Rectal Cancer
Conditions
Keywords
5-FU, cetuximab, radiation, adenocarcinoma of the rectum, neoadjuvant therapy
Brief summary
The standard treatment for rectal cancer is to receive the chemotherapeutic drug 5-fluorouracil (5-FU) with radiation therapy before having surgery to remove the rectal cancer. This is known as neoadjuvant chemoradiotherapy. The purpose of this research study is to determine if Cetuximab improves the benefits of neoadjuvant chemoradiotherapy when given with 5-FU and radiation therapy.
Detailed description
The epidermal growth factor receptor (EGFR) present in normal and tumor cells is involved in signaling pathways affecting cellular growth, differentiation, proliferation and programmed cell death. Overexpression of EGFR has been associated with poorer prognosis in colorectal cancer. Cetuximab targets and blocks EGFR and has been shown to be safe and effective in treating colorectal cancer and head and neck cancers. The primary hypothesis is that cetuximab in combination with standard 5-FU and radiation as neoadjuvant therapy would improve pathological complete response (pCR) compared to the historical rate (30% versus 10%). The regimen would be considered promising if 5 or more of 25 evaluable participants achieve pCR. The probability of observing this outcome is 0.91 and 0.10 if the true pCR rate is 30% and 10%, respectively.
Interventions
DRUGCetuximab
DRUG5-Fluorouracil
RADIATIONRadiation
Sponsors
Massachusetts General Hospital
Beth Israel Deaconess Medical Center
Brigham and Women's Hospital
Bristol-Myers Squibb
Dana-Farber Cancer Institute
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
* Histologically confirmed adenocarcinoma of the rectum that begins within 15cm of the anal verge as determined by sigmoidoscopy and/or colonoscopy, with no evidence of distant metastatic disease. A complete colonoscopy to the cecum is recommended prior to initiating protocol therapy. * Staging with transrectal ultrasound or endorectal coil Magnetic resonance imaging (MRI) to confirm clinical stage of T3 or T4 or lymph node positive rectal adenocarcinoma * Tumor is K-ras wildtype by method of choice at respective institution (testing codons 12 and 13) * Performance status: Eastern Cooperative Oncology Group Performance Score (ECOG PS) less than or equal to 2 * 18 years of age or older * No evidence of metastatic disease by abdominal/pelvic (Computed tomography) CT and chest imaging * Adequate bone marrow, renal,and hepatic function as outlined in protocol * All patients will be evaluated by a surgeon and considered a candidate for definitive surgery * Coumadin or heparin management for line care of other indications is permitted. The International Normalised Ratio (INR) will be monitored weekly in patients taking coumadin.
Exclusion criteria
* Prior treatment for this malignancy * Prior history of pelvic radiation therapy * Prior history of 5-FU based or EGFR receptor inhibitor therapy * Prior history of an allergic reaction to a monoclonal antibody * Uncontrolled serious medical or psychiatric illness * Significant history of uncontrolled cardiac disease * Sexually active women of childbearing potential must use an effective method of birth control during the course of the study * Unwilling to agree to pre and post-cetuximab sigmoidoscopy and biopsy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response Rate | Disease is assessed at the time of surgery which in this study cohort occurred up to 24 weeks from date of registration. | Pathological complete response (pCR) rate is the percentage of participants who achieve pCR defined as no evidence of tumor cells in the surgical specimen including the lymph nodes (down-staging to pathological T0, N0 after planned neoadjuvant therapy). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Local Recurrence Rate | CT scans for surveillance recommended yearly x 3 years from date of surgery with additional scanning at discretion of treating oncologist. Mean follow-up for this study cohort was 4.4 years from study entry, up to 7.9 years. | Local recurrence rate is the percentage of participants experiencing recurrence within the pelvis. |
| Complete Resection Rate | Disease is assessed at the time of surgery which in this study cohort occurred up to 24 weeks from date of registration. | Complete resection rate is the percentage of participants having all gross disease removed by the surgeon at the time of operation. |
| Incidence of Grade 4 Treatment-Related Toxicity | Disease is assessed through the time of surgery which in this study cohort occurred up to 24 weeks from date of registration. | All grade 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on NCI Common Toxicity Criteria for Adverse Events version 3 (CTCAEv3) as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 4 AE of any type during the time of observation. |
| 1-Year Overall Survival Rate | Mean follow-up for this study cohort was 4.4 years from study entry, up to 7.9 years. | 1-year overall survival is the percentage of participants remaining alive 1 year from study entry. |
| Distant Recurrence Rate | CT scans for surveillance recommended yearly x 3 years from date of surgery with additional scanning at discretion of treating oncologist. Mean follow-up for this study cohort was 4.4 years from study entry, up to 7.9 years. | Distant recurrence rate is the percentage of participants experiencing recurrence outside the pelvis. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 1-Year Disease-Free Survival Rate | CT scans for surveillance recommended yearly x 3 years from date of surgery with additional scanning at discretion of treating oncologist. Mean follow-up for this study cohort was 4.4 years from study entry, up to 7.9 years. | Disease-Free Survival Rate is the percentage of participants remaining alive without disease progression. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled from May 2008 through July 2012.
