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

Sponsor

Swiss Group for Clinical Cancer Research (Other)

Overall Status

Completed

CT.gov ID

NCT01107639

Collaborator

(none)

297

Enrollment

Locations

Arms

102.4

Actual Duration (Months)

5.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Gastroesophageal Junction Esophageal Cancer	Biological: cetuximab Drug: cisplatin Drug: docetaxel Procedure: adjuvant therapy Procedure: neoadjuvant therapy	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

297 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

May 27, 2010

Actual Primary Completion Date :

Oct 6, 2016

Actual Study Completion Date :

Dec 9, 2018

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Progression-free survival (PFS) [time from randomization to a defined event.]
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

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Landeskrankenhaus	Feldkirch	Austria	A-6807
2	Universitätsklinik für Innere Medizin I	Innsbruck	Austria	A-6020
3	Krankenhaus Barmherzige Schwestern Linz	Linz	Austria	A-4010
4	Krankenhaus der Elisabethinen Linz GmbH	Linz	Austria	A-4010
5	Universitätsklinikum der PMU Salzburg	Salzburg	Austria	A-5020
6	Klinikum Wels-Grieskirchen GmbH	Wels	Austria	A-4600
7	Universitätsklinik für Innere Medizin	Wien	Austria	1090
8	Hôpital Avicenne	Bobigny	France	93000
9	Centre Hospitalier Général	Béziers	France	34525
10	Hôtel Dieu Estaing	Clermont Ferrand	France	63003
11	CHU Le Bocage	Dijon Cedex	France	21079
12	Centre Georges-François Leclerc	Dijon	France	21079
13	Centre Bourgogne	Lille	France	59000
14	CHRU de Lille	Lille	France	59037
15	Clinique François Chénieux	Limoges	France	87000
16	CHU la TIMONE	Marseille	France	13385
17	CH Régional de la Source	Orleans	France	45067
18	CH Saint Jean	Perpignan Cedex	France	66046
19	Hôpital Haut Leveque	Pessac Cedex	France	33604
20	CHU	Rennes Cedex 9	France	35033
21	CHU de Saint Etienne - Hôpital Nord	St Priest En Jarez	France	42277
22	Clinique Ste Anne	Strasbourg	France	67000
23	Hôpital Purpan	Toulouse	France	31509
24	Charite University Hospital - Campus Virchow Klinikum	Berlin	Germany	D-13353
25	Universitaetsklinikum Duesseldorf	Duesseldorf	Germany	D-40225
26	Kliniken Essen - Mitte	Essen	Germany	D-45136
27	Universitaetsklinikum Freiburg	Freiburg	Germany	D-79106
28	SLK-Kliniken Heilbronn GmbH	Heilbronn	Germany	74078
29	Klinikum Herford	Herford	Germany	D-32049
30	Klinikum Ludwigsburg	Ludwigsburg	Germany	D-71640
31	Universitaetsklinikum Giessen und Marburg GmbH	Marburg	Germany	D-35043
32	Klinikum der Universitaet Muenchen - Grosshadern Campus	Munich	Germany	D-81377
33	Staedtisches Klinikum Solingen	Solingen	Germany	D-42653
34	Klinikum Stuttgart - Katharinenhospital	Stuttgart	Germany	70174
35	Universitaetsklinikum Tuebingen	Tuebingen	Germany	D-72076
36	Szent Laszlo Korhaz	Budapest	Hungary	1097
37	Hirslanden Klinik Aarau	Aarau	Switzerland	CH-5001
38	Kantonsspital Aarau	Aarau	Switzerland	CH-5001
39	Kantonsspital Baden	Baden	Switzerland	CH-5404
40	St. Claraspital AG	Basel	Switzerland	CH-4016
41	Universitaetsspital-Basel	Basel	Switzerland	CH-4031
42	Inselspital Bern	Bern	Switzerland	CH-3010
43	Kantonsspital Bruderholz	Bruderholz	Switzerland	CH-4101
44	Kantonsspital Graubuenden	Chur	Switzerland	CH-7000
45	Hopital Cantonal Universitaire de Geneve	Geneva	Switzerland	CH-1211
46	Centre Hospitalier Universitaire Vaudois	Lausanne	Switzerland	CH-1011
47	Kantonsspital Liestal	Liestal	Switzerland	CH-4410
48	Kantonsspital Olten	Olten	Switzerland	CH-4600
49	Hôpital du Valais (RSV)-CHCVs	Sion	Switzerland	1951
50	Kantonsspital - St. Gallen	St. Gallen	Switzerland	CH-9007
51	Regionalspital	Thun	Switzerland	3600
52	Ospedale Italiano	Viganello	Switzerland	CH-6962
53	Kantonsspital Winterthur	Winterthur	Switzerland	CH-8400
54	Onkozentrum Klinik im Park	Zurich	Switzerland	8038
55	Klinik Hirslanden	Zurich	Switzerland	CH-8032
56	City Hospital Triemli	Zurich	Switzerland	CH-8063
57	UniversitaetsSpital Zuerich	Zurich	Switzerland	CH-8091