POWERRANGER: Preoperative Chemotherapy vs. Chemoradiation in Esophageal / GEJ Adenocarcinoma

Sponsor

Dr. Gordon Buduhan (Other)

Overall Status

Recruiting

CT.gov ID

NCT01404156

Collaborator

CancerCare Manitoba (Other), University of Toronto (Other), London Health Sciences Centre (Other)

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The best treatment for resectable esophageal or gastroesophageal adenocarcinoma is unknown. Although an operation to remove the esophagus is the most common treatment, previous studies have shown that patients live longer when either perioperative (before and after surgery) chemotherapy or preoperative (before surgery) chemotherapy plus radiation is given, compared to surgery alone. However it is unknown which of these treatments (perioperative chemotherapy or preoperative chemoradiation) is more effective in improving survival. A study where patients with resectable esophageal / GE junction cancer are chosen at random to receive one of the two preoperative treatments would help determine if one form of treatment improves survival compared to the other.

Patients with localized esophageal / GE junction cancer (adenocarcinoma) will be randomized to receive either preoperative and postoperative chemotherapy or preoperative chemoradiation followed by surgery.

The main objective of this pilot trial is to determine the possibility of conducting a larger study with many centers participating. If this study proves to be feasible with enough patients enrolled and able to tolerate treatments without major side effects then we can hopefully proceed to perform a larger multi-center trial to look for survival outcome differences between patients who receive preoperative chemotherapy and those who receive preoperative chemoradiation. The results of this trial would ultimately help us choose the most effective treatment of resectable esophageal cancer and hopefully improve survival.

Condition or Disease	Intervention/Treatment	Phase
Esophageal Cancer Adenocarcinoma, Esophageal Adenocarcinoma, Gastroesophageal Junction	Drug: (Epirubicin Cisplatin 5-Fluorouracil / Xeloda) OR 5-Fluorouracil Leucovorin Oxaliplatin Docetaxel Other: Carboplatin paclitaxel plus concurrent radiotherapy	Phase 2/Phase 3

Detailed Description

OBJECTIVE To determine the feasibility of a randomized trial of neoadjuvant chemotherapy vs. neoadjuvant chemoradiation for patients with resectable adenocarcinoma of the esophagus or gastroesophageal junction.

RESEARCH PLAN Phase III randomized 2-arm parallel group pilot study

1:1 randomization to A) or B)

TREATMENT REGIMEN A) PERIOPERATIVE CHEMOTHERAPY (OPTION of CHEMO REGIMEN 1 or 2) 1) FLOT - Four x 14 day cycles FLOT preoperatively and 4 cycles postoperatively: 5-Fluorouracil 2600 mg/m², day 1 IV every 14 days Leucovorin 200 mg/m², day 1, IV., every 14 days Oxaliplatin 85 mg/m², day 1, IV, every 14 days Docetaxel 50mg/m2, day 1, IV, every 14 days

ECF / ECX - Three x 21-day cycles ECF preoperatively and 3 cycles postoperatively (within 4-10 weeks after surgery): Epirubicin (50 mg/m²,) day 1 IV Cisplatin: 60 mg/m², day 1 IV 5-Fluorouracil: 200 mg/m², daily for 21 days by continuous IV infusion 5-FU may be substituted with Capecitabine (Xeloda) 625mg/m2, BID (ECX)

NEOADJUVANT CHEMORADIATION

-carboplatin and paclitaxel given on days 1, 8, 15, 22 and 29

paclitaxel: 50 mg / m2 IV
carboplatin: dosed to an area under the curve of 2, by Calvert formula Radiation Therapy 45-50.4 Gy in 25-28 fractions of 1.8 Gy/fraction, 5 fractions/wk 45-50.4 Gy in 25-28 fractions of 1.8 Gy/fraction, 5 fractions/wk Upon completion of neoadjuvant therapy, all patients will be considered for surgery.

Patients will be deemed acceptable for surgery provided:

repeat imaging performed after neoadjuvant therapy does not demonstrate distant metastases or local invasion of the primary tumor into vital structures (heart, great vessels, trachea)
maintenance of adequate performance status and ability to tolerate esophagectomy

Surgery will be performed preferably within 8 weeks of completion of neoadjuvant therapy.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

PreOperative Treatment With chEmotheRapy or chemoRAdiatioN in esophaGeal or gastroEsophageal adenocaRcinoma

Actual Study Start Date :

Sep 1, 2015

Anticipated Primary Completion Date :

Jun 1, 2021

Anticipated Study Completion Date :

