FOLFOX-based transarterial infusion chemotherapy for unresectable colorectal cancer: protocol of an open-label, multicentre, randomised, controlled, phase II trial

Abstract

Introduction

Colorectal cancer (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, intravenous chemotherapy (IVC), radiotherapy, immunotherapy, targeted therapy and their combinations. As a mainstream systemic treatment for CRC, IVC leads to widespread drug distribution but relatively low intratumoural drug accumulation. Compared with IVC, transarterial infusion chemotherapy (TAIC) involves selective arterial catheterisation to deliver chemotherapeutic agents directly to the tumour feeding vessels. Hepatic tumours receive their blood supply predominantly through branches of the hepatic artery. Hepatic artery infusion chemotherapy (HAIC) yields significantly superior outcomes compared with 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 unresectable CRC (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.

Methods and analysis

This is a prospective, multicentre, randomised, open‐label clinical trial. The uCRC is defined as inability to achieve an R0 resection owing to locally advanced CRC with clinical T4 disease confirmed by MRI or CT and/or synchronous liver metastases. This study only includes microsatellite stable or proficient mismatch repair uCRC. A total of 50 eligible patients will be randomly assigned to either the IVC group or the TAIC group. Patients in the IVC group will receive FOLFOX (fluorouracil, leucovorin, oxaliplatin)-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 colorectal liver metastases, cetuximab or bevacizumab will be administered according to the RAS and BRAF status and the primary tumour site. The primary endpoint is the objective response rate. This study is scheduled to commence on 10 January 2026, and complete follow-up on 31 December 2027. The first subject was enrolled on 20 March 2026. To date, one subject in the IVC group and six subjects in the TAIC group have been enrolled.

Ethics and dissemination

The present study protocol has been approved by the Medical Ethics Committee of Guang’anmen Hospital, China Academy of Chinese Medical Sciences (ethical approval number 2025-268 KY). On completion of the study, data cleaning and analysis will be performed, and the results will be disseminated at academic conferences and in international peer-reviewed journals. This trial has been registered at ClinicalTrials.gov. The statistical analysis plan will be finalised and approved before the database lock. The final version is retained in the study documentation and will be made available to support the transparency and interpretation of the study results.

Trial registration number

NCT07333053.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This is a prospective, multicentre, randomised, open‐label clinical trial designed to compare the differences in efficacy between intensive transarterial infusion chemotherapy (TAIC), followed by sequential intravenous chemotherapy (IVC) and IVC alone in the treatment of unresectable colorectal cancer (uCRC).

• Preliminary study yielded promising outcomes, supporting TAIC as a potential strategy for uCRC.

• The planned sample size is 50 patients, and this relatively small sample size may reduce the statistical power of this study.

• Due to clear differences between TAIC and IVC, blinding is not feasible for this study.

Introduction

Colorectal cancer (CRC) is the third leading cause of new cancer cases and the second leading cause of cancer-related deaths worldwide.¹ Currently, surgical resection remains the curative treatment of choice for patients with localised CRC. Unfortunately, due to the asymptomatic nature of CRC in its early stages, the majority of patients are diagnosed at an advanced stage, at which point surgical resection is no longer a viable option. For reasonably healthy unresectable CRC (uCRC) patients, first-line therapy consists of either oxaliplatin-based regimens or irinotecan-based regimens.^{2 3} To improve clinical outcomes, chemotherapy can be combined with bevacizumab to target the vascular endothelial growth factor (VEGF) pathway or with cetuximab to target the epidermal growth factor receptor (EGFR).^4–6 Bevacizumab-combined chemotherapy is the preferred first-line treatment for patients with RAS/BRAF-mutated mCRC.^{7 8} Nevertheless, intravenous chemotherapy (IVC) is limited by severe toxic side effects due to the non-specificity of chemotherapeutic agent. In patients with KRAS wild-type advanced or mCRC, 96% experience at least one adverse event during IVC.⁹ Accordingly, for patients presenting advanced-stage CRC who are not candidates for surgery, there is an urgent need for a more effective therapeutic approach with fewer side effects.

