Multiple primary tumors patient developed microsatellite stable gastric cancer after cadonilimab treatment for liver cancer: A case report

Abstract

BACKGROUND

Multiple primary malignant tumors refer to the occurrence of two or more primary malignant tumors in the same organ or multiple organs or tissues at the same time or successively in the same patient, and can occur anywhere in the body. The treatment guidelines for patients with multiple primary malignant tumors are currently controversial.

CASE SUMMARY

A 51-year-old male patient with liver cancer and portal hypertension received 42 months of co-treatment with atezolizumab and bevacizumab. After that, the disease was rated stable disease. The patient was then diagnosed with gastric cancer. Since the patient was not sensitive to anti-programmed death ligand 1 immunosuppressive agents, a co-treatment with oxaliplatin, tegafur, apatinib, and cadonilimab was selected after multidisciplinary consultation and the patient’s agreement. After four cycles of treatment, partial response and stable disease were observed in gastric and liver cancers, respectively. Surgical treatment was performed considering the high-risk factors of gastrointestinal bleeding in patients with gastroesophageal varices. Postoperative pathology showed that the Tumor Regression Grade was 1. Moreover, the genetic testing of postoperative tumor specimens indicated negative programmed death ligand 1 and microsatellite stability. In addition, the latest follow-up indicated an 8 and 40-month progression-free survival in gastric and liver cancer patients, respectively. Currently, the patient is receiving postoperative immunotherapy with cadonilimab.

CONCLUSION

Cadonilimab not only treats microsatellite stability gastric cancer patients but can also be used for liver cancer treatment.

Key Words: Gastric cancer; Liver cancer; Multiple primary malignant tumors; Cadonilimab; Case report

Core Tip: The incidence of multiple primary malignant tumors is gradually increasing worldwide. There are still many controversies and challenges in the treatment of multiple primary malignant tumors due to the different pathological types, pathogenesis and treatment methods. We report a case of a patient diagnosed with both liver cancer and microsatellite instability gastric cancer following treatment with cadonilimab. The latest follow-up revealed progression-free survival of 8 months for gastric cancer and 40 months for liver cancer. This study provides a reference for further study of multiple primary gastrointestinal tumors.

INTRODUCTION

Multiple primary malignant tumors (MPMT) refer to the occurrence of two or more primary malignant tumors in the same organ or multiple organs or tissues at the same time or successively in the same patient, and can occur anywhere in the body. According to the time interval between the diagnosis of the primary malignancy and the second malignancy, it is divided into synchronous malignancy and metachronous malignancy. The former refers to the occurrence of more than two malignant tumors within 6 months, and the latter refers to the occurrence of two malignant tumors more than 6 months[1,2]. In China, it was found that malignant tumors of the digestive system accounted for the first proportion of MPMT, followed by tumors of the respiratory system[3]. At present, there is no clear standard for the treatment of MPMT, but the guidelines for the diagnosis and treatment of multiple and unknown primary tumors of the Chinese anti-Cancer Association 2023 advocate treatment according to the treatment principle of each primary tumor. According to different tumor location, pathological stage and general condition, the corresponding treatment plan was selected. Based on disciplinary protocols and multidisciplinary consultation, we treated a patient with both liver and gastric cancer with cadonilimab.

CASE PRESENTATION

Chief complaints

Melena after eating for 1 week.

History of present illness

In October 2023, the patient was admitted to the hospital because of melena for 1 week and discomfort after eating.

History of past illness

The 51-year-old male patient was diagnosed with hepatitis C combined with alcoholic cirrhosis, splenomegaly, and portal hypertension in November 2017. Hepatitis C virus treatment and computed tomography (CT) were followed up. In April 2019, the patient was diagnosed with stage Ia primary liver cancer (Figure 1A). According to the 2018 Chinese Society of Clinical Oncology (CSCO) guidelines for the diagnosis and treatment of primary liver cancer, transarterial chemoembolization (TACE) was performed in May 2019 (Figure 1B). The abdominal CT in April 2020 showed that the liver lesion in the right lobe of the liver had increased, and radiofrequency ablation of the liver cancer lesion was performed. In January 2021 in tip: Review of the right liver lobe hepatic cell carcinoma lesions, judged to be primary liver cancer stage Iva (Figure 1C). Atezolizumab (1200 mg) combined with bevacizumab (1 g) was administered according to the 2020 CSCO guidelines for the diagnosis and treatment of primary liver cancer. A total of 18 cycles of treatment were administered.

Figure 1 Imaging changes of liver lesions after treatment. A: In April 2019; B: In May 2019; C: In January 2021; D: In October 2023.

Personal and family history

The patient had a 30-year history of smoking and a 10-year history of alcohol consumption.

Physical examination

No special positive findings were found on admission examination.

