Abstract
Background/Aim: Colorectal cancer (CRC) has the third-highest incidence among human cancers. Advancements in chemotherapy and targeted therapy have improved the treatment outcomes for patients with CRC. However, the management of patients with unresectable metastatic CRC (mCRC) continues to be a significant challenge for clinicians worldwide, particularly for those with microsatellite stability (MSS) and the BRAF V600E mutation, as they are associated with the poorest prognosis. Case Reports: The present study describes two patients with unresectable MSS, BRAF V600E-mutated stage IV metastatic CRC using a biweekly alternating regimen of irinotecan and oxaliplatin combined with capecitabine and bevacizumab. Case 1 stabilized after alternating treatment, whereas Case 2 progressed after alternating treatment, with progression-free survival (PFS) of 20+ and 24.5 months, respectively. Circulating levels of carcinoemryonic antigen (CEA) dropped to near normal in both cases. A partial response (PR) was determined for both cases. Conclusion: The two cases suggest that an alternating chemotherapy regimen of oxaliplatin and irinotecan, combined with capecitabine and bevacizumab is effective in the treatment of MSS, BRAF V600E-mutated stage IV metastatic CRC. The progression-free survival was significantly prolonged (both exceeding 20 months) compared to the first-line standard chemotherapy regimen for this disease. With a good balance between toxicity and efficacy, this alternating chemotherapy regimen can be considered as a potential first-line option for microsatellite-stable metastatic colon cancer.
- BRAFV600E mutation
- metastatic colorectal cancer
- stage IV
- alternating chemotherapy
- oxaliplatin
- irinotecan
- capecitabine
- bevacizumab
- microsatellite stability
- survival
- CEA
- case report
The GLOBOCAN 2020 survey states that colorectal cancer (CRC) ranks third in incidence and second in mortality among all cancers worldwide (1). In China, the incidence of CRC ranks second among all cancers and the mortality ranks fourth. The incidence of CRC is increasing year by year (2). Approximately 20% of CRCs have developed distant metastasis when first diagnosed, and 50% of patients develop distant metastasis throughout the course of the disease (3, 4). For patients with advanced metastatic CRC (mCRC), chemotherapy is mainly used, supplemented by immune, targeted and radiation therapy. The overall treatment strategy needs to consider multiple factors. In terms of molecular biology, the patient’s RAS/BRAF/Her-2 status and the degree of microsatellite instability are the most important (5). The incidence of BRAF mutation in mCRC is 8-15%, which can lead to activation of the MAPK pathway, causing cancer-cell differentiation and proliferation, as well as metabolism and growth alterations. It is more likely to occur in females and the right colon (6).
mCRC patients with BRAF-gene mutations have a poor prognosis. Among them, the BRAF V600E mutation is the most common BRAF-gene mutation. The risk of death in patients carrying the BRAF V600E mutation is twice that of patients carrying wild-type BRAF. Standard therapy is mostly ineffective in these patients, and only half of them can receive second-line chemotherapy (7). Pooled analysis data show that the median progression-free survival (PFS) and median overall survival (mOS) of patients with BRAF-mutated mCRC are 7.4 months and 11.7 months, respectively, which are much lower than those of patients with the wild-type BRAF gene (7, 8). How to effectively treat CRC patients harboring BRAFV600E mutations with MSS remains a clinical challenge.
In the present study we describe two cases of right-sided stage IV mCRC with MSS and BRAF V600E mutations. Both patients were treated with an alternating chemotherapy regimen of oxaliplatin and irinotecan combined with capecitabine and bevacizumab with PFS of more than 20 months.