Transarterial infusion chemotherapy (TAIC) may confer potential therapeutic benefits in patients with uCRC. TAIC increases the intratumoural concentrations of chemotherapeutic agents and lowers systemic toxicity by delivering high-concentration drugs directly into the tumour via superselective catheterisation of tumour-feeding arteries. Studies have confirmed that hepatic artery infusion chemotherapy (HAIC) with floxuridine achieves up to a 400-fold higher intratumoural drug exposure relative to IVC and allows for administration of systemic chemotherapy at near-full doses.^10–12 Correspondingly, HAIC has been shown to yield significantly better outcomes than conventional transarterial chemoembolisation or IVC.^{13 14} The superior therapeutic response is mainly attributed to the direct and sufficient contact between the chemotherapeutic agents and tumour cells. The elevated concentration gradient across blood vessels and tumour tissue further enhances the penetration of chemotherapeutic agents into tumour cells. Together with prolonged drug exposure of tumour cells, these two mechanisms jointly account for the enhanced antitumour responses.¹⁵ Fluorouracil, leucovorin, oxaliplatin (FOLFOX)-based HAIC has been recommended as an alternative therapy for advanced hepatocellular carcinoma (HCC) by the Chinese Society of Clinical Oncology. HAIC has also been widely recognised and incorporated into the guidelines issued by the Japan Society of Hepatology since October 1995.¹⁶ In the current Pan-Asian-adapted European Society for Medical Oncology Guidelines, HAIC is recommended as the first-line option for patients with advanced non-metastatic HCC complicated with macrovascular invasion.¹⁷ In locally advanced intrahepatic cholangiocarcinoma, HAIC in combination with IVC can offer long-term durable disease control compared with IVC alone.^{18 19} CRC is predominantly grown through angiogenesis. Anatomically, proximal colon cancers are supplied by the superior mesenteric artery, while lesions originating from the distal transverse colon and more distal colonic segments are fed by the inferior mesenteric artery. Rectal cancers are vascularised by the superior, middle and inferior rectal arteries. Drawing on the successful clinical experience of HAIC as a therapeutic modality for liver tumour, we have designed a phase II trial to compare the differences in clinical efficacy and safety between the sequential IVC after intensive TAIC and IVC alone in patients with uCRC.

We hypothesise that intensive FOLFOX-based TAIC, followed by FOLFOX-based IVC, might be an effective alternative therapeutic regimen for patients with uCRC. This treatment strategy is designed to achieve tumour downstaging, lower the risks of locoregional recurrence and distant metastasis, and improve long-term survival outcomes. Previous studies have demonstrated that CRC patients with microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) do not benefit from 5-fluorouracil-based chemotherapy. Accordingly, this study only includes patients with microsatellite stable/pMMR uCRC.²⁰

Methods and analysis

Patient and public involvement

Patients or the public will not be involved in the design, conduct, reporting or dissemination plans for this study.

Hypothesis

We hypothesise that intensive TAIC followed by sequential IVC yields superior clinical efficacy compared with IVC alone for the treatment of uCRC.

Study design

This is a prospective, multicentre, randomised, 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 on 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. Randomisation will be conducted by an independent trial statistician via a secure system with complete allocation concealment using the permuted block randomisation method. Stratification factors consist of primary tumour location, presence of liver metastases, RAS/BRAF mutational status and participating study centre. 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 colorectal liver metastases (CRLM), targeted agent selection is determined based on the RAS and BRAF mutational status and the primary tumour location.

The trial schematic workflow and participant disposition flow chart are presented in figures 1 and 2, respectively.

Figure 1. The flow chart of the clinical trial process. FOLFOX, fluorouracil, leucovorin, oxaliplatin; IVC, intravenous chemotherapy; TAIC, transarterial infusion chemotherapy.

Figure 2. The flow chart of participants throughout the clinical trial. IVC, intravenous chemotherapy; TAIC, transarterial infusion chemotherapy.

