Programmed cell death 1 inhibitor sintilimab plus S-1 and gemcitabine for liver metastatic pancreatic ductal adenocarcinoma

Abstract

BACKGROUND

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis. When it metastasizes to the liver, treatment options become particularly limited and challenging. Current treatment options for liver metastatic PDAC are limited, and chemotherapy alone often proves insufficient. Immunotherapy, particularly programmed cell death 1 (PD-1) inhibitors like sintilimab, shows potential efficacy for various cancers but has limited reports on PDAC. This study compares the efficacy and safety of sintilimab plus S-1 and gemcitabine vs S-1 and gemcitabine alone in liver metastatic PDAC.

AIM

To explore the feasibility and effectiveness of combined PD-1 inhibitor sintilimab and S-1 and gemcitabine (combination group) vs S-1 and gemcitabine used alone (chemotherapy group) for treating liver metastatic pancreatic adenocarcinoma.

METHODS

Eligible patients were those with only liver metastatic PDAC, an Eastern Cooperative Oncology Group performance status of 0-1, adequate organ and marrow functions, and no prior anticancer therapy. Participants in the combination group received intravenous sintilimab 200 mg every 3 weeks, oral S-1 40 mg/m² twice daily on days 1-14 of a 21-day cycle, and intravenous gemcitabine 1000 mg/m² on days 1 and 8 of the same cycle for up to eight cycles or until disease progression, death, or unacceptable toxicity. Participants in the chemotherapy group received oral S-1 40 mg/m² twice daily on days 1-14 of a 21-day cycle and intravenous gemcitabine 1000 mg/m² on days 1 and 8 of the same cycle for up to eight cycles. Between June 2020 and December 2021, 66 participants were enrolled, with 32 receiving the combination treatment and 34 receiving chemotherapy alone.

RESULTS

The group receiving the combined therapy exhibited a markedly prolonged median overall survival (18.8 months compared to 10.3 months, P < 0.05) and progression-free survival (9.6 months vs 5.4 months, P < 0.05). compared to the chemotherapy group. The incidence of severe adverse events did not differ significantly between the two groups (P > 0.05).

CONCLUSION

The combination of PD-1 inhibitor sintilimab with S-1 and gemcitabine demonstrated effectiveness and safety for treating liver metastatic PDAC, meriting further investigation.

Key Words: Immunotherapy; Programmed cell death 1 inhibitor; Sintilimab; Chemotherapy; Metastatic; Pancreatic ductal adenocarcinoma

Core Tip: This study aimed to explore the feasibility and effectiveness of combining the programmed cell death 1 inhibitor sintilimab with S-1 and gemcitabine (combination group) vs using S-1 and gemcitabine alone (chemotherapy group) for treating liver metastatic pancreatic adenocarcinoma. The combination of programmed cell death 1 inhibitor sintilimab with S-1 and gemcitabine demonstrated effectiveness and safety for treating liver metastatic pancreatic ductal adenocarcinoma, meriting further investigation.

INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor prognosis[1]. When it metastasizes to the liver, treatment options become particularly limited and challenging. The liver’s role in detoxification, metabolism, and protein synthesis makes any therapeutic intervention targeting liver metastases especially critical due to potential toxicity. A multidisciplinary approach involving surgeons, oncologists, radiologists, and pathologists is essential for treating liver metastatic PDAC. Surgical resection offers the best chance for long-term survival but is often not feasible due to the aggressive nature of PDAC and its tendency to spread. In such cases, palliative treatments aim to improve quality of life and prolong survival.

Systemic chemotherapy is a cornerstone treatment for liver metastatic PDAC, often combining agents such as gemcitabine, fluorouracil, and platinum-based drugs. However, the side effects of chemotherapy, including nausea, vomiting, fatigue, and hair loss, can significantly impact the patient’s quality of life. Radiation therapy is another treatment option to shrink tumors and relieve symptoms, but it must be carefully administered to minimize damage to healthy liver tissue. Increasing interest in palliative care addresses the physical, psychological, and social challenges faced by patients with liver metastatic PDAC.

