Abstract
In this trial, the feasibility and efficacy of neoadjuvant chemotherapy with targeted agents in the treatment of patients with locally advanced rectal cancer were evaluated. In this single-center, prospective, randomized controlled trial, we randomly assigned (1 : 1) patients with locally advanced rectal cancer with wild-type RAS/BRAF gene to two groups: 5 cycles of modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin combination regimen (modified FOLFOX6, mFOLFOX6) concurrent with 25 times radiotherapy or 5 cycles of mFOLFOX6 plus cetuximab, all with subsequent total mesorectal excision (TME) resection and adjuvant chemotherapy. We performed a random assignment by a computer-generated random number sequence. The primary end point was the R0 resection rate. The secondary end points were rates of pathologic complete response, downstaging, adverse events, postoperative complications, preventive enterostomy and low anterior resection syndrome. From January 6, 2020 to October 28, 2022, 80 patients were assigned and evaluated. In the mFOLFOX6-RT and mFOLFOX6-Cet groups, the rate of R0 resection was 96.7 and 96.9% (p = 1.000); the rate of pathological complete response (pCR) was 23.3 and 21.9% (p = 0.891); and the rate of downstaging (ypStage 0 to 1) was 53.3 and 53.1% (p = 1.000), respectively. No statistical differences between the two groups were observed in the incidence of adverse events and postoperative complications. Additionally, lower rates of preventive enterostomy and low anterior resection syndrome were shown in the mFOLFOX6-Cet group compared to the mFOLFOX6-RT group. The neoadjuvant treatment strategy of mFOLFOX6 with cetuximab is feasible and promising for patients with locally advanced rectal cancer, even superior to mFOLFOX6 with radiotherapy.
INTRODUCTION
As the third most common cancer worldwide, colorectal cancer (CRC) accounts for approximately 10% of cancer-related deaths.1) In particular, the incidence of rectal cancer is increasing in young patients.2) Neoadjuvant chemoradiation (nCRT) combined with total mesorectal excision (TME) followed by adjuvant chemotherapy is the standard treatment for locally advanced rectal cancer.3,4) nCRT reduces local recurrence rate, improves tumor downstaging rate, and promotes the sphincter preservation rate, even achieving pathological complete response (pCR).5)
However, preoperative radiotherapy reduces the integrity of excised specimens, increases the difficulty of operation, and leads to postoperative anastomose-related complications.6,7) Moreover, low anterior resection syndrome (LARS) is a common postoperative complication of rectal cancer, which seriously affects the QOL. With the support of a standardized TME surgical protocol and en bloc resection of the tumor, the removal of local micrometastases and lymph nodes was ensured, which resulted in a reduced local recurrence rate.8) The neoadjuvant therapy with chemotherapy alone is gradually gaining traction.
The modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin combination regimen (modified FOLFOX6, mFOLFOX6) is the standard chemotherapy regimen for colorectal cancer and has been used in neoadjuvant chemotherapy (NAC) in several studies,9–11) achieving better R0 resection rate and compliance, and fewer adverse reactions. However, the evidence that it improves long-term survival is equivocal. Patients with distant metastases are usually treated with molecularly targeted agents to improve survival. Its systemic effects may also effectively prevent distant micrometastases. Moreover, the rationale for this strategy12) is to eliminate potential micrometastases as early as possible and prevent the adverse effects of radiotherapy. Therefore, we chose the treatment strategy of NAC with molecular targeted agents for LARC and compared its feasibility and efficacy with the traditional nCRT strategy.
PATIENTS AND METHODS
Study Design and PatientsThis study was a single-center, randomized controlled study from the Affiliated Ganzhou Hospital of Nanchang University in Jiangxi, China. Patients were randomly assigned (1 : 1) to two groups: 5 cycles of mFOLFOX6 concurrent with 25 times radiotherapy (mFOLFOX6-RT group) or 5 cycles of mFOLFOX6 plus cetuximab (mFOLFOX6-Cet group), all with subsequent TME surgery and adjuvant chemotherapy (Fig. 1). The study evaluates feasibility and efficacy of the mFOLFOX6-Cet versus mFOLFOX6-RT. The local ethics committee of the Affiliated Ganzhou Hospital of Nanchang University approved the protocol (No.20220620). Written informed consent was obtained from the participants. This trial followed the principles of the Declaration of Helsinki and Good Clinical Practice guidelines.
