Efficacy and Safety Study of the Combined Modality Therapy in Adenocarcinoma of the Esophago-gastric Junction

February 2, 2013 updated by: Tomasz Skoczylas, Medical University of Lublin

Efficacy and Safety Study of the Combined Modality Therapy in Patients With Potentially Resectable, Locally Advanced Adenocarcinoma of the Esophago-gastric Junction With Preoperative Chemo- and Chemoradiation Followed by Surgical Resection

The high cancer related mortality has remained a significant issue of health care in Poland, Europe and worldwide. The decreasing incidence rate for carcinoma of the distal stomach and a marked trend of increasing incidence for adenocarcinoma of the esophago-gastric junction and esophagus has been observed in the developed countries. The most eminent drawback of majority commonly cited randomized trials is heterogenicity of cancer patient population. The epidemiological, pathological, and clinical data clearly suggest that adenocarcinoma of the esophago-gastric junction is the entirety different both from adenocarcinoma of the esophagus and adenocarcinoma of the stomach. The experience in a combined modality therapy for adenocarcinoma of the esophago-gastric junction have been extrapolated from studies on esophageal or gastric cancer, where the investigated population involved in part patients with carcinoma of the esophago-gastric junction. The proposed study has been designed to achieve the following objectives:

  • The assessment of safety and efficacy of a combined modality therapy in homogenous patient population with adenocarcinoma of the esophago-gastric junction excluding individuals with adenocarcinoma of the esophagus or the stomach;
  • The assessment of safety of a combined modality therapy in a form of chemo- and chemoradiotherapy related toxicity and impact of chemo- and chemoradiotherapy on postoperative morbidity or mortality rates;
  • The assessment of efficacy of a combined modality therapy in a form of rate of response of the tumor to chemo- and chemoradiotherapy and a curative resection rate.
  • The assessment of efficacy of a combined modality therapy in a form of cancer free survival and overall survival.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Adenocarcinoma of the esophago-gastric junction (AEG) represents an aggressive disease with poor prognosis. Surgery is the traditional mainstay of treatment for patients presenting with locally advanced disease, defined as transmural invasion with or without lymph node involvement. Surgical approach may differ, but the principal is to achieve wide mural clearance, negative margins, and perform an adequate lymphadenectomy. Although surgery is the primary modality that can cure patients, the majority of patients reveal recurrence leading to death within 2 years after resection. The incidence of locoregional relapse in most series and in phase II and phase III trials ranges from 25% to 60%, and 20-30% of these patients have no evidence of distant metastases. Median survival with surgery alone for localized disease remains poor, and ranges from 13 to 19 months with 5-year survival rates at best approximately 40%. To improve a long-term outcome in patients with esophageal and gastric cancers a combined modality therapy concept has been investigating for many years. The experience in a combined modality therapy for adenocarcinoma of the esophago-gastric junction have been extrapolated from studies on esophageal or gastric cancer, where the investigated population involved in part patients with AEG.

The most eminent drawback of majority commonly cited randomized trials is heterogenicity of cancer patients population. Most of them overlap between esophageal adenocarcinoma and squamous cell carcinoma or between adenocarcinoma of the esophagus, esophagogastric junction and the stomach. When the investigators reviewed the composition of the most prominent 10 studies population including 3171 patients with easophageal and gastric cancer the investigators identified 911 (28.7%) patients with AEG. The remaining pooled population involved 1173 (36.9%) patients with adenocarcinoma of the esophagus, 598 (18.9%) patients with squamous cell carcinoma of the esophagus and 775 (24.4%) patients with adenocarcinoma of the stomach. Only 1 randomized controlled trial concerned exclusively patients with AEG. In this study preoperative chemoradiotherapy resulted in a 16% increase of 3-year survival. Although its superiority was not proven (p=0.07), these data provide evidence that preoperative chemoradiotherapy may improve survival and should be further investigated. Interestingly, the survival benefit was evident although the postoperative mortality was more than doubled (10.2% versus 3.8%) by adding chemotherapy. Although this study did not meet its accrual goals and could not provide statistical significance, the improvement in both local cancer free and overall survival suggest that preoperative chemoradiotherapy appears most valuable modality treatment to cure patients with localized AEG. As it is more than evident that major response to preoperative treatment is an important prognostic factor future trials should aim to optimize preoperative treatment by combining all treatment modalities.

