Unresectable Colorectal Cancer
Conditions
Keywords
Transarterial Infusion Chemotherapy, Bevacizumab, Cetuximab, Colorectal Cancer, FOLFOX Protocol, Unresectable, Clinical Trial
Brief summary
This is a prospective, multicenter, randomized, open-label clinical trial. It aims to investigate whether intensive transarterial infusion chemotherapy (TAIC) followed by sequential intravenous chemotherapy (IVC) is clinically more effective than IVC alone in the treatment of unresectable colorectal cancer (uCRC).
Detailed description
CRC is the third leading cause of new cancer cases and the second leading cause of cancer-related deaths worldwide. Current therapeutic modalities for CRC include surgical resection, IVC, radiotherapy, immunotherapy, targeted therapy, and their combinations. As a mainstream systemic treatment for CRC, IVC leads to widespread drug distribution but relatively low intratumoral drug accumulation. Compared with IVC, TAIC involves selective arterial catheterization to deliver chemotherapeutic agents directly to the tumor feeding vessels. Hepatic tumors receive their blood supply predominantly through branches of the hepatic artery. Hepatic artery infusion chemotherapy (HAIC) yields significantly superior outcomes compared to IVC and is currently widely employed for the treatment of primary and secondary hepatic malignancies. HAIC in combination with IVC can offer long-term durable disease control in the clinical treatment of liver cancer compared with IVC. CRC is also predominantly grown through angiogenesis. Therefore, we raise the question whether sequential IVC administered after intensive TAIC achieves better clinical efficacy than IVC alone for the treatment of uCRC. However, no prospective clinical trials have been conducted to compare the efficacy of these two strategies. This prospective study was therefore designed to fill this clinical knowledge gap. We hypothesize that intensive TAIC followed by sequential IVC yields superior clinical efficacy compared with IVC alone for the treatment of uCRC. This is a prospective, multicenter, randomized, open-label clinical trial. It aims to investigate whether intensive TAIC followed by sequential IVC is clinically more effective than IVC alone in the treatment of uCRC. Eligible patients will be randomly allocated into two groups upon enrolment: the intervention group (TAIC group) and the control group (IVC group). Patients will be randomly assigned at a 1:1 ratio with no blinding implemented. Randomization will be conducted by an independent trial statistician via a secure system with complete allocation concealment using the permuted block randomization method. Stratification factors consist of primary tumor location, presence of liver metastases, RAS/BRAF mutational status, and participating study center. Patients in the control group will receive FOLFOX-based IVC every 2 weeks for a total duration of 8 weeks. Patients in the TAIC group will receive FOLFOX-based TAIC at Week 0 and Week 4 and receive FOLFOX-based IVC at Week 2 and Week 6. For patients with CRLM, targeted agent selection is determined based on the RAS and BRAF mutational status and the primary tumor location. The primary endpoint is ORR. The secondary endpoints include Quality-of-life (QoL), clinical complete response (cCR) rate, pathological complete response (pCR) rate, the rate of conversion to resection (CTR), overall survival (OS), progression-free survival (PFS), and AEs. Primary and secondary efficacy analyses will be conducted for both the intention-to-treat (ITT) population and the per-protocol (PP) population. Safety analyses will be based on patients who received at least one dose of the assigned study treatment. Categorical variables will be presented as counts and percentages, while continuous variables will be presented as means with standard deviations or medians with interquartile ranges, as appropriate. Pearson's chi-square test or Fisher's exact test will be used for between-group comparisons of categorical variables. Continuous variables will be compared using Student's t-test or the Mann-Whitney U test as appropriate. Longitudinal QoL scores will be analyzed using linear mixed-effects models for repeated measurements, which naturally accommodate missing data under the missing at random assumption. For time-to-event endpoints of OS and PFS, the Kaplan-Meier method and Cox proportional hazards regression analysis will be applied. Between-group survival differences will be assessed using the log-rank test. Hazard ratios (HRs) with 95% confidence intervals (CIs) will be estimated from Cox regression models. All statistical tests will be two-sided, and a P value \< 0.05 will be considered statistically significant. All statistical analyses will be performed using the current version of R software. Patients in the IVC group will receive FOLFOX-based IVC every 2 weeks for a total duration of 8 weeks. The FOLFOX regimen consists of oxaliplatin (85 mg/m²) and leucovorin (400 mg/m²), each administered as a 2-hour intravenous infusion, and fluorouracil (2400 mg/m²) administered as a 44-hour continuous intravenous infusion. For patients with CRLM, targeted therapy will be selected according to RAS/BRAF status and primary tumor side. Cetuximab will be administered by intravenous injection for the treatment of RAS/BRAF wild-type left-sided CRLM. Bevacizumab will be administered by intravenous injection for the treatment of RAS/BRAF wild-type right-sided CRLM and RAS/BRAF mutant CRLM irrespective of primary tumor location. Patients in the TAIC group will receive FOLFOX-based TAIC at Week 0 and Week 4 and receive FOLFOX-based IVC at Week 2 and Week 6. The FOLFOX-based TAIC consists of oxaliplatin (85 mg/m²) and leucovorin (400 mg/m²), each administered as a 2-hour transarterial infusion, and fluorouracil (2400 mg/m²) administered as a 44-hour continuous transarterial infusion. The IVC and targeted therapy regimens are the same as those in the IVC group. The dosage-calculation strategies of anticancer drugs, drug exposure and infusion durations, and supportive care, including symptom management and prevention of complications, do not differ significantly between TAIC and IVC groups. Treatment will be continued until disease progression (PD), unacceptable toxicity, or surgical resection. Prior to each TAIC procedure, the right femoral artery will be punctured using the Seldinger technique according to tumour vascular supply. A microcatheter will be advanced into the tumour-feeding branch of the superior mesenteric artery, inferior mesenteric artery or internal iliac artery. Chemotherapeutic agents will be administered through the microcatheter.