Laboratory examinations

Laboratory tests showed hemoglobin (111 g/L), platelet (100 × 10⁹ g/L), and other blood cell counts were normal. Coagulation, liver and kidney functions, electrolytes, and lipids were normal. A stool occult blood test was positive. Tumor markers were: Alpha-fetoprotein (6.86 ng/mL), carcinoembryonic antigen (2.11 ng/mL), and cancer antigen 125 (20.07 U/mL). Testing for hepatitis C antibodies was positive.

Imaging examinations

Immunological examination: Postoperative gastric lesions immunohistochemical results cytokeratin (CK, +), CD20 (-), CK7 (+ in some cells), and Ki-67 (about 60%) (Figure 2).

Figure 2 Immunohistochemical results of gastric cancer in March 2024 (40 ×). A: Cytokeratin (+); B: CD20 (-); C: Cytokeratin 7 (+ in some cells); D: Ki-67 (about 60%).

Electronic gastroduodenoscopy examination: A 3 cm × 3.5 cm protruding lesion from the fundus to the anterior wall of the greater curvature of the stomach (Figure 3A). After 4 cycles of neoadjuvant therapy, gastroscopy showed that the original lesion at the esophagogastric junction had disappeared (Figure 3B and C).

Figure 3 Gastroscopic changes of gastric lesions after treatment. A: In October 2023; B: In December 2023; C: In March 2024.

Abdominal CT scan: The scan showed that the gastric lesions shrank after the neoadjuvant treatment (Figure 4A and B) and the number of lymph nodes around the cardia was less than before (Figure 4D and E).

Figure 4 Imaging changes of gastric lesions after treatment. A: In October 2023; B: In February 2024; C: In March 2024; D: In October 2023; E: In February 2024; F: In March 2024.

FINAL DIAGNOSIS

He had stage IIIB primary liver cancer and cT3N1M0 stage IIb adenocarcinoma of the esophagogastric junction. These two tumors are metachronous and multigenic (Figures 1C and 4A).

TREATMENT

After undergoing targeted therapy and immunotherapy, the patient achieved stable disease (SD) of liver cancer, but developed gastric cancer. For subsequent therapy, we considered the possibility that the patient might have low expression of programmed death ligand 1 (PD-L1). Genetic testing is necessary. The patient and his family declined testing. According to the 2022 CSCO guidelines for the diagnosis and treatment of gastric cancer, our team recommends neoadjuvant therapy or direct surgical resection for esophagogastric junction tumors. After multidisciplinary consultation and discussion, the patient’s family’s wishes for neoadjuvant therapy were taken into account. At the end of October 2023, the patient received 4 cycles of cadonilimab (500 mg/time/per 3 weeks), 4 cycles of apatinib (250 mg per day/per 3 weeks), 4 cycles of tegafur (40 mg twice a day/per 3 weeks), and 4 cycles of oxaliplatin (130 mg/m³/ per 3 weeks). Blood routine, liver and kidney function, electrolytes, chest X-ray and electrocardiogram were evaluated before and after treatment. During the treatment, thrombocytopenia occurred at the second and fourth treatment, and the lowest platelet count was 33 × 10⁹/L. Human interleukin-11 was injected to increase platelets. The secondary adverse reactions were graded as grade 2 according to Common Terminology Criteria for Adverse Events 5.0. In addition, no other adverse reactions occurred. After 4 cycles of neoadjuvant therapy in February 2024, gastroscopy showed that the original lesion uplift at the esophagogastric junction had basically disappeared (Figure 4B). The abdominal CT showed that the patient was in accordance with gastric adenocarcinoma yT3N0M0 stage IIb, the number of lymph nodes around the cardia was less than before, and the CT signs of liver cirrhosis and gastric fundus and esophageal varices were similar to those before (Figure 4E). The lesion in the right lobe of the liver was similar to that before.

For the patient with high risk factors of esophagogastric varices, after multidisciplinary discussion and understanding of the disease, the patient and family members had a strong willingness to undergo surgery. In March 2024, radical resection of proximal radical gastrectomy + pericardial devascularization + vagotomy will be performed (Figure 4C). The pathological results of postoperative gastric cancer specimens showed that ypT2N0M0 stage I and tumor regression grade 1. Nerve, vascular, cutting edge, lymph node negative. Immunohistochemistry showed CK (+), CD20 (-), CK7 (+ in some cells) and Ki-67 (about 60%) (Figure 2). Gene detection of postoperative pathological specimens showed PD-L1 negative and microsatellite stability (MSS) (Table 1). The ECOG score was 5, and the efficacy was evaluated as partial response (PR). The specific diagnosis and treatment process is shown in Figure 5.

Figure 5 Treatment process. TACE: Transarterial chemoembolization; T + A: Atezolizumab + bevacizumab.

Table 1 Postoperative pathological genetic testing.

