Trial Title:
Localized Treatment Versus Palliative Chemotherapy in CRC Patients With 10 or More CRLM
NCT ID:
NCT06208371
Condition:
Colorectal Neoplasms Malignant
Conditions: Official terms:
Colorectal Neoplasms
Neoplasms
Conditions: Keywords:
Colorectal liver metastases
Overall survival
Locoregional treatment
Palliative chemotherapy
Randomized Clinical Study
Study type:
Interventional
Study phase:
Phase 3
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
The participants who meet the inclusion criteria will be grouped using a stratified block
randomization method. The stratification factors include the entire RAS/BRAF gene
(wild-type vs. mutated), the number of liver metastases (10-20 vs. >20), and the location
of the primary lesion (left vs. right). The random grouping of participants will be
accomplished using our center's Interactive Web Response System (IWRS). The participants
will be randomly assigned to either the liver-localized treatment group or the palliative
chemotherapy group in a 2:1 ratio.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Surgical resection and/or ablation therapy and/or SBRT
Description:
Participants may receive surgical resection and/or ablation therapy and/or stereotactic
body radiotherapy
Arm group label:
Liver-localized treatment group
Intervention type:
Drug
Intervention name:
Palliative Chemotherapy
Description:
Participants in this group may continue the original systemic chemotherapy regimen.
Patients with tumor control after 10-12 cycles can either transition to maintenance
treatment or temporarily suspend treatment until disease progression, at which point they
switch to a second-line treatment regimen.The selection of second-line and subsequent
treatment regimens follows CSCO guidelines and clinical practices.
Arm group label:
Palliative chemotherapy only group
Summary:
The goal of this clinical trial is to investigate the effectiveness of localized
interventions in improving the 5-year survival rate for colorectal cancer patients with
≥10 liver metastases. We aim to answer the following question:
Can localized interventions, including surgery and/or ablation and/or stereotactic body
radiotherapy (SBRT), enhance the 5-year survival rate compared to palliative chemotherapy
alone in patients with ≥10 colorectal liver metastases (CRLM)?
Participants in this study, who have achieved disease control through chemotherapy, will
undergo either localized interventions (surgery and/or ablation and/or SBRT) or receive
palliative chemotherapy alone. Researchers will compare the survival outcomes between
these groups to determine the potential benefits of localized interventions for patients
with ≥10 CRLM.
Detailed description:
Colorectal cancer is one of the most common malignant tumors, ranking second globally in
cancer-related mortality. In recent years, both the incidence and mortality rates of
colorectal cancer in China have shown a gradual upward trend. According to literature
reports, 20% of colorectal cancer patients are diagnosed with liver metastases (CRLM),
and as the disease progresses, up to 50% of patients may develop liver metastases, a
primary cause of treatment failure for these patients. Surgical resection of liver
metastases remains the main curative treatment for colorectal cancer patients, with
5-year and 10-year survival rates reaching 33% and 23%, respectively. However, only
15%-20% of patients are eligible for liver surgery. Advances in targeted drugs and
systemic chemotherapy in recent years have improved the response rate of colorectal
cancer patients with liver metastases. Several clinical studies confirm that neoadjuvant
chemotherapy can reduce the size and stage of liver metastases, allowing initially
unresectable patients the opportunity for surgical intervention. Simultaneously, various
local treatment modalities for colorectal liver metastases, including surgery, ablation
therapy, and stereotactic body radiotherapy (SBRT), have evolved, aiming to achieve no
evidence of disease (NED).
However, not all patients benefit from liver metastasis surgical resection, and the
number of liver metastases is a crucial factor influencing the prognosis of colorectal
cancer patients undergoing liver surgery. In the 1970s and 1980s, it was considered a
contraindication for surgery if there were more than 3 liver metastatic lesions. In a
subsequent phase II clinical trial, the CLOCC study, 119 initially unresectable
colorectal cancer patients with fewer than 10 metastatic lesions were randomized into
either palliative chemotherapy (control group) or systemic chemotherapy combined with
liver ablation ± surgical resection (experimental group). The overall survival of
patients in the combination therapy group was significantly higher than that in the
palliative chemotherapy group (HR=0.58, 95% CI 0.38-0.88, p=0.01). The 3-year, 5-year,
and 8-year survival rates in the combination therapy group were 56.9%, 43.1%, and 35.9%,
respectively, confirming that for colorectal cancer patients with fewer than 10
unresectable liver metastases, the efficacy of systemic chemotherapy combined with
surgery and ablation therapy is superior to palliative chemotherapy alone.
