FOLFOXIRI for First-Line Treatment of Unresectable Colorectal Cancer with Liver Metastases in a Resource-Limited Setting

doi:10.21203/rs.3.rs-4831430/v1

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Research Article

FOLFOXIRI for First-Line Treatment of Unresectable Colorectal Cancer with Liver Metastases in a Resource-Limited Setting

https://doi.org/10.21203/rs.3.rs-4831430/v1

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Purpose

FOLFOXIRI is a standard treatment for unresectable colorectal cancer (CRC) liver metastases. However, limited data exists on its safety and effectiveness in low-to-middle income countries (LMICs). This prospective study addresses this gap in a Vietnamese LMIC setting.

Methods

We enrolled 92 patients with unresectable CRC liver metastases between 2022 and 2023. All patients received FOLFOXIRI every two weeks, with routine G-CSF prophylaxis to prevent neutropenia. A multidisciplinary team (MDT) assessed diagnoses and treatment responses. Outcomes were R0/R1 resection rate, progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), adverse events (AEs), and recurrence-free survival (RFS) for surgical patients.

Results

The median patient age was 56 years, with a male predominance (70.7%). The primary tumors were located in the left colon (42.4%), rectum (37%) and right colon (20.7%). Thirty-two patients (34.8%) experienced severe (grade 3 or higher) AEs, with thrombocytopenia (13.1%) and anemia (9.8%) being the most frequent. Most patients (72/87, 82.9%) achieved a partial response. The ORR and DCR were 85.1% and 95.4%, respectively. Fifty-seven patients (62%) achieved resectability, and 54 (58.7%) underwent radical surgery. The R0/R1 resection rate was 88.9%. The median PFS and OS for all patients were 13 and 22 months, respectively. The median RFS of surgical patients was 14 months.

Conclusions

FOLFOXIRI improves the response rates, R0/R1 resection rates, and survivals for patients with CRC liver metastases. Future research is neccessary to improve prognosis of patients while minimizing toxicities.

Trial registration number:

NCT05362825 dated 5th May 2022

Neoadjuvant chemotherapy

Colorectal cancer

Liver metastasis

Survival

Response

Colorectal cancer (CRC) represents a significant global health burden, ranking as the third most common cancer and the second leading cause of cancer-related death worldwide. Approximately 50% of all patients will develop metastases, and 25% have distant metastatic lesions at diagnosis [1]. Liver is the most frequent organ for CRC metastasis, with approximately 15–25% of patients with CRC present with liver metastases at initial diagnosis, and nearly 25% still having liver metastasis after surgical resection of the primary tumor [2, 3].

Fortunately, advancements in chemotherapy have improved outcomes for patients with initially unresectable CRC liver metastases. Studies suggest that robust upfront chemotherapy regimens can convert tumors to a resectable state in 20–40% of these patients [4]. However, there is still no consensus on the optimal chemotherapy regimen for patients with initially unresectable CRC liver metastases. Currently, the backbone of management is the triplet therapy combining 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI). While less intensive doublet regimens (e.g., FOLFIRI or FOLFOX) offer some benefit, they generally result in lower rates of curative surgery compared to the triplet regimen [5]. The integration of targeted therapies, such as anti-epidermal growth factor receptor (EGFR) antibodies, into doublet or triplet regimens has shown promise in enhancing response rates [6, 7]. Therefore, targeted therapy has been recommended to be included in the first-line treatment for patients with advanced CRC [8].

Unfortunately, due to the high cost of targeted agents, there is underutilization of these effective therapies in low-to-middle income countries (LMICs), leading to a lower survival rate for patients with CRC liver metastases [9]. Therefore, it is crucial to explore and implement more intensified chemotherapy regimens as a potential alternative in LMIC settings. These regimens aim to downstage the disease and improve survival outcomes for patients who may not have access to expensive targeted therapies. Fortunately, the FOLFOXIRI regimen has been shown to be effective and may offer similar benefits to doublet chemotherapy combined with targeted therapy [10]. Several trials support the adoption of more intense chemotherapy regimens as the first-line treatment, but with a cost of increased toxicity [11]. However, evidence of the clinical benefits and tolerability of triplet regimens for advanced CRC in the LMIC setting remains scarce.

Our institution is one of the largest oncological centers in Southern Vietnam, covering a population of nearly 50 million people. We have utilized the FOLFOXIRI regimen as the first-line treatment for patients with advanced CRC since 2022. This study aims to assess the oncological outcomes and toxicity of the FOLFOXIRI regimen as upfront treatment in patients with initially unresectable CRC liver metastases. Findings from our study can provide valuable real-world data on the clinical benefits and tolerability of triplet chemotherapy for advanced CRC in an LMIC setting.

