Esophageal Cancer
Conditions
Keywords
Therapeutic, Drug Therapy, combination, Radiotherapy
Brief summary
The purpose of this study is to determine whether the treatment of locally advanced esophageal squamous cell carcinoma (ESCC)with cetuximab in combination with paclitaxel, cisplatin and radiation improve clinical outcomes.
Detailed description
Esophageal cancer is the sixth leading cause of cancer death worldwide. Over the past 2 decades, well-designed clinical trials have documented the clinical benefits of combination of chemotherapy and radiation for localized esophageal cancer, either as primary therapy or in neoadjuvant setting. Paclitaxel, a radiation sensitizer, has important single-agent activity in esophageal cancer. Paclitaxel-based chemoradiation has been the framework for the recent Radiation Therapy Oncology Group (RTOG) trials of nonoperative management of esophageal cancer. Accumulating clinical evidence suggests that epidermal growth factor receptor (EGFR) represents a viable target in the treatment of esophageal cancer. EGFR expression is associated with poor prognosis. Cetuximab, a monoclonal antibody, binds specifically to EGFR on both normal and tumor cells and competitively inhibits the binding of EGF and other ligands, such as transforming growth factor (TGF)-α. Preclinical models have suggested synergy between cetuximab, paclitaxel, cisplatin and radiation. For patients with locally advanced head and neck cancer, the combination of cetuximab and radiation has demonstrated both response and survival benefit. With all these, the investigators hypothesize that treatment of locally advanced esophageal squamous cell carcinoma (ESCC)with cetuximab in combination with paclitaxel, cisplatin and radiation may further improve clinical outcomes. This trial results will be important as it may support further studies for setting the new treatment standard for ESCC.
Interventions
Cetuximab,injection,loading dose400 mg/m\^2,(Day1 in Week1) followed by 250 mg/m\^2(Day1, every week for Weeks 2-8)
DRUGPaclitaxel
Paclitaxel,injection,loading dose 45 mg/m\^2,(Day1 in every week for Weeks 2-8)
DRUGCisplatin
Cisplatin,injection,loading dose 20 mg/m\^2,(Day1 in every week for Weeks 2-8)
RADIATIONRadiation
Radiation, External beam therapy, total 59.4 Gy , 33 fractions, 1.8 Gy per fraction.(Day 1-Day 5 in every week 2-week 8).
Sponsors
Chinese Academy of Medical Sciences
Peking University Cancer Hospital & Institute
Hebei Fourth Hospital
Jiangsu Cancer Institute & Hospital
RenJi Hospital
The Affiliated Cancer Hospital of Zhengzhou University
West China Hospital
Shandong Cancer Hospital and Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Inpatients or outpatients, ≥ 18 years of age * Histologically confirmed primary (non-recurrent) ESCC fulfilling one of the following criteria (AJCC Staging System) * cervical esophageal carcinoma, stage Ⅱ-Ⅲ * upper thoracic esophageal carcinoma, stage Ⅱ-Ⅲ, or mid-thoracic esophageal carcinoma, stage Ⅱ-Ⅲ,which is medically unfit for surgery, surgery been refused and patient medically able to tolerate chemo-radiation. * Evidence of unidimensional measurable disease as per Response Evaluation Criteria in Solid Tumours (RECIST). * ECOG Performance status of 0-1 * Effective contraception for both male and female patients if the risk of conception exists * Adequate bone marrow reserves: neutrophil (ANC) count ≥ 1500 /mm\^3, platelet count ≥ 100,000 /mm\^3, hemoglobin ≥ 9 g/dl * Adequate renal function: serum creatinine ≤ 1.5 mg/dl and/or calculated creatinine clearance ≥ 60 ml/min * Adequate hepatic function: bilirubin level ≤ 1.5 x ULN, ASAT & ALST ≤ 1.5 x ULN * Tumor tissue available for KRAS biomarker test * Signed written informed consent prior to study entry
Exclusion criteria
* Previous chest radiotherapy, systemic chemotherapy, and major esophageal surgery * Concurrent chronic systemic immune therapy, targeted therapy not indicated in this study protocol * Multiple primary carcinomas of the esophagus * Pregnancy (confirmed by serum or urine β-HCG) or lactation period; * Uncontrolled diabetes, hypertension, and severe cardiac or pulmonary disease * Unable to comprehend the study requirements or who are not likely to comply with the study parameters; * Distant metastasis * Second malignancy, except for curable non-melanoma skin cancer, cervical cancer in situ, or malignant disease, free for ≥ 5 years * Known grade 3 or 4 allergic reaction to any of the study treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Overall Response Rate (RR) | 1 to 3 month after therapy | The overall response rate was defined as the numbers of patients with a complete response (CR) or partial response (PR). CR was defined as no target lesion at follow-up computed tomography scan and barium swallow examination 3-6 weeks after completion of chemo-radiation. PR was defined at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Toxicity | Every week during treatment and 1 month after therapy | All patients were regularly monitored for possible adverse events, which were graded according to National Cancer Institute Common Toxicity Criteria version 3.0. |