Trial organisation, ethics approval

This study is an independent, investigator-initiated, investigator-designed and investigator-led clinical trial conducted at Guang’anmen Hospital (ethical approval number 2025-268 KY). A total of 12 domestic medical centres with expertise in gastroenterology, interventional radiology and medical oncology will participate in this trial to ensure adequate subject recruitment. All investigational products will be supplied by the pharmacy department of each participating centre. To facilitate subject enrolment and improve compliance, priority access and fast-track services will be offered for outpatient visits, inpatient bed reservation, follow-up evaluations and clinical consultations. All eligible subjects must sign the written informed consent form prior to randomisation. To improve adherence with the intervention protocol, patients and their families will be contacted by a research assistant who will remind them to complete scheduled treatment and routine follow-up visits. If there are any amendments to the informed consent form during this clinical study, the revised version must receive another written approval from the ethics committee prior to implementation. Subjects shall re-sign the updated informed consent form to provide renewed consent before receiving continued study interventions.

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 tumour 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 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 performance status score ≤2.

9. All the patients in this study are required to sign an informed consent form.

Exclusion criteria

1. Patients have other primary malignant tumours.

2. Patients with recurrent CRC.

3. Patients with distant metastases besides synchronous hepatic metastases (eg, pulmonary, bone or brain metastases).

4. For patients with CRLM, the MDT consensus recommends a liver-first treatment strategy to avoid the risk of rapid hepatic lesion progression.

5. CRC patients with gastrointestinal perforation.

6. Patients with malignant bowel obstruction refractory to conservative management.

7. Patients are allergic to the antitumour agents.

8. Women pregnant, breastfeeding or planning to become pregnant.

9. Patients receiving other antitumour therapies, such as chemotherapy, targeted therapy or radiotherapy.

10. Patients with MSI-H/dMMR CRC.

Withdrawal criteria

Subjects may withdraw voluntarily from the trial at any time for any reason on personal decision.

Sample size

The primary endpoint of this study is objective response rate (ORR). The null hypothesis of ORR is 50%,²¹ and the alternative hypothesis is 90.5% derived from unpublished pilot study data. The sample size was calculated to estimate a two-sample proportion with a difference of 40.5%. With a 90% power and a two-sided alpha of 0.05, the required sample size is 44 subjects. Considering a dropout rate of 10%, a total of 50 subjects are required.

Study endpoints and assessment

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.

ORR is defined as the percentage of patients achieving CR or partial response (PR) according to the Response Evaluation Criteria in Solid Tumour (RECIST) 1.1 for CRC and modified RECIST criteria for CRLM.^{22 23} QoL will be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-Core 30 (C30). The scores of each EORTC QLQ-C30 scale will be calculated in accordance with the EORTC scoring manual. Between-group comparisons of treatment-baseline changes in each scale score will be performed using analysis of variance. The best health response (improvement, no change or deterioration) is considered the proportion of patients with a clinically meaningful change (defined as a ≥10-point change from baseline). The cCR is defined as no visible tumour on imaging. The pCR is defined as the absence of invasive neoplastic cells on microscopic evaluation of the tumour during surgery. 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: (1) following four cycles of conversion therapy, simultaneous or staged complete surgical resection of the primary tumour and liver metastases can be performed. (2) The primary lesion can be resected en bloc with R0 margins. (3) 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. (4) Patients maintain acceptable general status and have no additional distant metastases precluding local radical treatment. (5) Regional lymph node metastases are amenable to complete surgical resection. OS is calculated from the date of randomisation until death. PFS is defined as the time from randomisation to progression or death. AEs include chemotherapy-related and catheter-related complications, which will be graded in accordance with the National Cancer Institute Common Terminology Criteria for AEs, version 6.0.

Assessments will be performed at baseline, prior to the third treatment cycle and at week 8 after baseline. The laboratory examinations, contrast-enhanced CT or MRI of the abdomen and pelvis, QoL questionnaire and AEs will be documented at every cycle of treatment. To better assess therapeutic response, lesion dimensions in the rectum will be evaluated by MRI, and those in the colon by CT. An independent central imaging core laboratory will perform central blinded analysis of all imaging data.

Statistical analysis

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 SDs or medians with IQRs, as appropriate. Pearson’s χ² 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 analysed 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. HRs with 95% CIs will be estimated from Cox regression models. All statistical tests will be two-sided, and a p<0.05 will be considered statistically significant. All statistical analyses will be performed using the current version of R software.