The inclusion criteria are (1) histopathologically confirmed rectal adenocarcinoma with wild-type RAS/BRAF gene; (2) age ≥18 and ≤75 years; (3) tumors clinically diagnosed as clinical TNM II (cT3-4N0M0) or cTNM III (T1-4N1-2M0); (4) lesions 4 to 12 cm from the anal verge; and (5) an Eastern Cooperative Oncology Group (ECOG) score ≤1. The exclusion criteria are (1) prior radiotherapy or chemotherapy; (2) the presence of other cancers; and (3) comorbidities of inflammatory bowel disease.
Random Assignment and MaskingAccording to the order of eligible patients, they were randomly allocated to the either mFOLFOX6-Cet group or the mFOLFOX6-RT group by the predetermined random plan. Random assignment was performed by a computer-generated random number sequence in this trial. A researcher sequentially handed participants envelopes that concealed random numbers and group numbers. After screened and informed consent, patients were assigned to corresponding groups. Treatment allocation was not masked.
Treatment ProtocolThe treatment protocol was shown in Fig. 1. Patients received radiotherapy at 1.8 to 2.0 Gy each time, a total of 25 times, with a total radiotherapy dose of 45.0 to 50.4 Gy. The chemotherapy regimen of mFOLFOX6 is oxaliplatin 85 mg/m2 intravenously for 2 h, leucovorin 400 mg/m2 intravenously for 2 h, and 5-fluorouracil 400 mg/m2 intravenously followed by 2.4 g/m2 continuous intravenous infusion for 48 h. Cases in the mFOLFOX6-RT group were treated with five cycles of mFOLFOX6 with concurrent radiotherapy. Patients in the mFOLFOX6-Cet group received five cycles of mFOLFOX6 plus cetuximab. All patients were regularly followed up after TME surgery and postoperative adjuvant chemotherapy with 7 cycles of mFOLFOX6.
After 5 cycles of mFOLFOX6 treatment, tumor resectability was reassessed by digital examination and imaging studies (colonoscopy and magnetic resonance imaging (MRI)/computed tomography (CT)). TME surgery was performed 4–8 weeks after NAC for resectable tumors. Postoperative complications were evaluated according to the Clavien–Dindo classification.13) After effective neoadjuvant therapy and R0 resection, postoperative mFOLFOX6 chemotherapy was recommended.
Patients in the mFOLFOX6-Cet group received cetuximab at an initial dose of 400 mg/m2 as a 2-h intravenous infusion, followed by subsequent weekly doses of 250 mg/m2 administered as a 1-h intravenous infusion. The cetuximab treatment was administered concurrently with each cycle of mFOLFOX6 chemotherapy for a total of five cycles.
Study End Points and DefinitionThe primary end point of was the R0 resection rate which was interpreted as macroscopically or pathologically free surgical margins from tumor invasion. The secondary end points were rates of pCR, downstaging, adverse events, postoperative complications, preventive enterostomy and LARS.
All resection specimens were examined by pathologists according to TNM classification and tumor regression grade (TRG).14) TRG was graded semiquantitatively as 0 to 3. The pCR was defined as TNM stage ypT0N0M0 in patients with LARC after neoadjuvant therapy. In this study, the downstaging was understood as the ypTNM stage of 0 to 1 in patients with LARC after neoadjuvant therapy.
Adverse events that occurred after neoadjuvant therapy were graded according to the Common Terminology Criteria for Adverse Events (version 3). LARS refers to a combination of symptoms of severe intestinal dysfunction including flatulence and/or fecal incontinence, urinary urgency, and frequent bowel movements in patients after treatment.15)
Statistical AnalysisMeasurement data were expressed as mean ± standard deviation (S.D.) and tested by Student’s t-test and the Mann–Whitney U test. Count data were performed using count and percentage and analyzed by Fisher’s exact test or χ2 test, whereas ranked data were analyzed using non-parametric Wilcoxon rank sum test. All statistical analyses were performed with IBM SPSS Statistics 26. The criterion for statistical difference was p < 0.05.
