Trial of Preoperative Therapy for Gastric and Esophagogastric Junction Adenocarcinoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Gastric Cancer

Intervention / Treatment
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* Drug: Epirubicin + cisplatin + 5-fluorouracil OR epirubicin + cisplatin + capecitabine OR epirubicin + oxaliplatin + capecitabine OR 5-Fluorouracil + leucovorin + oxaliplatin + docetaxel
* Radiation: Preoperative chemoradiotherapy
* Procedure: Gastric resection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven adenocarcinoma of the stomach or gastroesophageal junction (GEJ) that is: 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. 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: Bone marrow: Haemoglobin >=90 g/L, Absolute neutrophil count (ANC) >=1.5 x 10⁹ /L, White blood cell count >=3 x 10⁹ /L, Platelet count >=100 x 10⁹ /L Hepatic: Serum bilirubin <=1.5 x upper limit of normal (ULN), aspartate aminotransferase (AST) and/or alanine transaminase (ALT) <=3.0 x ULN 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: Clinically significant sensorineural hearing impairment (audiometric abnormalities without corresponding clinical deafness will not be regarded as a contraindication to cisplatin) Severe tinnitus Renal impairment (GFR <=50ml/min) Peripheral neuropathy >=grade 2 Inability to tolerate intravenous hydration e.g due to cardiac disease Co-morbidities (based on clinical judgement by the investigator) that in the view of the investigator would preclude the safe administration of cisplatin.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Preoperative chemoradiotherapy<br>2 cycles preoperative chemotherapy with: epirubicin + cisplatin + 5-fluorouracil. (5-fluorouracil may be replaced with capecitabine). OR epirubicin + oxaliplatin + capecitabine OR 3 cycles of 5-fluorouracil +Leucovorin + oxaliplatin + docetaxel 5 weeks preoperative chemoradiotherapy. Gastric resection. 3 cycles adjuvant chemotherapy with: epirubicin + cisplatin + 5-fluorouracil. (5-fluorouracil may be replaced with capecitabine). OR epirubicin + oxaliplatin + capecitabine OR 4 cycles of 5-fluorouracil +Leucovorin + oxaliplatin + docetaxel | Drug: Epirubicin + cisplatin + 5-fluorouracil OR epirubicin + cisplatin + capecitabine OR epirubicin + oxaliplatin + capecitabine OR 5-Fluorouracil + leucovorin + oxaliplatin + docetaxel<br>* 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)<br>* Other names: Taxotere, Docetere;Radiation: Preoperative chemoradiotherapy<br>* 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.<br>Procedure: Gastric resection<br>* 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.<br>|
| Active Comparator: Preoperative chemotherapy<br>3 cycles preoperative chemotherapy with: epirubicin + cisplatin + 5-fluorouracil. (5-fluorouracil may be replaced with capecitabine). OR epirubicin + oxaliplatin + capecitabine OR 4 cycles of 5-fluorouracil +Leucovorin + oxaliplatin + docetaxel Gastric resection. 3 cycles adjuvant chemotherapy with: epirubicin + cisplatin + 5-fluorouracil. (5-fluorouracil may be replaced with capecitabine) OR epirubicin + oxaliplatin + capecitabine OR 4 cycles of 5-fluorouracil +Leucovorin + oxaliplatin + docetaxel | Drug: Epirubicin + cisplatin + 5-fluorouracil OR epirubicin + cisplatin + capecitabine OR epirubicin + oxaliplatin + capecitabine OR 5-Fluorouracil + leucovorin + oxaliplatin + docetaxel<br>* 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)<br>* Other names: Taxotere, Docetere;Procedure: Gastric resection<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| Surgical complete resection rate (R0) | The complete macroscopic resection of gross tumour with negative surgical margins. | At the time of surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastric cancer, Stomach cancer, Chemoradiotherapy, Surgery, Chemotherapy, Neoadjuvant