Trial of Preoperative Therapy for Gastric and Esophagogastric Junction Adenocarcinoma

Gastric Cancer Clinical Trial

— TOPGEAR  

Official title:

A Randomised Phase II/III Trial of Preoperative Chemoradiotherapy Versus Preoperative Chemotherapy for Resectable Gastric Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01924819
• Other study ID #: AG0407GR
• Secondary ID: ACTRN12609000035
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: September 2009
• Est. completion date: December 31, 2026

Study information

• Verified date: March 2022
• Source: Australasian Gastro-Intestinal Trials Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Gastric cancer remains a significant global public health problem. Although in developed countries its incidence has dramatically decreased, on a worldwide scale it is still a leading cause of cancer-related deaths. Surgery is the only potentially curative treatment for gastric cancer. Although the survival rates for patients with early stage disease (stage 1A and 1B) are good, this subgroup of patients constitutes only 20% of those undergoing resection. The majority of patients will have locally advanced or metastatic disease at presentation, which has an extremely poor prognosis. The current five-year survival rate for gastric cancer in Western countries is approximately 20-30%, a figure that has improved little over the past 30 years. The intervention arm in TOPGEAR consists of pre-operative chemotherapy, pre-operative chemoradiotherapy, surgery and post-operative chemotherapy. The control arm consists of pre-operative chemotherapy, surgery and post-operative chemotherapy. The primary objective of TOPGEAR is to investigate whether the addition of chemoradiotherapy to chemotherapy is superior to chemotherapy alone in the neoadjuvant setting by improving pathological complete response rates in the first instance, and subsequently overall survival, in patients undergoing adequate surgery (D1+ dissection) for resectable gastric cancer.

Description:

Purpose: The purpose of this phase II/III clinical trial is to determine if pre-operative chemoradiotherapy improves overall survival in participants with resectable gastric cancer. Trial details: Participants will be randomised to receive either pre-operative chemotherapy or pre-operative chemoradiotherapy. The will undergo surgery and then receive further post-operative chemotherapy. Participants will be followed up for 5 years after treatment.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 574
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically proven adenocarcinoma of the stomach or gastroesophageal junction (GEJ)

that is:

1. Stage IB (T1N1 only, T2N0 not eligible) - IIIC, i.e. T3 - T4 and/or node positive, according to American Joint Committee on Cancer (AJCC) 7th edition.

2. Considered operable following initial staging investigations (surgeon believes that an R0 resection can be achieved) (GEJ tumours are defined as tumours that arise in the cardia or at the GEJ that do not involve more than 2cm of the lower esophagus, i.e. Siewert Type II and Siewert Type III)

• Age >=18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Adequate organ function defined as follows:

1. Bone marrow: Haemoglobin >=90 g/L, Absolute neutrophil count (ANC) >=1.5 x 10? /L, White blood cell count >=3 x 10? /L, Platelet count >=100 x 10? /L

2. Hepatic: Serum bilirubin <=1.5 x upper limit of normal (ULN), aspartate aminotransferase (AST) and/or alanine transaminase (ALT) <=3.0 x ULN

3. Renal: Serum creatinine <=0.150 mmol/L, Calculated creatinine clearance >=50 mL/min

• Disease which can be radically treated with radiotherapy to 45 Gy with standard fractionation
• Any patient with a history of ischaemic heart disease and abnormal ECG, or who is over 60 years of age should have a pre-treatment evaluation of cardiac function with a multigated acquisition (MUGA) scan or echocardiogram. Patients will only be included if the left ventricular ejection fraction is >=50%.
• Written informed consent obtained before randomization
• Negative pregnancy test for women of childbearing potential within 7 days of commencing study treatment. Males and females of reproductive potential must agree to practice adequate contraceptive measures.

Exclusion Criteria:

• Evidence of metastatic disease
• Prior chemotherapy or radiotherapy
• Patients with a past history of cancer in the 5 years before randomization except for the following. Patients with squamous or basal cell carcinoma of the skin that has been effectively treated, and patients with carcinoma in situ of the cervix that has been treated by operation only are eligible, even if they were diagnosed and treated within the 5 years before randomization.
• Patients with other significant underlying medical conditions that may be aggravated by the study treatment or are not controlled
• Pregnant or lactating females or female patients of childbearing potential who have not been surgically sterilized or are without adequate contraceptive measures
• Cardiac failure and other contraindications to epirubicin
• Patients with impaired gastrointestinal absorption for whatever reason
• Patients medically unfit for cisplatin chemotherapy due to one or more of the

following reasons:

1. Clinically significant sensorineural hearing impairment (audiometric abnormalities without corresponding clinical deafness will not be regarded as a contraindication to cisplatin)

2. Severe tinnitus

3. Renal impairment (GFR <=50ml/min)

4. Peripheral neuropathy >=grade 2

5. Inability to tolerate intravenous hydration e.g due to cardiac disease

6. Co-morbidities (based on clinical judgement by the investigator) that in the view of the investigator would preclude the safe administration of cisplatin.