Ethics Approval and Consent to ParticipateThe trial was conducted according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of the Affiliated Ganzhou Hospital of Nanchang University in Jiangxi, China. Written informed consent was obtained from individual or guardian participants.
RESULTS
Patient Characteristics and Neoadjuvant ChemotherapyFrom January 6, 2020 to October 28, 2022, 80 patients from our research center were enrolled and assigned in the study (Fig. 2). In age, sex, BMI, CEA, neoplasm diameter, ECOG-PS, location of the tumor and cTNM stage, the demographics and clinical characteristics showed no significant differences (all p > 0.05) between mFOLFOX6-RT and mFOLFOX6-Cet groups (Table 1).
Table 1. Characteristics of Patients
| Variables | mFOLFOX6-RT (n = 40) | mFOLFOX6-Cet (n = 40) | p-Value |
|---|
| Age (years) | 50.8 ± 12.1 | 53.6 ± 12.5 | 0.302 |
| Male, n (%) | 23 (57.5%) | 27 (67.5%) | 0.489 |
| BMI (kg/m2) | 22.4 ± 2.9 | 22.8 ± 2.8 | 0.562 |
| CEA (ng/mL) | 4.7 ± 7.3 | 10.2 ± 19.9 | 0.108 |
| Neoplasm diameter (cm) | 5.1 ± 1.6 | 4.6 ± 1.4 | 0.099 |
| ECOG-PS, n (%) | | | 0.293 |
| 0 | 33 (82.5%) | 28 (70.0%) | |
| 1 | 7 (17.5%) | 12 (30.0%) | |
| Location of the tumor,a) n (%) | | | 1.000 |
| Ra | 14 (35.0%) | 13 (32.5%) | |
| Rb | 26 (65.0%) | 27 (67.5%) | |
| Clinical T stage, n (%) | | | 0.731 |
| cT2 | 2 (5.0%) | 1 (2.5%) | |
| cT3 | 19 (47.5%) | 24 (60.0%) | |
| cT4a | 14 (35.0%) | 11 (27.5%) | |
| cT4b | 5 (12.5%) | 4 (10.0%) | |
| Clinical N stage, n (%) | | | 0.274 |
| cN0 | 14 (35.0%) | 14 (35.0%) | |
| cN1 | 22 (55.0%) | 17 (42.5%) | |
| cN2 | 4 (10.0%) | 9 (22.5%) | |
| cTNM stage, n (%) | | | 1.000 |
| II | 14 (35.0%) | 14 (35.0%) | |
| III | 26 (65.0%) | 26 (65.0%) | |
Values were expressed as mean (S.D. = standard deviation) or n (%). a) Ra: Above the peritoneal reflection, Rb: Below the peritoneal reflection.
Of the 80 patients eligible for preoperative neoadjuvant therapy, 69 completed neoadjuvant treatment, including 34 patients (85.0%) with mFOLFOX6-RT and 35 patients (87.5%) with mFOLFOX6-Cet. The reasons for discontinuation were adverse effects for 2 patients (5.0%) in Group mFOLFOX6-RT plus 2 patients (5.0%) in Group mFOLFOX6-Cet and patient wishes for 4 cases (10.0%) in Group mFOLFOX6-RT plus 3 cases (7.5%) in Group mFOLFOX6-Cet. The incidence of the most common severe adverse events (grade 3 to 4 toxicities), including leukopenia, neutropenia, and nausea/vomiting, was higher in the mFOLFOX6-Cet group than in the mFOLFOX6-RT group without statistical difference (Table 2). Radiotherapy-related complications occurred only in the mFOLFOX6-RT group, such as proctitis (12.5%) and dermatitis (14.0%).
