Radiation Therapy and Chemotherapy, With or Without Cetuximab, Followed by Surgery in Treating Patients With Locally Advanced Esophageal Cancer That Can Be Removed by Surgery

Multimodal Therapy With and Without Cetuximab in Patients With Locally Advanced Esophageal Carcinoma - An Open-Label Phase III Trial

RATIONALE: Radiation therapy uses high-energy x-rays and to kill tumor cells. Drugs used in chemotherapy, such as docetaxel and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether giving radiation therapy together with chemotherapy is more effective with or without cetuximab in treating patients with esophageal cancer.

PURPOSE: This randomized phase III trial is studying giving radiation therapy together with chemotherapy, with or without cetuximab, followed by surgery in treating patients with locally advanced esophageal cancer that can be removed by surgery.

Study Overview

• Status: Completed
• Conditions: Esophageal Cancer; Adenocarcinoma of the Gastroesophageal Junction
• Intervention / Treatment: Biological: cetuximab; Drug: cisplatin; Drug: docetaxel; Procedure: adjuvant therapy; Procedure: neoadjuvant therapy

Detailed Description

OBJECTIVES:

Primary

• To determine the efficacy of neoadjuvant radiochemotherapy comprising docetaxel, cisplatin, and radiotherapy in combination with cetuximab followed by surgery and adjuvant cetuximab versus neoadjuvant radiochemotherapy comprising docetaxel, cisplatin, and radiotherapy followed by surgery in patients with locally advanced esophageal carcinoma.

Secondary

• To compare the toxicity of the two therapy arms.
• To determine patterns of failure overall and with regard to histology.
• To evaluate economic aspects in a subproject and to perform a radiotherapy quality assurance program.

OUTLINE: This is a multicenter study. Patients are stratified according to center, histology (adenocarcinoma vs squamous cell carcinoma), primary tumor (T2 vs T3-4), and gender (male vs female). Patients are randomized to 1 of 2 treatment arms.

• Arm A:

  • Induction chemotherapy (docetaxel and cisplatin) and concurrent cetuximab Patients receive docetaxel IV over 1 hour and cisplatin IV over 1 hour on day 1 and cetuximab IV over 1-2 hours on day 1, 8, and 15. Treatment repeats every 21 days for 2 courses.
  • Chemotherapy (docetaxel and cisplatin), cetuximab, and concurrent radiotherapy Beginning in week 7, patients receive cetuximab IV over 1 hour, docetaxel IV over 30 minutes, cisplatin IV over 1 hour on days 43, 50, 57, 64, and 71 and undergo radiotherapy 5 days a week for 5 weeks. Patients then undergo surgery 4-7 weeks after completion of radiotherapy.
  • Adjuvant cetuximab Beginning 3-6 weeks after completion of surgery, patients receive cetuximab IV over 1-2 hours once every 2 weeks for a total of 6 doses.
• Arm B: Patients receive induction chemotherapy comprising docetaxel IV and cisplatin IV for 2 courses as in arm A. Beginning in week 7, patients receive docetaxel IV, cisplatin IV, and concurrent radiotherapy for 5 weeks as in arm A. Patients then undergo surgery 4-7 weeks after completion of radiotherapy.

After completion of study therapy, patients are followed up at 1 (arm B) or 6 (arm A) months, every 3 months for 3 years, and then every 6 months for 2 years.