All above mentioned discrepancies regarding the optimal treatment for AEG brought the investigators to an idea to design a study testing safety and efficacy of three-phase combined modality therapy accommodating induction taxane-based triple chemotherapy followed by concurrent chemoradiotherapy with 45Gy as a total dose of irradiation and subsequent surgical resection in homogenous population of patients with clearly defined AEG. Taking into account the results from recent phase II and III trials the proposed combined modality regimen suggests substantial response to the neoadjuvant therapy and promising highly effective loco-regional cancer clearance with moderate and acceptable tolerance despite a complex and extensive treatment.

Study Type

Interventional

Enrollment (Anticipated)

100

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Poland
    • Lubelskie
      • Lublin, Lubelskie, Poland, 20-081
        • Recruiting
        • Second Department of General & Gastrointestinal Surgery & Oncological Surgery of the Alimantary Tract, Medical University of Lublin
        • Contact:
        • Principal Investigator:
          • Grzegorz Wallner, Professor
        • Principal Investigator:
          • Andrzej Dąbrowski, Professor
        • Sub-Investigator:
          • Witold Zgodziński, MD, PhD
        • Sub-Investigator:
          • Marek Majewski, MD, PhD
        • Principal Investigator:
          • Tomasz Skoczylas, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • patients of both gender, aged more than 18, with histopathologically confirmed adenocarcinoma of the esophagogastric junction
  • medically fit to undergo a major surgery with planned thoracotomy and in general condition allowing to tolerate chemo- or chemoradiotherapy (Karnofsky Performance Status ≥70, ECOG 0-1).
  • Carcinoma of the esophagogastric junction defined as adenocarcinoma involving esophagogastric junction when its epicenter is localized within 5cm proximally or 5cm distally to the anatomical esophagogastric junction with subclassification to 3 topographic types (type I between 5cm and 1cm above; type II between 1cm above and 2cm below; type III between 2cm and 5cm below anatomic junction of the esophagus and the stomach).
  • Potentially resectable, local or locoregional cancer with clinical staging cT2-4aN0-3M0.
  • The intended number of randomized patients has been set as 100: 50 patients randomized to each therapeutic arm with assumption, that 80% of randomized patients will complete the treatment protocol.

Exclusion Criteria:

  • disseminated cancer
  • poor general condition (KI <70)
  • adenocarcinoma of the stomach
  • adenocarcinoma of the esophagus

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Combined therapy
The combined modality therapy will be consisted of preoperative chemoradiotherapy (Docetaxel, Oxaliplatin, 5-Fluorouracil, 45Gy) for type I i II cancer or preoperative chemotherapy (Docetaxel, Oxaliplatin, 5-Fluorouracil) for type III cancer and followed by surgery.
Other: preoperative chemo- and chemoradiotherapy
2 cycles of triple regimen chemotherapy consisting of docetaxel (75mg/m2 iv infusion), oxaliplatin (130mg/m2 iv infusion) and 5-fluorouracil (750mg/m2 iv infusion followed by fractionated irradiation (total dose 45Gy in 25 fractions of 1,8Gy) combined with chemotherapy consisting of 3 cycles of 1-day chemotherapy with docetaxel (50mg/m2 iv infusion) and oxaliplatin (85mg/m2 iv infusion
Other Names:
  • irradiation
  • docetaxel,
  • oxaliplatin,
  • 5-fluorouracil,
Active Comparator: Surgery
The extent of surgery will be associated with the topographic type of carcinoma of the esophagogastric junction: type I - subtotal esophagectomy with superior gastric resection, splenectomy and two-field mediastinal lymph node dissection; type II and III - total gastrectomy with distal esophagectomy, splenectomy and D2 with mediastinal inferior lymph node dissection.
Procedure: Surgical resection
The extent of surgery will be associated with the topographic type of carcinoma of the esophagogastric junction: type I - subtotal esophagectomy with superior gastric resection, splenectomy and two-field mediastinal lymph node dissection; type II and III - total gastrectomy with distal esophagectomy, splenectomy and D2 with mediastinal inferior lymph node dissection.
Other Names:
  • gastrectomy
  • esophagectomy,