Table 2. Neoadjuvant Chemotherapy
| Variables | mFOLFOX6-RT (n = 40) | mFOLFOX6-Cet (n = 40) | p-Value |
|---|
| Reason for discontinuation, n (%) |
| Adverse effect | 2 (5.0%) | 2 (5.0%) | 1.000 |
| Patient’s wish | 4 (10.0%) | 3 (7.5%) | 1.000 |
| No. of cycles, n (%) | | | 1.000 |
| 1–2 | 2 (5.0%) | 1 (2.5%) | |
| 3–4 | 4 (10.0%) | 4 (10.0%) | |
| 5 | 34 (85.0%) | 35 (87.5%) | |
| Incidence of adverse events,a) n (%) | | | 1.000 |
| ≤ Grade 3 | 23 (57.5%) | 22 (55.0%) | |
| ≥ Grade 3 | 17 (42.5%) | 18 (45.0%) | |
| Grade 3/4 toxicities, n (%) |
| Leukopenia | 9 (22.5%) | 13 (32.5%) | 0.453 |
| Neutropenia | 8 (20.0%) | 15 (37.5%) | 0.137 |
| Nausea/vomiting | 5 (12.5%) | 7 (17.5%) | 0.755 |
| Diarrhea | 4 (10.0%) | 0 (0.0%) | 0.116 |
| Electrolyte disturbance | 2 (5.0%) | 2 (5.0%) | 1.000 |
| Elevated liver enzymes | 1 (2.5%) | 2 (5.0%) | 1.000 |
| Acneiform rash | 1 (2.5%) | 2 (5.0%) | 1.000 |
| Radiation proctitis | 5 (12.5%) | 0 (0.0%) | 0.055 |
| Radiation dermatitis | 7 (14.0%) | 0 (0.0%) | 0.016 |
Values were expressed as n (%). a) Adverse events were graded according to the Common Terminology Criteria for Adverse Events (version 3).
Of the 34 patients who completed neoadjuvant therapy with mFOLFOX6-RT, 30 underwent surgery. Thirty-two of thirty-four patients in mFOLFOX6-Cet group had surgery. Though no statistical difference in R0 resection rate was observed between the two groups (RT vs. Cet: 96.7 vs. 96.9%; p = 1.000), cases requiring preventive enterostomy in mFOLFOX6-Cet group were significantly less than cases in mFOLFOX6-RT group (RT vs. Cet: 76.7 vs. 46.9%; p = 0.020). The overall incidence of postoperative complications was similar between the two groups (p = 0.778), as were grade I/II (p > 0.05) and III/IV (p > 0.778) complications (Table 3).
Table 3. Summary of Surgical Outcomes
| Variables | mFOLFOX6-RT (n = 30) | mFOLFOX6-Cet (n = 32) | p-Value |
|---|
| R0 resection, n (%) | 29 (96.7%) | 31 (96.9%) | 1.000 |
| Need for preventive enterostomy, n (%) | | | 0.020 |
| Yes | 23 (76.7%) | 15 (46.9%) | |
| No | 7 (23.3%) | 17 (53.1%) | |
| Postoperative complications, n (%) | | | 0.778 |
| Yes | 9 (30.0%) | 8 (25.0%) | |
| No | 21 (70.0%) | 24 (75.0%) | |
| Complication grading,a) n (%) | | | |
| I/II | 5 (16.7%) | 6 (18.8%) | 1.000 |
| III/IV | 4 (13.3%) | 2 (6.3%) | 0.418 |
| Grade 3/4 complication, n (%) | | | |
| Surgical-site infection | 1 (3.3%) | 0 (0.0%) | 0.484 |
| Anastomotic leakage | 1 (3.3%) | 1 (3.1%) | 1.000 |
| Intraabdominal abscess | 1 (3.3%) | 0 (0.0%) | 0.484 |
| Urinary complications | 2 (6.7%) | 1 (3.1%) | 0.607 |
Values were expressed as n (%). a) Postoperative complications were evaluated according to the Clavien–Dindo classification.
The incidence of LARS was observed in stages. No statistical difference in the incidence of LARS between mFOLFOX6-RT and mFOLFOX6-Cet groups was found before neoadjuvant treatment, the 1st, 3rd, 6th and 12th month after surgery (Fig. 3). The incidences of LARS in mFOLFOX6-RT (73.3%) and mFOLFOX6-Cet (62.5%) groups were the highest one month after surgery, and the statistical difference between the two groups (43.3 vs. 15.6%; p = 0.025) was revealed before TME surgery.