Study design and population

This was a prospective observational study conducted between January 2022 and June 2023 at the Oncology Center, Cho Ray Hospital, Ho Chi Minh City, Vietnam. The study enrolled all patients with a diagnosis of unresectable CRC liver metastases. The study was conducted in accordance with the standards of Good Clinical Practice and the Declaration of Helsinki. The institutional ethics committee approved the study (No. 1277/GCN-HDDD, dated 18 February 2022). Written informed consent was obtained from all participants before their inclusion in the study. The protocol was registered on clinicaltrials.gov (NCT05362825).

Inclusion criteria were: (i) age between 18 and 75 years old, (ii) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, (iii) a diagnosis of initially unresectable metastatic CRC assessed by a multidisciplinary team (MDT) due to the presence of multiple liver lesions, curative resection resulting in < 30% liver remnant, or curative resection required complex procedure, and (iv) adequate organ function as evidenced by normal bone marrow function (hemoglobin ≥ 10.0 mmol/L, absolute neutrophil count ≥ 1.5 × 10⁹/L, and platelet count ≥ 100 × 10⁹/L), normal renal function (serum creatinine ≤ 1.5 × upper limit of normal [ULN] and creatinine clearance ≥ 30 mL/min), and normal liver function (serum bilirubin ≤ 2 × ULN and serum transaminases ≤ 5 × ULN).

Exclusion criteria were (i) recurrent CRC, (ii) CRC with extrahepatic metastases, (iii) prior systemic or local treatment for liver metastases, (iv) previous adjuvant chemotherapy or chemotherapy for metastases, (v) unmeasurable lesions based on the response evaluation criteria in solid tumors (RECIST) version 1.1, and (vi) presence of a second primary malignancy.

Treatments

All patients received the FOLFOXIRI regimen every two weeks. The treatment continued until (i) evidence of disease progression, (ii) unacceptable toxicity, (iii) eligibility for radical surgery, (iv) patient refusal, or (v) after a maximum of 12 cycles. The regimen comprised irinotecan 165 mg/m² over 60 min, followed by oxaliplatin 85 mg/m², leucovorin 400 mg/m² intravenous, and a 48-hour continuous infusion of 5-FU 2400 mg/m² [12].

To prevent adverse events (AEs) related to the treatment, several supportive medications were administered. Pegfilgrastim (granulocyte-colony stimulating factor [G-CSF]) was given subcutaneously 24 hours after completing the 5-FU infusion, as a standard prophylaxis of neutropenia. A combination of intravenous palonosetron (0.25 mg) and dexamethasone (8 mg) was administered one hour before each treatment cycle as the antiemetic prophylaxis. Atropine 0.25 mg was given subcutaneously for prophylaxis of cholinergic reaction of irinotecan. Loperamide was administered orally at a dose of 2 mg every 2 hours to manage diarrhea if needed.

In case of severe side effects, the following dose adjustments were implemented. A 20% reduction in the dose of 5-FU, irinotecan and oxaliplatin was applied for recurrent episodes of grade 3–4 diarrhea, thrombocytopenia, or prolonged febrile neutropenia. A 20% reduction in the dose of oxaliplatin was implemented for persistent grade 3–4 peripheral neuropathy.

Treatment response was evaluated every 8–9 weeks. If the MDT deemed the patient suitable for surgery, surgical intervention was offered. For patients with progressive disease, the treating physician could decide to switch to a different chemotherapy regimen. If the patient achieved a complete or partial response after 12 cycles but surgery was still not feasible, they were switched to a maintenance regimen with oral capecitabine 1500mg/m² every three weeks until disease progression, unacceptable toxicity, or patient refusal.

Patient evaluation

Assessment before treatment included a detailed medical history and physical examination, blood count tests, biochemistry, electrocardiogram, carcinoembryonic antigen (CEA) levels, genetic tests analyzed for mutations in KRAS, NRAS, and BRAF genes, and computed tomography (CT) scan and magnetic resonance imaging (MRI) evaluated the primary colorectal tumor and any liver metastases. The MDT meeting, including various specialists like oncologists, surgeons, radiologists, and pathologists, reviewed the patient’s case and treatment plan.

