Research ArticleOriginal Article

Clinical outcomes of second-line chemotherapy in patients with advanced pancreatic adenocarcinoma: a real-world study

Yuxiao Liu, Xiaofan Guo, Peijun Xu, Yuning Song, Jing Huang, Xingyun Chen, Wenbo Zhu, Jihui Hao and Song Gao
Cancer Biology & Medicine July 2024, 20240036; DOI: https://doi.org/10.20892/j.issn.2095-3941.2024.0036

Abstract

Objective: Little progress has been made in recent years using first-line chemotherapy, including gemcitabine combined with nab-paclitaxel, FOLFIRINOX, and NALIRIFOX, for advanced pancreatic adenocarcinoma (APC). In addition, the optimal second-line chemotherapy regimen has not been determined. This study aimed to compare the effectiveness of different types of second-line chemotherapy for APC.

Methods: Patients with APC who received first-line treatment from January 2008 to January 2021 were considered eligible for this retrospective analysis. The primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS), respectively.

Results: Four hundred and thirty-seven and 617 patients were treated with 5-fluorouracil- and gemcitabine-based chemotherapy as first-line treatment, respectively. Demographic and clinical features, except age and liver metastasis, were comparable between the two groups (P < 0.05). The median OS was 8.8 and 7.8 months in patients who received a 5-fluorouracil- and gemcitabine-based combined regimen for first-line therapy, respectively (HR = 1.244, 95% CI = 1.090–1.419; P < 0.001). The median OS was 5.6 and 1.9 months in patients who received second-line chemotherapy and supportive care, respectively (HR = 0.766, 95% CI = 0.677–0.867; P < 0.001). The median PFS was not significantly differently between gemcitabine or 5-fluorouracil monotherapy and combination therapy.

Conclusions: A 5-fluorouracil- or gemcitabine-based combined regimen was shown to be as effective as a single 5-fluorouracil or gemcitabine regimen as second-line therapy for patients with APC.

keywords

Introduction

The 5-year overall survival (OS) of patients with pancreatic cancer was 12% in 20231,2. The prognosis of advanced pancreatic adenocarcinoma (APC) is poor. The current first-line chemotherapy regimens for patients with APC include irinotecan (IRI), oxaliplatin, leucovorin, and 5-fluorouracil (5-FU) (FOLFIRINOX), liposomal irinotecan (nal-IRI)3, oxaliplatin, leucovorin (LV), and 5-FU (NALIRIFOX4,5), gemcitabine (Gem) plus albumin-bound (nab) paclitaxel (AG6), or Gem plus S-1 (GS7). Most patients undergo disease progression due to chemotherapy resistance. Patients receive different treatment regiments based on their physical condition8. In most cases, patients treated with 5-FU-based regimen receive AG, although the evidence is limited9-13. Single-agent treatments, such as Gem or capecitabine, may be used to treat patients with a poor Eastern Cooperative Oncology Group (ECOG) performance score. Patients who fail to respond to Gem-based treatment would receive a 5-FU-based combined regimen, such as modified (m) FOLFIRINOX14,15, NALIRIFOX16, 5-FU, LV, and IRI (FOLFIRI17,18), 5-FU, LV, and nal-IRI (NALIRI19-21), or LV, 5-FU, and oxaliplatin (FOLFOX22,23).

The PANCREOX trial showed that median OS was inferior in patients assigned to the mFOLFOX6 compared to the 5-FU/LV group (6.1 months vs. 9.9 months; P = 0.02) who received prior first-line treatment with Gem24. The NAPOLI-1 study16 proved that patients who did not respond to Gem-based treatment and were given NALIRI had prolonged OS compared to patients who received 5-FU/LV therapy [median OS = 6.1 months vs. 4.2 months, hazard ratio (HR) = 0.67; P = 0.012]. The U.S. Food and Drug Administration (FDA) approved nal-IRI as second-line therapy for treatment of patients with metastatic pancreatic cancer after progression following Gem-based therapy in October 2015. The MPACA-3 study25 demonstrated that the mFOLFIRINOX group exhibited superior survival compared to the S-1 monotherapy group (P < 0.05), irrespective of OS and progression-free survival (PFS). The efficacy of other second-line treatments has also been investigated in several real-world studies. For example, a retrospective multicenter observational study from Korea26 included 378 patients with APC who received nal-IRI plus 5-FU/LV or FOLFIRINOX as second-line therapy. However, the results showed no significant difference in survival outcomes and overall response rates. In the subgroup analysis, the median OS of the nal-IRI plus 5-FU/LV group was significantly longer than the FOLFIRINOX group among patients > 70 years of age (10.4 months vs. 9.5 months, HR = 3.20, 95% CI = 1.28–8.02; P = 0.013). In contrast, the FOLFIRINOX group had a better OS than the nal-IRI+5-FU/LV group among patients < 70 years of age (9.8 months vs. 6.6 months, HR = 0.60, 95% CI = 0.40–0.88; P = 0.01). In addition, the FOLFIRINOX group had more grade 3 or higher adverse events than the nal-IRI+5-FU/LV group but nal-IRI was more expensive. Another study17 reported that the FOLFIRI group had a superior median OS than the FOLFOX group (9 months vs. 5 months; P < 0.01), although the sample size was small.