Recent advances in targeted therapies and immunotherapy offer promising treatment options. Targeted therapies, such as tyrosine kinase inhibitors and monoclonal antibodies, block specific molecular pathways involved in cancer growth. Immunotherapy harnesses the patient’s immune system to attack cancer cells, and has shown encouraging results in clinical trials. Current treatment options for liver metastatic PDAC are limited, and chemotherapy alone often proves insufficient. Immunotherapy, particularly programmed cell death 1 (PD-1) inhibitors such as sintilimab, shows potential efficacy for various cancers but there are limited reports on PDAC[2-6]. This study compares the efficacy and safety of sintilimab plus S-1 and gemcitabine vs S-1 and gemcitabine alone in liver metastatic PDAC.

MATERIALS AND METHODS

Patient eligibility

Eligible patients were aged 45-70 years with histologically or cytologically confirmed liver metastatic pancreatic cancer and an estimated life expectancy of at least 12 weeks. They had an Eastern Cooperative Oncology Group performance status of 0-1, no prior treatment for pancreatic cancer, and adequate hematological, hepatic, and renal functions. All patients provided written informed consent. Pretreatment staging included computed tomography of the chest and abdomen. Patients with obstructive jaundice underwent biliary drainage before treatment.

Exclusion criteria

Patients were excluded if they had active infections, severe diarrhea, active gastroduodenal ulcers, pleural effusion, ascites, drug hypersensitivity, concomitant malignancies, heart or renal disease, mental disorders, were pregnant or lactating, or were of childbearing age not using effective contraception.

Patient characteristics

Sixty-six patients were enrolled from June 2020 to December 2021 at the First Affiliated Hospital of Yangtze University, Jingzhou, China. Patient characteristics are listed in Table 1. There were no significant differences in baseline characteristics between the two groups (P > 0.05). Treatment decisions were made by the patients after being informed of the advantages and disadvantages of the two treatment options (Table 1).

Table 1 Patient characteristics, n.

Characteristics	Combination group	Chemotherapy group
Age (years)
Median	54	56
Range	45-70	48-68
Gender
Male	18	15
Female	14	19
Performance status
0	26	27
1	6	7
Number of liver metastases
1-3	22	25
> 3	10	09

Treatment schedule

In the combination group, participants received: (1) Intravenous sintilimab 200 mg every 3 weeks; (2) Oral S-1 40 mg/m² twice daily on days 1-14 of a 21-day cycle; and (3) Intravenous gemcitabine 1000 mg/m² on days 1 and 8 of the same cycle for up to eight cycles. In the chemotherapy group, participants received: (1) Oral S-1 40 mg/m² twice daily on days 1-14 of a 21-day cycle; and (2) Intravenous gemcitabine 1000 mg/m² on days 1 and 8 of the same cycle for up to eight cycles.

Evaluation

All patients were included in response and toxicity evaluations. Biochemical tests and complete blood cell counts were assessed on days 1 and 8 of each cycle. Tumor markers carcinoembryonic antigen and carbohydrate antigen 19-9 were measured every 4-6 weeks. Tumor response was evaluated every 4-6 weeks by computed tomography or magnetic resonance imaging using Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria. Adverse events were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Objective responses and adverse events were confirmed by an external review committee. Overall survival (OS) was calculated from treatment initiation to follow-up or death. Progression-free survival (PFS) was calculated from treatment initiation to documented disease progression or death.