During treatment, patients were monitored every two weeks with physical examinations, blood count tests, and assessments of liver and kidney function. AEs were assessed using the common terminology criteria for AEs (CTCAE) version 5.0. Any delays in treatment cycles and dose adjustments were recorded. Tumor response was evaluated every 8 weeks using CT scan and MRI, following the response evaluation criteria in solid tumors (RECIST) version 1.1.

Resectability was assessed by the MDT panel based on specific criteria that included ensuring sufficient remaining healthy liver tissue after surgery. Patients were categorized as having (1) resectable, (2) potentially resectable, or (3) permanently unresectable CRC liver metastases. For resectable and potentially resectable cases, a detailed surgical plan considering the type of resection, number of stages, and need for portal vein embolization was outlined.

In cases of radical surgery, the chemotherapy was stopped, and surgery was typically performed within 2–4 weeks. The primary colorectal tumor and liver metastases could be removed in one or separate surgeries, depending on the surgeons’ judgment. Surgical techniques for the primary tumor could involve laparoscopic or open approaches, colectomy or low anterior rectal resection with regional lymphadenectomy. Liver surgery could also be open or laparoscopic, aiming to preserve as much healthy tissue as possible. Radiofrequency ablation (RFA) might be used during surgery for small, unresectable liver tumors. Surgical margins of both colon and liver tumors were examined to assess complete removal of cancer cells. R0 resection was defined as > 1 mm surgical margin without residual tumor, R1 was microscopic residual tumor, and R2 was macroscopic residual tumor.

After surgery, rectal additional radiotherapy might be considered if lymph node involvement was present. Patients with complete tumor removal were monitored with regular CT/MRI scans and CEA levels every 3 months. Patients without R0 resection received oral capecitabine until disease progression, unacceptable toxicity, or patient refusal.

Outcomes

To assess the effectiveness and safety of the FOLFOXIRI regimen, outcomes included R0/R1 resection rate, progression-free survival (PFS), overall survival (OS), objective response, disease control, early tumor shrinkage (ETS), depth of response (DpR), toxicity (according to CTCAE version 5.0), postoperative complications (according to the Clavien Dindo grading system) [13], pathological complete response rate of resected lesions, and recurrence-free survival (RFS).

PFS was defined as time from the start of treatment until disease progression or death from any cause. OS was defined as time from the start of the treatment to death from any cause. Objective response was defined as having partial or complete response, while disease control included patients who had objective response or stable disease, according to RECIST version 1.1. ETS was the percentage change in tumor size after eight weeks of treatment compared to baseline. DpR was the greatest percentage change in tumor size observed during treatment, in the absence of new lesions or progression of non-target lesions, when compared with baseline. RFS (applicable to surgery patients only) was defined as time from radical surgery until disease progression or death from any cause. For PFS, OS, and RFS, patients without the corresponding events were censored on their last visit date.

Statistical analysis

Patient characteristics, AEs, and treatment outcomes were summarized using median and interquartile range (IQR) for continuous variables, and frequency and percentage for categorical variables. Survival outcomes (PFS, OS, and RFS) were analyzed using the Kaplan-Meier method and reported as median survival time and Kaplan-Meier probability at specific time points (6, 12, 18, and 24 months) with their corresponding 95% confidence intervals (CIs). Kaplan-Meier curves were used to visually present the survival probability for all patients and subgroups defined by whether they underwent surgery or not. Factors associated with toxicity (grade 3 or worse AEs) and achieving resectability were explored using logistic regression models. Results were reported by odds ratios (ORs) and their corresponding 95% CIs and p values. All analyses were performed using the statistical software R version 4.1.3.

Patient characteristics

Between January 2022 and June 2023, 97 patients with initially unresectable CRC liver metastases were treated at our center. Among them, 92 patients were included in the study and received the FOLFOXIRI regimen (Fig. 1). Following the chemotherapy, 54 patients were able to proceed with radical surgery. The remaining 38 patients did not undergo surgery due to various reasons, including unresectability as assessed by the MDT (14 patients), progressive disease (11 patients), death (6 patients), or refusal of chemotherapy (4 patients) or surgery (3 patients).

The median age was 56 years and males predominated (70.7%) (Table 1). The most frequent site of the primary tumor was the left colon (42.4%), followed by the rectum (37%) and right colon (20.7%). Forty-one patients (44.6%) had more than five liver metastases. KRAS mutations were identified in 32 patients (34.8%), whereas NRAS (2 patients) and BRAF^V600E mutations (no case) were infrequent. The main reasons of initial unresectability were multiple lesions spread across two liver lobes (63%) and the need for a complex procedure due to the tumor’ location near vital organs (26.1%). Twelve patients (13%) had already undergone resection of the primary tumor before participating in the study. The median number of chemotherapy cycles was 10 (IQR: 8–12). Patients were followed for a median of 20 months (IQR: 16–22).

