Colorectal Cancer, Metastases
Conditions
Keywords
Colorectal Cancer, Metastasis, Neoadjuvant Therapy
Brief summary
The purpose of this study is to determine the effect of short-duration pre-operative FOLFOX based therapy on postoperative problems after liver surgery for patients with metastatic colorectal cancer.
Detailed description
Although early stage, localized colon and rectal cancers are associated with 5 year survival rates of nearly 90%, only a minority of patients present with localized disease. Unfortunately, at the time of their initial presentation, approximately 35% of patients with colon or rectal cancer have metastatic disease. Nearly two thirds of these patients with stage IV disease have evidence of extrahepatic spread and have a median overall survival rate of 8-10 months in the absence of further treatment. Even with the most intensive chemotherapeutic regimens, the median overall survival for these patients ranges from 12 months to 20 months. However, a small subset of patients with stage IV disease has isolated hepatic metastatic disease and can undergo resection. The patients with completely resected liver metastases enjoy a significantly higher overall five-year survival, which is as high as 58% in carefully selected patients. Ten-year overall survival has been reported in 22% of patients. Despite this improvement, the five-year disease-free survival for these patients is at best 35%, with hepatic recurrences occurring in 46%. The fact that adjuvant chemotherapy improves the three-year survival rate for stage II disease and five-year survival rates for stage III disease implies that it can treat micrometastatic disease in some fraction of patients. Because micrometastatic disease is likely the cause of the high recurrence rate in patients who undergo liver resection, there is a clear biologic rationale for using postoperative adjuvant chemotherapy after liver resection. Although this strategy is a common practice in many centers, no convincing data that this improves survival have been reported. A large randomized phase III trial (EORTC 40983) examining this question is currently ongoing and effect on survival has not yet been reported. Given that systemic chemotherapy after liver resection remains of unproven benefit at the present time, many have wondered if preoperative treatment might have more promise in improving recurrence rates.
Interventions
DRUGCetuximab
DRUGBevacizumab
DRUGLeucovorin
DRUGOxaliplatin
DRUGFluorouracil
Sponsors
Washington University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Synchronous or metachronous colorectal metastases * Technically resectable liver metastases * Four or fewer metastases * No tumors in porta hepatis * Resection of no more than 70% of liver needed * Medically suitable candidate for major liver resection * FDG-PET scan without metastatic disease outside the liver
Exclusion criteria
* Near-obstructing or obstructing colon lesions in patients in whom combined resection is planned (as delay for preoperative chemotherapy would be medially impossible) * Treatment with FOLFOX or cetuximab within 12 months * Treatment with irinotecan within 12 months * Abnormal liver function (ALT or AST \> 5x ULN, bilirubin \> 3x ULN) * Body mass index \>/= 35 kg/m² (as the risk for steatohepatitis is increased) * Renal insufficiency (Cr \> 2.5mg/dL) * Interstitial lung disease (because cetuximab has been rarely associated with development of interstitial lung disease) * ECOG performance score \>/= 3 * Patients unable to give informed consent * Pregnant patient (as cetuximab is a Class C drug) * Peripheral neuropathy \>/= grade II (as oxaliplatin causes neuropathy to worsen)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Postoperative Complication Rate | 30 days following surgery | Fraction of patients with any grade of complication I-V |
| Major Postoperative Complication Rate | 30 days following surgery | Fraction of patients with any complication grades IV and V |
| All-cause Mortality | 30 days following surgery | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Liver Injury Scale Score (0-27) | Time of surgery (approximately 11-16 weeks) | — |
| Postoperative Recurrence Patterns | Up to 5 years | Liver only vs distant disease |
