Colorectal Cancer Metastatic
Conditions
Keywords
CAIRO3, DCCG, colorectal cancer, induction, metronomic chemotherapy, observation, capecitabine, bevacizumab, oxaliplatin
Brief summary
The optimal duration of systemic treatment in patients with advanced colorectal cancer is unknown. In this study the effects of bevacizumab and low-dose continuous chemotherapy with capecitabine is investigated in patients who have responded to 6 courses of oxaliplatin, capecitabine and bevacizumab (induction treatment, at standard doses). This treatment is continued until progression or severe toxicity. This regimen is compared to the effects a observation without treatment after the induction treatment. In case of disease progression, induction treatment will be reintroduced.
Detailed description
Standard 1st-line treatment for patients with advanced colorectal cancer currently consists of chemotherapy plus bevacizumab. With this approach the median overall survival is approximately 20 months, and progression-free survival in first-line approximately 9-11 months. The optimal duration of treatment is unknown. Current data suggest that the efficacy of bevacizumab is dependent on concomitant use of chemotherapy. However, oxaliplatin almost invariably gives rise to neuropathy after 6-8 cycles. Prolonged use of capecitabine is associated with e.g. hand-foot syndrome. Lastly, the prolonged use of these agents is associated with considerable costs. Evidence, mainly preclinical, suggests that continuous dosing metronomic chemotherapy may be more efficacious than interval-chemotherapy given at MTD. In this study the concept of metronomic chemotherapy is explored by administering a continuous daily instead of the usual 2 weeks-on/1 week-off oral dosing regimen of low-dose capecitabine plus bevacizumab as maintenance therapy after induction combination chemotherapy given at MTD plus bevacizumab.
Interventions
Ca 1250 mg/m2 daily orally continuously, B 7.5 mg/kg i.v. q 3 w
OTHERobservation
observation after induction treatment
Sponsors
Koningin Wilhelmina Fonds
Sanofi
Hoffmann-La Roche
Dutch Colorectal Cancer Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Before the start of induction therapy: Inclusion Criteria: * Histological proof of colorectal cancer (in case of a single metastasis, histological or cytological proof of this lesion should be obtained); * Distant metastases (patients with only local recurrence are not eligible); * Unidimensionally measurable disease (\> 1 cm on spiral CT scan or \> 2 cm on chest X-ray; liver ultrasound is not allowed). Serum CEA may not be used as a parameter for disease evaluation; * In case of previous radiotherapy, at least one measurable lesion should be located outside the irradiated field. * Ongoing or planned first line treatment with 6 cycles of Xeloda, Eloxatin, and Avastin.
Exclusion criteria
* Prior adjuvant treatment for stage II/III colorectal cancer ending within 6 months before the start of induction treatment * Any prior adjuvant treatment after resection of distant metastases * Previous systemic treatment for advanced disease At randomisation: Inclusion criteria: * WHO performance status 0-1 (Karnofsky PS \> 70%); * Disease evaluation with proven SD, PR or CR according to RECIST after 6 cycles of MTD chemotherapy performed in week 3-4 of the 6th cycle induction therapy, and randomisation performed in week 3-5 of the 6th cycle (see time table); * Laboratory values obtained ≤ 2 weeks prior to randomisation: adequate bone marrow function (Hb \> 6.0 mmol/L, absolute neutrophil count \> 1.5 x 109/L, platelets \> 100 x 109/L), renal function (serum creatinine ≤ 1.5x ULN and creatinine clearance, Cockroft formula, \> 30 ml/min), liver function (serum bilirubin ≤ 2 x ULN, serum transaminases ≤ 3 x ULN without presence of liver metastases or ≤ 5x ULN with presence of liver metastases); * Life expectancy \> 12 weeks; * Age \>= 18 yrs; * Negative pregnancy test in women with childbearing potential; * Expected adequacy of follow-up; * Institutional Review Board approval; * Written informed consent
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Progression-free survival after re-introduction of MTD chemotherapy and bevacizumab (PFS2) | study duration |
Secondary
| Measure | Time frame |
|---|---|
| Response rate during re-introduction of MTD chemotherapy and bevacizumab | study duration |
| Toxicity | study duration |
| Progression-free survival between observation versus maintenance therapy (PFS1) | study duration |
| Overall survival | study duration |
| Translational research | study duration |
| Quality of life | study duration |
Countries
Netherlands
Outcome results
None listed