Adjusted gemcitabine plus S-1 regimen as first‑line chemotherapy in unresectable advanced pancreatic cancer: a long-term survival case report

Introduction

Pancreatic cancer (PC) remains the sixth leading cause of cancer-related mortality in China, accounting for 8% of 5-year survival rates as of 2022 (1,2). Surgical resection represents the only curative option for PC; however, few of patients qualify for radical surgery at diagnosis due to limitations in early detection modalities. With most cases presenting as unresectable at diagnosis, systemic chemotherapy becomes the primary therapeutic modality. For patients with unresectable locally advanced or metastatic PC and preserved performance status, current guidelines recommend doublet chemotherapy regimens (3,4). Gemcitabine plus S-1 (GS) combination therapy remains a standard first-line regimen for unresectable PC in China (5). Standard daily S-1 dosing frequently necessitates treatment discontinuation due to grade 3/4 hematological toxicity or non-hematological adverse events (6). A previous study demonstrated that alternate-day S-1 dosing achieves comparable tumor control while reducing mucosal and hematologic toxicity (7). This approach improves treatment adherence while maintaining comparable survival outcomes (6). We here present a modified GS regimen employing dose-adjusted S-1 scheduling (80 mg/m² on alternate days) combined with standard gemcitabine dosing. This strategy achieved prolonged progression-free survival in a case with 5-year overall survival. This modified regimen may serve as a viable alternative first-line chemotherapy for patients with the standard GS regimen intolerance. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-274/rc).

Case presentation

A 61-year-old female with a 1-year history of intermittent epigastric pain presented to our institution in January 2020. Her medical comorbidities included chronic hepatitis B (30 years), chronic gastritis (2 years), and type 2 diabetes mellitus (4 months), managed with entecavir and acarbose respectively. Laboratory investigations demonstrated marked elevation of tumor markers [carbohydrate antigen 19-9 (CA19-9) >1,000 U/mL, cancer antigen 125 (CA125) 459.3 U/mL, alpha-fetoprotein (AFP) 8.84 ng/mL] with concurrent hypoalbuminemia (33.6 g/L) and mild transaminitis [alanine transaminase (ALT) 47 U/L, aspartate transaminase (AST) 49 U/L]. Liver function assessment yielded a Child-Pugh score of 6 (8). Abdominal computed tomography (CT) revealed a 59 mm × 20 mm pancreatic head mass encroaching on the retroperitoneum, accompanied by multiple hepatic metastases (maximum 21 mm × 18 mm) and left portal vein trunk occlusion. Histopathological confirmation of pancreatic ductal adenocarcinoma (PDAC) established a T3N0M1 clinical staging. Following multidisciplinary tumor board evaluation, the patient received the standard GS chemotherapy (gemcitabine 1,000 mg/m² on days 1, 8; S-1 80 mg/m² daily ×14 days, 21-day cycle) (Figure 1). All procedures performed in this study were in accordance with the Research Ethics Committee of Guangzhou First People’s Hospital, Guangzhou, China (approval No. F-2024-005-01) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 1 GS regimen schema. (Upper panel) Standard GS regimen: gemcitabine 1,000 mg/m² intravenously on days 1 and 8, combined with consecutive daily oral S-1 (80 mg/m² twice daily) for 14 consecutive days, repeated every 21 days. (Lower panel) Modified alternate-day GS regimen: gemcitabine 1,000 mg/m² intravenously on days 1 and 8, combined with alternate-day oral S-1 (80 mg/m² twice daily) administered over 21-day cycles. GS, gemcitabine plus S-1.

Following one cycle of standard GS therapy, the patient developed grade 3 neutropenia and stomatitis, alongside grade 1 diarrhea. Through sequential multidisciplinary reassessment and shared decision-making, the regimen was modified to the adjusted GS regimen (gemcitabine 1,000 mg/m² on days 1, 8; S-1 80 mg/m² on alternate days) (Figure 1), effectively mitigating treatment-related toxicity while maintaining dose intensity.