• Study Type: Interventional
• Enrollment (Actual): 297
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Feldkirch, Austria, A-6807
    • Landeskrankenhaus
  • Innsbruck, Austria, A-6020
    • Universitätsklinik für Innere Medizin I
  • Linz, Austria, A-4010
    • Krankenhaus Barmherzige Schwestern Linz
  • Linz, Austria, A-4010
    • Krankenhaus der Elisabethinen Linz GmbH
  • Salzburg, Austria, A-5020
    • Universitätsklinikum der PMU Salzburg
  • Wels, Austria, A-4600
    • Klinikum Wels-Grieskirchen GmbH
  • Wien, Austria, 1090
    • Universitätsklinik für Innere Medizin
• France
  • Bobigny, France, 93000
    • Hôpital Avicenne
  • Béziers, France, 34525
    • Centre Hospitalier Général
  • Clermont Ferrand, France, 63003
    • Hôtel Dieu Estaing
  • Dijon, France, 21079
    • Centre Georges-François Leclerc
  • Dijon Cedex, France, 21079
    • Chu Le Bocage
  • Lille, France, 59037
    • CHRU de Lille
  • Lille, France, 59000
    • Centre Bourgogne
  • Limoges, France, 87000
    • Clinique Francois Chenieux
  • Marseille, France, 13385
    • CHU La Timone
  • Orleans, France, 45067
    • CH Régional de la Source
  • Perpignan Cedex, France, 66046
    • CH Saint Jean
  • Pessac Cedex, France, 33604
    • Hopital Haut Leveque
  • Rennes Cedex 9, France, 35033
    • CHU
  • St Priest En Jarez, France, 42277
    • CHU de Saint Etienne - Hopital Nord
  • Strasbourg, France, 67000
    • Clinique Ste Anne
  • Toulouse, France, 31509
    • Hopital Purpan
• Germany
  • Berlin, Germany, D-13353
    • Charite University Hospital - Campus Virchow Klinikum
  • Duesseldorf, Germany, D-40225
    • Universitaetsklinikum Duesseldorf
  • Essen, Germany, D-45136
    • Kliniken Essen - Mitte
  • Freiburg, Germany, D-79106
    • Universitaetsklinikum Freiburg
  • Heilbronn, Germany, 74078
    • SLK-Kliniken Heilbronn GmbH
  • Herford, Germany, D-32049
    • Klinikum Herford
  • Ludwigsburg, Germany, D-71640
    • Klinikum Ludwigsburg
  • Marburg, Germany, D-35043
    • Universitaetsklinikum Giessen und Marburg GmbH
  • Munich, Germany, D-81377
    • Klinikum der Universitaet Muenchen - Grosshadern Campus
  • Solingen, Germany, D-42653
    • Staedtisches Klinikum Solingen
  • Stuttgart, Germany, 70174
    • Klinikum Stuttgart - Katharinenhospital
  • Tuebingen, Germany, D-72076
    • Universitaetsklinikum Tuebingen
• Hungary
  • Budapest, Hungary, 1097
    • Szent Laszlo Korhaz
• Switzerland
  • Aarau, Switzerland, CH-5001
    • Kantonsspital Aarau
  • Aarau, Switzerland, CH-5001
    • Hirslanden Klinik Aarau
  • Baden, Switzerland, CH-5404
    • Kantonsspital Baden
  • Basel, Switzerland, CH-4031
    • Universitaetsspital-Basel
  • Basel, Switzerland, CH-4016
    • St. Claraspital AG
  • Bern, Switzerland, CH-3010
    • Inselspital Bern
  • Bruderholz, Switzerland, CH-4101
    • Kantonsspital Bruderholz
  • Chur, Switzerland, CH-7000
    • Kantonsspital Graubuenden
  • Geneva, Switzerland, CH-1211
    • Hôpital Cantonal Universitaire de Genève
  • Lausanne, Switzerland, CH-1011
    • Centre Hospitalier Universitaire Vaudois
  • Liestal, Switzerland, CH-4410
    • Kantonsspital Liestal
  • Olten, Switzerland, CH-4600
    • Kantonsspital Olten
  • Sion, Switzerland, 1951
    • Hôpital du Valais (RSV)-CHCVs
  • St. Gallen, Switzerland, CH-9007
    • Kantonsspital - St. Gallen
  • Thun, Switzerland, 3600
    • Regionalspital
  • Viganello, Switzerland, CH-6962
    • Ospedale Italiano
  • Winterthur, Switzerland, CH-8400
    • Kantonsspital Winterthur
  • Zurich, Switzerland, CH-8063
    • City Hospital Triemli
  • Zurich, Switzerland, CH-8091
    • UniversitaetsSpital Zuerich
  • Zurich, Switzerland, 8038
    • Onkozentrum Klinik im Park
  • Zurich, Switzerland, CH-8032
    • Klinik Hirslanden

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed esophageal carcinoma

• Meets the following criteria:

  • Resectable, locally advanced disease as determined by the combination of CT scan, endoluminal ultrasound (EUS), PET scan, and a multidisciplinary team discussion

    • T2, N1-3; T3, any N; or T4a, any N (if technically resectable with curative intent [R0] as decided by a multidisciplinary team discussion)

