Preface
Gastric cancer and colorectal cancer are common malignancies of the digestive tract, ranking 5th and 4th in incidence and mortality, respectively, while colorectal cancer ranks 3rd and 2nd, respectively1,2. At present, the treatment of gastric and colorectal cancer mainly includes surgery, radiotherapy, and systemic therapy including chemotherapy, targeted therapy, and immunotherapy. The emergence of new drugs and technologies has greatly improved the clinical application of chemotherapy and provided clinicians with new treatment methods. This article describes the diagnosis and treatment of 1 patient with gastroesophageal junction adenocarcinoma and 2 patients with concurrent colorectal cancer liver metastasis using the simultaneous infusion regimen of leucovorin/5-FU, in order to provide reference for clinical practice.
Case 1
Basic information
- The patient is a 68-year-old male.
- History of present illness: Admitted to the hospital for more than 1 month due to choking sensation after eating.
- Anamnesis: history of "hypertensiveness" and "Parkinson's disease", regular medication, and history of "right inguinal hernia repair".
- ECOG score 1 point.
Baseline check
-
tumor marker testing:
癌胚抗原(CEA):15.74ng/mL、糖类抗原199(CA199):362.46U/mL、CA242:>200IU/mL、CA50:179.43IU/mL。
- Gastroscopy: a raised and depressed lesion can be seen at the cardia entrance, the bottom moss is dirty, the texture is brittle, the contact is easy to bleed, and the marginal mucosa is like a bank.
- Gastroscopic pathology: cardia mucosa (poorly differentiated adenocarcinoma).
- Immunohistochemical markers: CD56 (-), CgA (-), Syn (-), S100 (-), Ki-67 (90%+).
-
imaging tests:
Baseline thoraco-abdominal and pelvic CT showed irregular thickening of the cardia and gastric curvature wall, considering Ca, and multiple swollen lymph nodes below the cardia, paragastric curvature, and retroperitoneum, considering metastasis.
Figure 1.Baseline CT examination of the thoracoabdominal pelvis
Clinical diagnosis
- 胃食管结合部腺癌cT3-4aN+M0 (IIIA-IIIC期)
Treatment
- On January 17, 2023, oxaliplatin 150mg + levofinic acid for injection 6 vialcovorins + 5-fluorouracil (5-FU) 0.5, 4.0 were infused with CIV46h for 4 cycles.
- On March 25, 2023, the CT scan of the thoracoabdominal pelvis showed that the wall of the cardia and gastric curvature was irregularly thickened, and the extent was slightly smaller than before, and the lymph nodes below the cardia, next to the gastric curvature and retroperitoneum were slightly larger, and metastasis was considered to be smaller than before (maximum diameter of 10mm).
- After 4 cycles, the efficacy was assessed as a partial response (PR).
Figure 2.CT changes after treatment
- On April 5, 2023, the patient underwent laparoscopic-assisted radical proximal gastrectomy (tubular gastric anastomosis) under general anesthesia.
- Intraoperative exploration: no obvious metastasis in the abdominopelvic cavity, palpable mass under the cardia with a size of about 2*2cm, no breakthrough through the serous surface, opening the omental sac for exploration, no tumor breakthrough on the serous surface, and no tumor spread and planting in the omental sac.
Post-treatment evaluation
- (proximal gastric) chronic inflammation with ulcer formation, focal granulation tissue and fibrous tissue proliferation, inflammatory cell diffuse, no clear cancer residue, combined with medical history, consistent with post-chemotherapy changes, no cancer involvement at the two incisions, no cancer metastasis in lymph nodes (0/19), one of which was found fibrous tissue and mucus lake formation, consistent with post-treatment changes.
- Immunohistochemistry: CK (-), EMA (-).
- Tumor regression grade (TRG): grade 0.
Summary of the case
The elderly patient was diagnosed with gastroesophageal junction adenocarcinoma (cT3-4aN+M0). Enrollment in the study "Clinical observation of the efficacy and safety of digestive tract tumors treated with 5-FU/levonovorin concomitant infusion regimen". After treatment with oxaliplatin + levovorin/5-FU concurrent infusion regimen, the efficacy was evaluated as PR after 4 cycles. After the conditions for surgical resection were met, laparoscopic-assisted radical proximal gastrectomy was performed under general anesthesia. The postoperative evaluation of TRG was grade 0, indicating that the treatment before surgery was effective. Recent follow-up tests have shown that the whole body is in a tumor-free state (NED).
Disease 2
Basic information
- The patient was a 51-year-old male with a PS score of 0.