The ITT population includes all randomised patients, analysed according to their assigned treatment group regardless of protocol adherence, treatment modification, crossover between treatments or treatment discontinuation. Patients who withdraw from the study, modify treatment or receive crossover treatment will generally be excluded from the PP population. Patients with radiologically confirmed progressive disease (PD) before treatment discontinuation will be retained in the PP population and classified as PD. For the primary endpoint of ORR, missing outcome data will be conservatively classified as PD. This missing data handling strategy will be consistently applied to all secondary binary endpoints, including cCR rate, pCR rate and CTR rate. For time-to-event endpoints, patients lost to follow-up will be censored at the last confirmed survival date in the Kaplan-Meier analysis. For patients who achieve resectability within four cycles of chemotherapy, the last evaluable tumour imaging assessment prior to surgery will be carried forward to impute missing endpoint data. Patients who discontinue the study will be actively contacted to record withdrawal reasons and complete scheduled assessments to minimise follow-up loss. As a sensitivity analysis, missing primary endpoint data will be imputed under the missing at random assumption using multiple imputation by chained equations. For QoL analyses, multiple imputation by chained equations will also be performed as a sensitivity analysis to evaluate the robustness of the primary mixed-effects model results.

The primary endpoint analysis is confirmatory. All secondary endpoint analyses and subgroup analyses are exploratory, and no formal multiple comparison adjustment will be performed. Predefined subgroup analyses will evaluate treatment effect modification according to primary tumour site, presence or absence of liver metastases, RAS/BRAF molecular status, study centre and other potential efficacy-related covariates. Treatment-by-subgroup interaction terms will be incorporated into Cox regression models for time-to-event outcomes and logistic regression models for binary efficacy outcomes to test subgroup effect heterogeneity. Binary outcomes will be summarised with relative risks and 95% CIs, time-to-event outcomes with HRs and 95% CIs and continuous outcomes with mean differences and 95% CIs. Subgroup and adjusted analyses will only be conducted when the sample size and event number within each subgroup are adequate to ensure stable statistical estimates.

Data collection and management

Demographic data, clinical characteristics, laboratory results, radiographic findings, treatment details, outcomes and other relevant information will be collected at subject enrolment. All clinical data will be documented by the investigator in the subject’s medical record and in the electronic case report forms (eCRFs). The investigator shall ensure that all sections of the eCRFs are completed correctly and that all entries are verified against source data. The eCRFs shall be filled out according to the specified CRF Completion Guidelines. The correctness of entries in the eCRFs shall be confirmed by the dated signature of the principal investigator. In case of withdrawal of a patient, the reason for withdrawal shall be ascertained and documented in detail. For participants, the date of last follow-up will be adopted as the censoring date. Final data validation for plausibility, consistency and completeness will be conducted on study completion.

Study interventions

IVC group

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 tumour 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 tumour location.

TAIC group

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. Before placing a microcatheter into the feeding artery of the CRC, transarterial chemoembolisation is performed for the liver metastases in patients with CRLM. The iodised oil emulsion is prepared by mixing 4 mL of iodized oil with 20 mg of oxaliplatin powder. Through the microcatheter, 0.5 mL of the iodised oil emulsion is slowly injected into the liver tumours via the feeding arterial branches. The technical endpoint of embolisation is the absence of additional tumour staining or stasis/near stasis of the tumour-feeding arteries. 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 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.

Criteria for modifying allocated interventions

Toxicity will be assessed following each cycle of chemotherapy. Dose suspension or modification will be implemented based on toxicity grade. Medicines such as antihypertensives and antidiabetics can continue to be used. Liver protection medicine, granulocyte colony-stimulating factor and thrombopoietin can be used if hepatic injury or myelosuppression occurs. Analgesics and other symptomatic supportive treatment are permitted. Traditional Chinese medicines and additional anticancer treatments are prohibited during the study period.