Participants by arm
| Arm | Count |
|---|---|
| Cetuximab With Standard 5-FU and Radiation Cetuximab: Participants first receive cetuximab at the initial dose of 400 mg/m2 intravenously (IV) administered over 120 minutes, followed by weekly infusions at 250 mg/m2 over 60 minutes. Cetuximab is given as single agent during the first 3 weeks on study and then in combination with 5-FU and radiation.
Radiation: Radiation therapy given as standard of care is initiated after the 3rd dose of cetuximab with a total dose of 50.4 Gray (Gy) in 28 fractions over approximately 5.5 weeks.
5-FU: Participants receive 5-Fluorouracil (5-FU) continuous infusion through central venous access at 225 mg/m2/day given 7 days a week starting day 1 of radiation (no later than 3 days) and lasting the duration of radiation therapy.
Duration of neoadjuvant therapy is estimated to be 9 weeks. Surgery follows at week 13-17. Sigmoidoscopy is performed for biopsy prior to the 1st dose and after 3rd dose of cetuximab before the initiation of radiation and/or 5-FU. | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Cetuximab With Standard 5-FU and Radiation |
|---|---|
| Age, Continuous | 56 years |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 13 |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 6 / 13 |
Outcome results
Primary
Pathological Complete Response Rate
Pathological complete response (pCR) rate is the percentage of participants who achieve pCR defined as no evidence of tumor cells in the surgical specimen including the lymph nodes (down-staging to pathological T0, N0 after planned neoadjuvant therapy).
Time frame: Disease is assessed at the time of surgery which in this study cohort occurred up to 24 weeks from date of registration.
Population: The analysis dataset is comprised of all enrolled patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab With Standard 5-FU and Radiation | Pathological Complete Response Rate | 30.8 percentage of participants |
Secondary
1-Year Overall Survival Rate
1-year overall survival is the percentage of participants remaining alive 1 year from study entry.
Time frame: Mean follow-up for this study cohort was 4.4 years from study entry, up to 7.9 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab With Standard 5-FU and Radiation | 1-Year Overall Survival Rate | 100.0 percentage of participants |
Secondary
Complete Resection Rate
Complete resection rate is the percentage of participants having all gross disease removed by the surgeon at the time of operation.
Time frame: Disease is assessed at the time of surgery which in this study cohort occurred up to 24 weeks from date of registration.
Population: The analysis dataset is comprised of all enrolled patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab With Standard 5-FU and Radiation | Complete Resection Rate | 100.0 percentage of participants |
Secondary
Distant Recurrence Rate
Distant recurrence rate is the percentage of participants experiencing recurrence outside the pelvis.
Time frame: CT scans for surveillance recommended yearly x 3 years from date of surgery with additional scanning at discretion of treating oncologist. Mean follow-up for this study cohort was 4.4 years from study entry, up to 7.9 years.
Population: The analysis dataset is comprised of all enrolled patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab With Standard 5-FU and Radiation | Distant Recurrence Rate | 0.0 percentage of participants |
Secondary
Incidence of Grade 4 Treatment-Related Toxicity
All grade 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on NCI Common Toxicity Criteria for Adverse Events version 3 (CTCAEv3) as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 4 AE of any type during the time of observation.
Time frame: Disease is assessed through the time of surgery which in this study cohort occurred up to 24 weeks from date of registration.
Population: The analysis dataset is comprised of all enrolled patients.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cetuximab With Standard 5-FU and Radiation | Incidence of Grade 4 Treatment-Related Toxicity | 3 Participants |
Secondary
Local Recurrence Rate
Local recurrence rate is the percentage of participants experiencing recurrence within the pelvis.
Time frame: CT scans for surveillance recommended yearly x 3 years from date of surgery with additional scanning at discretion of treating oncologist. Mean follow-up for this study cohort was 4.4 years from study entry, up to 7.9 years.
Population: The analysis dataset is comprised of all enrolled patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab With Standard 5-FU and Radiation | Local Recurrence Rate | 0.0 percentage of participants |
Other Pre-specified
1-Year Disease-Free Survival Rate
Disease-Free Survival Rate is the percentage of participants remaining alive without disease progression.
Time frame: CT scans for surveillance recommended yearly x 3 years from date of surgery with additional scanning at discretion of treating oncologist. Mean follow-up for this study cohort was 4.4 years from study entry, up to 7.9 years.
Population: The analysis dataset is comprised of all enrolled patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab With Standard 5-FU and Radiation | 1-Year Disease-Free Survival Rate | 100.0 percentage of participants |