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

Esophageal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01107639
• Other study ID #: SAKK 75/08
• Secondary ID: 2009-016584-10EU
• Status: Completed
• Phase: Phase 3
• Start date: May 27, 2010
• Est. completion date: December 9, 2018

Study information

• Verified date: May 2019
• Source: Swiss Group for Clinical Cancer Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 297
• Est. completion date: December 9, 2018
• Est. primary completion date: October 6, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Adenocarcinoma
• Adenocarcinoma of the Gastroesophageal Junction
• Esophageal Cancer
• Esophageal Neoplasms

Intervention

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

Drug:
• cisplatin
Cisplatin 75 mg/m2 1h infusion d1, 22 Cisplatin 25 mg/m2 1h infusion weekly x5
• docetaxel
Docetaxel 75 mg/m2 1h infusion d1, 22 Docetaxel 20 mg/m2 1/2h infusion weekly x5

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

Locations

Country	Name	City	State
Austria	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	Klinikum Wels-Grieskirchen GmbH	Wels
Austria	Universitätsklinik für Innere Medizin	Wien
France	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 Cedex
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	Orleans
France	CH Saint Jean	Perpignan Cedex
France	Hôpital Haut Leveque	Pessac Cedex
France	CHU	Rennes Cedex 9
France	CHU de Saint Etienne - Hôpital Nord	St Priest En Jarez
France	Clinique Ste Anne	Strasbourg
France	Hôpital Purpan	Toulouse
Germany	Charite University Hospital - Campus Virchow Klinikum	Berlin
Germany	Universitaetsklinikum Duesseldorf	Duesseldorf
Germany	Kliniken Essen - Mitte	Essen
Germany	Universitaetsklinikum Freiburg	Freiburg
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	Tuebingen
Hungary	Szent Laszlo Korhaz	Budapest
Switzerland	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	Hôpital du Valais (RSV)-CHCVs	Sion
Switzerland	Kantonsspital - St. Gallen	St. Gallen
Switzerland	Regionalspital	Thun
Switzerland	Ospedale Italiano	Viganello
Switzerland	Kantonsspital Winterthur	Winterthur
Switzerland	City Hospital Triemli	Zurich
Switzerland	Klinik Hirslanden	Zurich
Switzerland	Onkozentrum Klinik im Park	Zurich
Switzerland	UniversitaetsSpital Zuerich	Zurich

Sponsors (1)

Lead Sponsor	Collaborator
Swiss Group for Clinical Cancer Research

Countries where clinical trial is conducted

Austria,  France,  Germany,  Hungary,  Switzerland, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Progression-free survival after surgery		from date of surgery to an event as defined in PFS.
Secondary	Adverse events according to CTCAE version 4.0 and major postoperative complications		during treatment and follow-up period.
Secondary	Pathological remission		Assessed according to the tumor regression model of Mandard
Secondary	Overall survival		time from trial randomization to the date of death from any cause
Secondary	Time to locoregional failure after R0 resection		from date of surgery to date of first documented loco-regional failure
Secondary	Time to systemic failure after R0 resection		from date of surgery to date of first documented systemic failure
Secondary	In-hospital mortality		occurring after surgery but while the patient remains in hospital
Secondary	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