Pathologic Characteristics and FindingsThe rate of pCR (23.3 vs. 21.9%; p = 0.891) was similar between mFOLFOX6-RT and mFOLFOX6-Cet. In addition, no significant differences between the two groups were shown in CRM < 1 mm, differentiation grade, no. of LNs harvested, pT stage, pN stage, lympho-vascular invasion, extranodal tumor deposits and perineural invasion (all p > 0.05; Table 4). Similar response rates were found between the two groups, in terms of ypStage 0 to 1 rate (53.3 vs. 53.1%; p = 1.000) and the rate of TRG 0 to 1 (60.0 vs. 56.3%; p = 0.802).
Table 4. Pathologic Outcomes
| mFOLFOX6-RT (n = 30) | mFOLFOX6-Cet (n = 32) | p-Value |
|---|
| CRM < 1 mm, n (%) | 3 (10.0%) | 2 (6.3%) | 0.667 |
| Differentiation Grade, n (%) | | | 0.103 |
| Well/Moderate | 23 (76.7%) | 23 (71.9%) | |
| Poor | 6 (20.0%) | 3 (9.4%) | |
| Mucinous | 1 (3.3%) | 6 (18.8%) | |
| No. of LNs harvested | 18.1 ± 5.7 | 16.4 ± 5.2 | 0.223 |
| Pathologic T stage, n (%) | | | 0.908 |
| pT1 | 1 (3.3%) | 0 (0.0%) | |
| pT2 | 8 (26.7%) | 10 (31.3%) | |
| pT3 | 17 (56.7%) | 19 (59.4%) | |
| pT4a | 3 (10.0%) | 2 (6.3%) | |
| pT4b | 1 (3.3%) | 1 (3.1) | |
| Pathologic N stage, n (%) | | | 0.931 |
| pN0 | 19 (63.3%) | 21 (65.6%) | |
| pN1 | 8 (26.7%) | 7 (21.9%) | |
| pN2 | 3 (10.0%) | 4 (12.5%) | |
| With lymphovascular invasion, n (%) | 6 (20.0%) | 7 (21.9%) | 0.856 |
| With extranodal tumor deposits, n (%) | 6 (20.0%) | 6 (18.8%) | 0.901 |
| With perineural invasion, n (%) | 12 (40.0%) | 13 (40.6%) | 0.960 |
| pCR, n (%) | 7 (23.3%) | 7 (21.9%) | 0.891 |
| ypStage, n (%) | | | 1.000 |
| 0–I (downstaging) | 16 (53.3%) | 17 (53.1%) | |
| II–III | 14 (46.7%) | 15 (46.9%) | |
| TRG, n (%) | | | 0.802 |
| 0–1 | 18 (60.0%) | 18 (56.3%) | |
| 2–3 | 12 (40.0%) | 14 (43.8%) | |
Values were expressed as mean (S.D. = standard deviation) or n (%). Abbreviations: CRM, circumferential resection margin; LN, lymph node; pCR pathologic complete response; TRG, tumor regression grading.
DISCUSSION
Our prospective trial showed the efficacy and superiority of mFOLFOX6 with cetuximab for LARC with wild-type RAS/BRAF gene. Initial results from our study demonstrated that compared with mFOLFOX6 concurrent with radiotherapy, mFOLFOX6 plus cetuximab preoperatively obtained comparable R0 resection, pCR and downstaging rates and acceptable toxicity. Our study also found that patients receiving mFOLFOX6-Cet had lower incidences of preventive enterostomy and LARS, compared with mFOLFOX6-RT. These preliminary results suggest that a strategy of combining mFOLFOX6 with cetuximab may be a new option for neoadjuvant treatment in LARC.