Interventions
PROCEDURETransarterial infusion chemotherapy (TAIC)
TAIC can increase the local intra-tumoral concentrations of chemotherapeutic agents by intensifying drug delivery into the tumor via super-selective catheterization of the tumor-feeding artery, and meanwhile reduce systematic toxicity.
PROCEDUREIntravenous Chemotherapy（IVC）
Intravenous administration of chemotherapeutic agents is the mainstay of chemotherapy.
Sponsors
Guang'anmen Hospital of China Academy of Chinese Medical Sciences
Liaoning Cancer Hospital & Institute
The Rocket Force Characteristic Medical Center
Second Affiliated Hospital of Nanchang University
Affiliated Hospital of Hebei University
The First Hospital of Qinhuangdao
The Central Hospital of Handan City
The First People's Hospital of Jiujiang City
Changzhi Medical College
Zibo Boshan District Traditional Chinese Medicine Hospital
Hebei Yixian Hospital
Baoding Mancheng District People's Hospital
The Shanghai Yangpu Central Hospital
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
Study population: Patients who meet all inclusion criteria and none of the
Exclusion criteria
are eligible for enrolment and study treatment. Inclusion criteria: 1. Age ≥ 18 years old; 2. Histopathologically confirmed CRC adenocarcinoma; 3. Locally advanced CRC confirmed as clinical T4 stage on CT/MRI imaging, with or without synchronous liver metastases; 4. For patients with CRLM, hepatic tumor burden shall be lower than the burden of the primary colorectal lesion. Consequently, the multidisciplinary team (MDT) agree by consensus that CRC should be a priority target for treatment. 5. No prior administration of chemotherapy, targeted therapy or radiotherapy for the current malignancy; 6. Adequate haematological, heart, liver and renal functions are required, with the following specific criteria: white blood cell count≥4×109 /L, neutrophils≥1.5×109 /L, platelets≥100×10⁹ /L, haemoglobin≥100 g/L, total bilirubin≤34.2 μmol/L, aspartate aminotransferase≤100 IU/L, alanine aminotransferase≤100 IU/L, serum creatinine ≤133 μmol/L or creatinine clearance rate≥60 mL/min, and urine protein/creatinine\<1; 7. Estimated survival is more than 3 months; 8. Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2; 9. All the patients in this study are required to sign an informed consent form.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate | 8 weeks | Objective response rate is defined as the percentage of patients achieving complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 for CRC and modified RECIST criteria for CRLM. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Health-related quality of life | 8 weeks | Health-related quality of life was assessed using the European Organization for Research and Treatment of Cancer (EORTC) 30-item QoL Questionnaire (EORTC QLQ-C30). The EORTC QLQ-C30 consists of 30 items covering five functioning scales (physical, social, emotional, role, and cognitive), nine symptom scales (fatigue, nausea/vomiting, pain, dyspnea, sleep disturbances, appetite loss, constipation, diarrhea, and financial impact), and a global health status scale. Referring to a recall period of one-week (except for physical function, which does not refer to a recall period at all), patients indicate their answers on a 4-point Likert scale. Linear converted scale scores range from 0 to 100. Higher scores on the functioning scales and on the global health status scale indicate better functioning, whereas higher scores on the symptom scales indicate greater symptom burden. |
| Clinical complete response | 8 weeks | Clinical complete response is defined as no visible tumor on imaging examination. |
| Pathological complete response | 8 weeks | The pathological complete response is defined as the absence of invasive neoplastic cells upon microscopic examination of the tumor during surgery. |
| The rate of conversion to resectable status | 8 weeks | Assessment of resectability represents a complex biological and technical decision; definitions of resectability vary substantially and are contingent on technical expertise, institutional surgical volume, institutional experience, and access to multidisciplinary oncological care. For the present clinical trial, the following resectability criteria will be applied: (i) Following 4 cycles of conversion therapy, simultaneous or staged complete surgical resection of the primary tumor and liver metastases can be performed. (ii) The primary lesion can be resected en bloc with R0 margins. (iii) Liver metastases can be treated with radical ablation alone or combined with radical surgical resection to achieve R0 margins; the future liver remnant constitutes no less than 30%-40% of the total liver volume. (iv) Patients maintain acceptable general status and have no additional distant metastases precluding local radical treatment. (v) Regional lymph node metastases are amenable to complete surg |
| Overall survival | 3 years | Overall survival is calculated from the date of randomisation until death. Participants who are alive at the time of analysis were censored at the date of the latest time seen alive. |
| Progression-free survival | 3 years | PFS is defined as the time from randomization to progression or death. |
Countries
China
Contacts
CONTACTQuanda Liu Chief physician, MD
CONTACTJunpeng Wang, MD
PRINCIPAL_INVESTIGATORQuanda Liu, MD
Guang'anmen Hospital of China Academy of Chinese Medical Sciences
Outcome results
None listed