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

Official title

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

Overview

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.

Interventions

• Radiation Neoadjuvant radiotherapy (arm A)
  1.8 Gy fractions 5 days per week in 23 fractions to a total dose of 41.4 Gy.
• Drug Carboplatin, paclitaxel
  Carboplatin AUC 2 + Paclitaxel 50mg/m2 weekly x 5 (day 1, 8, 15, 22, 29), starting same day as radiotherapy
• Procedure Esophagectomy
  Esophagectomy performed within 8 weeks after termination of chemoradiotherapy
• Radiation Neoadjuvant radiotherapy (arm B)
  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.
• Drug Carboplatin, paclitaxel
  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).
• Drug Cisplatin, paclitaxel
  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.
• Drug Oxaliplatin, calcium folinate, 5-fluorouracil
  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.
• Procedure Esophagectomy
  Esophagectomy only in case of residual or recurrent locoregional cancer.

Primary outcome measures

• Overall survival [Time frame: 3 years after randomisation]
• Global Health-related quality of life (HRQOL) [Time frame: 1 year after randomisation]
• Eating restrictions [Time frame: 1 year after randomisation]

Secondary outcome measures (12)

• Health related quality of life of Cancer patients [Time frame: At randomisation but before start of treatment and thereafter 6, 12, 24, 36 and 60 months after randomisation]
• Health related quality of life, oesophageal specific. [Time frame: At randomisation but before start of treatment and thereafter 6, 12, 24, 36 and 60 months after randomisation]
• Health related quality of life, general health [Time frame: At randomisation but before start of treatment and thereafter 6, 12, 24, 36 and 60 months after randomisation]
• Event-free survival [Time frame: 5 years after randomisation]
• Loco-regional and distant relapse rates [Time frame: 5 years after randomisation]
• Histopathological response according to Mandard in operated patients [Time frame: 5 years after randomisation]
• Health economy [Time frame: At baseline and 6, 12, 24, 36 and 60 months after randomisation]
• Surgical complications [Time frame: After surgery in operated patients, up to 5 years after randomisation]
• Treatment-related adverse events and toxicity [Time frame: Up to 5 years after randomisation]
• Nutritional outcomes - weight [Time frame: Up to 5 years after randomisation]
• Nutritional outcomes - dysphagia [Time frame: Up to 5 years after randomisation]
• Gender stratified analyses of all endpoints [Time frame: Up to 5 years after randomisation]

Eligibility criteria

Inclusion criteria

• Histopathologically confirmed SCC of the esophagus in locally advanced stages cT1 N+ or cT2-4a any N, M0, according to current (8th) version of of the AJCC TNM classification.
• Technically resectable disease according to the local multidisciplinary team conference (MDT)/tumor board.
• Performance status ECOG 0-1.
• Adequate organ function.
• Women of childbearing potential (WOCBP\*) must have a negative serum or urine pregnancy test.
• Patients of childbearing/reproductive potential should use highly effective method of birth control measures during the study treatment period and for at least five months after the last study treatment.
• Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment.
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
• Before patient registration/randomization, written informed consent must be given according to ICH/GCP/GDPR and national/local regulations.

Exclusion criteria

• M1 according to current (8th) version of of the AJCC TNM classification.
• cT4b according to current (8th) version of of the AJCC TNM classification.
• Primary tumor not resectable without laryngectomy.
• Impaired renal, hepatic, cardiac, pulmonary or endocrine status that compromises the eligibility of the patient for multimodality treatment with chemoradiotherapy followed by esophagectomy.
• Subjects not considered likely to tolerate multimodality treatment with chemoradiotherapy followed by esophagectomy.
• Subjects with previous malignancies are excluded unless a complete remission or complete resection was achieved at least 5 years prior to study entry.
• Prior or concomitant treatment with radiotherapy or chemoradiotherapy with potential overlap of radiotherapy fields.
• Known uncontrollable hypersensitivity to the components of the chemotherapeutic agents used in the trial regimens.
• Inability to fully understand and digest study patient information or to comply with study instructions due to language difficulty or cognitive failure such as dementia or severe psychiatric disorder.

(Criteria slightly shortened)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Sweden · 6 centers

• Linköpings universitetssjukhus — Linköping
• Skånes universitetssjukhus — Lund
• Örebro universitetssjukhus — Örebro
• Karolinska University Hospital — Stockholm
• Norrlands universitetssjukhus — Umeå
• Akademiska sjukhuset — Uppsala

Norway · 3 centers

• Oslo universitetssykehus — Oslo
• Universitetssykehuset Nord-Norge — Tromsø
• St Olavs Hospital — Trondheim

Canada · 1 center

• McGill University Health Centre — Montreal

Ireland · 1 center

• Cancer Clinical Trials Unit (CCTU) at St. James's Hospital — Dublin

Taiwan · 1 center

• Chang Gung Memorial Hospital — Linkou District

Publications

• Nilsson M, Olafsdottir H, Alexandersson von Dobeln G, Villegas F, Gagliardi G, Hellstrom M, Wang QL, Johansson H, Gebski V, Hedberg J, Klevebro F, Markar S, Smyth E, Lagergren P, Al-Haidari G, Rekstad LC, Aahlin EK, Wallner B, Edholm D, Johansson J, Szabo E, Reynolds JV, Pramesh CS, Mummudi N, Joshi A, Ferri L, Wong RK, O'Callaghan C, Lukovic J, Chan KK, Leong T, Barbour A, Smithers M, Li Y, Kang PMID 35912196

Identifiers

NCT: NCT04460352 · NEEDS

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