Follow-up and assessments

Following four cycles of conversion therapy, the MDT will assess tumour resectability. Patients who achieve CR or PR and fulfil R0 resection criteria will undergo surgical resection followed by 3 months of adjuvant capecitabine plus oxaliplatin (CAPOX) or mFOLFOX6.²⁴ Patients with PR or stable disease (SD) who are ineligible for R0 resection will receive four additional cycles of conversion therapy, followed by multidisciplinary reassessment of resectability. Patients with PR or SD on re-evaluation who remain ineligible for R0 resection will proceed to maintenance therapy. Following conversion therapy with oxaliplatin-based chemotherapy with or without bevacizumab, maintenance with LV5FU2 plus bevacizumab will be preferred. Conversely, for patients whose conversion therapy combines oxaliplatin-based chemotherapy and cetuximab, maintenance with LV5FU2 plus cetuximab will be recommended.²⁵

Monitoring

An independent Data and Safety Monitoring Board (DSMB) will be established to monitor ethical conduct, participant recruitment, AEs, data quality and other issues every 2 weeks. The interim analysis will be planned after completing 4 weeks of intervention, and its results will be discussed at the meeting of DSMB. If the panel concludes that the risks of the therapy outweigh the benefits such that further study is unwarranted, the trial may be terminated prematurely.

Auditing

The investigators agree to allow the auditors, inspectors and monitors to have direct access to the trial records for review. The investigator will make every effort to help with the performance of the audits and inspections, giving access to all necessary facilities, data and documents.

Protocol version

Version 2.0.

Discussion

CRC is one of the most common malignancies of the digestive tract, associated with substantial morbidity and mortality. Despite the emergence of numerous screening programmes aimed at reducing CRC incidence, among newly diagnosed CRC cases, 20% of patients present with metastatic disease, and another 25% of those initially presenting with localised disease will subsequently develop metastases. This results in difficulties in curative surgical control and subsequent tumour-related deaths.⁵ For patients with unresectable disease, treatment objectives include maximal tumour shrinkage and inhibition of further tumour proliferation and dissemination. Radiotherapy, IVC, targeted therapy and immunotherapy are the leading strategies for controlling disease in such patients. IVC plays an important role in advanced CRC, but the effectiveness of cytotoxic chemotherapy is often limited by acquired drug resistance or intolerable toxicity effects.²¹ Preoperative chemoradiotherapy followed by surgical resection is the standard treatment for locally advanced rectal cancer (LARC). Nevertheless, the pCR rate is merely 10%–15%, and the distant metastasis rate exceeds 30%.²⁶ The major barrier to the use of immune checkpoint inhibitors (ICIs) in CRC is that ICIs exert therapeutic effects only in patients with MSI-high CRC, which accounts for less than 15% of all CRC cases.²⁷ Although IVC with or without a targeted biologic agent is the NCCN-endorsed and ESMO-endorsed standard of care, its clinical benefit remains modest. In conclusion, current therapies still have limitations in effectively controlling this complex disease. Consequently, new approaches need to be developed to improve the treatment efficacy for these patients.

Research conducted in recent decades has demonstrated that IVC administered to patients with CRC, especially those with CRLM, prolongs OS to nearly 20 months, thereby establishing IVC as the backbone of advanced CRC treatment.^{28 29} The FOLFOX has been widely used as a first-line chemotherapy regimen for patients with advanced CRC. The phase III FOxTROT trial confirmed that 6 weeks of oxaliplatin-fluoropyrimidine-based neoadjuvant chemotherapy yielded marked histopathological downstaging, fewer incomplete resections, and better 2-year disease control.³⁰ Compared with the 6-week neoadjuvant chemotherapy regimen evaluated in the FOxTROT trial, the 12-week FOLFOX regimen in the phase III OPTICAL trial was associated with a higher pCR rate and potentially improved OS.³ Despite this favourable clinical efficacy of the 12-week regimen, its chemotherapy completion rate was only 58%, which was markedly lower than the 87% reported in the FOxTROT trial. Meanwhile, long-term use of oxaliplatin is constrained by its cumulative toxicity. Although clinical strategies, including magnesium and calcium infusions or gabapentin, have been adopted to mitigate this adverse effect, peripheral neuropathy is dose-dependent and frequently irreversible once established.³¹ Therefore, a shorter duration of FOLFOX-based chemotherapy may spare patients from toxic effects and reduce health expenditures. To date, the optimal duration of neoadjuvant chemotherapy for CRC remains undefined. A 6-week to 12-week range is suggested, considering treatment needs and efficacy.

