The simultaneous infusion regimen of levofolin/5-FU for injection has helped to benefit the whole process of conversion therapy for colorectal cancer liver metastases

Preface

The liver is the most important target organ for hematogenous metastasis of colorectal cancer, and liver metastasis of colorectal cancer (CRLM) is one of the key and difficult points in the treatment of colorectal cancer, and liver metastasis is also the main cause of death for colorectal cancer patients¹. About 40%~50% of patients develop liver metastases during the course of colorectal cancer², of which 80%~90% of liver metastases cannot be radically resected initially¹. Choosing the appropriate conversion regimen can transform the initial unresectable liver metastases into resectable. This article introduces a case of CRLM conversion therapy with a targeted drug containing levofolin/5-FU concurrent infusion, and the patient finally reached the state of no evidence of disease (NED), which is expected to bring enlightenment to clinical practice.

Patient Disease Examples

Basic information

• The patient is a 37-year-old male. 174cm, 55kg, body surface area (BSA): 1.63m².
• History of present illness: the main reason is "diarrhea with blood in the stool for more than 1 month".

• In March 2022, the patient developed diarrhea, and the effect was not good after self-medication, and then he developed blood in the stool, and the amount increased progressively, and he was admitted to an external hospital. Colonoscopy showed that a lumpy mucosa was bulging about 10cm from the anal margin, rough in texture, narrow in lumen, and the endoscope barely passed; Biopsy showed high-grade intraepithelial neoplasia of the rectum, considering the superficial tissue of the tumor. CT scan of the chest and abdomen showed a mass in the rectal-sigmoid junction area and multiple metastases in the liver.

• Anamnesis: denial of contact with epidemic areas and infected waters, no smoking and alcohol habits, denial of family genetic history and history of similar diseases.
• ECOG score: 0-1 point

INVESTIGATIONS

• Liver MRI (2022-04-29): Multiple (>5) abnormal signal shadows were seen in the liver parenchyma, and the larger one was about 6.5cm in diameter.

Fig.1 Liver MRI (April 29, 2022)

• Pelvic MRI (May 7, 2022): Mass in the intestinal lumen at the distal end of the sigmoid colon, localized thickening of the intestinal wall, about 40 mm × 18 mm, contrast-enhanced scanning, multiple swollen lymph nodes in the fat space around the sigmoid colon.

Fig.2 Pelvic MRI (May 7, 2022)

• Whole-body bone scintigraphy (ECT, 26 May 2022) showed no significant abnormalities.

Fig.3 Whole body bone scintigraphy (26 May 2022)

• Aneurysm (April 28, 2022): CEA 23.78 ng/mL, CA199 > 1200.00 U/mL, CA125 10.50 U/mL.
• Genetic testing (9 May 2022):

• KRAS/NRAS/BRAF基因野生型;
• 肿瘤突变负荷（TMB）：TMB-L（3.48 Muts/Mb）；
• 微卫星不稳定（MSI）：MSI-L（微卫星不稳定度较低）；
• PD-L1表达：TPS＜1% 。

Clinical/molecular diagnostics

• Clinical diagnosis: sigmoid malignancy cT3NxM1 stage IVA; pathological high-grade intraepithelial neoplasia; Secondary malignancy of the liver.
• Molecular diagnostics: RAS/BRAF dual wild type.

Treatment

• Preoperative conversion therapy

• On May 4, 2022, mFOLFOX (lexadine [oxaliplatin] 130mg d1 + 5-Fu 500mg iv d1, 3500mgciv 46h + levonfolinate sodium 300mg d1) regimen chemotherapy was given for 1 cycle.
• On May 18, 2022, June 1, 2022, June 15, 2022, and June 28, 2022, "cetuximab 800mg combined with mFOLFOX (lexadine [oxaliplatin] 130mg d1+5-Fu 500mg iv d1,3500mgciv 46h + levonofinate sodium 300mg d1) was given for 4 cycles.

• First efficacy evaluation

• MRI (July 4, 2022) After sigmoid colon K treatment, the lesion was significantly smaller than that before (May 7, 2022); Multiple liver metastases, smaller than the previous (April 29, 2022).

Figure 4 MRI (July 4, 2022)

• Tumor markers decreased significantly during chemotherapy.

