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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 7  |  Page : 2027-2032

mFOLFOX4 with or without radiation in neoadjuvant treatment of locally advanced middle and low rectal cancer


1 Department of Phamarcy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
2 Department of Colorectal and Anal Surgery, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China

Date of Submission11-Jun-2022
Date of Decision19-Sep-2022
Date of Acceptance14-Oct-2022
Date of Web Publication11-Jan-2023

Correspondence Address:
Haiyi Liu
Departments of Colorectal and Anal Surgery, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/ Cancer Hospital Affiliated to Shanxi Medical University, No. 3 New Zhigong Street, Xinghualing District, Taiyuan - 030013
China
Zhiying Hao
Departments of Phamarcy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/ Cancer Hospital Affiliated to Shanxi Medical University, No. 3 New Zhigong Street, Xinghualing District, Taiyuan - 030013
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_1207_22

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 > Abstract 


Context: Neoadjuvant therapy can reduce the recurrence rate of locally advanced middle and low rectal cancer. Radiation therapy can not only bring benefits but also produce acute and late toxicity, which will affect the quality of life and organ function of patients; the application of neoadjuvant chemotherapy can avoid the toxicity of radiotherapy.
Aims: To investigate the efficiency and side effects of preoperative modified FOLFOX4 (mFOLFOX4) chemotherapy with or without radiotherapy for locally advanced middle and low rectal cancer (LAMLRC).
Methods and Material: This study included 431 patients with LAMLRC receiving mFOLFOX4 chemotherapy independently or combined with radiotherapy before operation. The basic information, efficacy indicators, and adverse reactions of the two groups were recorded in detail. Side effects were evaluated using the Common Terminology Criteria for Adverse Events v. 3.0.
Statistical Analysis Used: Statistical analyses were conducted using SPSS (Statistical Package for Social Science, IBM SPSS Statistics, Version 22). Mann-Whitney test and Chi-square test were used for comparative analysis. Statistical significance was defined as P < 0.05.
Results: Of 128 patients who met the inclusion criteria, 52 received neoadjuvant chemotherapy (NCT), and 76 received neoadjuvant chemoradiotherapy (NCRT). The average operation time in the NCT group was 2.71 h, and that in the NCRT group was 3.35 h (P = 0.005). The pathological complete remission rates in the NCT and NCRT groups were 1.9% and 17.1%, respectively (P = 0.007). There was no significant difference in the T-stage decline rate and lymph node positive rate between the two groups. There were higher rates of leukopenia (32.7% vs. 57.9%; P < 0.05) and diarrhea (0% vs. 9.2%; P < 0.05) in the NCRT group. The 3-year overall survival rates in the NCT and NCRT groups were 80.3% and 82.8% (P = 0.715), respectively, and the respective 3-year disease-free survival rates were 68.8% and 70.5% (P = 0.966).
Conclusions: NCT with mFOLFOX4 independently resulted in a lower pathological complete remission rate, with less toxicity and shorter operation time. NCT with mFOLFOX4 has certain clinical usefulness.

Keywords: Disease-free survival, locally advanced middle and low rectal cancer, mFOLFOX4, neoadjuvant therapy, overall survival


How to cite this article:
Yan H, Zhang Y, Hao Z, Lu Y, Liu H. mFOLFOX4 with or without radiation in neoadjuvant treatment of locally advanced middle and low rectal cancer. J Can Res Ther 2022;18:2027-32

How to cite this URL:
Yan H, Zhang Y, Hao Z, Lu Y, Liu H. mFOLFOX4 with or without radiation in neoadjuvant treatment of locally advanced middle and low rectal cancer. J Can Res Ther [serial online] 2022 [cited 2023 Jan 27];18:2027-32. Available from: https://www.cancerjournal.net/text.asp?2022/18/7/2027/367456

Authors Hongxia Yan and Yixun Zhang contributed equally to this work.





 > Introduction Top


Rectal cancer is a common malignant tumor of the alimentary tract. It has a higher incidence in developed countries, which is gradually increasing in low-risk areas of Asia along with lifestyle changes.[1] Most patients with rectal cancer have locally advanced diseases. Surgery has been the primary method of treating rectal cancer. However, for patients with locally advanced middle and low rectal cancer (LAMLRC), the effect of surgical treatment alone is unsatisfactory, and a high local recurrence rate is the major reason causing treatment failure.[2],[3] Since the past few years, with the gradual improvement of neoadjuvant therapy,[4],[5] several patients with locally advanced diseases could undergo preoperative treatment for a certain time to achieve radical resection due to large tumor volume. The treatment reduces the size of the tumor to a resectable level, significantly improving the radical resection rate. Neoadjuvant therapy includes neoadjuvant chemotherapy (NCT) and neoadjuvant chemoradiotherapy (NCRT).