Targeted agents are considered to be novel weapons to enhance neoadjuvant efficacy. Thus, various studies have been conducted to introduce targeted drugs into neoadjuvant therapy for CRC.³² Newly emerging strategies incorporating targeted therapies such as VEGF receptor inhibitors or EGFR inhibitors in combination with FOLFOX or FOLFIRI chemotherapy have improved median OS (mOS) up to 31 months.^{5 33} Representative therapeutic antibodies used for CRLM treatment are bevacizumab and cetuximab. Recent investigations have suggested that right or left-sided primary tumour origin affects survival and response to biologic therapy. Compared with IVC alone, IVC plus bevacizumab reduces mortality among patients with right and left-sided CRC, whereas IVC plus cetuximab reduces mortality only among patients with left-sided tumours and is associated with significantly higher mortality for right-sided tumours.⁷ The FIRE-3 study confirmed that the survival advantage of cetuximab over bevacizumab exists only in patients with left-sided primary tumours. Bevacizumab treatment yields superior PFS and OS in patients with right-sided tumours.⁵ Beyond primary tumour location, RAS and BRAF mutation status are also important determinants for the selection of targeted agents. Previously published reports suggest that cetuximab is associated with improved survival compared with bevacizumab in patients with RAS/BRAF wild-type, left-sided primary tumours. Patients with RAS wild-type, right-sided CRLM and those with RAS/BRAF mutant CRLM derive greater benefit from chemotherapy plus bevacizumab.^{34 35} Therefore, evaluation of RAS and BRAF mutational status and primary tumour location is essential to guide the selection of targeted therapies.

Recent developments in minimally invasive interventional radiology techniques have significantly improved the treatment of various solid tumours. Considering the limited tumour response of current first-line IVC, FOLFOX-based TAIC seems to be a promising approach for CRC patients who have limited benefits from IVC.

Currently, relevant clinical trials with positive results have been conducted. Secco et al³⁶ reported long-term results of an early pilot study on 20 patients with sigmoid colon adenocarcinoma treated with 6 sessions of preoperative transarterial infusion of mitomycin-C (each lasting 6 hours) followed by curative surgery. At 5-year follow-up, the overall recurrence rate and OS rate were 30% and 70%, respectively. Braun et al³⁷ carried out a retrospective study of 107 patients with LARC. 52 patients underwent preoperative intra-arterial selective polychemotherapy with subsequent radical surgery. Transarterial infusion of adriamycin and fluorouracil was conducted once a day, with each session lasting 120–150 min and a total of three sessions. 55 patients received surgery alone. At 5 years overall, the ORR and OS rate in the preoperative intra-arterial selective polychemotherapy group and the surgery alone group were 64.8% and 35%, respectively. We also searched ClinicalTrials.gov to identify ongoing, recently completed, or unpublished trials. Currently, on ClinicalTrials.gov, only one trial (NCT05307198) has been registered that uses TAIC for CRC treatment up to August 2026. NCT05307198 is a trial of oxaliplatin-based TAIC combined with capecitabine and an anti-PD-1 antibody for LARC. We also found one study (NCT05340231) that included a large sample of patients with uCRC treated with transarterial chemoembolisation. These patients included in these studies only received intraoperative or postoperative chemotherapy drug transfusions within a short time frame. Therefore, in terms of the study population or duration of drug exposure, our clinical trial differs from those studies.

In conclusion, TAIC has great potential as a new alternative therapy for patients with uCRC.³⁸ However, although studies have demonstrated the effectiveness of TAIC in treating CRC, there is still a need for large-sample size randomised controlled trials to provide high-level evidence to support its use. With the participation of more medical centres and the advancement of ongoing related clinical studies, TAIC may provide an alternative first-line option for uCRC patients worldwide.

Ethics and dissemination

This study will be conducted in compliance with the principles of the Declaration of Helsinki. The study protocol has been approved by the Ethics Committee of Guang’anmen Hospital of China Academy of Chinese Medical Sciences, and written informed consent shall be obtained from all patients. Guang’anmen Hospital of China Academy of Chinese Medical Sciences shall supervise the research, including study design, data collection, analysis, interpretation and reporting. Results are planned to be disseminated through publications in peer-reviewed journals and presentations at national and international conferences. Participants will be informed that their personal information will be kept anonymous and confidential.