Case Report
Case 1, male, 70 years old, was hospitalized at Mingguang City People’s Hospital with abdominal pain and bloody stool in August 2021. Colonoscopy demonstrated multiple polyps in the colon. Abdominal computed tomography (CT) showed transverse colon cancer with multiple liver metastases, plasma-membrane invasion, and paraneoplastic and abdominal lymph-node enlargement (Figure 1). The patient underwent right hemicolectomy in September 2021. The pathological results were a 6×5×2 cm tubular papillary adenocarcinoma of medium-low differentiation, with vascular and neural invasion, multiple lymph-node metastasis, and bilateral pelvic-floor implantation foci. Pathologic examination indicated PMS2(+); MSH2(+); MSH6(+); MLH1(+); HER-2(1+); Ki67(+) 70%; PD1(−); PDL1 (CPS score 10). Genetic testing showed a BRAF V600E mutation and MSS-stability. The patient was diagnosed with right-colon adenocarcinoma with peritoneal, hepatic and pelvic metastases, T3N3M1c, stage IV. From September 2021 to March 2022, the patient was given bevacizumab (300 mg) d1, d15 + oxaliplatin mannitol (150 mg) d1, irinotecan (260 mg) d15+ capecitabine (1.5 g) bid d1-7, d15-21 for 6 cycles (bevacizumab was not used in the first cycle), then changed to maintenance treatment with bevacizumab + capecitabine for 14 days (Figure 2). Mild I° gastrointestinal reactions occurred after chemotherapy. On August 8, 2022, abdominal CT indicated liver metastases were reduced, indicating a partial response (PR) (Figure 1). From September 2022 to March 2023, the patient underwent over nine cycles of bevacizumab (400 mg) d1+ capecitabine (1.5 g) bid d1-d14 for maintenance therapy (Figure 2). The last imaging review was in May 2023 (Figure 1), when abdominal CT showed multiple liver metastases similar to the CT on August 8th, 2022. Abdominal CT on August 8, 2022, demonstrated the best efficacy evaluation is partial response (PR) (↓74.8%). The patient’s carcinoembryonic antigen (CEA) continued to decrease to near normal levels during the treatment period (Figure 3). PFS reached 20+ months.
Computed tomography (CT) scans of the patient in Case 1 obtained before and after alternating chemotherapy. Tumor masses (arrows) can be seen in the liver of the patient before initiation of alternating chemotherapy (A, D). The masses (arrows) were significantly reduced in size on CT after six cycles of alternating chemotherapy with oxaliplatin and irinotecan, combined with capecitabine and bevacizumab and nine months of maintenance therapy with bevacizumab and capecitabine (B, C, E, F), indicating a partial response (PR) to alternating treatment.
Treatment timeline of Case 1. CAP: Capecitabine; OXA: oxaliplatin; IRI: irinotecan; BEV: bevacizumab; PFS: progression-free survival.
Change in the tumor marker carcinoemryonic antigen (CEA) in the patient in Case 1 after alternating chemotherapy: serum CEA gradually decreased from very high to near normal after treatment.
Case 2, female, 59 years old, was found to have an elevated CEA and positive fecal occult-blood test on physical examination in October 2020 and was diagnosed with right-colon cancer on colonoscopy. Pathological analysis indicated moderate-to-poorly-differentiated adenocarcinoma, 70 cm from the anus. Cancer emboli were seen in the vasculature. Radical surgery for right-colon cancer was performed on November 3, 2020. During the operation, the mass was found to be located near the hepatic flexure of the transverse colon, invading the serosa, and multiple tumors were seen at the root of the mesocolon next to the abdominal aorta. Postoperative pathology revealed a 3×2.5×1 cm moderately-to-poorly-differentiated adenocarcinoma, with metastasis seen in multiple lymph nodes around the intestines. Gene testing showed: a BRAF V600E mutation, a TP53 mutation, and microsatellite stability. The patient was diagnosed with right-colon adenocarcinoma with abdominal metastasis, T3N2bM1, stage IV. On November 25, 2020, postoperative follow-up CT showed scattered abdominal nodules, large implantation metastasis, multiple enlarged left-supraclavicular lymph nodes as well as enlarged lymph nodes in the abdominal, retroperitoneal, and posterior to the foot-of-the-diaphragm areas (Figure 4). From November 30, 2020, to July 15, 2021, the patient received bevacizumab (300 mg) d1, d15 + oxaliplatin mannitol (135 mg) d1, irinotecan (240 mg) d15 + capecitabine (1.5 g) bid d1-7, d15-21, alternating chemotherapy for six cycles (Figure 5). Compared to the previous CT on November 25, 2020, the CT on August 2, 2021, showed smaller multiple enlarged lymph nodes in the abdominal cavity, retroperitoneum, posterior crura of the diaphragm, left supraclavicular region and next to the iliac vessels, suggesting that the best efficacy evaluation is partial response (PR) (↓70.5%) (Figure 4). Chemotherapy induced agranulocytosis was accompanied by low-grade fever, which improved after treatment with leukocyte elevation. From August 3, 2021, to Jun 22, 2022, the patient underwent 13 cycles of maintenance therapy with bevacizumab (500 mg) d1 + capecitabine (1.5 g) bid d1-14 (Figure 5). After treatment, the patient’s CEA was significantly reduced to near normal compared with previous measurements (Figure 6). The patient did not go to the hospital regularly for follow-up visits due to personal reasons and developed new abdominal lymph-node metastasis according to the CT on Dec 17, 2022. The patient’s progression-free survival reached 24.5 months, and the overall survival reached over 30 months.