- Anamnesis: "diabetes" history for 10 years, denying "hypertension, coronary heart disease, chronic bronchitis" and other medical history.
Baseline check
- (CEA 266.76 ng/ML𞀈CA199 70.34 U/mL).
- CT chest: multiple small nodules in both lungs.
- 腹部B超:肝内多发低密度灶.
- Pathology report: The broken glands of the sigmoid colon mucosa showed high-grade intraepithelial neoplasia, and adenocarcinoma could not be excluded.
Figure 3.Baseline liver imaging
Clinical diagnosis
- Simultaneous liver metastases of colorectal cancer, initially unresectable
Treatment
- On February 20, 2023, oxaliplatin 150mg + irinotecan 260mg + leucovorin calcium (CF) 600mg + 5-Fu5.0civ 44h chemotherapy once
- On February 22, 2023, genetic testing showed that KRAS, NRAS, BRAF were not mutated, Her2(-), MSS type, UGT1A1 6/6
- On April 4, 2023, cetuximab 800mg + oxaliplatin 150mg + irinotecan 260mg + levonilfovorin 6 vials + 5-FU 5.0 were infused with CIV44h at the same time for 4 cycles of treatment
Figure 4. Liver imaging after treatment
- After 4 cycles, the efficacy was assessed as PR
- On June 4, 2023, laparoscopic liver tumor resection + laparoscopic radical sigmoid cancer resection + laparoscopic cholecystectomy was performed;
- Intraoperative exploration: there was no ascites in the abdominal cavity, the tumor was located in the sigmoid colon, part of the serous membrane was invaded, the serous membrane was not broken, and no enlarged lymph nodes were found in the mesangium. Several metastases were visible under the liver capsule, with 3 in the left lateral lobe, 1 in the left medial lobe, and 4 in the right anterior lobe.
Postoperative pathology
- Moderately differentiated adenocarcinoma (colon), full-thickness invasion, with interstitial fibrous tissue proliferation and inflammatory cell infiltration, combined with clinical history, consistent with post-chemotherapy changes, no cancer involvement at both incisions, and no cancer metastasis in lymph nodes (0/23).
- Fibrous tissue hyperplasia with necrosis, calcification, histiocytes, and multinucleated giant cell reactions, with a small number of degenerative nuclear macrocytes in foci.
- Moderately differentiated adenocarcinoma (left lateral lobe liver) with fibrous tissue hyperplasia and focal calcification, combined with medical history and immunohistochemical results, consistent with colorectal cancer metastasis. Chronic inflammation (gallbladder).
- Immunohistochemistry: intestinal masses MLH1 (+), PMS2 (+), MSH6 (+), MSH2 (+), suggestive of microsatellite stability, Her2 (2+, FISH detection recommended), Ki-67 (+, 70%), liver masses CK7 (-), CK19 (+), CK20 (+), CDX2 (+), Villin (+).
Tumor Regression Grade (TRG)
- Level 0
Summary of the case
The patient was diagnosed with simultaneous colorectal cancer liver metastases, initially unresectable. The goal of treatment is no evidence of disease (NED). Patients are first given oxaliplatin + irinotecan + CF + 5-Fu. Genetic testing showed that there were no mutations in KRAS, NRAS, BRAF, Her2(-), MSS type, UGT1A1 6/6. Patients were given 4 cycles of cetuximab + oxaliplatin + irinotecan + levofolinic acid/5-FU concurrent infusion regimen. Imaging examination showed that there were multiple tumors in the liver, which were significantly reduced and shrunk compared with the previous film, and surgical resection was considered. After laparoscopic liver tumor resection + laparoscopic radical sigmoid cancer resection + laparoscopic cholecystectomy, the pathology report showed that the treatment before surgery was effective. The recent review showed that the liver and kidney function were normal, no serious adverse reactions were observed during the medication, and the efficacy was assessed as stable disease (SD).
Case 3
Basic information
- The patient is a 47-year-old male.
- History of present illness: In February 2022, due to unexplained diarrhea, poor appetite, constipation, and abdominal distention, he went to the local hospital for B-ultrasound examination and found multiple liver masses.
Baseline check
- Abdominal CT showed sigmoid colon mass, considering colon Ca with peripheral lymph node metastasis, multiple liver metastases, and multiple small lymph nodes in the mesenteric area.
- 血液检查:Hb 151g/L、总胆红素24.2umol/L、直接胆红素7.5umol/L、间接胆红素16.7umol/L、ALT 123.9U/L,AST 120.3U/L。
- Colonoscopy: sigmoid colon cancer.
- Biopsy showed adenocarcinoma (sigmoid colon mucosa).
