Clinical trial NCT02316535: Low-dose Capecitabine Adjuvant Chemotherapy for Elderly Patients With Stage II/III Colorectal Cancer
Official title: Low-dose Versus Standard-dose Capecitabine Adjuvant Chemotherapy for Chinese Elderly Patients With Stage II/III Colorectal Cancer: A Randomized, Phase 3 Non-inferiority Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Colorectal Neoplasms
Keywords: colorectal cancer
stage II/III
elderly
adjuvant chemotherapy
capecitabine
non-inferiority
Lead sponsor: West China Hospital
Sponsor class: OTHER
First posted: 2014-12-15
Enrollment: 710
Sex: ALL
Minimum age (years): 70
Maximum age (years): 90
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Approximately half of colorectal cancer (CRC) patients were first diagnosed after 70 years old. However, compared with younger patients, elderly patients were often undertreated in chemotherapy due to their impaired tolerance. Recently, there have been great controversy on adjuvant chemotherapy strategy for stage II/III CRC patients. As an oral fluoropyrimidine, capecitabine has been demonstrated to be equivalent to i.v. 5-Fu/leucovorin regimen in stage III CRC patients. In light of fewer adverse effects and better flexibility, capecitabine was regarded as an ideal alternative for elderly CRC patients, but the optimal dosage for stage II/III elderly CRC patients still remains inconclusive. Our trial expected to prospectively randomized 710 postoperative stage II/III elderly CRC patients (between 70 and 90 years of age) to adjuvant mono-chemotherapy with a standard dose of capecitabine (2500 mg/m2/day) or a reduced dose (2000 mg/m2/day). This is a non-inferiority phase 3 trial with a primary endpoint of 3-year disease free survival (DFS), and other outcomes include 3-year overall survival(OS), completion rate, toxic and adverse effects and quality of life(Qol). By this trial, we aimed to achieve more precise evidence on the individualized adjuvant chemotherapy strategy for stage II/III elderly CRC patients.

Detailed description: An estimated 1,200,000 newly diagnosed colorectal cancer(CRC) cases arose worldwide every year, and CRC has become the third most common malignances in China. Especially in urban areas of China, rapid growth of CRC patients has considerably increased the burden of disease. It is well believed that multi-discipline treatment(MDT) including surgery, chemoradiotherapy and target therapy based on individualized characteristics will benefit CRC patients significantly.

Generally, stage II (T3-4N0M0) and stage III (TanyN1-2M0) colorectal carcinoma can be resected by surgery. In 1990s, National Institutes of Health (NIH) suggested that adjuvant chemotherapy should be applied to stage II/III CRC patients to improve their outcomes. As for stage II CRC, results from the QUASA study indicated that adjuvant chemotherapy could improve 5-year overall survival by 3% to 4% for stage II CRC patients. Currently, most of the global guidelines such as National Comprehensive Cancer Network (NCCN) guidelines still recommended adjuvant chemotherapy for stage II/III CRC patients.

In western countries, approximately 50% of the CRC patients were firstly diagnosed after 70 years old. It was reported that in 1980s, the median age of CRC diagnosis in China was 50. However, in 2005 it had reached 58 years old and has kept increasing in recent years. Limited by age-related organ function decline and comorbid conditions, elderly people shows impaired physical and mental tolerance for chemotherapy. Generally for stage II/III CRC patients, both elderly and younger patients shares common principles of chemotherapy, while a large-scale retrospective analysis based on the ACCENT database showed that among all the CRC cases included, patients with the age ≥ 70 only accounted for 17.1%, much lower than normal. Similarly, Shrag and colleagues reported in their investigation that the proportion of patients ≥75 years old undergoing chemotherapy was substantially lower than patients ≤ 75 years old. These evidence implied that elderly CRC patients held much lower acceptance and completion rate of chemotherapy. With respect to outcomes, a pooled analysis including 3351 CRC cases with adjuvant chemotherapy reported no significant difference on both efficacy and adverse effects among groups of various age, indicating elderly patients could achieve the same benefits from adjuvant chemotherapy. Thus, it is essential to improve the acceptance and completion rate by modifying chemotherapy regimen for elderly CRC patients to achieve better prognosis. There was no random controlled trial focusing on the adjuvant chemotherapy for stage II/III elderly CRC patients.