Jun 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Neoadjuvant Chemotherapy NEOADJUVANT CHEMOTHERAPY (OPTION of CHEMO REGIMEN 1 or 2) 1) FLOT - Four x 14 day cycles FLOT preoperatively and 4 cycles postoperatively (within 4-10 weeks after surgery): 5-Fluorouracil 2600 mg/m², day 1 IV every 14 days Leucovorin 200 mg/m², day 1, IV., every 14 days Oxaliplatin 85 mg/m², day 1, IV, every 14 days Docetaxel 50mg/m2, day 1, IV, every 14 days 2) ECF / ECX - Three x 21-day cycles ECF preoperatively and 3 cycles postoperatively (within 4-10 weeks after surgery): Epirubicin (50 mg/m²,mg per square meter of body-surface area) by intravenous bolus on day 1 IV Cisplatin: 60 mg/m², mg per square meter intravenously with hydration on day 1 IV 5-Fluorouracil: 200 mg/m², mg per square meter daily for 21 days by continuous intravenous infusionIV infusion 5-FU may be substituted with Capecitabine (Xeloda) 625mg/m2 PO BID (ECX)	Drug: (Epirubicin Cisplatin 5-Fluorouracil / Xeloda) OR 5-Fluorouracil Leucovorin Oxaliplatin Docetaxel NEOADJUVANT CHEMOTHERAPY (OPTION of CHEMO REGIMEN 1 or 2) 1) FLOT - Four x 14 day cycles FLOT preoperatively and 4 cycles postoperatively (within 4-10 weeks after surgery): 5-Fluorouracil 2600 mg/m², day 1 IV every 14 days Leucovorin 200 mg/m², day 1, IV., every 14 days Oxaliplatin 85 mg/m², day 1, IV, every 14 days Docetaxel 50mg/m2, day 1, IV, every 14 days 2) ECF / ECX - Three x 21-day cycles ECF preoperatively and 3 cycles postoperatively (within 4-10 weeks after surgery): Epirubicin (50 mg/m²,mg per square meter of body-surface area) by intravenous bolus on day 1 IV Cisplatin: 60 mg/m², mg per square meter intravenously with hydration on day 1 IV 5-Fluorouracil: 200 mg/m², mg per square meter daily for 21 days by continuous IV infusion 5-FU may be substituted with Capecitabine (Xeloda) 625mg/m2, PO BID (ECX) Other Names: ECF/ECX or FLOT
Experimental: Neoadjuvant Chemoradiation 1) -carboplatin and paclitaxel given on days 1, 8, 15, 22 and 29 paclitaxel: 50 mg / m2 IV over 1 hour carboplatin: dosed to an area under the curve of 2, by Calvert formula, as a 1 hour IV infusion Radiation Therapy Concurrent radiation therapy will begin within 24 hours of initiation of chemotherapy for patients randomized to chemoradiation treatment. Dose specifications: Phase 1: Total radiation prescription dose 45 Gy given in 25 fractions of 1.8 Gy per fraction, 5 fractions / week, one treatment / day, starting on the first day of first cycle of chemotherapy. Phase 2: (GTV only) Boost is not mandatory and up to the discretion of radiation oncologist. Total radiation prescription dose 5.4 Gy given in 3 fractions of 1.8 Gy per fraction, 5 fractions / week, one treatment.	Other: Carboplatin paclitaxel plus concurrent radiotherapy 5 cycles carboplatin and paclitaxel given on days 1, 8, 15, 22 and 29 preoperatively: paclitaxel: 50 mg / m2 IV over 1 hour carboplatin: dosed to an area under the curve of 2, by Calvert formula, as a 1 hour IV infusion Radiation Therapy Concurrent radiation therapy will begin within 24 hours of initiation of chemotherapy for patients randomized to chemoradiation treatment. 1. Dose specifications: Phase 1: Total radiation prescription dose 45 Gy given in 25 fractions of 1.8 Gy per fraction, 5 fractions / week, one treatment / day, starting on the first day of first cycle of chemotherapy. This total radiation dose option is acceptable if boost dose is not possible due to clinical reasons or dosimetric constraints. Phase 2: (GTV only) Boost is not mandatory and up to the discretion of radiation oncologist. Total radiation prescription dose 5.4 Gy given in 3 fractions of 1.8 Gy per fraction, 5 fractions / week, one treatment .

Arm

Intervention/Treatment

Active Comparator: Neoadjuvant Chemotherapy

NEOADJUVANT CHEMOTHERAPY (OPTION of CHEMO REGIMEN 1 or 2) 1) FLOT - Four x 14 day cycles FLOT preoperatively and 4 cycles postoperatively (within 4-10 weeks after surgery): 5-Fluorouracil 2600 mg/m², day 1 IV every 14 days Leucovorin 200 mg/m², day 1, IV., every 14 days Oxaliplatin 85 mg/m², day 1, IV, every 14 days Docetaxel 50mg/m2, day 1, IV, every 14 days 2) ECF / ECX - Three x 21-day cycles ECF preoperatively and 3 cycles postoperatively (within 4-10 weeks after surgery): Epirubicin (50 mg/m²,mg per square meter of body-surface area) by intravenous bolus on day 1 IV Cisplatin: 60 mg/m², mg per square meter intravenously with hydration on day 1 IV 5-Fluorouracil: 200 mg/m², mg per square meter daily for 21 days by continuous intravenous infusionIV infusion 5-FU may be substituted with Capecitabine (Xeloda) 625mg/m2 PO BID (ECX)

Drug: (Epirubicin Cisplatin 5-Fluorouracil / Xeloda) OR 5-Fluorouracil Leucovorin Oxaliplatin Docetaxel