Content	Results	Methodology
PD-L1	Negative	NGS
Microsatellite analysis	MSS	NGS

PD-L1: Programmed death ligand 1; MSS: Microsatellite stability; NGS: Next-generation sequencing.

OUTCOME AND FOLLOW-UP

Currently, the patient has achieved 6-month progression-free survival (PFS) for gastric cancer and 40-month PFS for liver cancer. In order to make the patient to achieve a higher survival in combination with cadonilimab for efficacy and safety of patients, continue to use cadonilimab postoperative immune therapy.

DISCUSSION

Surgery is the most commonly used radical treatment of liver cancer. However, for liver cancer patients with some complications, surgical treatment is not the recommended treatment. Here, the patient had primary liver cancer which was complicated by portal hypertension syndrome and he failed to respond to TACE treatment. According to the patient’s condition and the CSCO guidelines on first-line treatment, the atezolizumab + bevacizumab (T + A) regimen was employed. After 18 cycles of T + A therapy, the patient achieved SD in liver cancer and a PFS of 32 months. However, during the treatment of liver cancer, melena developed unprovoked, and the patient was then diagnosed with gastric cancer of cT3N1M0 stage IIb, which was advanced. The diagnosis of a new cancer raised the suspicion for insensitivity to anti-PD-L1 immunosuppressive agents. Therefore, whether atezolizumab should be used for the subsequent treatment of gastric cancer was questioned. Studies have confirmed that atezolizumab has a certain therapeutic effect on patients with gastric cancer. In the DANTE trial, the addition of the PD-L1 inhibitor atezolizumab to fluorouracil, leucovorin, oxaliplatin, and docetaxel resulted in a higher pathological complete response rate than fluorouracil, leucovorin, oxaliplatin, and docetaxel alone in gastric cancer patients[4]. Therefore, to assess if atezolizumab should be continued or switched to another immunotherapy and which drug combination should be used for neoadjuvant therapy, a multidisciplinary committee was formed.

In China, most gastric cancer patients are diagnosed at advanced stages, and the overall 5-year survival rate is < 50%. In the treatment of advanced gastric cancer, surgery alone cannot increase the survival rate. Furthermore, even after radical gastrectomy, advanced gastric cancer still has a high rate of distant metastasis and local recurrence, and its 5-year survival rate is about 25%-30%[5-7]. Currently, surgery is the main treatment for advanced gastric cancer; however, the comprehensive treatment strategy of combining chemotherapy, targeted therapy, and immunotherapy is also being explored. DRAGON IV trial is a phase III clinical trial to evaluate the efficacy and safety of immunotherapy combined with targeted drugs and chemotherapy in the perioperative treatment of resectable gastric adenocarcinoma. The results of this trial have confirmed that the comprehensive treatment without targeted chemotherapy could significantly improve the pathological complete response rate of patients[8].

Before the immune therapy, genetic testing of related biomarkers, such as the tumor mutational burden, PD-L1, and microsatellite instability (MSI), is performed to assess the treatment strategy[9]. Due to the strong heterogeneity of gastric cancer, the results of genetic testing are inaccurate because of the samples and detection time limitations. In this case, the family members refused genetic testing after knowing the advantages and disadvantages of genetic testing in detail. Moreover, when gastric cancer patients are not sensitive to atezolizumab, selecting an alternative immune drug is challenging for the multidisciplinary committee. KEYNOTE-059 and -062 have indicated that for high expression of PD-L1 in gastric cancer patients, the treatment of the PD-L1 single resistance effect is more significant[10,11]. Therefore, for negative or low PD-L1 expression patients the efficacy of PD-L1 immunotherapy such as, PD-L1 inhibitors is limited, therefore, the combination of different drugs such as bispec-specific antibodies and antibody-drug conjugate should be employed[12].

Cadonilimab is the first bispecific antibody drug independently developed in China, which can block both PD-1 and cytotoxic T-lymphocyte associated protein 4 signaling pathways. It is a symmetric quadrivalent bispecific antibody with a crystallizable fragment, Fc. Reduced antibody-dependent cytotoxicity was observed in the absence of Fc receptor binding[13,14]. AK104-201 confirmed the efficacy and safety of carboinide monotherapy vs combination chemotherapy in the treatment of advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Furthermore, for combined positive score (CPS) ≥ 1 and CPS < 1 patients, the modified overall survival of AK104 combined with chemotherapy were 17.41 and 14.65 months, respectively, indicating that cadonilimab could increase the survival of advanced gastric cancer patients with low or no PD-L1 expression. Compared to the listed immunosuppressant in reduced or negative PD-L1 expression patients, cadonilimab not only benefits high PD-L1 expression patients but also promotes excellent curative effects in reduced or negative PD-L1 expression patients[15].