Fig.5 Changes in tumor markers during chemotherapy

• He visited the clinic on July 7, 2022, and it is recommended to continue the evaluation after 2 cycles of treatment with the "cetuximab + mFOLFOX" regimen.
• On July 12, 2022 and July 26, 2022, he continued to receive chemotherapy with the regimen of "cetuximab 800mg combined with mFOLFOX (lexadine [oxaliplatin] 130mg d1 + 5-Fu 500mg iv d1, 3500mgciv 46h + levonovorin sodium 300mg d1) for 2 cycles.
• On August 4, 2022, he was seen again, and after multidisciplinary diagnosis and treatment (MDT), it was recommended that the intestine and liver could be resected, and it was planned to be resected in stages.

• Preoperative testing

• There were no obvious abnormalities in blood routine and biochemistry.
• 肿瘤标记物：AFP:4.1ng/mL、CEA :2.3ng/mL 、CA199: 20.8U/mL。
• Circulating tumor cell CTC: 4 pcs/5ml, reference range: 0-1 pcs/5ml.
• Enhanced CT of abdomen (August 2, 2022): scattered hypodense foci in the liver, the length and diameter of the larger right lobe of the liver are about 33mm, and there are no enlarged lymph nodes retroperitoneally.
• Colonoscopy showed (August 8, 2022): An irregular mass was visible 15cm from the anal margin, occupying 1/2 of the intestinal cavity, with erosion and necrosis on the surface and hard texture.

• Metachronous surgery

• On August 9, 2022, he underwent "robotic Dixon surgery" under general anesthesia, and no cancer was involved in the postoperative pathology: (margins). Ulcerative adenocarcinoma (after chemotherapy, rectum) is grade II differentiated, invading the subserous layer without clear vasculature invasion. Mesenteric root lymph nodes (0/3), paraintestinal lymph nodes (0/12).
• 免疫组化：CDX2（+）、CK20（+）、D2-40（-）、HER-2（-）FISH阴性无扩增、Ki-67（90%+）、MLH1（+）、MSH2（+）、MSH6（+）、PMS2（+）、SATB2（+）。
• Genetic testing: RAS/BRAF did not detect mutations.
• On September 5, 2022, partial hepatic lobectomy, special hepatic segmentectomy (left lateral lobe + left posterior lobe + left anterior lobe) + complex intestinal adhesion release + radiofrequency ablation of liver tumor was performed under general anesthesia.
• Intraoperative contrast-enhanced ultrasound showed that there were many liver tumors, a total of 7 liver tumors, 3 in the left lateral lobe, 1 in the left inner lobe (not shown by two-dimensional ultrasound, and radiofrequency was shown on angiography), 1 in the right anterior lobe, 2 in the right posterior lobe, the tumor diameter was 1.5-3.3cm, the boundary was clear, there was no capsule, there was no enlargement of the hepatic portal lymph nodes, there was no cancer thrombus in the main stem of the portal vein and the left and right branches, the intraoperative was smooth, the bleeding was 200ml, no blood transfusion, and the patient was returned to the ward after surgery.

• Postoperative adjuvant chemotherapy

• On October 10, 2022, October 24, 2022, November 7, 2022, November 21, 2022, and December 5, 2022, the regimen chemotherapy of "cetuximab 800mg in combination with mFOLFOX (lexadine [oxaliplatin] 130mg d1 + 5-Fu 500mg iv d1, 3500mgciv 46h + levonfolinate sodium 300mg d1) was continued on October 10, 2022, October 24, 2022, November 7, 2022, November 21, 2022, and December 5, 2022.
• The patients were treated with chemotherapy for 12 weeks before and after surgery.

• Secondary efficacy assessment

• In the case of rectal MT liver MET, the changes after partial liver resection and radiofrequency ablation of liver tumors showed basic necrosis of intrahepatic lesions compared with the previous film (October 17, 2022); liver cysts; Complex cyst of the left kidney.

Fig.6 Upper abdominal noncontrast + contrast + diffusion-weighted imaging (DWI) + magnetic resonance cholangiopancreatography (MRCP) (December 21, 2022)

• After rectal MT surgery, no recurrence or metastases were found in the pelvis: the left peripheral of the prostate had abnormal signals, and inflammatory foci were possible; Sacral duct cysts.

Figure 7 Pelvic noncontrast + enhancement (August 17, 2023)

• Postoperative maintenance chemotherapy

• 于January 3, January 16, January 30, February 13, February 27, March 13, March 27, April 10, April 24, May 8, May 22, June 5, 2023 予西妥古单抗 800mg 联合5-Fu 500mg IV D1,3500mgCIV 46H + 左亚叶酸钠300mg d1方案维持化疗12 cycles.

