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

• ClinicalTrials.gov Identifier: NCT04460352
• Recruitment Status: Recruiting
• First Posted: July 7, 2020
• Last Update Posted: March 31, 2022
• Sponsor: Karolinska University Hospital
• Collaborators: University of Leipzig; The Swedish Research Council
• Information provided by (Responsible Party): Magnus Nilsson, Karolinska University Hospital

Tracking Information

• First Submitted Date: June 25, 2020
• First Posted Date: July 7, 2020
• Last Update Posted Date: March 31, 2022
• Actual Study Start Date: November 27, 2020
• Estimated Primary Completion Date: September 18, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 1, 2020)

Overall survival [ Time Frame: 5 years after randomisation ]

When 266 events have occurred

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 1, 2020)

• Global Health-related quality of life (HRQOL) [ Time Frame: 1 year after randomisation ]
  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).
• 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 ]
  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).
• 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 ]
  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).
• 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 ]
  The EuroQoL Group's EQ-5D-5L questionnaire consisting of five dimensions ranging from No problems to Extreme problems or Unable to care.
• Event-free survival [ Time Frame: 5 years after randomisation ]
  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.
• Loco-regional and distant relapse rates [ Time Frame: 5 years after randomisation ]
  Including the relation of relapse location to the radiation field
• Histopathological response according to Mandard in operated patients [ Time Frame: 5 years after randomisation ]
  ypTNM including total and metastatic lymph node count, tumor free resection margins, R0
• Health economy [ Time Frame: At baseline and 6, 12, 24, 36 and 60 months after randomisation ]
  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
• Surgical complications [ Time Frame: After surgery in operated patients, up to 5 years after randomisation ]
  According to the Esophagectomy Complications Consensus Group (ECCG) and classified according to Clavien-Dindo
• Treatment-related adverse events and toxicity [ Time Frame: Up to 5 years after randomisation ]
  NCI-CTCAE Criteria version 5.0
• Nutritional outcomes - weight [ Time Frame: Up to 5 years after randomisation ]
  Weight development. Weight (in kg) will be measured at all visits.
• Nutritional outcomes - dysphagia [ Time Frame: Up to 5 years after randomisation ]
  Dysphagia will be evaluated at all visits according to the CTC adverse event scale, grading from 0 (no problems) to 4 (worst problems).
• Gender stratified analyses of all endpoints [ Time Frame: Up to 5 years after randomisation ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)

Brief Summary

NEEDS is a pragmatic open-label, randomised, controlled, phase III, multicenter trial with non-inferiority design with regard to the primary endpoint overall survival and superiority for the experimental intervention definitive chemoradiotherapy with regard to the main secondary endpoint global health related quality of life (HRQOL) 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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Esophageal Squamous Cell Carcinoma

Intervention

• 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
  Other Name: Neoadjuvant chemotherapy
• 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).
  Other Name: Neoadjuvant Platin-Taxane Regimen (alternative 1)
• 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.
  Other Name: Platinum-Fluoropyrimidine Regimens (alternative 2a)
• 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.
  Other Name: Platinum-Fluoropyrimidine Regimens (alternative 2b)
• Procedure: Esophagectomy
  Esophagectomy only in case of residual or recurrent locoregional cancer.

Study Arms

• Active Comparator: Control arm (A)

  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,

  Interventions:

  • Radiation: Neoadjuvant radiotherapy (arm A)
  • Drug: Carboplatin, paclitaxel
  • Procedure: Esophagectomy
• Experimental: Experimental arm (B)

  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.

  Interventions:

  • Radiation: Neoadjuvant radiotherapy (arm B)
  • Drug: Carboplatin, paclitaxel
  • Drug: Cisplatin, paclitaxel
  • Drug: Oxaliplatin, calcium folinate, 5-fluorouracil
  • Procedure: Esophagectomy

• 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 X, Kong FM, Chao YK, Crosby T, Bruns C, van Laarhoven H, van Berge Henegouwen M, van Hillegersberg R, Rosati R, Piessen G, de Manzoni G, Lordick F. 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. Front Oncol. 2022 Jul 13;12:917961. doi: 10.3389/fonc.2022.917961. eCollection 2022.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 1, 2020): 1200
• Original Estimated Enrollment (submitted: July 1, 2020): 1000
• Estimated Study Completion Date: December 31, 2031
• Estimated Primary Completion Date: September 18, 2026 (Final data collection date for primary outcome measure)

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Magnus Nilsson, MD, PhD; +46-707-375186; magnus.nilsson@ki.se

Contact: Mats Hellström; +46-8-51773677; mats.hellstrom@sll.se

• Listed Location Countries: Norway, Sweden

Administrative Information

• NCT Number: NCT04460352
• Other Study ID Numbers: NEEDS
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Magnus Nilsson, Karolinska University Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Karolinska University Hospital
• Original Study Sponsor: Same as current

Collaborators

• University of Leipzig
• The Swedish Research Council

Investigators

• Study Chair: Magnus Nilsson, MD, PhD; Karolinska University Hospital
• Study Chair: Florian Lordick, MD, PhD; Leipzig University Medical Center

• PRS Account: Karolinska University Hospital
• Verification Date: March 2022