Adenocarcinoma of the Gastroesophageal Junction, Esophageal Cancer
Conditions
Keywords
adenocarcinoma of the esophagus, adenocarcinoma of the gastroesophageal junction, stage II esophageal cancer, stage III esophageal cancer, stage IV esophageal cancer
Brief summary
RATIONALE: Monoclonal antibodies, such as panitumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as cisplatin and docetaxel, work in different ways to kill tumor cells or stop them from growing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving combination chemotherapy together with panitumumab and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This phase II trial is studying how well giving panitumumab together with docetaxel, cisplatin, radiation therapy, and surgery works in treating patients with newly diagnosed, locally advanced esophageal cancer or cancer of the gastroesophageal junction.
Detailed description
OBJECTIVES: Primary * To determine the pathologic complete response rate in patients with newly diagnosed, locally advanced adenocarcinoma of the distal esophagus or gastroesophageal junction treated with neoadjuvant panitumumab and combination chemoradiotherapy followed by surgery. Secondary * To determine the near-complete pathologic response rate in the primary tumor (≤ 10% residual viable cancer). * To determine the overall survival and disease-free survival rates of these patients. * To determine the safety profile of this regimen. OUTLINE: Patients receive panitumumab IV over 1 hour, docetaxel IV over 1 hour, and cisplatin IV over 1-2 hours on day 1 in weeks 1, 3, 5, 7, and 9. Patients also undergo radiotherapy once daily 5 days a week beginning in week 5 and continuing for 5.5 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Beginning 6-9 weeks after completion of chemoradiotherapy, patients with no evidence of metastatic disease undergo esophagectomy. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 1 year OR every 6 months for 3 years.
Interventions
BIOLOGICALpanitumumab
DRUGcisplatin
DRUGdocetaxel
PROCEDUREneoadjuvant therapy
PROCEDUREtherapeutic conventional surgery
RADIATIONradiation therapy
Sponsors
National Cancer Institute (NCI)
Amgen
Alliance for Clinical Trials in Oncology
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. ≥ 18 years old 2. ECOG/Zubrod Performance Status 0-1 3. Biopsy-proven resectable primary (nonrecurrent) adenocarcinoma of the distal esophagus or GE junction (Siewert Type I or II) * Siewert Type I: adenocarcinoma of the distal esophagus * Siewert Type II: adenocarcinoma of the esophago-gastric junction/real cardia 4. Pre-registration EUS, CT of chest and upper abdomen, and PET must support a clinical stage of T3N0M0, T2-3N1M0 or T2-3N0-1M1a (celiac adenopathy must be ≤ 2 cm by EUS). Clinically staged T1 tumors and T2N0M0 tumors are not eligible. N1 does not require biopsy/FNA. Note: Patients requiring a stent for nutrition must have staging examinations and scans completed before stent placement. 5. No definitive radiological evidence of distant metastases. 6. No pre-existing grade 2 or greater peripheral neuropathy (CTCAE v3) of any etiology. 7. Adequate bone marrow, hepatic and renal function prior to registration: * WBC ≥ 3,000/mm³ * ANC ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Hemoglobin ≥ 9.5 g/dL * Creatinine ≤ 1.5 mg/dL * Total bilirubin ≤ 3 mg/dL * AST (SGOT) ≤ 2.0 times upper limit of normal (ULN) * ALT (SGPT) ≤ 2.0 times ULN * Alkaline phosphatase ≤ 2.0 times ULN * Albumin ≥ 2.0 g/dL OR prealbumin ≥ 15 mg/dL * Magnesium ≥ lower limit of normal (LLN) 8. Patient must be evaluated before registration by medical oncologist, radiation oncologist and surgeon and deemed fit for protocol therapy and surgery. 9. No prior invasive malignancy, unless disease-free for ≥ 5 years prior to registration (Exceptions: non-melanoma skin cancer, in-situ cancers). 10. Non-pregnant and non-breast feeding. Female participants of child-bearing potential must have a negative urine or serum pregnancy test prior to registration. Perimenopausal participants must be amenorrheic ≥ 12 months to be considered not of childbearing potential. All patients of reproductive potential must agree to use an an effective method of birth-control while receiving study therapy and for six months after completion of therapy. 11. No prior chest or upper abdomen radiotherapy; prior therapy with cisplatin, docetaxel, panitumumab or other anti-EGFR therapy or prior esophageal or gastric surgery (Exception: prior surgery to treat reflux disease) 12. No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psyschiatric illness/social situations that would limit compliance with study requirements. 