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pathological response to treatment
Time Frame: 6-12 weeks after chemoradiotherapy
Pathological response to treatment assessed as a tumor regresion grade in histopahological assessment of the surgical specimen
6-12 weeks after chemoradiotherapy

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical response to treatment
Time Frame: 5 weeks after chemoradiotherapy
Clinical response to treatment based on the modified RECIST criteria measured by CT
5 weeks after chemoradiotherapy
The curative resection (R0) rate
Time Frame: 6-12 weeks after chemoradiotherapy
The curative resection (R0) rate defined by the assessment of proximal, distal and circumferential margins
6-12 weeks after chemoradiotherapy
chemoradiotherapy related toxicity
Time Frame: 6-12 weeks after chemoradiotherapy
The rate and intensity of chemo- and chemoradiotherapy related toxicity
6-12 weeks after chemoradiotherapy
postoperative complications rate
Time Frame: 30 days after surgical resection
The rate and intensity of postoperative morbidity and mortality
30 days after surgical resection
Overall and cancer free survival
Time Frame: 5 years from onset of the chemoradiotherapy
Overall and cancer free survival
5 years from onset of the chemoradiotherapy
Quality of life changes
Time Frame: 5 years after the onset of cheemoradiotherapy
Quality of life changes
5 years after the onset of cheemoradiotherapy
The rate of chemo- and chemoradiotherapy dose reduction
Time Frame: 11 weeks during chemo- and chemoradiotherapy
The rate of dose reduction due to chemotherapy or radiotherapy related toxicity
11 weeks during chemo- and chemoradiotherapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Medical University of Lublin

Investigators

  • Principal Investigator: Tomasz Skoczylas, MD, PhD, Second Department of General & Gastrointestinal Surgery & Surgical Oncology of the Alimentary Tract, Medical University of Lublin
  • Principal Investigator: Grzegorz Wallner, Professor, Second Department of General & Gastrointestinal Surgery & Surgical Oncology of the Alimentary Tract, Medical University of Lublin
  • Principal Investigator: Andrzej Dąbrowski, Professor, Second Department of General & Gastrointestinal Surgery & Surgical Oncology of the Alimentary Tract, Medical University of Lublin
  • Principal Investigator: Witold Zgodziński, MD, PhD, Second Department of General & Gastrointestinal Surgery & Surgical Oncology of the Alimentary Tract, Medical University of Lublin
  • Principal Investigator: Marek Majewski, MD, PhD, Second Department of General & Gastrointestinal Surgery & Surgical Oncology of the Alimentary Tract, Medical University of Lublin
  • Principal Investigator: Maria Mazurkiewicz, Professor, Department of Oncology, Medical University of Lublin, Lublin Oncology Center
  • Principal Investigator: Anna Brzozowska, MD, PhD, Department of Oncology, Medical University of Lublin, Lublin Oncology Center
  • Principal Investigator: Ludmiła Grzybowska-Szatkowska, MD, PhD, Department of Oncology, Medical University of Lublin, Lublin Oncology Center
  • Principal Investigator: Witold Krupski, Professor, Second Department of Radiology, Medical University of Lublin
  • Principal Investigator: Ewa Kurys-Denis, MD, PhD, Second Department of Radiology, Medical University of Lublin
  • Principal Investigator: Justyna Szumiło, Professor, Department of Clinical Pathomorphology, Medical University of Lublin
  • Principal Investigator: Agnieszka Fronczek, MD, Department of Clinical Pathomorphology, Medical University of Lublin

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2012

Primary Completion (Anticipated)

December 1, 2015

Study Completion (Anticipated)

December 1, 2020

Study Registration Dates

First Submitted

January 25, 2012

First Submitted That Met QC Criteria

January 31, 2012

First Posted (Estimate)

February 1, 2012

Study Record Updates

Last Update Posted (Estimate)

February 5, 2013

Last Update Submitted That Met QC Criteria

February 2, 2013

Last Verified

February 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EGC-0254/87/2011
  • UML-EGC-2011 (Other Identifier: UML)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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