Computed tomography (CT) scans of the patient in Case 2 obtained before and after alternating chemotherapy with oxaliplatin and irinotecan, combined with capecitabine and bevacizumab. Tumor masses (arrows) can be seen in the abdominal lymph nodes of the patient before initiation of alternating chemotherapy (A, C). The masses (arrows) were significantly reduced in size on CT after six cycles of treatment (B, D), indicating a partial response (PR) to alternating treatment.
Treatment timeline of Case 2. CAP: Capecitabine; OXA: oxaliplatin; IRI: irinotecan; BEV: bevacizumab; PFS: progression-free survival.
Change in the tumor marker carcinoemryonic antigen (CEA) in the patient in Case 2 after alternating chemotherapy: serum CEA gradually decreased from high to near normal after treatment.
Discussion
For patients with MSS-type, BRAF-mutated advanced right-side CRC, the first-line standard regimen is doublet or triplet (oxaliplatin (OXA), irinotecan (IRI) and fluorouracil) therapy combined with anti-VEGF therapy (bevacizumab) (5). The median overall survival of the patients is less than one year (9). The phase III clinical study TRIBE in 2014 and the phase II clinical study OLIVIA in 2015, both demonstrated that three-drug combination therapy significantly improved the objective response rate (ORR) and overall survival (OS) compared with the two-drug combination regimen (10, 11). However, the toxic effects associated with the three-drug combination therapy were also enhanced. Some retrospective studies have shown that although three-drug combination therapy has significant efficacy, it could increase adverse reactions, such as bone-marrow toxicity and diarrhea, especially in elderly patients in poor physical condition who cannot tolerate three-drug combination chemotherapy (12, 13).
The two cases in the present study had untreated stage IV right-colon cancer with BRAFV600E mutations and microsatellite stability (MSS). Their treatment employed a modified combination of alternating chemotherapy combined with anti-VEGF therapy. The two patients were given alternating oxaliplatin and irinotecan along with bevacizumab and capecitabine as induction therapy, followed by capecitabine and bevacizumab as maintenance therapy. The maintenance regimen included bevacizumab and capecitabine for over nine cycles. After completing the maintenance therapy, both patients achieved a partial response (PR). The progression-free survival was extended to 20+ months and 24.5 months, respectively, and no significant adverse reactions were reported during the treatment.
The alternating regimen in the present study used, third-generation platinum (oxaliplatin), and the topoisomerase I inhibitor (CPT-11) (irinotecan) along with capecitabine and bevacizumab. These chemotherapy drugs have different mechanisms of action and have synergistic efficacy without cross-drug resistance or increased toxic side effects (14, 15). In the treatment of advanced CRC, patients often change or terminate their regimen frequently due to drug resistance or intolerance to drug toxicity. Therefore, alternating chemotherapy with regimens containing irinotecan and oxaliplatin may reduce the development of drug-resistant cancer cells or prevent tumor resistance to the drugs and improve the efficacy of chemotherapy (16). Furthermore, the present alternating chemotherapy regimen can improve the patient’s tolerance to drug toxicity because of a relatively longer interval between the use of the two alternating drugs (17).
In conclusion, the two cases suggested that an alternating chemotherapy regimen with oxaliplatin and irinotecan, along with capecitabine and bevacizumab is effective in the treatment of MSS, BRAF V600E-mutated stage IV mCRC. With a good balance between toxicity and efficacy, the alternating chemotherapy regimen of oxaliplatin and irinotecan along with capecitabine and bevacizumab can be used as first-line options for initial treatment for microsatellite-stable colon cancer.
Footnotes
Authors’ Contributions
Yaoyi Zhang and Chen Yu designed the study and wrote the draft manuscript; Sheng Li and Xiaohui Li analyzed the data; Zhijian Yang and Robert M. Hoffman revised the manuscript.
Conflicts of Interest
None of the Authors have any conflicts of interest to declare in relation to this study.
- Received September 18, 2024.
- Revision received November 2, 2024.
- Accepted November 19, 2024.
- Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