Results of MOSAIC trial showed that adding oxaliplatin to 5-Fu/ leucovorin could significantly improve 5-year survival of stage II/III colon cancer patients, which made the oxaliplatin-based combine chemotherapy (Folfox, Xelox) be recommended by the latest guidelines. In the subgroup analysis of that trial, however, there was no significant improvement detected in stage II patients. Recent analysis from ACCENT database in 2013 indicated that elderly stage II/III CRC patients (≥ 70 yr) acquired no significant benefits from adding oxaliplatin to fluoropyrimidine-based chemotherapy, which suggested monochemotherapy might be a better option for elderly CRC patients.

Capecitabine ( Xeloda®) is the unique oral prodrug of 5-Fu recommended by global guidelines and especially International Society of Geriatric Oncology (SIOG), and it has been verified by clinical trials that in view of efficacy and safety, capecitabine monochemotherapy was equivalent to i.v. 5-Fu/ leucovorin adjuvant chemotherapy. With efficacy retained, a large group of patients prefer capecitabine due to oral administration which can remarkably enhance flexibility and compliance. These advantages make capecitabine a potential ideal choice for elderly patients. According to the NCCN guideline, the standard dosage of capecitabine was 1250mg/m2 .bid. It was well-established that different characteristics such as ethnicity, age and sex could alter the metabolism and change individual tolerance for drugs; hence, there are still controversies on the optimal dose of capecitabine in different populations. The X-Act trial provided a result that among elderly patients (≥ 70 yr) undergoing standard-dose capecitabine adjuvant chemotherapy(1250mg/m2 .bid), 51% of the patients required dose reduction to complete the whole treatment cycle, implying that the recommended 1250mg/m2 .bid. might be an overdose for elderly patients given the fact that only elderly patients with relatively better health (≤ 75 yr, ECOG≤1) were eventually included in X-ACT trial. Chang and colleagues have verified feasibility of a tailored-dose strategy with a starting dose at 1000 mg/m2 .bid in a single-arm study. The European Society for Medical Oncology (ESMO) has also recommended an option of 80% standard dosage (i.e. 1000 mg/m2 .bid) for elderly II/III CRC patients. However, no prospective trial has been conducted yet to confirm this reduced-dose strategy.

Based on current evidence and controversy above, we designed this non-inferiority, phase 3 clinical trial to explore the optimal dosage of capecitabine monochemotherapy for stage II/III elderly CRC patients. Following the results of sample size estimation, 710 postoperative (pT3-4NanyM0 or pTanyN+M0) elderly patients between 70 to 90 years of age were anticipated to be included and randomly divided into two groups (A and B). Patients in group A would receive the standard dose regimen (1,250 mg/m2 twice daily on days 1-14, and repeated on day 22); accordingly the patients in group B would receive the reduced dose regimen (1,000 mg/m2 twice daily on days 1-14, and repeated on day 22). The primary endpoint was 3-year disease free survival (DFS), other outcomes included 3-year overall survival (OS), completion rate, toxic and adverse effects and quality of life (Qol).

Eligibility criteria: Inclusion Criteria:

1. With informed consents
2. Histologically identified carcinoma of colon and rectum
3. pT3-4NanyM0 or pTanyN+M0(stage II/III)
4. age between 70 to 90
5. undergone R0 resection
6. ECOG ≤2
7. Stage II patients with microsatellite stable (MSS) or microsatellite low (MSL)

Exclusion Criteria:

1. With other types of malignances simultaneously
2. Creatinine clearance ≤ 70 ml/min
3. Undergone neoadjuvant chemotherapy
4. In anticoagulant therapy
5. Pregnant or lactating women
6. History of antineoplastic drugs
7. With other contraindications for chemotherapy

Primary outcomes:
measure: disease free survival
timeFrame: 3 years
Secondary outcomes:
measure: overall survival
timeFrame: 3 years
measure: toxic and adverse effects
timeFrame: 30 weeks
measure: completion rate
timeFrame: 24 weeks
measure: quality of life
timeFrame: 3 years
Other outcomes:
Locations:
city: Chengdu
country: China
facility: West China Hospital
state: Sichuan
Study officials:
affiliation: West China Hospital
name: Ziqiang Wang, MD/PhD
role: PRINCIPAL_INVESTIGATOR
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