• Postoperative second-line chemotherapy

• Liver MRI was re-examined, and there was a local progression in the liver to adjust the plan.
• 于June 26, July 10, July 24, August 8, 2023 予西妥古单单反 800mg + 开普拓 (伊立替康) 260mg + 5-Fu 500mg IV D1,3500mg CIV 46H + 左亚叶酸钠 300mg d1方案化疗4 cycles.
• On December 11, 2023, he underwent "partial lobectomy + radiofrequency ablation of liver tumor + complex intestinal adhesion release".

• Postoperative third-line chemotherapy

• The postoperative adjustment regimen was given on January 8, January 22, February 5, February 19, March 4, March 18, 2024 Avastin (bevacizumab) 300mg + Fu 500mg iv d1, 3500mgciv 46h + levonovorin sodium 300mg d1 + liposomal irinotecan 86mg.
• On March 22, 2024, the re-examination showed that after the comprehensive treatment of rectal MT liver MET, there was no recurrent survival lesion in the liver at present, and the disease was assessed to be stable (SD).
• On April 1 and April 15, 2024, chemotherapy was continued with the above regimen.

• Third efficacy evaluation

• After comprehensive treatment of rectal MT hepatic MET: there is no recurrence of viable lesions in the liver at present; Liver cyst, complex cyst of the left kidney, splenomegaly.

Fig.8 Upper abdominal contrast + enhancement + DWI + MRCP (March 22, 2024)

safety

• The patient tolerated chemotherapy drugs well, and there was no obvious gastrointestinal reaction and neurotoxicity after treatment.
• Grade II myelosuppression occurred during chemotherapy, which improved after symptomatic treatment.
• The main adverse reaction was the rash caused by cetuximab, which was assessed as grade 2 and improved after symptomatic treatment with minocycline and ofloxacin gel.

Summary of the case

The patient was diagnosed with multiple liver metastases of sigmoid colon cancer, and was judged to be a potentially resectable case by MDT, and after 7 cycles of bi-weekly treatment with cetuximab + mFOLFOX (lexadine [oxaliplatin] 130mg d1 + 5-Fu 500mg iv d1, 3500mgciv 46h + levonofinate sodium 300mg d1) for 7 cycles, metachronous radical resection of the primary and metastatic lesions was realized, and the conversion therapy was successful.

After conversion therapy, the patient continued to receive the original regimen of adjuvant therapy for 5 cycles, and then used cetuximab + 5-FU + levofolinate sodium maintenance therapy for 12 cycles. Subsequently, according to the progression of the disease, the treatment regimen was appropriately adjusted, but the second- and third-line therapy with targeted therapy + chemotherapy was still continued. It is important to note that the patient was on sodium levofinate throughout the course. Currently in NED status.

Summarize and think

The proportion of colorectal cancer patients with liver metastasis in the whole course of the disease is as high as 40%~50%. Liver metastasis is an important adverse factor affecting the long-term prognosis of colorectal cancer patients. Surgical resection of liver metastases is the only treatment option that may achieve an approximate curative outcome². Studies have shown that resection of the primary lesion and local treatment of liver metastases can significantly improve the median survival time of patients with CRLM³. For patients with CRLM who are judged to be initially unresectable, the tumor can be reduced by systemic drug therapy, and then the initial unresectable lesion can be transformed into a resectable lesion, i.e., conversion therapy². The patient's liver metastases were judged to be potentially resectable after MDT, and preoperative conversion therapy was undertaken.

According to the characteristics of patient metastasis, individualized selection of treatment regimens with high response rate can improve the success rate of conversion therapy. In recent years, a large number of retrospective studies have shown that the prognosis of patients with CRLM in the right half is significantly worse than that in the left half⁴. In addition, based on the results of multiple large randomized controlled clinical studies, anti-EGFR monoclonal antibody is more effective in the first-line treatment of RAS/BRAF wild-type mCRC in left bowel cancer, and the efficacy of combination chemotherapy is better than that of anti-VEGF monoclonal antibody plus chemotherapy⁵,⁶. Currently, NCCN/CSCO guidelines consistently recommend cetuximab + chemotherapy for conversion therapy to left-sided RAS/BRAF wild-type mCRC⁴,⁷,⁸. The patient's tumor was RAS/BRAF double wild-type left colon cancer, and cetuximab + chemotherapy was used for conversion therapy, and the final transformation was successful.