After a multidisciplinary discussion and the family’s agreement, the patient was given 4 cycles of neoadjuvant therapy comprising cadonilimab, oxaliplatin, tegafur, and apatinib. The patient developed progressive thrombocytopenia during this treatment, which although attributed to a treatment-related adverse effect, could be linked with splenomegaly due to the patient’s cirrhosis. After the completion of neoadjuvant therapy, the gastroscopy and the abdominal CT showed that the patient’s gastric lesions were significantly reduced, the size of para-cardia lymph nodes was decreased, whereas the liver cirrhosis, gastric fundal esophageal varices, and the liver lesions in the right lobe were similar to those as before. At this point, the patient was still in SD for liver cancer and in PR for gastric cancer. Before the treatment, it is essential to determine whether the patient should undergo surgery. The changes in collateral circulation caused by portal hypertension led to hypersplenism, hepatic insufficiency, as well as possible esophageal varices rupture and bleeding, which reduce survival rate and indicate poor prognosis in patients. In the presented case, radical gastrectomy and pericardial devascularization were performed in the patient. The pathological results of postoperative gastric cancer specimens showed tumor regression grade 1. Nerves, vessels, surgical margins, and lymph nodes were negative. To further clarify the effect of cadonilimab on the patient, genetic testing was performed on postoperative pathological specimens, which were PD-L1-negative and MSS.

The postoperative pathological genetic testing results were inconsistent with the hypothesis of low PD-L1 expression in this patient. In general, patients with MSI tumors benefit more from the immunotherapy[16]. MSI has been regarded as an important molecular marker for the prognosis and adjuvant treatment of colorectal cancer and other solid tumors[17]. However, most gastric cancers exhibit MSS, and a few indicate MSI[18,19]. To investigate which immunotherapy should be selected for patients with MSS was evaluated by the NICHE study performed in the Netherlands, which indicated that some MSS patients with early colon cancer could achieve major pathologic response in neoadjuvant therapy[20]. In REGONIVO, regorafenib and nivolumab resulted in a 36% objective response rate (ORR) in patients with MSS bowel cancer. However, the efficacy of cadonilimab in MSS tumor patients can be different from what is expected. A clinical case study published in December 2022 showed that cardonilib showed certain efficacy in patients with MSS advanced gastric cancer, and the patient finally achieved complete remission[21]. In addition, a study in October 2023 showed that the objective response rate of cardonilib combined with lenvatinib in patients with advanced liver cancer reached 35.6%[20]. Data on the safety and antitumor activity of cardonilib in patients with various cancers are available until 2023. Relevant studies have suggested that the drug can prolong the median survival time in patients with gastric cancer and liver cancer. At the same time, for gastric cancer patients with CPS < 1, studies have shown that cardonilib can improve the median survival time and objective response rate. On the basis of the available evidence, we believe that cardonilib has some efficacy in patients with gastric cancer and negative PD-L1 expression. In addition, the treatment of patients with unresectable hepatocellular carcinoma also showed good efficacy. Although guidelines provide an important basis for treatment selection in clinical cancer treatment, actual clinical practice does not completely rely on guidelines. Guideline updates often lag behind emerging research. Physicians may choose to use a new drug or combination therapy that is not yet included in guidelines but has shown promising efficacy in early clinical studies after a sufficient risk-benefit assessment. This not only provides patients with the opportunity to receive innovative treatments, especially when standard treatments are ineffective or unavailable, but also accumulates experience for future optimization of treatment strategies.

The patient achieved PR in gastric cancer and SD in liver cancer after neoadjuvant therapy with 4 cycles of cadonilimab. At the time of submission of the current manuscript, a PFS of 6 and 40 months were achieved for gastric and liver cancers, respectively, with no grade 3 or higher adverse effects. Currently, the patient is receiving postoperative immunotherapy with cadonilimab. Because of the safety and efficacy of cadonilimab observed in this case, it was concluded that cadonilimab is a promising bispecific antibody agent that can be employed for the treatment of gastric cancer patients with low PD-L1 expression and also for liver cancer patients. Based on the results, it was hypothesized that cadonilimab is a novel immunotherapy for pan-cancer acting as a broad-spectrum anticancer agent targeting low PD-L1 expression patients. However, to validate whether cadonilimab can become a new broad-spectrum anticancer drug for patients with low expression of PD-L1 in immunotherapy warrants further research.

CONCLUSION

In summary, further research is required to determine the optimal immunotherapy and comprehensive treatment regimen. The benefits of immunotherapy combined with other treatments are undeniable. However, this case has indicated that cadonilimab has high efficacy and safety, highlighting its potential in the treatment of PD-L1-negative patients with gastric and liver cancers. This study provided evidence for the application of cadonilimab as the first-line drug to treat tumor patients with negative expression of PD-L1 and MSS during the perioperative period.

ACKNOWLEDGEMENTS

The authors extend their heartfelt gratitude to their colleagues for their invaluable suggestions and support in the preparation of this article.