The patient demonstrated excellent protocol adherence to the adjusted GS regimen, experiencing only grade 1 leukopenia and stomatitis. Serial imaging in January 2021 revealed progressive tumor regression: pancreatic mass decreased to 33 mm × 20 mm with diminished hepatic metastases (maximum 17 mm × 12 mm). Corresponding tumor marker reduction [CA19-9: 122 U/mL vs. baseline >1,000 U/mL; CA125: 12.3 U/mL (normal)] confirmed treatment response (partial remission). Despite maintained radiological response, persistent left portal vein occlusion precluded surgical intervention. After completing 12 cycles of adjusted GS therapy without disease progression, maintenance S-1 monotherapy (alternate-day dosing) was initiated following gemcitabine discontinuation (Figure 2A). On May 2021, the imaging showed the tumor size at 25 mm × 18 mm, and the CA19-9 level decreased to 85.3 U/mL. October 2024 imaging showed stable disease (33 mm × 28 mm) with new-onset malignant ascites managed by hyperthermic intraperitoneal perfusion chemotherapy (recombinant endostatin + cisplatin). At last follow-up (November 2024; 58 months post-diagnosis), the patient maintained Eastern Cooperative Oncology Group performance status 2 and preserved Child-Pugh class A (score 7), reporting absence of abdominal pain. The treatment trajectory and representative imaging are summarized in Figure 2.

Figure 2 Treatment timeline and contrast-enhanced CT imaging findings. (A) The patient received one cycle of standard GS regimen with serious side effects and poor compliance, then followed 12 cycles of the adjusted GS regimen with low side effects and good compliance. (B) The enhanced CT images at key points. Red arrows denote the occupying pancreatic head lesion with retroperitoneal extension and encasement of the left portal vein trunk. CA19-9, carbohydrate antigen 19-9; CT, computed tomography; GS, gemcitabine plus S-1.

Discussion

Key findings

We report a histologically confirmed PDAC case demonstrating 5-year overall survival following first-line treatment with a dose-adjusted GS regimen (gemcitabine 1,000 mg/m² days 1, 8; S-1 80 mg/m² on alternate days), characterized by manageable toxicity profile and superior treatment adherence. The adjusted GS strategy is a viable alternative to the standard GS regimen.

Strengths and limitations

While this case illustrates an exceptional 5-year overall survival benefit with dose-modified GS chemotherapy in PDAC, the therapeutic efficacy remains hypothesis-generating and mandates rigorous multicenter validation. Our findings suggest modified GS regimens may enhance treatment tolerability while maintaining comparable survival outcomes, providing a feasible option for patients with standard regimen intolerance. These findings should be interpreted within the context of inherent limitations including: (I) single-arm design and single-center recruitment limit external validity, necessitating phase trials. (II) Absence of biomarker correlates [programmed death-ligand 1 (PD-L1) expression, circulating tumor DNA dynamics] precludes mechanistic insights into treatment hypersensitivity. (III) Dose-modification protocols were not formally assessed. Future multicenter randomized controlled trials are essential to confirm the regimen’s role in broader populations and elucidate optimal dosing protocols, biomarker predictors, and adjunctive supportive care approaches.