13. No history of interstitial lung disease (eg, pneumonitis or pulmonary fibrosis or any evidence of interstitial lung disease on baseline chest CT scan 14. No history of any medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risks associated with the study participation or investigational product(s) administration or may interfere with the interpretation of the results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Pathologic Complete Response Following Surgery | Post surgery | Pathologic complete response (pCR) was defined as no viable residual tumor cells. A cellular residual mucin pools should be noted but also considered a pathologic complete response. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Near-complete Response Rate (≤ 10% Residual Cancer in Primary Tumor Viable) | Post surgery | — |
| Percentage of Participants With 3-year Overall Survival | 3 years | Survival time was defined to be the length of time from start of study therapy to death due to any cause or until last follow-up (censored value). |
| Percentage of Participants With 2-year Disease-free Survival | 2 years | Disease-free survival was defined as the time from start of study therapy to documentation of disease recurrence. Participants who died without documentation of recurrence were considered to have had tumor recurrence at the time of death unless there was documented evidence that no recurrence occured before death. Participants who failed to return for evaluation after beginning therapy were censored for recurrence on the last day of therapy. Participants who experienced major treatment violations were censored for recurrence on the date the treatment violation occured. |
| Number of Participants With Frequent (>=15% Grade 3/4 Incidence) Adverse Events Regardless of Attribution | Week 1, 3, 5, 7, 9, 4-6 weeks after therapy and within 30 days post surgery | Adverse events were assessed by NCI CTCAE (Common Terminology Criteria for Adverse Events) v3.0. Grade 1= mild, grade 2= moderate, grade 3= severe, grade 4= life-threatening; and grade 5= death. |
Countries
United States
Participant flow
Recruitment details
Seventy participants were recruited between January 2009 to July 2011 from 24 institutions.
Pre-assignment details
Five participants were declared ineligible. One participant had a celiac lymph node \>2 cm and one participant had two primary tumors. Liver lesions were noted and not investigated in one participant. Two participants had Siewert type III tumors. These five participants were excluded from all analysis except adverse events.
Participants by arm
| Arm | Count |
|---|---|
| Docetaxel + Cisplatin + Panitumumab + RT Patients received docetaxel (40 mg/m\^2), cisplatin (40 mg/m\^2) and panitumumab (6 mg/kg) on weeks 1, 3, 5, 7, and 9 with radiotherapy (RT) (5040 cGy, 180 cGy/day x 28 days) beginning week 5. Resection was planned after completing chemotherapy (CRT). | 65 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 3 |
| Overall Study | Progression | 4 |
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Docetaxel + Cisplatin + Panitumumab + RT |
|---|---|
| Age, Continuous | 61 years |
| Body Mass Index (BMI) | 27.8 kg/m^2 |
| Clinical M Stage M0= No distant metastasis | 56 participants |
| Clinical M Stage M1a= Metastasis in celiac or cervical lymph nodes | 9 participants |
| Clinical N Stage N0= No regional lymph node metastasis | 13 participants |
| Clinical N Stage N1= Regional lymph node metastasis | 52 participants |
| Clinical T Stage T2 = Tumor invades muscularis propria | 7 participants |
| Clinical T Stage T3= Tumor invades adventitia | 58 participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 0= Asymptomatic and fully active | 37 participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 1= Symptomatic; fully ambulatory | 28 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 64 Participants |
| Region of Enrollment United States | 65 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 59 Participants |
| Tumor location (Siewert Type) I | 36 participants |
| Tumor location (Siewert Type) II | 29 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 70 / 70 |
| serious Total, serious adverse events | 46 / 70 |
Outcome results
Primary
Number of Participants With Pathologic Complete Response Following Surgery
Pathologic complete response (pCR) was defined as no viable residual tumor cells. A cellular residual mucin pools should be noted but also considered a pathologic complete response.