Table 1

Patient characteristics
	All patients (N = 92)	Non-surgery (N = 38)	Surgery (N = 54)
Age (years)	56 (50–62)	56 (50–62)	58 (50–63)
Sex male	65 (70.7%)	25 (65.8%)	40 (74.1%)
Nutritional status
Underweight (BMI < 18.5 kg/m²)	10 (10.9%)	5 (13.2%)	5 (9.3%)
Normal weight (18.5 ≤ BMI < 24.5 kg/m²)	66 (71.7%)	27 (71.1%)	39 (72.2%)
Overweight/obesity (BMI ≥ 24.5 kg/m²)	16 (17.4%)	6 (15.8%)	10 (18.5%)
BSA group (m²)
< 1.4 (female) or < 1.5 (male)	16 (17.4%)	10 (26.3%)	6 (11.1%)
≥ 1.4 (female) or ≥ 1.5 (male)	76 (82.6%)	28 (73.7%)	48 (88.9%)
ECOG performance status
0	52 (56.5%)	17 (44.7%)	35 (64.8%)
1	40 (43.5%)	21 (55.3%)	19 (35.2%)
Primary tumor site
Right colon	19 (20.7%)	9 (23.7%)	10 (18.5%)
Left colon	39 (42.4%)	19 (50.0%)	20 (37.0%)
Rectum	34 (37.0%)	10 (26.3%)	24 (44.4%)
Number of liver metastases
≤ 5	51 (55.4%)	18 (47.4%)	33 (61.1%)
> 5	41 (44.6%)	20 (52.6%)	21 (38.9%)
KRAS mutation	32 (34.8%)	15 (39.5%)	17 (31.5%)
NRAS mutation	2 (2.2%)	1 (2.6%)	1 (1.9%)
BRAF^V600E mutation	0 (0.0%)	0 (0.0%)	0 (0.0%)
Reason of initial unresectability
Multiple lesions in 2 lobes of liver	58 (63.0%)	29 (76.3%)	29 (53.7%)
Curative resection required complex procedure	24 (26.1%)	2 (5.3%)	22 (40.7%)
Curative resection leading to < 30% liver remnant	9 (9.8%)	7 (18.4%)	2 (3.7%)
Rapidly progressive cancer assessed by MDT	1 (1.1%)	0 (0.0%)	1 (1.9%)
Resection of primary tumor at baseline	12 (13.0%)	4 (10.5%)	8 (14.8%)
Baseline serum CEA (N = 91)
≤ 5 UI	11 (12.1%)	3 (7.9%)	8 (15.1%)
> 5 UI	80 (87.9%)	35 (92.1%)	45 (84.9%)
Number of chemotherapy cycles	10 (8–12)	9 (5–12)	10 (8–12)
Length of follow-up (months)	20 (16–22)	22 (17–24)	19 (15–22)
Summary statistics are median (25th -75th percentiles) and n (%).
BMI, body mass index; BSA, body surface area; CEA, carcinoembryonic antigen; ECOG, Eastern Cooperative Oncology Group; MDT, multidisciplinary team

Chemotherapy toxicity and response

All patients experienced at least one AE during treatment. The median number of AEs per each individual patient was 4 (IQR: 3–5) (Table 2). Thirty-two patients (34.8%) experienced a severe AE (grade 3 or higher). Four fatal AEs occurred, including febrile neutropenia (2 patients), colitis (1 patient), and bronchitis (1 patient) (Table 3). Dose reduction and dose interruption due to AEs occurred in 62 (67.4%) and 66 (71.7%) patients, respectively. Nine patients (9.8%) early discontinued the regimen due to AEs (Table 2).