- Genetic testing was perfected, and biochemistry was re-examined after 5 days of hepatoprotective therapy, and bilirubin decreased to normal, ALT 151.9U/L↑, and AST 319.4U/L↑
Clinical diagnosis
- Simultaneous colorectal cancer liver metastasis, initially unresectable, liver insufficiency
Treatment
- On March 9, 2022, irinotecan 200mg + levofinic acid 6 vials/5-FU 0.5 and 3.5 were infused with CIV for 46 hours at the same time
- 1周期后复查肝功能:ALT 72.2↓U/L,AST 211.5↓U/L
- NGS基因检测：KRAS（-）、BRAF（-）、Her2（-），Non MSI-H，Non TMB-H，TPS＜1%，CPS＜1，UGT1A1 6/6
- On March 24, 2022, cetuximab 800mg + irinotecan 280mg↑ + levofinic acid 6 vials/5-FU 0.5 and 3.5 were instilled with civ 46h at the same time
- 1周期后复查肝功能:ALT 82↓U/L,AST 61↓U/L
- After 4 cycles, the efficacy was assessed as PR
Figure 5.Imaging changes before and after treatment
Summary of the case
The patient was diagnosed with simultaneous colorectal cancer liver metastases, initially unresectable, and hepatic insufficiency. The goal of treatment is NED. First, patients were given irinotecan + levonovorin/5-Fu concomitant infusion regimen. Genetic testing showed that KRAS(-), BRAF(-), Her2(-), Non MSI-H, Non TMB-H, TPS<1%, CPS<1, UGT1A1 6/6. Patients were given a concomitant infusion regimen of cetuximab + irinotecan + levonofinic acid/5-FU. After 4 cycles, the efficacy was assessed as PR. The levels of ALT and AST continued to decrease during the treatment period, suggesting that the regimen could improve efficacy without impairing liver function. The most recent efficacy assessment was SD.
Summarize and think
The incidence of gastroesophageal junction adenocarcinoma has been increasing in the past 20 years, and its treatment strategy is often controversial due to the specificity of its anatomical location. However, many large clinical studies and consensus have affirmed the value of preoperative chemotherapy in reducing tumor diameter, improving R0 resection rate, and improving overall survival (OS) rate and progression-free survival (PFS) rate in esophageal adenocarcinoma and upper gastric cancer3. In the field of bowel cancer, chemotherapy remains the cornerstone of chemotherapy. Among them, leucovorin (LV) is a commonly used chemotherapy drug, which has undergone a long development process in the treatment of tumors, and plays an important role in the treatment of gastric cancer and colorectal cancer, especially the combination with 5-FU is a classic scheme in the treatment of colorectal cancer. In 2021, levofolinic acid for injection was approved for marketing. It has the following advantages: it contains only the left-handed active ingredient, excludes the right-handed interfering component, is a sodium salt preparation, has good solubility, and the package insert supports compatibility with 5-FU. Clinical studies have shown that concurrent infusion of levofinate/5-FU and sequential administration of calcium levofinate/5-FU are independent factors affecting the risk of survival. Levovorin/5-FU concomitant infusion significantly extended PFS by 7.5 months (20.3 months vs. 12.8 months) and reduced the risk of disease progression by 50%; OS was extended by 4.3 months (37.7 months vs. 33.4 months) and drug configuration and administration time were saved by 132.5 minutes, and the safety profile of the two was similar4,5.
This case included 1 case of gastroesophageal junction adenocarcinoma and 2 patients with concurrent colorectal cancer liver metastasis, both of which achieved good efficacy through the combination of levofolinate/5-FU simultaneous infusion regimen. It is worth noting that cases 2 and 3 are both patients with initial unresectable concurrent colorectal cancer liver metastases. According to domestic and international guidelines, for initial unresectable concurrent liver metastases, primary lesions without related symptoms are not recommended to be resected first, and systemic treatment is recommended. For wild-type initial unresectable concurrent liver metastases, cetuximab + chemotherapy is preferred. In case 2, the patient was given 4 cycles of cetuximab + oxaliplatin + irinotecan + levofolinic acid/5-FU simultaneous infusion regimen, and the imaging examination showed that the multiple tumors in the liver were significantly reduced and shrunk compared with before, and surgical resection was performed after evaluation, and the postoperative pathology showed that systemic treatment was effective. In case 3, in addition to the initial unresectable, the patient also showed liver insufficiency, and after genetic testing, the patient was given cetuximab + irinotecan + levofolinic acid/5-FU simultaneous infusion regimen, and after 4 cycles, the efficacy was evaluated as PR. The levels of ALT and AST continued to decrease during the treatment period. It suggests that this therapy is not only effective, but also does not impair liver function. At present, the "clinical observation of the efficacy and safety of gastrointestinal tumors treated with 5-FU/levonilinic acid concomitant infusion regimen" is still ongoing, and it is expected that this regimen will bring benefits to more patients.