The chemotherapy regimen of concurrent radiotherapy and chemotherapy in the National Comprehensive Cancer Network was 5-fluorouracil (5-FU) or capecitabine alone. Capecitabine combined with irinotecan was added to the chemotherapy regimen of concurrent radiotherapy and chemotherapy in the guidelines of the Chinese Society of Clinical Oncology for the diagnosis and treatment of colorectal cancer. Data from the National Surgical Adjuvant Breast and Bowel Project C-07 (NSABP C-07) and Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trials indicate that compared with leucovorin (LV) and fluorouracil alone, oxaliplatin combined with LV and fluorouracil (FOLFOX) dramatically improved the disease-free survival (DFS) and overall survival (OS) of stage III rectal cancer. To date, several chemotherapy schemes have been used for the neoadjuvant treatment of locally advanced rectal cancer, such as FOLFOX6, capecitabine plus oxaliplatin (XELOX), FOLFOXIRI, and cetuximab combined with capecitabine and oxaliplatin.[6],[7],[8],[9] In addition, FOLFOX-based chemotherapy has been widely used in neoadjuvant therapy.

There were large individual differences between 5-FU in clinical use. Pharmacological studies have demonstrated that 5-FU exhibits the best efficacy in a specific AUC range (20–30 mg·h/L). When the AUC of 5-FU is lower or higher than this range, it will reduce the clinical efficacy and increase toxicity.[10] The dose of 5-FU is directly related to the therapeutic effect and side effects in the treatment of advanced colorectal cancer. Patients' sensation during treatment is increasingly becoming an important factor in measuring treatment options. The modified FOLFOX4 (mFOLFOX4) regimen demonstrated certain clinical benefits at low doses and low side effects. The present study was designed to compare the mFOLFOX4 regimen with or without radiation, which was used as a neoadjuvant therapy for LAMLRC, in terms of efficiency and toxicity.


 > Subjects and Methods Top


Ethics

The experimental protocols involving patients in this study were approved by the Ethical Committee of Shanxi Province Cancer Hospital (approval No. 202024), and the study was conducted according to the ethical principles described in the Declaration of Helsinki. All patients provided informed consent.

Study design and patients

Eligible patients were confirmed of the pathological diagnosis of rectal adenocarcinoma and received first treatment. All patients underwent baseline examination, including enhanced computed tomography (CT) of the chest, abdomen, and pelvis to exclude metastatic disease, and enhanced pelvic magnetic resonance imaging (MRI) to determine local clinical staging, including location, tumor size, and the involvement of lymph nodes. Patients with clinically confirmed stage III (T4 or T3-4N+) tumors with a distal margin of <10 cm from the anal margin were included in the study. Participants had a WHO performance status (PS) of 0–2 and underwent surgery performed by the same treatment group. Patients with metastatic disease, intestinal obstruction or perforation, insufficient treatment cycle, and non-mFOLFOX4 treatment were excluded [Figure 1]. Data regarding the gender, age at diagnosis, PS, tumor location, stage, treatment regimen, survival, and toxicity were recorded from patient files.
Figure 1: Flowchart of included patients

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Treatments

Neoadjuvant chemotherapy

Patients in the NCT group received three cycles of preoperative chemotherapy. After 2–4 weeks of chemotherapy, the efficacy of the treatment was evaluated. The chemotherapy regimen was mFOLFOX4, which consisted of 85 mg/m2 oxaliplatin plus 100 mg/m2 l-LV or 200 mg/m2 dl-LV and 400 mg/m2 bolus 5-FU on day 1 followed by 1600 mg/m2 5-FU as a 46-h infusion every 14 days.

Neoadjuvant chemoradiotherapy

All patients in this group were treated with 40- to 50-Gy radiotherapy and received the same period of chemotherapy of three cycles. Chemotherapy was the same as in the NCT group. Patients were evaluated 4–6 weeks after chemoradiotherapy.

Both groups received radical surgery and underwent more than four cycles of postoperative adjuvant chemotherapy.

Definition of outcomes

The efficacy of the neoadjuvant therapy was evaluated using solid tumor efficacy evaluation criteria version 1.1, including complete remission (CR), partial remission, stable disease, and disease progression (PD). Side effects were evaluated using the Common Terminology Criteria for Adverse Events v. 3.0. Downstaging was defined by comparing the imaging installment before neoadjuvant therapy and the pathological staging after surgery. We compared the descending stage, pathological CR (pCR) rate, and lymph node metastasis. The operation time, DFS rate, and OS rate of patients after the two different neoadjuvant treatments were analyzed. Adverse events in the two groups were monitored during treatment and for 28 days after the last medication.