Comparison with similar researches

In recent years, the alternate-day administration of S-1 has been reported to reduce adverse side effects without impairing treatment effectiveness. A phase II clinical study comparing alternate-day and daily administration of S-1 for advanced PC as first-line chemotherapy (9) showed that the median overall survival after the alternate-day regimen, progression-free survival, and time to treatment failure were 8.4, 5.5, and 3.9 months, respectively. It indicated that, compared to the standard daily administration of S-1, the alternate-day schedule ensured excellent safety, treatment continuity, and health-related quality of life (9). In another phase II study that compared S-1 alternate-day oral therapy with the standard daily regimen as a first-line treatment in patients with unresectable advanced PC, the median overall survival was 9.4 months for the alternate-day group and 10.4 months for the daily group, suggesting the non-inferiority of alternate-day treatment to daily treatment (10). In a phase II study of alternate-day treatment with S-1 as second-line chemotherapy in advanced PC, the efficacy of alternate-day therapy was similar to that of consecutive-day therapy, with few toxicities in the alternate-day administration of S-1 (11). By using the alternate-day regimen as a basic treatment that promises few side effects, a previous study contributed to the development of combination chemotherapy, which maintains the efficacy of each individual drug (9). Several studies assessing the feasibility of alternate-day S-1 administration with oxaliplatin and irinotecan (SOXIRI) as the triple combination chemotherapy in patients with unresectable PDAC reported an increase in medium-term overall survival to 12.1–17.7 months (12-14). To date, few studies have reported combination chemotherapy with the alternate-day administration of gemcitabine in PC treatment. Our long-term survival case may offer a potential strategy for patients who are intolerant of the side effects of the GS regimen. Most importantly, our reported case had a long-term survival to 58 months since the diagnosis of PC.

Explanations of findings

Treatment strategies for PC are aimed at prolonging survival and improving patients’ quality of life. Patients with locally advanced PC may undergo neoadjuvant therapy (3,4,15), such as chemotherapy, which transforms the tumor into a resectable state. The case reported in this paper was diagnosed as unresectable advanced PC with a tumor in the pancreatic body and the retroperitoneal space, and with multiple liver metastases and a truncated left branch of the portal vein. Hence, chemotherapy with the standard GS regimen was the treatment of choice for this patient. In China, standard GS is one of the recommended first-line chemotherapies for unresectable PC (5). Two previous phase II studies of the GS regimen reported high response rates of 44.4–48.5% and good median overall survival of 10.1–12.5 months in metastatic PC (7,16). The GS regimen has been reported to be superior in prolonging the progression-free survival of patients with locally advanced and metastatic PC (6). However, the serious adverse events caused by the GS regimen should not be overlooked. Reportedly, the GS regimen results in significantly more incidences of grade 3 or worse leukopenia, neutropenia, thrombocytopenia, rash, diarrhea, vomiting, and stomatitis than gemcitabine monotherapy does (6,17). In this reported case, the patient also experienced severe adverse events of neutropenia (G3), stomatitis (G3) and diarrhea (G1) within one cycle of the standard GS regimen. With the adjusted GS treatment, this patient showed good compliance for the good treatment efficacy and mild adverse events as leukopenia (G1) and stomatitis (G1), while diarrhea and neutropenia disappeared.

Implications and actions needed

For patients with unresectable advanced PC demonstrating intolerance to standard GS regimen (e.g., grade ≥2 hematological toxicity), the dose-adjusted GS regimen (gemcitabine 1,000 mg/m² days 1, 8; S-1 80 mg/m² alternate days) may serve as a first-line treatment alternative, as evidenced by 58-month overall survival in our index case. A future multicenter randomized controlled trial is warranted to validate this strategy’s superiority in maintaining treatment efficacy.

Conclusions

We report a 58-month overall survival in an unresectable advanced PC patient with portal vein thrombosis, achieving stable disease following dose-adjusted GS chemotherapy. This modified regimen demonstrates comparable tumor control while reducing grade 3/4 toxicity, positioning it as a first-line alternative for patients with PDAC. Further research, including a future multicenter randomized controlled study, is warranted to systematically evaluate the efficacy and safety of this adjusted strategy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-274/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-274/prf

