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

NCT ID: NCT01107639

Last Updated: 2020-10-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 297 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-05-27
• Study Completion Date: 2018-12-09

Brief Summary

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.

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.

Conditions

Adenocarcinoma of the Gastroesophageal Junction; Esophageal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

cetuximab

Intervention Type: BIOLOGICAL

Loading dose 400 mg/m2 2h infusion Weekly: 250 mg/m2 1h infusion

cisplatin

Intervention Type: DRUG

• Cisplatin 75 mg/m2 1h infusion d1, 22
• Cisplatin 25 mg/m2 1h infusion weekly x5

docetaxel

Intervention Type: DRUG

• Docetaxel 75 mg/m2 1h infusion d1, 22
• Docetaxel 20 mg/m2 1/2h infusion weekly x5

adjuvant therapy

Intervention Type: PROCEDURE

During the adjuvant phase, all infusions, given every two weeks, will be at a dose of 500mg/m².

neoadjuvant therapy

Intervention Type: PROCEDURE

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.

Without additional immunotherapy

Standard therapy without immunotherapy (cetuximab).

Group Type: ACTIVE_COMPARATOR

cisplatin

Intervention Type: DRUG

• Cisplatin 75 mg/m2 1h infusion d1, 22
• Cisplatin 25 mg/m2 1h infusion weekly x5

docetaxel

Intervention Type: DRUG

• Docetaxel 75 mg/m2 1h infusion d1, 22
• Docetaxel 20 mg/m2 1/2h infusion weekly x5

Interventions

cetuximab

Loading dose 400 mg/m2 2h infusion Weekly: 250 mg/m2 1h infusion

Intervention Type: BIOLOGICAL

cisplatin

• Cisplatin 75 mg/m2 1h infusion d1, 22
• Cisplatin 25 mg/m2 1h infusion weekly x5

Intervention Type: DRUG

docetaxel

• Docetaxel 75 mg/m2 1h infusion d1, 22
• Docetaxel 20 mg/m2 1/2h infusion weekly x5

Intervention Type: DRUG

adjuvant therapy

During the adjuvant phase, all infusions, given every two weeks, will be at a dose of 500mg/m².

Intervention Type: 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.

Intervention Type: PROCEDURE

Other Intervention Names

Erbitux; Taxotere or generic product

Eligibility Criteria

Inclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Swiss Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Thomas Ruhstaller, MD

Role: STUDY_CHAIR

Cantonal Hospital of St. Gallen

Michael Stahl, MD

Role: STUDY_CHAIR

Kliniken Essen-Mitte

Locations

Landeskrankenhaus

Feldkirch, , Austria

Universitätsklinik für Innere Medizin I

Innsbruck, , Austria

Krankenhaus Barmherzige Schwestern Linz

Linz, , Austria

Krankenhaus der Elisabethinen Linz GmbH

Linz, , Austria

Universitätsklinikum der PMU Salzburg

Salzburg, , Austria

Universitätsklinik für Innere Medizin

Vienna, , Austria

Klinikum Wels-Grieskirchen GmbH

Wels, , Austria

Centre Hospitalier Général

Béziers, , France

Hôpital Avicenne

Bobigny, , France

Hôtel Dieu Estaing

Clermont-Ferrand, , France

Centre Georges-François Leclerc

Dijon, , France

CHU Le Bocage

Dijon, , France

Centre Bourgogne

Lille, , France

CHRU de Lille

Lille, , France

Clinique François Chénieux

Limoges, , France

CHU la TIMONE

Marseille, , France

CH Régional de la Source

Orléans, , France

CH Saint Jean

Perpignan, , France

Hôpital Haut Leveque

Pessac, , France

CHU

Rennes, , France

CHU de Saint Etienne - Hôpital Nord

Saint-Priest-en-Jarez, , France

Clinique Ste Anne

Strasbourg, , France

Hôpital Purpan

Toulouse, , France

Charite University Hospital - Campus Virchow Klinikum

Berlin, , Germany

Universitaetsklinikum Duesseldorf

Düsseldorf, , Germany

Kliniken Essen - Mitte

Essen, , Germany

Universitaetsklinikum Freiburg

Freiburg im Breisgau, , Germany

SLK-Kliniken Heilbronn GmbH

Heilbronn, , Germany

Klinikum Herford

Herford, , Germany

Klinikum Ludwigsburg

Ludwigsburg, , Germany

Universitaetsklinikum Giessen und Marburg GmbH

Marburg, , Germany

Klinikum der Universitaet Muenchen - Grosshadern Campus

Munich, , Germany

Staedtisches Klinikum Solingen

Solingen, , Germany

Klinikum Stuttgart - Katharinenhospital

Stuttgart, , Germany

Universitaetsklinikum Tuebingen

Tübingen, , Germany

Szent Laszlo Korhaz

Budapest, , Hungary

Hirslanden Klinik Aarau

Aarau, , Switzerland

Kantonsspital Aarau

Aarau, , Switzerland

Kantonsspital Baden

Baden, , Switzerland

St. Claraspital AG

Basel, , Switzerland

Universitaetsspital-Basel

Basel, , Switzerland

Inselspital Bern

Bern, , Switzerland

Kantonsspital Bruderholz

Bruderholz, , Switzerland

Kantonsspital Graubuenden

Chur, , Switzerland

Hopital Cantonal Universitaire de Geneve

Geneva, , Switzerland

Centre Hospitalier Universitaire Vaudois

Lausanne, , Switzerland

Kantonsspital Liestal

Liestal, , Switzerland

Kantonsspital Olten

Olten, , Switzerland

Kantonsspital - St. Gallen

Sankt Gallen, , Switzerland

Hôpital du Valais (RSV)-CHCVs

Sion, , Switzerland

Regionalspital

Thun, , Switzerland

Ospedale Italiano

Viganello, , Switzerland

Kantonsspital Winterthur

Winterthur, , Switzerland

Onkozentrum Klinik im Park

Zurich, , Switzerland

Klinik Hirslanden

Zurich, , Switzerland

City Hospital Triemli

Zurich, , Switzerland

UniversitaetsSpital Zuerich

Zurich, , Switzerland

Countries

Austria; France; Germany; Hungary; Switzerland

References

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.

Reference Type: RESULT

PMID: 29635438 (View on PubMed)

von Holzen U, Schmidt S, Hayoz S, Steffen T, Grieder F, Bartsch D, Schnider A, Knoefel WT, Piessen G, Kettelhack C, Marti WR, Schafer M, Fugger R, Koigsrainer A, Gloor B, Furrer M, Gerard 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 Medikamentose Tumortherapie (AGMT), the Federation Francophone de Cancerologie Digestive (FFCD)/Federation 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.

Reference Type: DERIVED

PMID: 33055589 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32111181 (View on PubMed)

Other Identifiers

2009-016584-10

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EU-21024

Identifier Type: -

Identifier Source: secondary_id

CDR0000669249

Identifier Type: -

Identifier Source: secondary_id

SAKK 75/08

Identifier Type: -

Identifier Source: org_study_id