Table 2

Chemotherapy toxicity
	All patients (N = 92)	Non-surgery (N = 38)	Surgery (N = 54)
Number of AEs per individual	4 (3–5)	4 (3–6)	4 (3–5)
Grade of the most severe AE
Grade 1	12 (13.0%)	3 (7.9%)	9 (16.7%)
Grade 2	48 (52.2%)	15 (39.5%)	33 (61.1%)
Grade 3	18 (19.6%)	10 (26.3%)	8 (14.8%)
Grade 4	10 (10.9%)	6 (15.8%)	4 (7.4%)
Grade 5	4 (4.3%)	4 (10.5%)	0 (0.0%)
Any grade 3 or worse AEs	32 (34.8%)	20 (52.6%)	12 (22.2%)
Any dose reduction due to AEs	62 (67.4%)	24 (63.2%)	38 (70.4%)
Any dose interruption due to AEs	66 (71.7%)	27 (71.1%)	39 (72.2%)
Early discontinuation due to AEs	9 (9.8%)	7 (18.4%)	1 (1.9%)
Summary statistics are median (25th -75th percentiles) and n (%).
AE, adverse event

Table 3

All adverse events during chemotherapy treatment
	Any grade	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Weight loss	54 (58.7%)	47 (51.1%)	7 (7.6%)	0	0	0
Anemia	48 (52.2%)	23 (25%)	16 (17.4%)	8 (8.7%)	1 (1.1%)	0
Thrombocytopenia	47 (51.1%)	11 (12%)	24 (26.1%)	11 (12%)	1 (1.1%)	0
Vomiting	40 (43.5%)	9 (9.8%)	31 (33.7%)	0	0	0
Diarrhea	27 (29.3%)	5 (5.4%)	18 (19.6%)	3 (3.3%)	1 (1.1%)	0
Fatigue	25 (27.2%)	13 (14.1%)	12 (13%)	0	0	0
Liver transaminases increased	25 (27.2%)	21 (22.8%)	4 (4.3%)	0	0	0
Anorexia	19 (20.7%)	14 (15.2%)	5 (5.4%)	0	0	0
Peripheral sensory neuropathy	9 (9.8%)	9 (9.8%)	0	0	0	0
Neutropenia	8 (8.7%)	4 (4.3%)	1 (1.1%)	0	1 (1.1%)	2 (2.2%)
Gastritis	8 (8.7%)	5 (5.4%)	3 (3.3%)	0	0	0
Colitis	7 (7.6%)	0	4 (4.3%)	2 (2.2%)	0	1 (1.1%)
Hiccups	6 (6.5%)	2 (2.2%)	4 (4.3%)	0	0	0
Bowel obstruction	5 (5.4%)	0	0	0	5 (5.4%)	0
Gout	5 (5.4%)	1 (1.1%)	4 (4.3%)	0	0	0
Stomatitis	5 (5.4%)	4 (4.3%)	1 (1.1%)	0	0	0
Abdominal pain	4 (4.3%)	2 (2.2%)	2 (2.2%)	0	0	0
Oxaliplatin hypersensitivity reaction	3 (3.3%)	0	1 (1.1%)	2 (2.2%)	0	0
Diabetes	2 (2.2%)	0	1 (1.1%)	0	1 (1.1%)	0
Reflux esophagitis	2 (2.2%)	1 (1.1%)	1 (1.1%)	0	0	0
Renal failure	2 (2.2%)	2 (2.2%)	0	0	0	0
Bronchitis	1 (1.1%)	0	0	0	0	1 (1.1%)
Cellulitis	1 (1.1%)	0	0	0	1 (1.1%)	0
Appendicitis	1 (1.1%)	0	0	0	1 (1.1%)	0
Ileus	1 (1.1%)	0	0	1 (1.1%)	0	0
Schizophrenia	1 (1.1%)	0	0	1 (1.1%)	0	0
Bleeding	1 (1.1%)	0	1 (1.1%)	0	0	0
Xerosis	1 (1.1%)	0	1 (1.1%)	0	0	0
Urinary tract infection	1 (1.1%)	0	1 (1.1%)	0	0	0
Constipation	1 (1.1%)	0	1 (1.1%)	0	0	0
Skin inflammation	1 (1.1%)	0	1 (1.1%)	0	0	0
Epididymitis	1 (1.1%)	0	1 (1.1%)	0	0	0
Laryngitis	1 (1.1%)	0	1 (1.1%)	0	0	0
COVID-19	1 (1.1%)	1 (1.1%)	0	0	0	0
Headache	1 (1.1%)	1 (1.1%)	0	0	0	0
Sore throat	1 (1.1%)	1 (1.1%)	0	0	0	0
Potassium decreased	1 (1.1%)	1 (1.1%)	0	0	0	0
Insomnia	1 (1.1%)	1 (1.1%)	0	0	0	0
Hair loss	1 (1.1%)	1 (1.1%)	0	0	0	0
Summary statistics are n (%).
Percentages are calculated from all 92 patients.