NEOADJUVANT CHEMOTHERAPY (OPTION of CHEMO REGIMEN 1 or 2) 1) FLOT - Four x 14 day cycles FLOT preoperatively and 4 cycles postoperatively (within 4-10 weeks after surgery): 5-Fluorouracil 2600 mg/m², day 1 IV every 14 days Leucovorin 200 mg/m², day 1, IV., every 14 days Oxaliplatin 85 mg/m², day 1, IV, every 14 days Docetaxel 50mg/m2, day 1, IV, every 14 days 2) ECF / ECX - Three x 21-day cycles ECF preoperatively and 3 cycles postoperatively (within 4-10 weeks after surgery): Epirubicin (50 mg/m²,mg per square meter of body-surface area) by intravenous bolus on day 1 IV Cisplatin: 60 mg/m², mg per square meter intravenously with hydration on day 1 IV 5-Fluorouracil: 200 mg/m², mg per square meter daily for 21 days by continuous IV infusion 5-FU may be substituted with Capecitabine (Xeloda) 625mg/m2, PO BID (ECX)

Other Names:

ECF/ECX or FLOT

Experimental: Neoadjuvant Chemoradiation

1) -carboplatin and paclitaxel given on days 1, 8, 15, 22 and 29 paclitaxel: 50 mg / m2 IV over 1 hour carboplatin: dosed to an area under the curve of 2, by Calvert formula, as a 1 hour IV infusion Radiation Therapy Concurrent radiation therapy will begin within 24 hours of initiation of chemotherapy for patients randomized to chemoradiation treatment. Dose specifications: Phase 1: Total radiation prescription dose 45 Gy given in 25 fractions of 1.8 Gy per fraction, 5 fractions / week, one treatment / day, starting on the first day of first cycle of chemotherapy. Phase 2: (GTV only) Boost is not mandatory and up to the discretion of radiation oncologist. Total radiation prescription dose 5.4 Gy given in 3 fractions of 1.8 Gy per fraction, 5 fractions / week, one treatment.

Other: Carboplatin paclitaxel plus concurrent radiotherapy

5 cycles carboplatin and paclitaxel given on days 1, 8, 15, 22 and 29 preoperatively: paclitaxel: 50 mg / m2 IV over 1 hour carboplatin: dosed to an area under the curve of 2, by Calvert formula, as a 1 hour IV infusion Radiation Therapy Concurrent radiation therapy will begin within 24 hours of initiation of chemotherapy for patients randomized to chemoradiation treatment. 1. Dose specifications: Phase 1: Total radiation prescription dose 45 Gy given in 25 fractions of 1.8 Gy per fraction, 5 fractions / week, one treatment / day, starting on the first day of first cycle of chemotherapy. This total radiation dose option is acceptable if boost dose is not possible due to clinical reasons or dosimetric constraints. Phase 2: (GTV only) Boost is not mandatory and up to the discretion of radiation oncologist. Total radiation prescription dose 5.4 Gy given in 3 fractions of 1.8 Gy per fraction, 5 fractions / week, one treatment .

Outcome Measures

Primary Outcome Measures

compliance with assigned neoadjuvant treatment [5 weeks for chemoradiation arm, 6-8 weeks for chemotherapy arm]
- >60% patients allocated for randomization will start and complete treatment without major protocol violation
treatment response [5 weeks for chemoradiation arm, 6-8 weeks for chemotherapy arm]
>30% of patients in both treatment arms demonstrate partial or complete response as defined by Mandard TRG 1-3 on pathologic staging

Secondary Outcome Measures

survival [3 years]
3 year overall- and disease-free survival
EORTC QOL [baseline, 3, 6, 9, 12 months post treatment]
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30 Version 3.0

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

adenocarcinoma of esophagus or gastroesophageal junction; -cT1N1-3 or T2-4Nx; M0 by American Joint Committee on Cancer (AJCC) 7th Edition staging classification
proximal portion of the tumor at least 20 cm from the incisors on endoscopy, and extend no greater than 2 cm into the gastric cardia
tumor length < 8cm; diameter < 5 cm
age > 18 years
absolute neutrophil count (ANC) ≥ 1.5 x 109 / L
platelet count > 100 x 109 / L
creatinine clearance > 50 ml / min
bilirubin < 1.5x upper limit normal
FEV1 > 1.0 L
Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Exclusion Criteria

positive serum / urine pregnancy test for females of childbearing age
previous primary / recurrent malignancy in last 5 years (history of previous / current non-melanoma skin cancer or cervical in-situ carcinoma in last 5 years acceptable for inclusion in trial)
previous chemotherapy for esophageal cancer
previous radiation therapy that would overlap required radiation fields
major systemic illness(es) that would limit life expectancy <2 years
psychiatric / cognitive illness that would limit ability to give informed consent
(Patients will be reviewed by both a medical and radiation oncologist and deemed fit to undergo either neoadjuvant chemotherapy or chemoradiation, respectively)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Health Sciences Centre / CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3A 1R9
2	London Health Sciences Centre	London	Ontario	Canada	N6A 5W9
3	Toronto General Hospital / Princess Margaret Hospital	Toronto	Ontario	Canada