      • EUS-guided fine-needle aspiration (FNA) allowed, but determines nodal status only if positive FNA
    • No T1, any N, M0; or T2, N0, M0; T4a (due to infiltration of the trachea-bronchial tree or organ involvement that cannot be operated on with curative intent [R0] as decided by a multidisciplinary team discussion); T4b; or distant metastasis (M1)
  • Type I or II disease according to the Siewert classification
  • Squamous cell carcinoma (including basaloid-squamous cell and adenosquamous carcinoma) or adenocarcinoma of the thoracic esophagus or the esophagogastric junction (from 5 cm below the entrance of the esophagus into the thorax to the gastric cardia)
• Patients with obstructive tumors are eligible (obstructive tumors will be considered as locally advanced tumors)
• No cervical esophageal carcinoma and tumors involving the first 5 cm of the thoracic esophagus
• No airway infiltration in case of tumors at or above the tracheal bifurcation
• No peritoneal carcinomatosis in case of adenocarcinomas infiltrating the gastric cardia (i.e., esophagogastric junction carcinoma Siewert type I or II)

PATIENT CHARACTERISTICS:

• WHO performance status 0-1
• Neutrophil count ≥ 1.5 x 10^9/L
• Platelet count ≥ 100 x 10^9/L
• Creatinine clearance > 60 mL/min
• Bilirubin ≤ 1.0 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 2.5 times ULN
• AST ≤ 1.5 times ULN
• INR normal
• PTT ≤ 1.0 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 12 months after completion of study therapy
• FEV_1 ≥ 1.5 L OR ≥ 75% of the reference value
• Must be compliant and geographically proximal for staging and follow-up
• Considered operable (i.e., appropriate organ functions and ability to undergo general anesthesia)
• No other malignancies within the past 5 years except nonmelanomatous skin cancer or adequately treated carcinoma in situ of the cervix

• No severe or uncontrolled cardiovascular disease, including any of the following:

  • NYHA class III-IV congestive heart failure
  • Unstable angina pectoris
  • Myocardial infarction within the past 12 months
  • Significant arrhythmias
• No psychiatric disorder precluding understanding of information on trial related topics, giving informed consent, and answering questionnaires
• No active uncontrolled infection
• No serious underlying medical condition that, in the opinion of the investigator, could impair the ability of the patient to participate in the trial (e.g., uncontrolled diabetes mellitus or active autoimmune disease)
• No preexisting peripheral neuropathy > grade 1
• No definite contraindications for the use of corticosteroids and antihistamines as premedication
• No known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy or radiotherapy to the chest
• At least 30 days since prior treatment in another clinical trial
• No concurrent drugs contraindicated for use with the trial drugs
• No other concurrent anticancer treatments
• No other concurrent experimental drugs or investigational treatments

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Additional immunotherapy (cetuximab); All patients in the experimental arm will be given additional immunotherapy (cetuximab) during cycles 1 and 2, during RT and after surgery.	Biological: cetuximab; Loading dose 400 mg/m2 2h infusion Weekly: 250 mg/m2 1h infusion; Other Names: Erbitux; Drug: cisplatin; Cisplatin 75 mg/m2 1h infusion d1, 22; Cisplatin 25 mg/m2 1h infusion weekly x5; Drug: docetaxel; Docetaxel 75 mg/m2 1h infusion d1, 22; Docetaxel 20 mg/m2 1/2h infusion weekly x5; Other Names: Taxotere or generic product; Procedure: adjuvant therapy; During the adjuvant phase, all infusions, given every two weeks, will be at a dose of 500mg/m².; Procedure: neoadjuvant therapy; During the neoadjuvant phase, the first infusion of cetuximab should be at a dose of 400 mg/m² administered over a period of 2 hours and all subsequent infusions, given weekly, should be of 250 mg/m² over a period of 1 hour, unless any infusion related reaction was observed at a previous infusion. (The maximum infusion rate is 10 mg/min, corresponding to 2 mL/min ready-to-use solution.
Active Comparator: Without additional immunotherapy; Standard therapy without immunotherapy (cetuximab).	Drug: cisplatin; Cisplatin 75 mg/m2 1h infusion d1, 22; Cisplatin 25 mg/m2 1h infusion weekly x5; Drug: docetaxel; Docetaxel 75 mg/m2 1h infusion d1, 22; Docetaxel 20 mg/m2 1/2h infusion weekly x5; Other Names: Taxotere or generic product

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	time from randomization to one of the following events, whichever comes first: Tumor progression at any time (progression of primary tumor or local lymph nodes, appearance of new lesions); Recurrence at local, regional or distant site after surgery; Death from any cause	time from randomization to a defined event.