The most common AE occurred was weight loss, occurring in 54 patients (58.7%), although all cases were grade 1 or 2 (Table 3). Other frequent AEs included anemia (52.2%), thrombocytopenia (51.1%), vomiting (43.5%), diarrhea (29.3%), fatigue (27.2%), increased liver transaminases (27.2%), and anorexia (20.7%). Among these AEs, only anemia, thrombocytopenia, and diarrhea had grade 3 or worse cases. In addition to three fatal AEs (neutropenia, colitis, and bronchitis), eight patients experienced grade-4 AEs, including anemia, thrombocytopenia, diarrhea, neutropenia, bowel obstruction, diabetes, cellulitis, and appendicitis.

Out of 92 patients, five could not be assessed for tumor response due to death before evaluation (2 cases), refusal of treatment (2 cases), or peritoneal metastasis before the first MDT assessment (1 case). Among the remaining 87 patients, only two (2.3%) achieved a complete response (Table 4). The majority (72 patients, 82.8%) had partial response. The remaining had stable disease (9 patients, 10.3%) or progressive disease (4 patients, 4.6%). The objective response rate and disease control rate were 85.1% and 95.4% respectively. For the 83 patients with disease control, the median ETS and DpR were 35% (IQR: 24–47%) and 54% (38–64%), respectively. Fifty-seven patients (62%) achieved resectability, but three refused to undergo surgery.

Table 4

Response to the chemotherapy
	All patients (N = 87)	Non-surgery (N = 34)	Surgery (N = 53)
Tumor response
Complete response	2 (2.3%)	1 (2.9%)	1 (1.9%)
Partial response	72 (82.8%)	23 (67.6%)	49 (92.5%)
Stable disease	9 (10.3%)	6 (17.6%)	3 (5.7%)
Progressive disease	4 (4.6%)	4 (11.8%)	0 (0.0%)
Objective response	74 (85.1%)	24 (70.6%)	50 (94.3%)
Disease control	83 (95.4%)	30 (88.2%)	53 (100%)
Early tumor shrinkage (%) (N = 83)^@	35 (24–47)	33 (16–44)	37 (27–50)
Depth of response (%) (N = 83)^@	54 (38–64)	50 (33–58)	57 (44–66)
Early tumor shrinkage > 20%^#	72 (82.8%)	21 (61.8%)	51 (96.2%)
Summary statistics are n (%) and median (25th -75th percentiles).
^@Early tumor shrinkage and depth of response are calculated in patients with disease control (83 patients).
^#All four patients with progressive disease are considered as early tumor shrinkage of < 20%.

We found that most factors associated with an increased risk of severe AEs were associated with a lower rate of achieving resectability (Table 5). Three factors significantly associated with a higher risk of severe AEs were female sex, low BSA (< 1.4 m² for females or < 1.5 m² for males), and a primary tumor located in the right colon. Two factors significantly associated with a decreased rate of achieving resectability were low BSA and higher ECOG PS (1 versus 0).

Table 5

Factors associated with toxicity and achieving resectability
	Grade 3 or worse AEs			Achieved resectability
	OR	95% CI	p-value	OR	95% CI	p-value
Age (years)	1.04	0.99, 1.10	0.119	1.00	0.96, 1.04	0.979
Sex
Male	1	Ref		1	Ref
Female	3.53	1.39, 9.22	0.008	0.55	0.22, 1.38	0.201
Nutritional status
Underweight (BMI < 18.5 kg/m²)	1	Ref		1	Ref
Normal weight (18.5 ≤ BMI < 24.5 kg/m²)	0.80	0.21, 3.41	0.751	1.75	0.45, 6.90	0.412
Overweight/obesity (BMI ≥ 24.5 kg/m²)	0.68	0.13, 3.68	0.649	1.67	0.33, 8.61	0.532
BSA group (m²)
< 1.4 (female) or < 1.5 (male)	1	Ref		1	Ref
≥ 1.4 (female) or ≥ 1.5 (male)	0.24	0.07, 0.74	0.014	3.40	1.13, 11.0	0.032
ECOG performance status
0	1	Ref		1	Ref
1	1.24	0.52, 2.94	0.631	0.41	0.17, 0.95	0.040
Primary tumor site
Right colon	1	Ref		1	Ref
Left colon	0.63	0.20, 1.89	0.406	1.16	0.38, 3.53	0.786
Rectum	0.19	0.05, 0.66	0.010	2.50	0.77, 8.34	0.128
Number of liver metastases
≤ 5	1	Ref		1	Ref
> 5	0.78	0.32, 1.86	0.579	0.64	0.27, 1.49	0.301
KRAS mutation	1.48	0.60, 3.61	0.391	0.69	0.29, 1.67	0.411
Resection of primary tumor at baseline	0.14	0.01, 0.79	0.070	1.27	0.37, 5.07	0.719
Baseline serum CEA
≤ 5 UI	1	Ref		1	Ref
> 5 UI	0.61	0.17, 2.29	0.449	0.56	0.12, 2.11	0.421
BMI, body mass index; BSA, body surface area; CEA, carcinoembryonic antigen; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; OR, odds ratio