In addition, the patient was treated with a chemotherapy regimen containing levofolinate/5-FU concomitant throughout the course of the treatment, which made an important contribution to the success of the conversion therapy. In a large retrospective study in Italy⁹, the sodium-levofinate/5-FU regimen significantly prolonged median PFS by 7.5 months (20.3 versus 12.8 months, p=0.001) and reduced the risk of disease progression by 50% compared with the traditional calcium levofinate/5-FU sequential regimen; Median OS was 4.3 months longer (37.7 versus 33.4 months, p=0.0151) and the risk of death was reduced by 40 percent. The rates of hematologic and non-hematologic adverse events were similar in both groups.

Sodium levofinate for injection is different from the traditional leucovorin/calcium levofinate injection, which is a lyophilized powder injection, and this preparation technology effectively avoids the generation of impurities of leucovorin under aqueous conditions and then affects the efficacy. In addition, the traditional infusion of calcium salt and 5-FU at the same time will produce precipitation, which will not only affect the efficacy but also cause more adverse reactions of heart and kidney function, so it can only be infused sequentially. The sodium salt preparation made by the innovation of PH regulator in drug preparation can be infused with 5-FU at the same time, and the synergistic effect time is 3 times that of calcium salt, which realizes the full efficiency of 5-FU and brings more efficacy and safety benefits to patients! In the future, the application prospect of levonucovorin for injection is very promising.

Expert Profile

Prof. Jinli Li

• Department of Radiation Oncology, First Affiliated Hospital of Soochow University, Doctor of Medicine, Deputy Chief Physician, Master's Supervisor
• He is a member of the Radiation Oncology Committee of the Chinese Medical Education Association
• Member of the Youth Committee of the Radiation Oncology Physician Branch of Jiangsu Medical Doctor Association
• He is a member of the Cancer Rehabilitation and Palliative Care Professional Committee of Jiangsu Anti-Cancer Association
• Member of the Cancer Pain Group of the Pain Branch of Jiangsu Medical Association
• He is a member of the second session of the Multidisciplinary Collaborative Group for Tumor Diagnosis and Treatment of the Translational Medicine Professional Committee of Jiangsu Immunology Society
• As the first author, he has published more than 10 SCI and core journal papers in relevant professional journals at home and abroad, and his papers have won the second prize of Suzhou Natural Science Outstanding Academic Paper Award in 2016-2017
• Presided over 1 research project of Suzhou Science and Technology Development Plan; Presided over 1 open project of the State Key Laboratory of Radiation Medicine and Radiation Protection of Soochow University; Participated in a number of national and provincial natural science foundation research

Bibliography:

1. Surgeon Branch of Chinese Medical Doctor Association, et al. Guidelines for the diagnosis and comprehensive treatment of colorectal cancer liver metastasis in China (2023 edition). Chinese Journal of General Surgery. 2023; 32(1):1-29.

2. Zhang Yuyang, et al. Research progress on conversion therapy for colorectal cancer liver metastasis. Chinese Journal of Gastrointestinal Surgery. 2021; 24 (01): 85-93.

3.Ma XL, et al. Chin J Colorec Dis ( Electronic Edition ), April 2021, Vol.10, No.2:194.

4. Guidelines Working Committee of Chinese Society of Clinical Oncology. Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Colorectal Cancer 2023. Beijing: People's Medical Publishing House, 2023.

5. Colorectal Tumor Committee of Chinese Medical Doctor Association, et al. Chinese Expert Consensus on Targeted Therapy for Colorectal Cancer. Chinese Electronic Journal of Colorectal Diseases,2022,11(5):353-360.

6.Arnold D, et al. Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol. 2017 Aug 1; 28(8):1713-1729.

7.NCCN Clinical Practice Guidelines in Oncology:Colon Cancer (Version 1.2024)

8.NCCN Clinical Practice Guidelines in Oncology：Rectal Cancer（ Version 1.2024）.

9.Passardi A, et al. Prospective Observational Study Comparing Calcium and Sodium Levofolinate in Combination with 5-Fluorouracil in the FOLFIRI Regimen. Oncologist. 2021; 26(8):e1314-e1319.

Authors: Li Jinli, Wang Jianping, Xu Chao, Wang Qian

Editor: Ruth

审校：Robert

Typesetting: KIKI

Execution: Ryland

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