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival after surgery	from date of surgery to an event as defined in PFS.
Adverse events according to CTCAE version 4.0 and major postoperative complications	during treatment and follow-up period.
Pathological remission	Assessed according to the tumor regression model of Mandard
Overall survival	time from trial randomization to the date of death from any cause
Time to locoregional failure after R0 resection	from date of surgery to date of first documented loco-regional failure
Time to systemic failure after R0 resection	from date of surgery to date of first documented systemic failure
In-hospital mortality	occurring after surgery but while the patient remains in hospital
Time to progression (TTP)	Time to progression is defined as time from randomization to one of the following events, whichever comes first: - Tumor progression at any time. - Recurrence at local, regional or distant site after surgery. - Death due to tumor

Collaborators and Investigators

• Sponsor: Swiss Group for Clinical Cancer Research
• Investigators: Study Chair: Thomas Ruhstaller, MD, Cantonal Hospital of St. Gallen; Study Chair: Michael Stahl, MD, Kliniken Essen-Mitte

Publications and helpful links

General Publications

• Ruhstaller T, Thuss-Patience P, Hayoz S, Schacher S, Knorrenschild JR, Schnider A, Plasswilm L, Budach W, Eisterer W, Hawle H, Mariette C, Hess V, Mingrone W, Montemurro M, Girschikofsky M, Schmidt SC, Bitzer M, Bedenne L, Brauchli P, Stahl M; Swiss Group for Clinical Cancer Research (SAKK); German Esophageal Cancer Study Group; Austrian 'Arbeitsgemeinschaft Medikamentose Tumortherapie' (AGMT); Federation Francophone de Cancerologie Digestive (FFCD)/Federation de Recherche en Chirurgie (FRENCH). Neoadjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08). Ann Oncol. 2018 Jun 1;29(6):1386-1393. doi: 10.1093/annonc/mdy105.
• von Holzen U, Schmidt S, Hayoz S, Steffen T, Grieder F, Bartsch D, Schnider A, Knoefel WT, Piessen G, Kettelhack C, Marti WR, Schäfer M, Függer R, Köigsrainer A, Gloor B, Furrer M, Gérard MA, Hawle H, Walz MK, Alesina P, Ruhstaller T; Swiss Group for Clinical Cancer Research (SAKK), the German Esophageal Cancer Study Group, the Austrian Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT), the Fédération Francophone de Cancérologie Digestive (FFCD)/Fédération de Recherche en Chirurgie (FRENCH). Surgical Outcomes After Neoadjuvant Chemoradiation Followed by Curative Surgery in Patients With Esophageal Cancer: An Intergroup Phase III Trial of the Swiss Group for Clinical Cancer Research (SAKK 75/08). Ann Surg. 2022 Jun 1;275(6):1130-1136. doi: 10.1097/SLA.0000000000004334. Epub 2020 Aug 26.
• Fehr M, Hawle H, Hayoz S, Thuss-Patience P, Schacher S, Riera Knorrenschild J, Durr D, Knoefel WT, Rumpold H, Bitzer M, Zweifel M, Samaras P, Mey U, Kung M, Winterhalder R, Eisterer W, Hess V, Gerard MA, Templeton A, Stahl M, Ruhstaller T; Swiss Group for Clinical Cancer Research (SAKK); German Esophageal Cancer Study Group; Austrian Arbeitsgemeinschaft Medikamentose Tumortherapie (AGMT); Federation Francophone de Cancerologie Digestive (FFCD) / Federation de Recherche en Chirurgie (FRENCH). High thromboembolic event rate in patients with locally advanced oesophageal cancer during neoadjuvant therapy. An exploratory analysis of the prospective, randomised intergroup phase III trial SAKK 75/08. BMC Cancer. 2020 Feb 28;20(1):166. doi: 10.1186/s12885-020-6623-z.

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2010
• Primary Completion (Actual): October 6, 2016
• Study Completion (Actual): December 9, 2018

Study Registration Dates

• First Submitted: April 20, 2010
• First Submitted That Met QC Criteria: April 20, 2010
• First Posted (Estimate): April 21, 2010

Study Record Updates

• Last Update Posted (Actual): October 20, 2020
• Last Update Submitted That Met QC Criteria: October 19, 2020
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: squamous cell carcinoma of the esophagus; adenocarcinoma of the esophagus; stage IIB esophageal cancer; adenocarcinoma of the gastroesophageal junction; stage IIIA esophageal cancer; stage IIIB esophageal cancer; stage IIIC esophageal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Adenocarcinoma; Esophageal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Immunological; Docetaxel; Cisplatin; Cetuximab
• Other Study ID Numbers: SAKK 75/08; 2009-016584-10 (EudraCT Number); EU-21024; CDR0000669249

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No