To explore the impact of surgical resection on the survival of colorectal cancer patients
with ≥10 liver metastases after first-line treatment, several retrospective studies have
been conducted. A study by L. Viganò et al. found that in 106 colorectal cancer patients
with ≥8 metastatic lesions, the 5-year survival rate and 5-year recurrence-free survival
rate after surgical resection were 20.1% and 13.6%, respectively. There was no
significant difference in the 5-year survival rate among patients with 8-10, 10-15, and
≥15 metastatic lesions (p=0.848). Multifactorial analysis of patients with ≥ 8 metastatic
lesions showed that the presence of extrahepatic lesions before surgery (HR=2.38, 95% CI
1.23-4.60, p=0.010) and poor response to preoperative chemotherapy (HR=2.14, 95% CI
1.11-4.12, p=0.023) were independent risk factors for overall survival in patients with
≥10 CRLM. Another large observational study by M. A. Allard included 529 patients with
≥10 liver metastases, yielding an overall 5-year survival rate of 30%. Among the
colorectal cancer patients with ≥10 lesions, 68.4% (362/529) received chemotherapy before
surgery, and 96.3% of these patients underwent surgical resection when the disease was
controlled or stable. 72.8% patients underwent R0 or R1 ± ablation therapy, while 27.2%
underwent R2 resection or did not undergo surgical resection. Patients who underwent R0
resection and R1 resection ± ablation therapy had better 3-year and 5-year survival rates
than those who underwent R2 resection or did not undergo surgical resection (61% and 39%
vs. 29% and 5%; p<0.0001). The study also found that among these patients, there was no
significant difference in the 3-year and 5-year survival rates between those who
underwent R0 resection and R1 resection ± ablation therapy (73% and 45% vs. 60% and 44%;
p<0.72), and those who underwent R2 resection or did not undergo surgical resection (29%
and 6% vs. 28% and 0%; p=0.77). The results of this study also showed that among patients
with ≥10 CRLM, those who underwent MRI before surgery, achieved R0/R1 resection, and
received adjuvant therapy after surgery had a longer survival.
Furthermore, Lin et al. used univariate and multivariate analysis to identify ≥10 liver
metastases as an independent prognostic factor for colorectal cancer patients with CRLM
(HR=1.629; 95% CI 1.007-2.636; p=0.043). Subsequently, a retrospective study was
conducted specifically for colorectal cancer patients with liver metastases using 10
metastases as the cutoff value. The results showed that the conversion rate of patients
with ≥10 liver metastases (43.4%) was significantly lower than that of patients with <10
liver metastases (57.3%; p=0.001). Among successfully converted patients, the 2-year
survival rate of patients with <10 liver metastases was significantly higher than that of
patients with ≥10 liver metastases (89.9% [95% CI 82.5%-98.0%] vs. 58.2% [95% CI
42.2%-80.4%], p=0.008). In patients with ≥10 liver metastases, there was no significant
difference in the 2-year survival rate between those who successfully underwent
conversion surgery and those who did not (58.2% [95% CI 42.2%-80.4%] vs. 49.6% [95% CI
37.5%-65.7%], p=0.160). For patients with <10 CRLM, the 2-year survival rate of
successfully converted patients was significantly higher than that of those who did not
convert successfully (89.9% [95% CI 82.5%-98.0%] vs. 58.9% [95% CI 45.2%-76.7%],
p<0.001).
In summary, for colorectal cancer patients with liver metastases, adopting a locoregional
treatment approach can enhance the survival of those with <10 liver metastatic lesions.