No clear consensus has been established to date on the best second-line regimen for patients with metastatic pancreatic cancer who have failed first-line chemotherapy27. We previously conducted a real-world, single-center, retrospective analysis to assess and compare the effectiveness of different chemotherapy regimens as second-line treatment for patients with APC after progression following initial treatment.

Materials and methods

Study population

We reviewed patients with APC, including locally advanced pancreatic cancer and metastatic pancreatic cancer, who were treated with first-line chemotherapy between January 2008 and January 2021. The inclusion criteria were as follows: confirmed pancreatic adenocarcinoma based on cytologic or histopathologic findings; and patients with APC, including liver, lung, bone, and peritoneal metastases, who received first-line regimens (5-FU- or Gem-based therapy) and measurable lesions confirmed by computed tomography (CT) or magnetic resonance imaging (MRI). The exclusion criteria were as follows: incomplete medical records; incomplete pathologic and radiologic information; no chemotherapy; and no 5-FU- or Gem-based first-line chemotherapy. This study was approved by the Ethics Committee of Tianjin Medical University Cancer Institute & Hospital (Approval No. bc2024001).

Treatments and outcomes

The chemotherapy regimen choice was based on the physician’s assessment of the patient’s physical condition as well as the tumor burden. The second-line Gem- or 5-FU-based regimens were administered until disease progression or discontinued due to patient’s will or death. Tumor response evaluation was evaluated by CT or MRI in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary endpoint was OS, which is defined as the time from diagnosis of APC to any cause of death. The second endpoint was PFS, which is defined as the time from receiving second-line chemotherapy to disease progression or any cause of death, whichever occurred first.

Statistical analysis

The characteristics of patients were evaluated using Pearson’s chi-squared test and Wilcoxon rank-sum test. OS and PFS were analyzed using the Kaplan–Meier method and log-rank test. Univariate Cox proportional hazard analysis was used to evaluate the effect of clinicopathologic factors on OS and PFS. Multivariate Cox proportional hazard analysis was used to assess the impact of clinicopathologic factors on OS. The following variables were evaluated: age (> 63 years vs. ≤ 63 years); gender (female vs. male); location (head vs. body site other than the head); metastatic lesion size (> 4 cm vs. ≤ 4 cm); ECOG (≥ 3 vs. 0–2); primary tumor size (> 4 cm vs. ≤ 4 cm); distant metastasis (yes vs. no); chemotherapy (single 5-FU or Gem vs. combined regimen); and metastatic lesion site (liver, lung, bone, peritoneal, and lymph node metastases). All statistical analyses were performed with R for Windows (version 4.3.2). A P < 0.05 was considered statistically significant.