| Change in Tumor Size From Pretreatment to Preoperative CT Scan | Completion of neoadjuvant therapy (approximately 8 weeks) | -Compare total longest diameter from baseline to preoperative CT scan. |
| Effect of Preoperative Chemotherapy on Tumor Size | Upon completion of neoadjuvant chemotherapy (approximately 2 months) | Number of participants whose tumor size decreased from baseline to completion of preoperative chemotherapy. |
| Histologic Hepatic Toxicity at Surgery | Time of surgery (approximately 11-16 weeks) | — |
| Nonalcoholic Steatohepatitis Score (0-3) | Time of surgery (approximately 11-16 weeks) | * NASH Scoring * Steatosis \*\*\<5% = 0 \*\*5-33%=1 \*\*\>33-66%=2 \*\*\>66%=3 * Lobular inflammation \*\*No foci=0 \*\*\<2 foci per x 200 field=1 \*\*2-4 foci per x 200 field=2 \*\*\>4 foci per x 200 field=3 * Hepatocellular ballooning \*\*None=0 \*\*Few balloon cells = 1 \*\*Many cells/prominent ballooning=2 |
Countries
United States
Participant flow
Recruitment details
The study opened to participant enrollment on 06/06/2007 and closed to participants enrollment on 11/03/2009.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 - Wildtype Neoadjuvant therapy
Week 1
* Leucovorin 400 mg/m2 IV
* Oxaliplatin 85 mg/m2 IV Cetuximab 400 mg/m2 IV
* 5FU bolus 400 mg/m2
* 5FU CIVI 1200 mg/m2/day over 46 hours
Weeks 2, 4, 6, 8 \*Cetuximab 250 mg/m2 IV weekly
Weeks 3, 5, 7
* Leucovorin 400 mg/m2 IV
* Oxaliplatin 85 mg/m2 IV Cetuximab 400 mg/m2 IV
* 5FU bolus 400 mg/m2
* 5FU CIVI 1200 mg/m2/day over 46 hours
Wait 3-8 weeks after completion of therapy
Liver resection
Wait 4 weeks or until clinical status allows
Adjuvant Therapy
Week 1, 3, 5, 7, 9, 11, 13, 15
* Leucovorin 400 mg/m2 IV
* Oxaliplatin 85 mg/m2 IV Cetuximab 400 mg/m2 IV
* 5FU bolus 400 mg/m2
* 5FU CIVI 1200 mg/m2/day over 46 hours
Weeks 2, 4, 6, 8, 10, 12, 16
\*Cetuximab 250 mg/m2 IV weekly | 7 |
| Arm 2 K-Ras 12/13 Codon Mutation Neoadjuvant Therapy
Weeks 1, 3, 5
* Leucovorin 400 mg/m2 IV
* Oxaliplatin 85 mg/m2 IV
* Bevacizumab 5 mg/kg IV
* 5FU bolus 400 mg/m2
* 5FU CIVI 1200 mg/m2
Week 7
* Leucovorin 400 mg/m2 IV
* Oxaliplatin 85 mg/m2 IV
* 5FU bolus 400 mg/m2
* 5FU CIVI 1200 mg/m2
Wait 3-8 weeks after completion of therapy
Liver resection
Wait 4 weeks or until clinical status allows
Adjuvant Therapy
Weeks 1, 3, 5, 9, 11, 13
* Leucovorin 400 mg/m2 IV
* Oxaliplatin 85 mg/m2 IV
* Bevacizumab 5 mg/kg IV
* 5FU bolus 400 mg/m2
* 5FU CIVI 1200 mg/m2
Week 7, 15
* Leucovorin 400 mg/m2 IV
* Oxaliplatin 85 mg/m2 IV
* 5FU bolus 400 mg/m2
* 5FU CIVI 1200 mg/m2 | 2 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
Baseline characteristics
| Characteristic | Arm 1 - Wildtype | Arm 2 K-Ras 12/13 Codon Mutation | Total |
|---|---|---|---|
| Age, Continuous | 62 years | 62 years | 62 years |
| Gender Female | 3 Participants | 1 Participants | 4 Participants |
| Gender Male | 4 Participants | 1 Participants | 5 Participants |
| Region of Enrollment United States | 7 participants | 2 participants | 9 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 7 | 2 / 2 |
| serious Total, serious adverse events | 4 / 7 | 0 / 2 |
Outcome results
Primary
All-cause Mortality
Time frame: 30 days following surgery
Population: 4 participants did not have surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 - Wildtype | All-cause Mortality | 0 participants |
| Arm 2 K-Ras 12/13 Codon Mutation | All-cause Mortality | 0 participants |
Primary
Major Postoperative Complication Rate
Fraction of patients with any complication grades IV and V
Time frame: 30 days following surgery
Population: 4 participants did not have surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 - Wildtype | Major Postoperative Complication Rate | 25 percentage of participants |
| Arm 2 K-Ras 12/13 Codon Mutation | Major Postoperative Complication Rate | 0 percentage of participants |
Primary
Postoperative Complication Rate
Fraction of patients with any grade of complication I-V
Time frame: 30 days following surgery
Population: 4 participants did not have surgery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 - Wildtype | Postoperative Complication Rate | 25 percentage of participants |
| Arm 2 K-Ras 12/13 Codon Mutation | Postoperative Complication Rate | 0 percentage of participants |
Secondary
Change in Tumor Size From Pretreatment to Preoperative CT Scan
-Compare total longest diameter from baseline to preoperative CT scan.