| Participants With Overall Survival (OS) at 1 Year | 1 year from the date of diagnosis | — |
| Participants With Overall Survival (OS) at 3 Year | 3 year from the date of diagnosis | — |
| Participants With Progression Free Survival (PFS) | Recurrence or metastasis from the date of diagnosis | — |
| Number of Participants With K-ras Gene Mutation | 07/29/2010-09/30/2010 | DNA was extracted from tumor specimens.Screened for the presence of KRAS codon 12 and 13 mutations using a PCR clamping and melting curve technique. PCR amplification of the wild-type KRAS sequence was suppressed in this process by the incorporation in the reaction mix of a locked nucleic-acid oligomer16 spanning codons 12 and 13 of the KRAS gene. Post-PCR hybridization and melting curve analysis using fluorescently tagged oligonucleotides incorporated in the original PCR reaction permitted the identification and discrimination of distinct KRAS codon 12 and 13 missense mutations. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cetuximab, Concurrent Chemo-radiotherapy Cetuximab, injection, loading dose400 mg/m\^2,(Day1 in Week1) followed by 250 mg/m\^2(Day1, every week for Weeks 2-8) Paclitaxel, injection,45 mg/m\^2 (Day 1, every week for Weeks 2-8) Cisplatin, injection,20 mg/m\^2 (Day 1, every week for Weeks 2-8) radiation therapy, 59.4 Gy, 1.8 Gy/33 fractions,1 fraction daily, Days 1-5 every week for Weeks 2-7, and Days 1-3 for Week 8 | 55 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Protocol Violation | 6 |
| Overall Study | Withdrawal by Subject | 0 |
Baseline characteristics
| Characteristic | Cetuximab, Concurrent Chemo-radiotherapy |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 46 Participants |
| Age Continuous | 57.68 years STANDARD_DEVIATION 6.93 |
| Region of Enrollment China | 55 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 38 / 55 |
| serious Total, serious adverse events | 2 / 55 |
Outcome results
Primary
Number of Participants With Overall Response Rate (RR)
The overall response rate was defined as the numbers of patients with a complete response (CR) or partial response (PR). CR was defined as no target lesion at follow-up computed tomography scan and barium swallow examination 3-6 weeks after completion of chemo-radiation. PR was defined at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: 1 to 3 month after therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab, Concurrent Chemo-radiotherapy | Number of Participants With Overall Response Rate (RR) | 44 participants |
Secondary
Number of Participants With K-ras Gene Mutation
DNA was extracted from tumor specimens.Screened for the presence of KRAS codon 12 and 13 mutations using a PCR clamping and melting curve technique. PCR amplification of the wild-type KRAS sequence was suppressed in this process by the incorporation in the reaction mix of a locked nucleic-acid oligomer16 spanning codons 12 and 13 of the KRAS gene. Post-PCR hybridization and melting curve analysis using fluorescently tagged oligonucleotides incorporated in the original PCR reaction permitted the identification and discrimination of distinct KRAS codon 12 and 13 missense mutations.
Time frame: 07/29/2010-09/30/2010
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab, Concurrent Chemo-radiotherapy | Number of Participants With K-ras Gene Mutation | 53 participants |
Secondary
Number of Participants With Toxicity
All patients were regularly monitored for possible adverse events, which were graded according to National Cancer Institute Common Toxicity Criteria version 3.0.
Time frame: Every week during treatment and 1 month after therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab, Concurrent Chemo-radiotherapy | Number of Participants With Toxicity | 55 participants |
Secondary
Participants With Overall Survival (OS) at 1 Year
Time frame: 1 year from the date of diagnosis
Secondary
Participants With Overall Survival (OS) at 3 Year
Time frame: 3 year from the date of diagnosis
Secondary
Participants With Progression Free Survival (PFS)
Time frame: Recurrence or metastasis from the date of diagnosis