Funding: This study was partially supported by the Science and Technology Projects in Guangzhou (No. 2024A03J1016) and the Guangdong Medical Science and Research Foundation (No. A2024088).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-274/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the Research Ethics Committee of Guangzhou First People’s Hospital, Guangzhou, China (approval No. F-2024-005-01) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Han B, Zheng R, Zeng H, et al. Cancer incidence and mortality in China, 2022. J Natl Cancer Cent 2024;4:47-53. [Crossref] [PubMed]
2. Zeng H, Chen W, Zheng R, et al. Changing cancer survival in China during 2003-15: a pooled analysis of 17 population-based cancer registries. Lancet Glob Health 2018;6:e555-67. [Crossref] [PubMed]
3. Zhao Y, Tan HL, Chua DW, et al. Surgery and neoadjuvant therapy in locally advanced pancreatic cancer: an umbrella review of survival, resection outcomes, and cost-effectiveness. Gland Surg 2025;14:529-42. [Crossref] [PubMed]
4. Chen J, Wang D, Xiong F, et al. Pathological complete response following neoadjuvant chemotherapy with PD-1 inhibitor for locally advanced pancreatic cancer: case report. J Gastrointest Oncol 2024;15:2692-705. [Crossref] [PubMed]
5. General Office of National Health Commission. Standard for diagnosis and treatment of pancreatic cancer (2022 edition). J Clin Hepatol 2022;38:1006-15.
6. Ueno H, Ioka T, Ikeda M, et al. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol 2013;31:1640-8. [Crossref] [PubMed]
7. Sakuma K, Hosoya Y, Arai W, et al. Alternate-day treatment with S-1 in patients with gastric cancer: a retrospective study of strategies for reducing toxicity. Int J Clin Oncol 2010;15:166-71. [Crossref] [PubMed]
8. Tsoris A, Marlar CA. Use Of The Child Pugh Score In Liver Disease. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025.
9. Yamaue H, Satoi S, Kanbe T, et al. Phase II clinical study of alternate-day oral therapy with S-1 as first-line chemotherapy for locally advanced and metastatic pancreatic cancer. Cancer Chemother Pharmacol 2014;73:97-102. [Crossref] [PubMed]
10. Yamaue H, Shimizu A, Hagiwara Y, et al. Multicenter, randomized, open-label Phase II study comparing S-1 alternate-day oral therapy with the standard daily regimen as a first-line treatment in patients with unresectable advanced pancreatic cancer. Cancer Chemother Pharmacol 2017;79:813-23. [Crossref] [PubMed]
11. Ishikawa T, Kawashima H, Ohno E, et al. Randomized Phase II Study of Consecutive-Day versus Alternate-Day Treatment with S-1 as Second-Line Chemotherapy in Advanced Pancreatic Cancer. Oncology 2019;96:1-7. [Crossref] [PubMed]
12. Akahori T, Sho M, Yanagimoto H, et al. Phase II Study of the Triple Combination Chemotherapy of SOXIRI (S-1/Oxaliplatin/Irinotecan) in Patients with Unresectable Pancreatic Ductal Adenocarcinoma. Oncologist 2019;24:749-e224. [Crossref] [PubMed]
13. Wang F, Wang Y, Ren C, et al. Phase II study of SOXIRI (S-1/oxaliplatin/irinotecan) chemotherapy in patients with unresectable pancreatic ductal adenocarcinoma. Pancreatology 2024;24:241-8. [Crossref] [PubMed]
14. Yanagimoto H, Satoi S, Sho M, et al. Phase I study assessing the feasibility of the triple combination chemotherapy of SOXIRI (S-1/oxaliplatin/irinotecan) in patients with unresectable pancreatic ductal adenocarcinoma. Cancer Chemother Pharmacol 2016;77:35-41. [Crossref] [PubMed]
15. Pathak P, Weekes C. Need of the hour—advancements in treatment of pancreatic cancer. AME Clin Trials Rev 2024;2:109.
16. Nakamura K, Yamaguchi T, Ishihara T, et al. Phase II trial of oral S-1 combined with gemcitabine in metastatic pancreatic cancer. Br J Cancer 2006;94:1575-9. [Crossref] [PubMed]
17. Hamada C, Okusaka T, Ikari T, et al. Efficacy and safety of gemcitabine plus S-1 in pancreatic cancer: a pooled analysis of individual patient data. Br J Cancer 2017;116:1544-50. [Crossref] [PubMed]