Operative characteristics and survival outcomes

Among 54 patients who proceeded with radical surgery, most (39 patients, 72.2%) underwent simultaneous colectomy and hepatectomy (Table 6). Complications occurred in four patients (7.4%); all had bleeding. Two Clavien-Dindo grade-IV complications were anastomotic leakage and bowel obstruction. All resected colorectal tumors were classified as R0 resection, whereas 39/51 (76.5%) resected liver metastases were classified as R0 resection, the remaining were R1 resection. Overall, the proportion of R0, R1, and R2 for both colorectal tumor and liver metastases were 66.7%, 22.2%, and 11.1%, respectively.

Table 6

Operative characteristics
	N	Surgery group (N = 54)
Surgical method	54
Simultaneous colectomy and hepatectomy		39 (72.2%)
Two-stage colectomy and hepatectomy		3 (5.6%)
Hepatectomy only		9 (16.7%)
Colectomy only		3 (5.6%)
Any complications	54	4 (7.4%)
Clavien-Dindo classification	4
Grade I		1 (25.0%)
Grade II		1 (25.0%)
Grade IV		2 (50.0%)
Residual colorectal tumor classification	45
R0		45 (100%)
R1		0 (0%)
R2		0 (0%)
Residual liver metastases classification	51
R0		39 (76.5%)
R1		12 (23.5%)
R2		0 (0%)
Overall residual tumor classification	54
R0		36 (66.7%)
R1		12 (22.2%)
R2		6 (11.1%)
Pathological complete response for colorectal tumor	45	2 (4.4%)
Pathological complete response for liver tumor	51	9 (17.6%)
Summary statistics are n (%).

As expected, patients who underwent radical surgery had better PFS and OS compared to those without surgery (Fig. 2). The median PFS for all patients was 13 months, and the median OS was 22 months. For patients who underwent surgery, the median PFS was 14 months, and the median RFS was 11 months. Patients who did not have surgery had a median PFS of 6 months and a median of OS of 14 months (Table 7).

Table 7

Kaplan Meier probabilities and median survival time
	Median (95% CI)	Kaplan-Meier probability (95% CI) (%)
	(month)	6 months	12 months	18 months	24 months
Progression-free survival
All patients	13 (11–14)	80 (73–89)	54 (44–65)	17 (10–29)	8 (3–19)
Non-surgery	6 (5–9)	53 (39–71)	21 (11–39)	-	-
Surgery	14 (13–18)	100 (100–100)	77 (66–89)	29 (18–47)	13 (6–32)
Overall survival
All patients	22 (19-NA)	92 (87–98)	80 (72–89)	63 (53–75)	45 (33–60)
Non-surgery	14 (9–18)	82 (70–95)	55 (41–73)	29 (18–49)	15 (7–33)
Surgery	NA	100 (100–100)	98 (94–100)	90 (81–100)	70 (54–92)
Recurrence-free survival
Surgery	11 (8–13)	70 (59–84)	41 (30–57)	25 (15–42)	25 (15–42)
Summary statistics are median survival time (95% CI) and Kaplan-Meier survival probability (95% CI).
CI, confidence interval; NA, not available

This study offers valuable real-world data on the effectiveness and safety of FOLFOXIRI regimen in the treatment of unresectable CRC liver metastases in a LMIC setting. The chemotherapy was relatively safe with 15.2% grade-4-to-5 AEs and 9.8% early discontinuation due to AEs. The regimen achieved good objective response and disease control rates, and 58.7% of the patients underwent radical surgery. However, the patients still had poor survival with 2-year PFS and OS of 8% and 45% respectively.