Statistical analysis

Statistical analyses were conducted using SPSS (Statistical Package for Social Science, IBM SPSS Statistics, Version 22 for Macintosh; IBM Corp., Armonk, NY, USA). Differences between groups were evaluated using the Mann–Whitney test for continuous variables and the Chi-square test or Fisher's exact test for categorical variables. OS and DFS rates were determined using the Kaplan–Meier method, and comparisons were performed using log-rank tests. Statistical significance was defined as P < 0.05.


 > Results Top


General information

A total of 431 patients with LAMLRC received neoadjuvant therapy, and 128 patients met the inclusion criteria. These 128 patients, with a median age of 55 years (range = 27–81 years) were considered for this study, including 52 in the NCT group and 76 in the NCRT group. The Chi-square test revealed no significant differences in age, sex, T-stage, N-stage, tumor location, surgical approach, and pathomorphological typing between the two groups. There were six and nine patients without adjuvant treatment in the two groups, respectively. [Table 1] summarizes the patient and disease characteristics. In total, 46 (88.5%) patients in the NCT group and 67 (88.2%) in the NCRT group received more than four cycles of postoperative adjuvant chemotherapy.
Table 1: Patient and disease characteristics at study entry

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Treatment response

All 128 patients received the allocated preoperative therapy, and there were no statistical discrepancies between the two groups in terms of recent clinical efficacy, downstaging, or lymph node positive rate. In the NCT group, the lymph node positive rate and tumor downstaging rate were 53.8% and 25%, respectively. In the NCRT group, the respective tumor downstaging rate and lymph node positive rate were 28.9% and 38.2%. However, the pCR rate in the NCRT group was 17.1%, which was higher than that in the NCT group [Table 2]. After treatment, all patients underwent surgery. The operation time after NCT was shorter than that after NCRT (P = 0.005).
Table 2: Summary of Study Outcomes

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The median follow-up was 47.5 months (range = 2–72 months). Overall, 14 patients died in the NCT group, and 23 patients died in the NCRT group. At 3 years, the probability of OS was 80.3% in the NCT group and 82.8% in the NCRT group [P = 0.715, [Figure 2]]. The 3-year DFS rates were 68.8% and 70.5% in the NCT and NCRT groups, respectively [P = 0.966, [Figure 3]]. The univariate analysis revealed no significant association among OS, DFS, and administration of adjuvant chemotherapy.
Figure 2: Overall survival time of the patients in NCT and NCRT groups

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Figure 3: Disease-free survival analysis and comparison between NCT and NCRT groups

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Safety

After the neoadjuvant treatment, all patients experienced different degrees of adverse reactions, which primarily presented as neutropenia, leukopenia, anemia, thrombocytopenia, nausea and vomiting, diarrhea, and neurotoxicity [Table 3]. The most common grade 3 or worse adverse events were neutropenia, leukopenia, anemia, and nausea and vomiting, and the incidence of all these four events was higher in the NCRT group, but the differences were not significant. There were higher rates of leukopenia (32.7% vs. 57.9%; P < 0.05) and diarrhea (0% vs. 9.2%; P < 0.05) in the NCRT group, but the incidence of neutropenia, anemia, thrombocytopenia, nausea and vomiting, and neurotoxicity was similarly low in the two groups. One patient (1.3%) in the NCRT group had dysuria after radiotherapy. The adverse events had no impact on treatment compliance.
Table 3: Adverse Reactions Analysis

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 > Discussion Top


Radiotherapy in NCRT constantly induces inflammatory edema of the intestinal wall. As shown in [Table 2], the operation time in the NCRT group is longer than that in the NCT group, which may be due to fibrosis of surrounding tissues and edema of the tumor after pelvic radiotherapy, susceptibility to bleeding, and increased difficulty of surgical resection.[11] After neoadjuvant therapy, the clinical stage of patients with LAMLRC decreased, and there was no difference between patients receiving radiotherapy and patients not receiving radiotherapy (28.9% vs. 25%). The postoperative pathological results showed that 53.8% and 38.2% of patients in the NCT and NCRT groups had positive lymph nodes, respectively, with the positive rate of lymph nodes in the NCT group being higher (P = 0.079). These changes in the preoperative clinical stage in the two groups are inconsistent with the detection of postoperative lymph node positive rate, which may be associated with the different methods of evaluation indexes. In this study, CT or MRI was used as the imaging index to evaluate the efficacy before and after neoadjuvant therapy, and the prediction accuracy is between 30% and 60%.[12] The diameter of metastatic lymph nodes after NCRT was 4.9 ± 2.66 mm, but the imaging examination showed that its diameter should be >10 mm. The imaging examination could not determine the metastatic lymph nodes after NCRT, and hence it was difficult to conduct accurate N staging before the operation. The diameter of occult metastatic lymph nodes detected using anti-CK antibody immunohistochemistry in postoperative pathology was 3.2 ± 1.2 mm, suggesting that the detection rate of positive lymph nodes after NCT was higher than that after NCRT.[13]