In this study, cetuximab was used as a molecular targeted drug in neoadjuvant therapy to treat all patients with LARC with wild-type RAS/BRAF gene. Molecular targeted agents (cetuximab or bevacizumab) are used as one of the standard first-line treatments for metastatic colorectal cancer with RAS and BRAF wild-type. Better survival outcomes were achieved with cetuximab than bevacizumab for left-sided colorectal cancer.16,17) Tomida et al. evaluated the combination of CAPOX with bevacizumab and revealed that the 5-year overall survival, recurrence free survival, and local recurrence rates were 89.7, 72.4, and 13.9%, respectively.18) Aoyama et al. thought that mFOLFOX with molecularly targeted agents in the neoadjuvant therapy for LARC has an acceptable prognosis.19) Moreover, bevacizumab is known to be detrimental to wound healing. According to the above, cetuximab was chosen for this study instead of bevacizumab.
Of patients treated neoadjuvantly with mFOLFOX combined with cetuximab, treatment response evaluation (the rate of pCR and downstaging) and surgical radical extent (the rate of R0 resection and downstaging) were found to be comparable to those with mFOLFOX-RT. Zhang et al.20) revealed that patients who received neoadjuvant chemotherapy with mFOLFOXIRI and selective radiotherapy had an R0 resection rate of 99.0%, a downstaging rate of 42.7% and a pCR rate of 20.4%. The FOWARC trial21) indicated that using mFOLFOX plus radiotherapy, the R0 resection rate was 89.9%, the downstaging rate was 56.4% and the pCR rate was 27.5%. Schrag et al.22) showed that cases receiving a strategy of FOLFOX plus bevacizumab had an R0 resection rate of 100% and a pCR rate of 32%. R0 resection, pCR, and downstaging rates did not appear to differ significantly between NAC with radiotherapy and with targeted agents. Additionally, a prospective multicenter phase 2 study23) demonstrated there were no significant differences between KRAS wild-type patients and KRAS mutant patients in terms of R0 resection rate (100 vs. 95%) and pCR rate (18 vs. 15%). Based on our results, we believe that the strategy of mFOLFOX6 with cetuximab is effective in the neoadjuvant treatment of LARC.
From the results of adverse events incidence and grade 3/4 toxicities in the current study, similar toxicities were found between mFOLFOX6-RT and mFOLFOX6-Cet, except for radiotherapy-related complications. Patients with mFOLFOX6 plus cetuximab did not suffer from radiation damage and had a lower rate of preventive enterostomy than those with radiotherapy. Radiotherapy causes anorectal dysfunction, which seriously affects patients’ QOL. We used the LARS score to evaluate the severity of anorectal dysfunction and discovered that the incidence of LARS was higher in the mFOLFOX6-RT group than mFOLFOX6-Cet. A study24) found that the incidence of LARS in patients without preoperative radiotherapy was significantly lower than that in patients with preoperative radiotherapy. Additionally, the incidence of LARS in all patients increased significantly one month after TME surgery. TME, neoadjuvant radiotherapy and diverting stoma were reported to be independent prognostic factors for LARS.25,26) Therefore, the neoadjuvant regimen of mFOLFOX6 combined with cetuximab is superior to mFOLFOX6 concurrent with radiotherapy without compromising safety.
Several limitations of this trial deserve mention. The long-term efficacy and survival outcomes remain to be further observed. Although encouraging short-term results were revealed, many participants in the current study dropped out. A higher rate of preventive enterostomy in mFOLFOX6-RT may affect the analysis of postoperative LARS incidence. The subgroup analysis for the occurrence of LARS is necessary. Additionally, this study was limited to patients with RAS/BRAF wild-type genes.
CONCLUSION
The neoadjuvant chemotherapy combined with cetuximab was feasible and promising for the patients with LARC, even superior to mFOLFOX6 combined with radiotherapy, but further research is needed to determine its long-term superiority in reducing LARS.
Acknowledgments
We appreciate all authors for their efforts on the manuscript.
Funding
National Health Commission Foundation of Jiangxi, China, 202311911.
Author Contributions
Study design: Chuanyuan Liu; Data collection: Cailiang Zhong, Cheng Wu, Zhongjian Liao, and Weiwei Peng; Statistical analysis: Chuanyuan Liu, Hongquan Liu, and Cailiang Zhong; Manuscript writing: All authors; Final approval of manuscript: All authors; Accountable for all aspects of the work: All authors.
Conflict of Interest
The authors declare no conflict of interest.
Data Availability
Datasets are available from the corresponding author on reasonable request.
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