Edholm, MD

Anna Lindhoff Larsson, RN

Monika Meszaros, RN

Marit Bakos, RN

Jan Johansson, MD, PhD

Berit Sunde, RN, PhD

Maria Lampi, RN

Gabriella Alexandersson von Döbeln, MD, PhD

Birgitta Orrvik Olsson, RN

Agneta Karhu, RN

Bengt Wallner, MD, PhD

Lena Ekfjord, RN

Jakob Hedberg, MD, PhD

Linnea Sundström, RN

Eva Szabo, MD, PhD

Florian Lordick, MD, PhD

NEEDS is a pragmatic open-label, randomised, controlled, phase III, multicenter trial with non-inferiority design with regard to the first co-primary endpoint overall survival and superiority for the experimental intervention definitive chemoradiotherapy. A second co-primary endpoint is global health related quality of life (HRQOL) one year after randomisation. A third co-primary endpoint is eating restictions one year after randomisation.

The aim is to compare outcomes after neoadjuvant chemoradiotherapy with subsequent esophagectomy to definitive chemoradiotherapy with surveillance and salvage esophagectomy as needed in patients with resectable locally advanced squamous cell carcinoma (SCC) of the esophagus, with the aim to provide generalisable guidance for future clinical practice.

NEEDS is a pragmatic open-label, randomised, controlled, phase III, multicenter trial with non-inferiority design with regard to the three co-primary endpoints i) Overall survival and superiority for the experimental intervention definitive chemoradiotherapy; ii) Global health related quality of life (HRQOL) one year after randomisation; iii) Eating restictions one year after randomisation.

Chemoradiotherapy Followed by Planned Surgery or by Surveillance and Surgery Only When Needed for Oesophageal Cancer

NEoadjuvant Chemoradiotherapy for Esophageal Squamous Cell Carcinoma Versus Definitive Chemoradiotherapy With Salvage Surgery as Needed (NEEDS Trial)

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, version 3.0 (EORTC QLQ-C30). The two items assessing global health and overall quality of life are responded to in seven categories ranging from 1 (very poor) to 7 (excellent).

EORTC QLQ-OG25 instrument. This instrument consists of 25 items covering upper gastric symptoms or problems in four categories ranging from 1 (Not at all) to 4 (Very much).

EORTC HRQOL Questionnaire QLQ-C30 version 3.0, 28 items ranging from 1 (no problems at all) to 4 (very much) and two items assessing global health and overall quality of life are responded to in seven categories ranging from 1 (very poor) to 7 (excellent).

EORTC HRQOL gastresophageal-specific questionnaire EORTC QLQ-OG25. 25 items assessing symptoms or problems are responded to in four categories ranging from 1 (no problems) to 4 (very much).

The EuroQoL Group's EQ-5D-5L questionnaire consisting of five dimensions ranging from No problems to Extreme problems or Unable to care.

Time to relapse, initiation of any anti-tumor therapy beyond the study treatments (salvage surgery is considered a study treatment in the dCRT arm), or death, whichever comes first.

Including the relation of relapse location to the radiation field

ypTNM including total and metastatic lymph node count, tumor free resection margins, R0

Assessed including patient-level medical resource use and societal costs due to sick-leave and other non-medical costs. Quality-adjusted life years (QALYs) will be calculated using EQ-5D

According to the Esophagectomy Complications Consensus Group (ECCG) and classified according to Clavien-Dindo

Weight development. Weight (in kg) will be measured at all visits.

Dysphagia will be evaluated at all visits according to the CTC adverse event scale, grading from 0 (no problems) to 4 (worst problems).

Spots Global Cancer Trial Database for neoadjuvant radiotherapy (arm a)