Overall, injectable levonofolin has been a boon for patients with gastroesophageal junction adenocarcinoma and concomitant bowel cancer liver metastases. In particular, conversion therapy gives patients who are otherwise unresectable the opportunity to radically remove the tumor, which can help prolong their long-term survival and improve their prognosis. With the in-depth clinical research on the integrated treatment model, it is expected that more patients will benefit from clinical treatment in the future.
Expert Profile
Professor Zhu Chunrong
- Chief Physician, Associate Professor, Doctor of Clinical Medicine, Master's Supervisor
- Deputy Director of Administration and Director of the Ward of the Department of Oncology of the First Affiliated Hospital of Soochow University
- He is a member of the Standing Committee of the Multidisciplinary (MDT) Branch of Digestive Tract Oncology of the China Association for the Promotion of International Exchange in Health Care
- Member of the Colorectal Cancer Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
- Member of the Expert Committee on Precise and Individualized Prevention and Treatment of Tumors of the China Health Promotion Foundation
- Deputy head of the Oncology Group of the First Professional Committee of Integrated Traditional Chinese and Western Medicine of the Cross-Strait Medical and Health Exchange Association
- Member of the Tumor Drug Research Committee of the China Association of Traditional Chinese Medicine
- Vice Chairman of China Colorectal Cancer MDT Alliance, Chairman of Suzhou Branch of Jiangsu Branch
- Member of the Tumor Immunotherapy Professional Committee of the Chinese Medical Education Association
- Member of the Sino-American Oncology Association (SACA).
- Member of the expert group of the "100 Famous Doctors Forum" project of the China Anti-Cancer Association
- Member of the Translational Medicine Professional Committee of Jiangsu Immunology Society
- He is a standing member of the first colorectal cancer expert committee of Jiangsu Cancer Prevention and Treatment Alliance
- Member of the 1st Esophageal Cancer Expert Committee of Jiangsu Cancer Prevention and Treatment Alliance
- Member of the Standing Committee of Jiangsu Provincial Medical Record Management Committee
- Leader of the MDT Group of the Oncology Professional Committee of Suzhou Medical Association
- Member of the Microcirculation Professional Committee of Suzhou Medical Association
- Deputy head of the tumor microcirculation group of Suzhou Microcirculation Special Committee
- Deputy head of the Psychosomatic Oncology Group of the Psychosomatic Medicine Professional Committee of Suzhou Medical Association
- Director of Suzhou Branch of the Regional Industry-University-Research Project Alliance Council of Oncology Medical of China Soong Ching Ling Foundation Training and Exchange Center
- Forensic expert of the Physical Evidence Appraisal Institute of Suzhou Municipal Public Security Bureau
- The 4th Suzhou Medical Accident Technical Appraisal and Medical Damage Appraisal Expert
Bibliography:
1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021. 71(3): 209-249.
2. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021[J]. CA Cancer J Clin, 2021,71(1):7-33.
3. Liu Kai, Zhu Yunfeng, Yang Yuxian, et al. Interpretation of the Chinese Expert Consensus on the Surgical Treatment of Esophagogastric Junction Adenocarcinoma (2024 Edition). Chinese Journal of Gastrointestinal Surgery, 2024, 27(2): 127-131.
4. Romano FJ, Barbato C, Biglietto M, et al. Folinic acid in colorectal cancer: esquire or fellow knight? Real-world results from a mono institutional, retrospective study. Oncotarget. 2021 Feb 2; 12(3):221-229.
5. Passardi A, Monti M, Donati C, et al. Prospective Observational Study Comparing Calcium and Sodium Levofolinate in Combination with 5-Fluorouracil in the FOLFIRI Regimen. Oncologist. 2021 Aug; 26(8):e1314-e1319.
Authors: Zhu Chunrong, Xiong Feng, Zhu Yanbo, Sun Mengting, Zhu Rui
Editor: Robert
Typography: Uni
Execution: Faline
This platform aims to deliver more medical information to healthcare professionals. The content published on this platform should not be used as a substitute for professional medical guidance in any way, nor should it be regarded as diagnosis and treatment advice. If such information is used for purposes other than understanding medical information, the platform does not assume relevant responsibilities. This platform does not mean that it agrees with its descriptions and views on the published content. If copyright issues are involved, please contact us, and we will deal with it as soon as possible.