Time frame: Completion of neoadjuvant therapy (approximately 8 weeks)
Population: 2 participants did not have the CT scan prior to surgery as both did not complete preoperative chemotherapy due to adverse skin reactions to cetuximab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 - Wildtype | Change in Tumor Size From Pretreatment to Preoperative CT Scan | -23.8 percentage of change of longest diameter |
| Arm 2 K-Ras 12/13 Codon Mutation | Change in Tumor Size From Pretreatment to Preoperative CT Scan | -14.3 percentage of change of longest diameter |
Secondary
Effect of Preoperative Chemotherapy on Tumor Size
Number of participants whose tumor size decreased from baseline to completion of preoperative chemotherapy.
Time frame: Upon completion of neoadjuvant chemotherapy (approximately 2 months)
Population: 2 participants did not have the CT scan prior to surgery as both did not complete preoperative chemotherapy due to adverse skin reactions to cetuximab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 - Wildtype | Effect of Preoperative Chemotherapy on Tumor Size | 4 participants |
| Arm 2 K-Ras 12/13 Codon Mutation | Effect of Preoperative Chemotherapy on Tumor Size | 2 participants |
Secondary
Histologic Hepatic Toxicity at Surgery
Time frame: Time of surgery (approximately 11-16 weeks)
Population: 4 participants did not have surgery.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 - Wildtype | Histologic Hepatic Toxicity at Surgery | Not reported on pathology report | 1 participants |
| Arm 1 - Wildtype | Histologic Hepatic Toxicity at Surgery | Mild | 1 participants |
| Arm 1 - Wildtype | Histologic Hepatic Toxicity at Surgery | Aborted surgery | 1 participants |
| Arm 1 - Wildtype | Histologic Hepatic Toxicity at Surgery | None | 1 participants |
| Arm 2 K-Ras 12/13 Codon Mutation | Histologic Hepatic Toxicity at Surgery | None | 1 participants |
| Arm 2 K-Ras 12/13 Codon Mutation | Histologic Hepatic Toxicity at Surgery | Not reported on pathology report | 0 participants |
| Arm 2 K-Ras 12/13 Codon Mutation | Histologic Hepatic Toxicity at Surgery | Aborted surgery | 0 participants |
| Arm 2 K-Ras 12/13 Codon Mutation | Histologic Hepatic Toxicity at Surgery | Mild | 0 participants |
Secondary
Liver Injury Scale Score (0-27)
Time frame: Time of surgery (approximately 11-16 weeks)
Population: Data was not collected for this outcome measure as the study pathologist left the institution early prior to study closure.
Secondary
Nonalcoholic Steatohepatitis Score (0-3)
* NASH Scoring * Steatosis \*\*\<5% = 0 \*\*5-33%=1 \*\*\>33-66%=2 \*\*\>66%=3 * Lobular inflammation \*\*No foci=0 \*\*\<2 foci per x 200 field=1 \*\*2-4 foci per x 200 field=2 \*\*\>4 foci per x 200 field=3 * Hepatocellular ballooning \*\*None=0 \*\*Few balloon cells = 1 \*\*Many cells/prominent ballooning=2
Time frame: Time of surgery (approximately 11-16 weeks)
Population: 4 participants did not have surgery and are not included in this outcome measure.~The study pathologist left the university early prior to completion of study pathology for this study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 - Wildtype | Nonalcoholic Steatohepatitis Score (0-3) | Not reported on pathology report | 3 participants |
| Arm 1 - Wildtype | Nonalcoholic Steatohepatitis Score (0-3) | Aborted surgery | 1 participants |
| Arm 1 - Wildtype | Nonalcoholic Steatohepatitis Score (0-3) | Score 0 | 0 participants |
| Arm 2 K-Ras 12/13 Codon Mutation | Nonalcoholic Steatohepatitis Score (0-3) | Not reported on pathology report | 0 participants |
| Arm 2 K-Ras 12/13 Codon Mutation | Nonalcoholic Steatohepatitis Score (0-3) | Aborted surgery | 0 participants |
| Arm 2 K-Ras 12/13 Codon Mutation | Nonalcoholic Steatohepatitis Score (0-3) | Score 0 | 1 participants |
Secondary
Postoperative Recurrence Patterns
Liver only vs distant disease
Time frame: Up to 5 years
Population: 7 participants were not evaluable. 4 participants did not have surgery (3 in Arm 1, 1 in Arm 2). 1 participant had surgery but was not resectable (Arm 1) . 1 participant developed another primary cancer (Arm 1). 1 participant died before recurrence from hepatic failure (Arm 1).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 - Wildtype | Postoperative Recurrence Patterns | Liver only | 0 participants |
| Arm 1 - Wildtype | Postoperative Recurrence Patterns | Distant disease | 1 participants |
| Arm 2 K-Ras 12/13 Codon Mutation | Postoperative Recurrence Patterns | Liver only | 0 participants |
| Arm 2 K-Ras 12/13 Codon Mutation | Postoperative Recurrence Patterns | Distant disease | 0 participants |