Clinical trial NCT01107639: 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
Official title: Multimodal Therapy With and Without Cetuximab in Patients With Locally Advanced Esophageal Carcinoma - An Open-Label Phase III Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Adenocarcinoma of the Gastroesophageal Junction
Esophageal Cancer
Keywords: stage IIB esophageal cancer
adenocarcinoma of the esophagus
adenocarcinoma of the gastroesophageal junction
squamous cell carcinoma of the esophagus
stage IIIA esophageal cancer
stage IIIB esophageal cancer
stage IIIC esophageal cancer
Lead sponsor: Swiss Group for Clinical Cancer Research
Sponsor class: OTHER
First posted: 2010-04-21
Enrollment: 297
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Progression-free survival (PFS)
timeFrame: time from randomization to a defined event.
Secondary outcomes:
measure: Progression-free survival after surgery
timeFrame: from date of surgery to an event as defined in PFS.
measure: Adverse events according to CTCAE version 4.0 and major postoperative complications
timeFrame: during treatment and follow-up period.
measure: Pathological remission
timeFrame: Assessed according to the tumor regression model of Mandard
measure: Overall survival
timeFrame: time from trial randomization to the date of death from any cause
measure: Time to locoregional failure after R0 resection
timeFrame: from date of surgery to date of first documented loco-regional failure
measure: Time to systemic failure after R0 resection
timeFrame: from date of surgery to date of first documented systemic failure
measure: In-hospital mortality
timeFrame: occurring after surgery but while the patient remains in hospital
measure: Time to progression (TTP)
timeFrame: 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
Other outcomes:
Locations:
city: Feldkirch
country: Austria
facility: Landeskrankenhaus
city: Innsbruck
country: Austria
facility: Universitätsklinik für Innere Medizin I
city: Linz
country: Austria
facility: Krankenhaus Barmherzige Schwestern Linz
city: Linz
country: Austria
facility: Krankenhaus der Elisabethinen Linz GmbH
city: Salzburg
country: Austria
facility: Universitätsklinikum der PMU Salzburg
city: Wels
country: Austria
facility: Klinikum Wels-Grieskirchen GmbH
city: Wien
country: Austria
facility: Universitätsklinik für Innere Medizin
city: Bobigny
country: France
facility: Hôpital Avicenne
city: Béziers
country: France
facility: Centre Hospitalier Général
city: Clermont Ferrand
country: France
facility: Hôtel Dieu Estaing
city: Dijon Cedex
country: France
facility: CHU Le Bocage
city: Dijon
country: France
facility: Centre Georges-François Leclerc
city: Lille
country: France
facility: Centre Bourgogne
city: Lille
country: France
facility: CHRU de Lille
city: Limoges
country: France
facility: Clinique François Chénieux
city: Marseille
country: France
facility: CHU la TIMONE
city: Orleans
country: France
facility: CH Régional de la Source
city: Perpignan Cedex
country: France
facility: CH Saint Jean
city: Pessac Cedex
country: France
facility: Hôpital Haut Leveque
city: Rennes Cedex 9
country: France
facility: CHU
city: St Priest En Jarez
country: France
facility: CHU de Saint Etienne - Hôpital Nord
city: Strasbourg
country: France
facility: Clinique Ste Anne
city: Toulouse
country: France
facility: Hôpital Purpan
city: Berlin
country: Germany
facility: Charite University Hospital - Campus Virchow Klinikum
city: Duesseldorf
country: Germany
facility: Universitaetsklinikum Duesseldorf
city: Essen
country: Germany
facility: Kliniken Essen - Mitte
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Heilbronn
country: Germany
facility: SLK-Kliniken Heilbronn GmbH
city: Herford
country: Germany
facility: Klinikum Herford
city: Ludwigsburg
country: Germany
facility: Klinikum Ludwigsburg
city: Marburg
country: Germany
facility: Universitaetsklinikum Giessen und Marburg GmbH
city: Munich
country: Germany
facility: Klinikum der Universitaet Muenchen - Grosshadern Campus
city: Solingen
country: Germany
facility: Staedtisches Klinikum Solingen
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart - Katharinenhospital
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
city: Budapest
country: Hungary
facility: Szent Laszlo Korhaz
city: Aarau
country: Switzerland
facility: Hirslanden Klinik Aarau
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Baden
country: Switzerland
facility: Kantonsspital Baden
city: Basel
country: Switzerland
facility: St. Claraspital AG
city: Basel
country: Switzerland
facility: Universitaetsspital-Basel
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Bruderholz
country: Switzerland
facility: Kantonsspital Bruderholz
city: Chur
country: Switzerland
facility: Kantonsspital Graubuenden
city: Geneva
country: Switzerland
facility: Hopital Cantonal Universitaire de Geneve
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: Liestal
country: Switzerland
facility: Kantonsspital Liestal
city: Olten
country: Switzerland
facility: Kantonsspital Olten
city: Sion
country: Switzerland
facility: Hôpital du Valais (RSV)-CHCVs
city: St. Gallen
country: Switzerland
facility: Kantonsspital - St. Gallen
city: Thun
country: Switzerland
facility: Regionalspital
city: Viganello
country: Switzerland
facility: Ospedale Italiano
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zurich
country: Switzerland
facility: Onkozentrum Klinik im Park
city: Zurich
country: Switzerland
facility: Klinik Hirslanden
city: Zurich
country: Switzerland
facility: City Hospital Triemli
city: Zurich
country: Switzerland
facility: UniversitaetsSpital Zuerich
Study officials:
affiliation: Cantonal Hospital of St. Gallen
name: Thomas Ruhstaller, MD
role: STUDY_CHAIR
affiliation: Kliniken Essen-Mitte
name: Michael Stahl, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.