In recent years, the advancement of neoadjuvant therapy has substantially increased the chance of R0 surgery for CRC with liver metastases patients, increased the volume of the remaining liver following radical surgery, and improved survival [14, 15]. Around 80% of CRC liver metastases are unresectable at initial diagnosis, and over 10% are resectable following conversion therapy [16]. However, these patients have a similar 5-year survival rate to patients with resectable tumors at the initial diagnosis [17]. Therefore, when the initial treatment is successful, both conversion and neoadjuvant therapy likely improve the overall prognosis of patients with CRC liver metastases. In this study, over 80% of patients achieved objective response, and nearly 60% of patients underwent radical surgery after the chemotherapy. These findings are consistent with other studies, suggesting that FOLFOXIRI may lead to deeper tumor shrinkage and a higher conversion rate to resectability compared to doublet regimens [5, 18, 19]. As expected, patients who underwent surgery had a considerably better PFS and OS compared to those who did not. However, the 2-year PFS and OS rates in our study (8% and 45% respectively) need to be considered within the context of our LMIC setting. Limited access to advanced treatments and supportive care compared to high-income countries may influence these survival rates.

With regards to the safety outcome, FOLFOXIRI known to have a more complex safety profile compared to some other doublet chemotherapy regimens. Several studies have reported a higher incidence of diarrhea and neutropenia associated with FOLFOXIRI [6, 11, 18, 20–25]. While our study observed these side effects as well, thrombocytopenia and anemia emerged as the most common severe (grade 3 or worse) AEs. Neutropenia, a frequent concern with FOLFOXIRI, was less prevalent in our study. This is likely due to our routine use of G-CSF after each chemotherapy cycle. However, two out of the four chemotherapy-related deaths involved febrile neutropenia, highlighting the importance of preventive G-CSF use in this context. Anemia and thrombocytopenia, while more common than neutropenia in our study, were generally less severe. These AEs are primarily linked to oxaliplatin. Management typically involves reducing the oxaliplatin dose. We believe that factors such as close patient monitoring, G-CSF use, and prompt management of AEs contributed to the lower severity of these AEs in our study population. However, it is important to consider the patients’ health-related quality of life while undergoing this treatment regimen to fully understand the impact of these AEs.

Our study underscores the importance of the MDT in managing CRC liver metastases patients. The MDT brings together specialists from various disciplines, such as surgeons, oncologists, and radiologists, facilitating a more comprehensive approach to patient care. This collaborative approach offers several advantages, including improved diagnostic accuracy, reduced treatment delays, personalized treatment plans, enhanced treatment coordination [26], improved quality of life [27], and optimal clinical outcomes [28, 29]. Our hospital established a digestive tract tumor MDT in December 2021, holding regular case discussions to facilitate collaborative decision-making for patients throughout their treatment journey. This multidisciplinary approach likely contributed to the positive outcomes observed in our study.

This study has limitations. The absence of a comparison group and a relatively small sample size restrict the generalizability of our findings. Additionally, resource constraints and ethical considerations limited our ability to conduct a larger trial comparing FOLFOXIRI with other treatment options. Despite these limitations, our study provides valuable real-world data on the effectiveness and safety of FOLFOXIRI in a LMIC setting, contributing to the limited existing research on this topic in Vietnam.

In conclusion, the triplet FOLFOXIRI regimen can improve the response rate, R0/R1 resection rate, and survival for patients with unresectable CRC liver metastases. No new safety profile was recorded, but neutropenia can be reduced by using prophylactic G-CSF on each cycle. Future research in this area should focus on improving the prognosis of patients with CRC liver metastases while minimizing treatment-related toxicities. This may involve exploring treatment optimization strategies, investigating the use of targeted therapies alongside chemotherapy, and evaluating the cost-effectiveness of various treatment approaches within LMIC settings.

Acknowledgements: We would like to thank the staff of Cho Ray hospital, all participants in this study, and their families for their invaluable support.

Competing Interests: The authors have no relevant financial or non-financial interests to disclose.

Funding: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author Contributions:

VDTH: conceptualization, methodology, data collection, writing – original draft preparation

PMT: conceptualization, methodology, supervision, writing – review and editing

DTM: data collection, writing – review and editing

LTA: data collection, writing – review and editing

LVT: conceptualization, methodology, supervision, writing – review and editing

NHB: conceptualization, methodology, supervision, writing – review and editing

NLV: methodology, data analysis, writing – original draft preparation

Data Availability: The data that support the findings of this study are available from the corresponding author, NLV, upon reasonable request.

Ethics Approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Cho Ray hospital (No. 1277/GCN-HDDD, dated 18 February 2022).

Consent to Participate: Informed consent was obtained from all individual participants included in the study.

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FOLFOXIRI for First-Line Treatment of Unresectable Colorectal Cancer with Liver Metastases in a Resource-Limited Setting

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