Related Conditions & MeSH terms

• Gastric Cancer
• Stomach Neoplasms

Intervention

Drug:
• Epirubicin + cisplatin + 5-fluorouracil OR epirubicin + cisplatin + capecitabine OR epirubicin + oxaliplatin + capecitabine OR 5-Fluorouracil + leucovorin + oxaliplatin + docetaxel
Epirubicin 50 mg/m2 IV day 1, cisplatin 60 mg/m2 IV day 1, 5-fluorouracil 200 mg/m2/d IV 21 day continuous infusion (ECF chemotherapy). Epirubicin 50 mg/m2 IV day 1, Cisplatin 60 mg/m2 IV day 1, Capecitabine (X = Xeloda) 625mg/m2, bid days 1-21 (ECX chemotherapy) Epirubicin 50mg/m2 IV day 1, Oxaliplatin (O) 130mg/m2 IV day 1, Capecitabine 625mg/m2, bid days 1-21 (EOX chemotherapy) 5-Fluorouracil 2600 mg/m² IV 24 h infusion day 1, Leucovorin (L) 200 mg/m² IV day 1, Oxaliplatin 85 mg/m² IV day 1, Docetaxel (T) 50 mg/m² IV day 1 (FLOT chemotherapy)

Radiation:
• Preoperative chemoradiotherapy
Chemotherapy: Continuous infusional 5-fluorouracil 200mg/m2/day, 7 days per week, throughout the entire period of radiotherapy or capecitabine 825 mg/m2, oral tablet twice daily, days 1-5 of each week of radiotherapy (without weekends). Radiotherapy: 45 Gy of radiation in 25 fractions, five days per week for five weeks.

Procedure:
• Gastric resection
The acceptable resections are a total gastrectomy, a subtotal gastrectomy, and an esophagogastrectomy (Ivor-Lewis esophagogastrectomy for gastroesophageal junction cancers [Siewert Type II and Siewert Type III] invading up to but no more than 2cm of the lower esophagus). The minimum extent of the operation should be a D1+ lymph node dissection but it is recommended that a D2 dissection be performed or a D1+ for gastroesophageal junction cancers requiring an esophagogastrectomy.

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Adelaide	South Australia
Australia	Princess Alexandra Hospital	Brisbane	Queensland
Australia	Geelong Hospital	Geelong	Victoria
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Launceston General Hospital	Launceston	Tasmania
Australia	Austin Hospital	Melbourne	Victoria
Australia	Monash Medical Centre	Melbourne	Victoria
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	St Vincent's Hospital	Melbourne	Victoria
Australia	Sir Charles Gairdner Hospital	Nedlands	Western Australia
Australia	Calvary Mater Newcastle	Newcastle	New South Wales
Australia	Liverpool Hospital	Sydney	New South Wales
Australia	Nepean Hospital	Sydney	New South Wales
Australia	Prince of Wales Hospital	Sydney	New South Wales
Australia	Royal North Shore Hospital	Sydney	New South Wales
Australia	Royal Prince Alfred Hospital	Sydney	New South Wales
Australia	St George Hospital	Sydney	New South Wales
Australia	Westmead Hospital	Sydney	New South Wales
Australia	The Tweed Hospital	Tweed Heads	New South Wales
Australia	Wollongong Hospital	Wollongong	New South Wales
New Zealand	Auckland Hospital	Auckland
New Zealand	Dunedin Hospital	Dunedin
New Zealand	Waikato Hospital	Hamilton

Sponsors (5)

Lead Sponsor	Collaborator
Australasian Gastro-Intestinal Trials Group	European Organisation for Research and Treatment of Cancer - EORTC, National Health and Medical Research Council, Australia, NCIC Clinical Trials Group, Trans Tasman Radiation Oncology Group

Countries where clinical trial is conducted

Australia,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival	The interval from the date of randomisation to the date of death from any cause, or the date last known alive.	Up to 5 years
Secondary	Disease free survival	The time from the date of randomisation to the first observation of disease progression or death due to any cause.	Up to 5 years
Secondary	Pathological response rate	The extent of reduction in tumour size following pre-operative treatment, as determined by macroscopic and microscopic assessment of the tumour.	At time of surgery
Secondary	Proportion of participants with given grades of toxicities	The proportion of participants starting at least one cycle of treatment and the grades of the toxicities reported.	Up to 5 years
Secondary	Surgical complete resection rate (R0)	The complete macroscopic resection of gross tumour with negative surgical margins.	At the time of surgery