Interestingly, compared with previous studies, the pCR rate of mFOLFOX4 combined with radiotherapy in the neoadjuvant treatment of LAMLRC was similar to that in the CAO/ARO/AIO-04 study (17.1% vs. 17%) but lower than that of mFOLFOX6 combined with radiotherapy in the FOWARC study (17.1% vs. 27.5%). At 3 years, the probabilities of DFS and OS with mFOLFOX4 plus radiotherapy were similar to those reported previously (75% and 88.7% in the current study vs. 75.9% and 88.7% in the CAO/ARO/AIO-04 study vs. 77.2% and 89.1% in the FOWARC study).[14],[15] Moreover, patients who received only mFOLFOX4 NCT in this study were compared with those who received only mFOLFOX6 NCT in the FOWARC study, and the pCR rate and 3-year DFS and OS rates were also lower (1.9% vs. 6.6%, 70% vs. 73.5%, 85% vs. 90.7%).[15] However, the incidence of grade 3–4 chronic adverse effects of mFOLFOX4 neoadjuvant therapy with or without radiotherapy was lower than that reported previously (36% and 55.1% in CAO/ARO/AIO-04 and FOWARC studies, respectively).[14],[15]

However, different outcomes may arise from several different details in the present study. First, 27.9% of patients receiving mFOLFOX6 NCT alone in the FOWARC study were confirmed to be in stage II,[15] which is in contrast to stage III in the present study. Second, unlike four to six cycles of preoperative NCT in the FOWARC study, the patients in the present study received three cycles. Furthermore, the dosage of 5-FU in the chemotherapy regimen was different among those studies. In CAO/ARO/AIO-04 and FOWARC studies, the dosage of 5-FU was higher than that of mFOLFOX4. A recent study claimed that mFOLFOX6 and mFOLFOX4 exert similar adjuvant therapeutic effects in patients with advanced colorectal cancer, but the incidence of grade 1–2 nausea is slightly higher in the former than in the latter.[16] It has been reported that FOLFOX4 and mFOLFOX6 can be used as treatment regimens for stage III colorectal cancer. Their curative effects are similar, but the latter has a high proportion of grade 3 or 4 toxicity.[17],[18] The above analysis[14],[15],[16],[17],[18] shows that the same regimen is a combination of oxaliplatin, calcium folinate, and 5-FU. Under the fixed dose of oxaliplatin and calcium folinate, the clinical efficacy and toxicity of 5-FU are different with different doses. Kusano et al. reported that high-dose 5-FU therapy might result in a higher occurrence of grade 3 adverse events.[19] An appropriate dosage of 5-FU can result in higher clinical efficacy and lower adverse reactions to improve the compliance of patients and prolong their survival time. In a previous study, patients with rectal cancer received four to six cycles of mFOLFOX6 NCT before the operation and six to eight cycles of mFOLFOX6 adjuvant chemotherapy after the operation, but the outcome was high toxicity and poor patient compliance.[15] In the present study, patients with LAMLRC who received mFOLFOX4 NCT showed good clinical efficacy, low incidence of adverse reactions, and high quality of life.

Our study has some limitations. First, this was a retrospective nonrandomized controlled study with limited persuasion. Second, the pharmacokinetic parameters of 5-FU and the detection of drug metabolic enzymes related to treatment were lacking during treatment. The dose of 5-FU was directly related to the therapeutic effect and side effects in the treatment of advanced colorectal cancer. In the future, more prospective, multicenter clinical trials are required to explore the precise treatment with 5-FU for patients with colorectal cancer.


 > Conclusion Top


There was no obvious difference in the 3-year DFS and OS rates between patients who received mFOLFOX4 without radiotherapy and those who received mFOLFOX4 with radiotherapy. mFOLFOX4 NCT can independently and significantly shorten the operation time of patients with LAMLRC. It can also remarkably reduce the incidence of adverse reactions during treatment. As a neoadjuvant therapy, mFOLFOX4 demonstrates high curative efficiency and safety and has certain clinical applications.

Acknowledgements

We thank Xiaojin Han for reviewing and revising the manuscript.

Financial support and sponsorship

This study was supported by the National Key Research and Development Program ' Precision Medicine ' Specialized ' Colorectal Cancer Cohort Study '(NO. 2017YFC0908200).

Conflicts of interest

There are no conflicts of interest.



 
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