Aim of the study
The aim of this study is to demonstrate that capecitabine metronomic chemotherapy is non-inferior to capecitabine conventional chemotherapy as maintenance treatment, who have responded to 16-18 weeks first-line chemotherapy in mCRC.
Study design
The study design is a prospective, randomized, open label, phase II clinical trial (Figure 1). Those mCRC patients who respond well, stable disease (SD), partial response (PR) or complete response (CR) according to RECIST Criteria after 16-18 weeks of standard doublet chemotherapy as induction may enrolled into this study, randomly divided into capecitabine metronomic group or standard dosage group. Randomization was done by sealed envelope system. The maintenance treatments are continued until disease progression or severe toxicity. Furthermore, exploratory markers involving angiogenesis (serum VEGF, PDGF, Tie-1 and Tie2, etc) and immune function (CD clusters, serum tumor mutation burden (TMB), etc), are conducted via liquid biopsy (Figure 2).
Study objectives
The duration of disease control after randomization (progression free survival 2, PFS2) is primary endpoint. Meanwhile, progression free survival from induction treatment (PFS1), overall survival (OS), safety and quality of life (QoL) are secondary endpoints.
Study population
The study population consists of patients with unresectable metastatic colorectal cancer, who are scheduled for treatment with first-line doublet chemotherapy. Patients’ inclusion and exclusion criteria are defined as follows:
Inclusion criteria:
- Patients of an age from 18 to 75 years;
- Histopathologically confirmed colorectal adenocarcinoma and classified as technically unresectable (patients with only local recurrence are not eligible);
- No prior first line treatment of chemotherapy, radiotherapy, immunotherapy or targeted therapy; Adjuvant chemotherapy is allowed if it has been more than 6 months since the treatment was finished and there have been no signs of disease progression, neither during treatment nor during the 6 months following its completion.
- Life expectancy > 12 weeks;
- Eastern Cooperative Oncology Group (ECOG) performance status ≤1;
- At least one measurable lesion for assessment by computed tomography (CT) or magnetic resonance imaging (MRI);
- 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);
- Disease evaluation with proven SD, PR or CR according to RECIST after first-line induction treatment before randomization;
- Written informed consent should be obtained before randomization;
Exclusion criteria:
- Brain metastasis and with large amounts of pleural and abdominal effusion;
- Pregnancy or breastfeeding;
- Disease evaluation with Progression disease (PD) according to RECIST after first-line induction treatment;
- Previous systemic treatment for advanced disease;
- Major surgery or radiotherapy (except for antalgic surgery that does not include measurable target lesions) during the 4 weeks prior to inclusion in the study;
- Participation in another clinical trial with drugs within the previous 30 days;
- Neoplasm in the 2 years prior to entering the study, except for non-melanoma skin carcinoma or in situ cervix carcinoma;
- With symptomatic heart disease (arrhythmia, heart failure, or history of myocardial infarction);
- With active infection, active bleeding or serious metabolic disorder;
- Signs and symptoms, at the moment of entering the study, of acute or subacute bowel obstruction;
- Chronic immunological or hormonal treatment, except for hormone replacement treatment at physiological doses.
- Any geographical or social circumstance or any medical or psychological alteration that, in the investigator's opinion, will not allow the patient to conclude the study.
Study protocol
MDT
Ideally, patients will be discussed by the multi-disciplinary team (MDT) for colorectal cancer from Departments of Surgery, Oncology, Radiology, Pathology, Nutrition and Interventional medicine, etc.) of Ruijin Hospital, Shanghai Jiaotong University School of Medicine, and first-line chemotherapy regimen was formulated by the joint consultation of these experts.
First-line treatment regimens
Standard doublet chemotherapies were used as induction treatment which including mFOLFOX6 regimen (oxaliplatin 85mg/m2 iv d1, leucovorin 400mg/m2 iv d1, 5-fluorouracil 400mg/m2 iv d1, 5-fluorouracil 2400mg/m2 CIV 46h, q2w), FOLFIRI regimen (irinotecan 180mg/m2 iv d1, leucovorin 400mg/m2 iv d1, 5-fluorouracil 400mg/m2 iv d1, 5-fluorouracil 2400mg/m2 CIV 44h, q2w), XELOX regimen (oxaliplatin 135mg/m2 iv d1, capecitabine 1000mg/m2 bid po d1-14, q3w), XELIRI regimen (irinotecan 250mg/m2 iv d1, capecitabine 1000mg/m2 bid po d1-14, q3w). Total first-line treatments were 6 cycles for XELOX/XELIRI regimens, and 8 cycles for mFOLFOX6/FOLFIRI regimens.
Maintenance treatment regimens
Single-agent chemotherapy was used as maintenance treatment which including capecitabine metronomic chemotherapy (capecitabine 500mg bid po), capecitabine conventional chemotherapy (capecitabine 1000mg/m2 bid po, d1-14, q3w).
Outcome measurements
Evaluation of tumor response was performed every 8 weeks by the response evaluation in solid tumors criteria (RECIST)[17]. Toxicity was assessed after each cycle by using National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE)[18]. Quality of life was assessed after each cycle by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire.
Sample size calculation
This project is a non-inferior study. The patients were allocated into capecitabine metronomic chemotherapy group (experimental group) and capecitabine conventional chemotherapy group (control group) by 1:1. The noninferiority boundary in PFS was defined at 1.40 in reference to the results of trial reported by H. Y. Luo et al[19]. The HR for capecitabine maintenance group versus observation group in the trial was 0.54 and the reciprocal was 1.85, which leads to 1.43 as 50% survival benefit. So, boundary of 1.4 was used in this study. Considering a dropout rate of 20%, we estimated that 386 patients (193 in each group) would be needed to achieve 80% power at a one-sided α (significance level) of 0.025.
Statistical analysis
Those patients who do not follow the protocol of their assigned treatment arm will not be analyzed. The statistical analysis will be carried out using SPSS software (version 17.0; SPSS, Chicago, IL, USA). Descriptive statistics will be used for safety evaluation. Mean values and standard deviations (SDs) will be provided for continuous endpoints and frequency and percentage distributions will be provided for discrete data. PFS and OS will be estimated using the Kaplan-Meier method and their medians along with two-sided 95% Cis will be calculated. Comparisons between groups of patients will be made by the log-rank test. All statistical analysis will be carried out at a 5% level significance.