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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Esophageal Squamous Cell Carcinoma	Radiation: Neoadjuvant radiotherapy (arm A); Drug: Carboplatin, paclitaxel; Procedure: Esophagectomy; Radiation: Neoadjuvant radiotherapy (arm B); Drug: Cisplatin, paclitaxel; Drug: Oxaliplatin, calcium folinate, 5-fluorouracil	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1200 participants
• 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
• Official Title: NEoadjuvant Chemoradiotherapy for Esophageal Squamous Cell Carcinoma Versus Definitive Chemoradiotherapy With Salvage Surgery as Needed (NEEDS Trial)
• Actual Study Start Date: November 27, 2020
• Estimated Primary Completion Date: September 18, 2026
• Estimated Study Completion Date: December 31, 2031

Arms and Interventions

Arm	Intervention/treatment
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,	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
Experimental: Experimental arm (B); Definitive chemoradiotherapy followed by surveillance, and esophagectomy only in case of residual or recurrent locoregional cancer. Radiotherapy: Two alternative schemes: 1.8 Gy fractions five days per week in 28 fractions to a total dose of 50.4 Gy.; 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.	Radiation: Neoadjuvant radiotherapy (arm B); Two alternative schemes: 1.8 Gy fractions five days per week in 28 fractions to a total dose of 50.4 Gy.; 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.

Outcome Measures

Primary Outcome Measures :

1. Overall survival [ Time Frame: 5 years after randomisation ]
   When 266 events have occurred

Secondary Outcome Measures :

1. 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).
2. 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).
3. 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).
4. 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.
5. 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.
6. Loco-regional and distant relapse rates [ Time Frame: 5 years after randomisation ]
   Including the relation of relapse location to the radiation field
7. 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
8. 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
9. 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
10. Treatment-related adverse events and toxicity [ Time Frame: Up to 5 years after randomisation ]
    NCI-CTCAE Criteria version 5.0
11. Nutritional outcomes - weight [ Time Frame: Up to 5 years after randomisation ]
    Weight development. Weight (in kg) will be measured at all visits.
12. 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).
13. Gender stratified analyses of all endpoints [ Time Frame: Up to 5 years after randomisation ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Contacts

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

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

Locations

Norway

Oslo universitetssykehus; Recruiting

Oslo, Norway

Contact: Janne Christoffersen, RN jannec@ous-hf.no

Principal Investigator: Ghazwan Al-Haidari, MD, PhD

Universitetssykehuset Nord-Norge; Recruiting

Tromsø, Norway

Contact: Eirik Kjus Aahlin, MD, PhD eirik.kjus.aahlin@unn.no

Contact: Kristin Woll, RN kristin.woll@unn.no

Principal Investigator: Eirik Kjus Aahlin, MD, PhD

St Olavs Hospital; Recruiting

Trondheim, Norway

Contact: Marte Romundstad, RN marte.romunstad@stolav.no

Principal Investigator: Lars Cato Rekstad, MD, PhD

Sweden

Linköpings universitetssjukhus; Recruiting

Linköping, Sweden

Contact: David Edholm, MD david.edholm@regionostergotland.se

Contact: Anna Lindhoff Larsson, RN anna.lindhoff.larsson@regionostergotland.se

Skånes universitetssjukhus; Recruiting

Lund, Sweden

Contact: Monika Meszaros, RN monika.meszaros@skane.se

Contact: Marit Bakos, RN marit.bakos@skane.se

Principal Investigator: Jan Johansson, MD, PhD

Karolinska University Hospital; Recruiting

Stockholm, Sweden

Contact: Berit Sunde, RN, PhD berit.sunde@ki.se

Contact: Maria Lampi, RN maria.lampi@regionstockholm.se

Principal Investigator: Magnus Nilsson, MD, PhD

Sub-Investigator: Gabriella Alexandersson von Döbeln, MD, PhD

Norrlands universitetssjukhus; Recruiting

Umeå, Sweden

Contact: Birgitta Orrvik Olsson, RN birgitta.orrvikolsson@regionvasterbotten.se

Contact: Agneta Karhu, RN agneta.karhu@regionvasterbotten.se

Principal Investigator: Bengt Wallner, MD, PhD

Akademiska sjukhuset; Recruiting

Uppsala, Sweden

Contact: Lena Ekfjord, RN lena.ekfjord@akademiska.se

Principal Investigator: Jakob Hedberg, MD, PhD

Örebro universitetssjukhus; Recruiting

Örebro, Sweden

Contact: Linnea Sundström, RN linnea.sundstrom@regionorebrolan.se

Principal Investigator: Eva Szabo, MD, PhD

Sponsors and Collaborators

Karolinska University Hospital

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

More Information

• Responsible Party: Magnus Nilsson, Professor, Karolinska University Hospital
• ClinicalTrials.gov Identifier: NCT04460352
• Other Study ID Numbers: NEEDS
• First Posted: July 7, 2020
• Last Update Posted: March 31, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Magnus Nilsson, Karolinska University Hospital:

Neoadjuvant chemoradiotherapy; Definitive chemoradiotherapy with salvage surgery as needed

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Squamous Cell; Esophageal Squamous Cell Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Squamous Cell; Esophageal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases; Leucovorin; Paclitaxel; Albumin-Bound Paclitaxel; Carboplatin; Fluorouracil; Oxaliplatin; Calcium; Levoleucovorin; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Calcium-Regulating Hormones and Agents