Results

Patient characteristics

We reviewed the medical records of 1,368 patients with locally advanced or metastatic pancreatic adenocarcinoma who were treated with chemotherapy or 5-FU- or Gem-based first-line chemotherapy between January 2008 and January 2021. Patients who did not receive chemotherapy, or 5-FU- or Gem-based first-line chemotherapy and patients lacking clinical and imaging information to evaluate efficacy were excluded. Therefore, 1,054 patients with APC treated at Tianjin Medical University Cancer Institute & Hospital were included in the current study. The flow chart is shown in Figure 1. The demographics and disease characteristics are shown in Table 1. A total of 437 patients were treated with 5-FU-based first-line therapy, 46.9% of whom were female. Moreover, 617 patients were treated with Gem-based first-line therapy, 43.3% of whom were female. Patients in the Gem-based first-line therapy group were younger than the 5-FU-based first-line therapy group {≤ 63 years of age [n = 215 (49.2%)] vs. [n = 359 (58.2%)] and > 63 years of age [n = 222 (50.8%)] vs. [n = 258 (41.8%)]; P = 0.005}. Primary tumors were mainly located with the head of the pancreas in the Gem- and 5-FU-based first-line therapy group [296 (67.7%) vs. 401 (65%)]. Metastatic lesion size was 2.99 cm in the 5-FU-based first-line therapy group compared to 3.11 cm in the Gem-based first-line therapy group (P = 0.145). There was no significant difference in the ECOG performance status of patients who received 5-FU- and Gem-based first-line therapy (ECOG 0–2, 79.9% vs. 76.0%; ECOG ≥ 3, 20.1% vs. 24.0%; P = 0.161). No difference was detected in patients with distant metastases between the 2 groups (90.8% vs. 90.8%; P > 0.999). In our institution 5-FU-based second-line chemotherapy included single 5-FU, FOLFIRINOX, FOLFIRI, NALIRI, and FOLFOX, and Gem-based second-line chemotherapy included AG, Gem plus cyclophosphamide (GC), single Gem, Gem plus oxaliplatin (GEMOX), and Gem plus S-1 (GS). Two hundred and sixty-four (39.6%), 134 (10.7%), 101 (23.1%), 52 (11.9%), and 165 (37.8%) patients in the 5-FU-based first-line therapy group had liver, lung, peritoneum, bone, and lymph node metastases, respectively. The best efficacy evaluation for progressive disease (PD), partial response (PR), and stable disease (SD) were 116 (26.5%), 44 (10.1%), and 277 (63.4%) in the 5-FU-based first-line therapy patients who received the entire course of therapy. Four hundred and sixteen (67.4%), 180 (29.2%), 149 (24.1%), 69 (11.2%), and 254 (41.2%) had liver, lung, peritoneum, bone, and lymph node metastases in the Gem-based regimen first-line therapy group, respectively. The best efficacy evaluation for PD, PR, and SD were 177 (28.7%), 61 (9.9%), and 379 (61.4%) in the Gem-based regimen for first-line therapy patients who received the entire course of therapy. The clinical and pathologic characteristics of patients treated with single and combined regimens were assessed for the Gem- and 5-FU-based second-line therapy subgroups, as shown in Table 2. There were no significant differences in the baseline characteristics between the two subgroups.

Figure 1
Figure 1

Flow chart.

View this table:
Table 1

Patients’ characteristics

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Table 2

Baseline characteristics of different second-line therapy subgroups

First-line chemotherapy failure outcomes

The median OS was 6.6 months in the 5-FU combined and single regimen groups (log-rank, P = 0.631). The 5-FU combined regimen group had a similar PFS to the single 5-FU group [2.8 months vs. 2.7 months; P = 0.304 (log-rank)]. The median OS was 5.0 months in the Gem-based combined regimen group and 4.0 months in the single Gem group [P = 0.064 (log-rank)]. The median PFS was not statistically different between the Gem combined and single Gem regimen groups [2.6 months vs. 2.1 months; P = 0.068 (log-rank); Figure 2].

Figure 2
Figure 2

Kaplan–Meier curves for OS and PFS. (A) OS of 5-fluorouracil combined regimen group vs. single 5-fluorouracil group for second-line therapy. (B) OS of Gem-based combined regimen group vs. single Gem group for second-line therapy. (C) PFS of 5-fluorouracil combined regimen group vs. single 5-fluorouracil group for second-line therapy. (D) PFS of Gem-based combined regimen group vs. single Gem group for second-line therapy.

The median OS [5.7 months vs. 5.3 months; P = 0.298 (log-rank)] and PFS [2.7 months vs. 2.6 months; P = 0.098 (log-rank)] indicated that no significant differences existed between patients who received a combined regimen compared with single 5-FU/single Gem (Figure 3).

Figure 3
Figure 3

Kaplan–Meier curves for OS and PFS. (A) OS of combined regimen group vs. single 5-fluorouracil/single Gem group for second-line therapy. (B) PFS of combined regimen group vs. single 5-fluorouracil/single Gem group for second-line therapy.