RESULTS

Treatment efficacy

The objective response rate according to RECIST 1.0 criteria was 31.3% in the combination group and 20.6% in the chemotherapy group (P > 0.05). The disease control rate was 90.6% in the combination group and 73.5% in the chemotherapy group (P > 0.05). The median follow-up duration was 16.8 months in the combination group and 17.2 months in the chemotherapy group. The median PFS was 9.6 months in the combination group and 5.4 months in the chemotherapy group (P < 0.05). Median OS was 18.8 months in the combination group and 10.3 months in the chemotherapy group (P < 0.05). Univariable and multivariable analyses indicated that treatment allocation was the only independent prognostic factor for OS and PFS. There were no significant differences in treatment failure patterns and post-protocol intervention between the two groups (P > 0.05) (Table 2).

Table 2 Summary of tumor response and survival outcomes according to Response Evaluation Criteria in Solid Tumors 1.0 Criteria, n (%).

Outcomes	Combination group (n = 32)	Chemotherapy group (n = 32)	P value
Best tumor response
Complete response	0 (0)	0 (0)
Partial response	10 (31.3)	7 (20.6)	> 0.05
Stable disease	19 (59.4)	18 (52.9)	> 0.05
Progressive disease	3 (9.4)	9 (26.5)	> 0.05
Objective response rate	10 (31.3)	7 (20.6)	> 0.05
Disease control rate	29 (90.6)	25 (73.5)	> 0.05
Median OS, months (95%CI)	18.8 ± 2.6 (16.2-21.4)	10.3 ± 2.3 (8-12.6)	< 0.05
Median PFS, months (95%CI)	9.6 ± 3.1 (6.5-12.7)	5.4 ± 2.2 (3.3-7.7)	< 0.05

OS: Overall survival; CI: Confidence interval; PFS: Progression-free survival.

Toxicities

No unexpected toxicity was observed, and no treatment-related deaths occurred. The incidence of severe adverse events (grade 3-4) was 31.3% in the combination group and 23.5% in the chemotherapy group. The most frequent grade 3 adverse events in the combination group were leucopenia (18.8%), fatigue (6.3%), and anemia (3.1%). In the chemotherapy group, the most frequent grade 3 adverse events were leucopenia (11.8%), fatigue (5.9%), and anemia (2.9%) (Table 3).

Table 3 Adverse events occurring in the two groups, n.

	Combination group, grade 1	Combination group, grade 2	Combination group, grade 3	Combination group, grade 4	Chemotherapy group, grade 1	Chemotherapy group, grade 2	Chemotherapy group, grade 3	Chemotherapy group, grade 4
Leukopenia	14	10	5	1	12	9	3	1
Fatigue	15	9	2	0	17	8	2	0
Anemia	16	6	1	0	14	7	1	0
Nausea	22	11	1	0	21	12	1	0
Anorexia	13	8	0	0	12	9	0	0

DISCUSSION

Surgical resection is rarely feasible for liver metastases, making chemotherapy and radiation therapy the primary treatments aimed at prolonging survival and improving the quality of life. It is necessary to optimize patient selection to balance disease control, toxicity and quality of life, as many patients with metastatic PDAC are incurable with multidisciplinary treatment[7-11]. Many clinical trials have shown that gemcitabine combined with S-1 is an effective regimen with manageable toxicities in the treatment of advanced or metastatic pancreatic cancer and can be used as first-line therapy[12-16]. However, chemotherapy alone has limited efficacy[17-20]. In recent years, there has been intensive research on checkpoint inhibitor immunotherapy for PDAC[21]. Immunotherapy with anti-PD-1 can work in tandem with chemotherapy to lessen the tumor load by easing resistance to chemotherapy and altering the tumor microenvironment[22-26]. Ni et al[27] reported that first-line treatment with sintilimab plus gemcitabine combined with pancreatic high-intensity focused ultrasound in a patient with PDAC achieved a remarkable benefit of 11-month PFS and 20-month OS. Ye and Zheng[28] reported that a metastatic PDAC patient had a partial response to therapy with sintilimab plus S1, and the lesions had markedly diminished and were almost gone. In metastatic pancreatic cancer, such responses are seldom observed. Zhang et al[29] reported a good outcome with a PFS of 22 months following sintilimab monotherapy for metastatic PDAC. Based on these three case reports, combining these two treatments makes sense to enhance tumor control both locally and systemically. Nevertheless, clinical data supporting this is currently insufficient on the combination of sintilimab plus S-1 and gemcitabine.