Time frame: Post surgery
Population: All participants who have met the eligibility criteria that have signed a consent form and began treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Docetaxel + Cisplatin + Panitumumab + RT | Number of Participants With Pathologic Complete Response Following Surgery | 18 participants |
Secondary
Number of Participants With Frequent (>=15% Grade 3/4 Incidence) Adverse Events Regardless of Attribution
Adverse events were assessed by NCI CTCAE (Common Terminology Criteria for Adverse Events) v3.0. Grade 1= mild, grade 2= moderate, grade 3= severe, grade 4= life-threatening; and grade 5= death.
Time frame: Week 1, 3, 5, 7, 9, 4-6 weeks after therapy and within 30 days post surgery
Population: All recruited participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Docetaxel + Cisplatin + Panitumumab + RT | Number of Participants With Frequent (>=15% Grade 3/4 Incidence) Adverse Events Regardless of Attribution | Hemoglobin | 12 participants |
| Docetaxel + Cisplatin + Panitumumab + RT | Number of Participants With Frequent (>=15% Grade 3/4 Incidence) Adverse Events Regardless of Attribution | Lymphocytes | 30 participants |
| Docetaxel + Cisplatin + Panitumumab + RT | Number of Participants With Frequent (>=15% Grade 3/4 Incidence) Adverse Events Regardless of Attribution | Neutrophils | 12 participants |
| Docetaxel + Cisplatin + Panitumumab + RT | Number of Participants With Frequent (>=15% Grade 3/4 Incidence) Adverse Events Regardless of Attribution | Dehydration | 13 participants |
| Docetaxel + Cisplatin + Panitumumab + RT | Number of Participants With Frequent (>=15% Grade 3/4 Incidence) Adverse Events Regardless of Attribution | Esophagitis | 13 participants |
| Docetaxel + Cisplatin + Panitumumab + RT | Number of Participants With Frequent (>=15% Grade 3/4 Incidence) Adverse Events Regardless of Attribution | Nausea | 11 participants |
Secondary
Number of Participants With Near-complete Response Rate (≤ 10% Residual Cancer in Primary Tumor Viable)
Time frame: Post surgery
Population: All participants who have met the eligibility criteria that have signed a consent form and began treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Docetaxel + Cisplatin + Panitumumab + RT | Number of Participants With Near-complete Response Rate (≤ 10% Residual Cancer in Primary Tumor Viable) | 11 participants |
Secondary
Percentage of Participants With 2-year Disease-free Survival
Disease-free survival was defined as the time from start of study therapy to documentation of disease recurrence. Participants who died without documentation of recurrence were considered to have had tumor recurrence at the time of death unless there was documented evidence that no recurrence occured before death. Participants who failed to return for evaluation after beginning therapy were censored for recurrence on the last day of therapy. Participants who experienced major treatment violations were censored for recurrence on the date the treatment violation occured.
Time frame: 2 years
Population: All registered participants who have met the eligibility criteria.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Docetaxel + Cisplatin + Panitumumab + RT | Percentage of Participants With 2-year Disease-free Survival | 41.4 percentage of participants |
Secondary
Percentage of Participants With 3-year Overall Survival
Survival time was defined to be the length of time from start of study therapy to death due to any cause or until last follow-up (censored value).
Time frame: 3 years
Population: All registered participants who have met the eligibility criteria.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Docetaxel + Cisplatin + Panitumumab + RT | Percentage of Participants With 3-year Overall Survival | 38.6 percentage of participants |