However, significant controversy remains regarding whether surgical treatment
significantly improves the survival of colorectal cancer patients with ≥10 CRLM.
Currently, there is a lack of randomized controlled study data to address the question of
whether colorectal cancer patients with ≥10 CRLM can further benefit from chemotherapy
plus a surgical approach versus palliative chemotherapy alone.
To that end, the present study will focus on patients with ≥10 CRLM who have achieved
disease control in liver metastatic lesions after chemotherapy and can potentially attain
a disease-free state through surgery and/or ablation and/or stereotactic body
radiotherapy (SBRT). The primary objective of this study is to investigate whether
liver-localized intervention can improve the 5-year survival rate compared to palliative
chemotherapy, for colorectal cancer patients with ≥10 CRLM.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Age ≥ 18 years.
- Histologically confirmed colorectal adenocarcinoma.
- Baseline imaging (CT, MRI, or PET/CT as necessary) or pathological confirmation of
liver metastasis, with no extrahepatic metastasis (consideration for inclusion may
be given to lesions with a diameter less than 10mm in the lungs or lymph nodes if
metastasis is difficult to confirm or is suspected).
- Disease control (PR or SD) achieved after a minimum of 8 cycles of systemic
chemotherapy.
- Evaluation by a centralized liver surgeon expert group to confirm presence of ≥10
liver metastases, which can be managed through surgery and/or ablation and/or SBRT
to achieve NED. Non-resectability is defined as one or more of the following: ①
Unable to undergo R0 resection; ② Predicted insufficient remaining liver volume
after resection; ③ After resection, none of the three hepatic veins can be
preserved, and the preservation of residual liver inflow and outflow and bile ducts
cannot be guaranteed, and adjacent two liver segments cannot be preserved.
- Curative surgery possible for the primary colorectal lesion.
- Normal hematological, hepatic, and renal functions at baseline.
- Child-Pugh grade A liver function.
- ECOG performance status 0-1.
- Tolerability to undergo further surgery and chemotherapy.
- Life expectancy > 3 months.
- Signed written informed consent.
- Willing and able to undergo follow-up until death, study completion, or study
termination.
Exclusion Criteria:
- Definite presence of extrahepatic metastasis and/or primary tumor not amenable to
curative surgical resection.
- Severe arterial embolism or ascites.
- Bleeding tendencies or coagulation disorders.
- Hypertensive crisis or hypertensive encephalopathy.
- Severe uncontrollable systemic complications such as infection or diabetes.
- Clinically severe cardiovascular diseases such as cerebrovascular accident (within 6
months before enrollment), myocardial infarction (within 6 months before
enrollment), uncontrolled hypertension despite appropriate medical treatment,
unstable angina, congestive heart failure (NYHA 2-4), and arrhythmias requiring
medication.
- History or physical examination indicating central nervous system diseases (such as
primary brain tumor, uncontrollable epilepsy, any brain metastasis, or history of
stroke).
- Diagnosis of other malignant tumors within the past 5 years (excluding basal cell
carcinoma after radical surgery and/or cervical carcinoma in situ).
- Pregnant or lactating women.
- Women of childbearing potential not using or refusing to use effective non-hormonal
contraceptive methods (intrauterine devices, combined barrier contraceptive methods
with spermicidal gel, or sterilization) or men with reproductive potential.
- Inability or unwillingness to comply with the study protocol.
- Any other diseases, metastatic lesions causing functional impairment, or suspicious
findings in the physical examination indicating possible contraindications for the
use of investigational drugs or placing the patient at a high risk of
treatment-related complications.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Sun Yat-sen Cancer Center
Address:
City:
Guangzhou
Zip:
510060
Country:
China
Status:
Recruiting
Contact:
Last name:
Yuhong Li, PhD
Phone:
87342487
Phone ext:
020
Email:
liyh@sysucc.org.cn
Start date:
January 15, 2024
Completion date:
June 30, 2029
Lead sponsor:
Agency:
Sun Yat-sen University
Agency class:
Other
Source:
Sun Yat-sen University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06208371