Therefore, we performed this retrospective study to compare the efficacy and safety of sintilimab plus S-1 and gemcitabine vs S-1 and gemcitabine in patients with metastatic PDAC. The objective response rate based on the RECIST 1.1 criteria was 31.3% within the combination group and 21.9% within the chemotherapy group (P > 0.05). Meanwhile, the disease control rate based on the RECIST 1.1 criteria was 90.6% within the combination group and 78.1% within the chemotherapy group (P > 0.05). The median follow-up time was 16.8 months in the combination group and 17.2 months in the chemotherapy group. In the combination group, the median OS was 18.8 months, while in the chemotherapy group, it was 10.3 months (P < 0.05). For the median PFS, it was 9.6 months in the combination group and 5.5 months in the chemotherapy group (P < 0.05). Univariable and multivariable analyses (Cox regression model) showed that only treatment allocation was an independent prognostic factor of OS and PFS. During the follow-up period, no significant distinctions in the pattern of treatment failure and post-protocol intervention were found in both groups (all P > 0.05). These results are similar to the conclusions by Liu et al[30], who reported that Nab-paclitaxel plus S-1 with sintilimab in PDAC with only hepatic metastases resulted in a median OS of 16.8 months, and was better than that in the study by Fu et al[31], who reported that sintilimab plus modified FOLFIRINOX in patients with metastatic or recurrent pancreatic cancer resulted in a median overall OS of 10.9 months.

No unexpected toxicity was noticed and no treatment-related deaths happened in this study. There was no significant difference in the incidence of severe adverse events between the two groups (76.6% vs 73.3%, P > 0.05). In the combination group, the most common (≥ 10% incidence) adverse events of ≥ grade 3 were leukopenia in 12 cases (40%), anemia in 4 cases (13.3%) and fatigue in 5 cases (16.7%), while in the chemotherapy group were 10 leukopenia (33.3%), 3 anemia (10%), and 4 fatigue (13.3%).

Recent advances in targeted therapies and immunotherapy have provided new treatment options. Targeted therapies interfere with the cancer cell growth mechanisms, while immunotherapy harnesses the immune system to attack cancer cells. However, identifying patients likely to benefit from aggressive treatment remains challenging due to disease heterogeneity. Biomarkers and genetic profiling may help identify these patients, although these tools are still under development. This study demonstrated that the combination of sintilimab, S-1, and gemcitabine is both effective and safe for treating liver metastatic PDAC, providing longer OS and PFS compared to chemotherapy alone. Importantly, the combination treatment did not result in a significant increase in severe adverse events compared to chemotherapy alone. These findings suggest that this combination therapy could be a valuable addition to the treatment options for liver metastatic PDAC.

The limitations of this retrospective design include sample heterogeneity, potential selection bias and information bias, and a short follow-up period. Further investigation is warranted to confirm these results and to explore the potential of this combination therapy in personalized treatment strategies. Further investigation should include conducting larger, randomized clinical trials, multi-center prospective studies or examining the molecular biological mechanisms of the combination therapy to validate the efficacy and safety observed in this study. Additionally, research should focus on exploring potential biomarker screening strategies based on the results of this study to identify patients most likely to benefit from this combination therapy, thereby providing a basis for personalized treatment.

CONCLUSION

Sintilimab combined with S-1 and gemcitabine has shown promising results in the treatment of liver metastatic PDAC, offering a potential new treatment option that balances efficacy and safety. Continued research in this area could lead to more effective and personalized treatment strategies, ultimately improving outcomes for patients with this challenging condition.

ACKNOWLEDGEMENTS

The authors would like to thank the Department of Chemoradiotherapy, the First Affiliated Hospital of Yangtze University for providing experimental equipment and technical support.