It is noteworthy that the median OS was 8.8 and 7.8 months in the 5-FU- and Gem-based regimen first-line therapy groups, respectively (HR =1.244, 95% CI = 1.090–1.419; P < 0.001). The median OS was 5.6 and 1.9 months in the second-line chemotherapy and supportive care only groups, respectively (HR = 0.766, 95% CI = 0.677–0.867; P < 0.001; Figure 4).

Figure 4
Figure 4

Kaplan–Meier curves for OS. (A) OS of 5-fluorouracil-based regimen vs. Gem-based regimen group for first-line therapy. (B) OS of receiving second-line chemotherapy group vs. supportive care only group.

We performed univariate analysis on all available clinical factors. No differences in PFS were detected based on age (> 63 years vs. ≤ 63 years: HR = 1.033, 95% CI = 0.889–1.200; P = 0.675), gender (female vs. male: HR = 0.925, 95% CI = 0.797–1.075; P = 0.310), location (pancreatic head vs. pancreas other than the pancreatic head: HR = 1.002, 95% CI = 0.856–1.172; P = 0.984), liver metastasis (yes vs. no: HR = 1.073, 95% CI = 0.921–1.249; P = 0.368), lung metastasis (yes vs. no: HR = 0.900, 95% CI = 0.763–1.063; P = 0.214), bone metastasis (yes vs. no: HR = 0.998, 95% CI = 0.779–1.279; P = 0.987), peritoneal metastasis (yes vs. no: HR = 1.003, 95% CI = 0.836–1.202; P = 0.976), lymph node metastasis (yes vs. no: HR = 1.125, 95% CI = 0.965–1.311; P = 0.133), primary tumor size (> 4 cm vs. ≤ 4 cm: HR = 1.026, 95% CI = 0.884–1.191; P = 0.738), and metastatic lesion size (> 4 cm vs. ≤ 4 cm: HR = 0.928, 95% CI = 0.799–1.079; P = 0.332). ECOG performance status (≥ 3 vs. 0–2: HR = 2.361, 95% CI = 1.627–3.427; P < 0.001)28, distant metastasis (yes vs. no: HR = 1.296, 95% CI = 1.031–1.631; P = 0.026), and CA19-9 (> 200 U/mL vs. ≤ 200 U/mL: HR = 1.328, 95% CI = 1.140–1.546; P < 0.001)29 were factors associated with poor PFS based on univariate Cox regression analyses.

ECOG performance status (≥ 3 vs. 0–2: HR = 5.355, 95% CI = 4.555–6.296; P < 0.001), distant metastasis (yes vs. no: HR = 1.692, 95% CI = 1.371–2.089; P < 0.001), CA19-9 (> 200 U/mL vs. ≤ 200 U/mL: HR = 1.372, 95% CI = 1.212–1.552; P < 0.001), treatment (supportive care only vs. receiving chemotherapy; HR = 5.416, 95% CI = 4.624–6.344; P < 0.001)28,29, liver metastasis (yes vs. no: HR = 1.362, 95% CI = 1.199–1.546; P < 0.001), and lymph node metastasis (yes vs. no: HR = 1.136, 95% CI = 1.004–1.286; P = 0.044) were relative with poor OS (Figure 5). In addition, age (> 63 years vs. ≤ 63 years: HR = 1.102, 95% CI = 0.976–1.245; P = 0.116), gender (female vs. male: HR = 0.955, 95% CI = 0.846–1.078; P = 0.457), location (pancreatic head vs. pancreas other than the pancreatic head: HR = 1.034, 95% CI = 0.910–1.175; P = 0.607); primary tumor size (> 4 cm vs. ≤ 4 cm: HR = 1.075, 95% CI = 0.953–1.213; P = 0.241), metastatic lesion size (> 4 cm vs. ≤ 4 cm: HR = 1.081, 95% CI = 0.957–1.220; P = 0.211), lung metastasis (yes vs. no: HR = 1.038, 95% CI = 0.909–1.184; P = 0.582), bone metastasis (yes vs. no: HR = 1.165, 95% CI = 0.964–1.409; P = 0.115), and peritoneal metastasis (yes vs. no: HR = 1.138, 95% CI = 0.987–1.312; P = 0.075) were not independently associated with OS.To determine risk factors affecting the OS of patients treated with second-line therapy we conducted univariate and multivariate Cox regression analyses on the entire cohort (Table 3). By incorporating relevant univariate risk factors into the multivariate analyses of the entire cohort first-line treatment with Gem-based therapy (Gem-based vs. 5-FU-based: HR = 1.428, 95% CI = 1.261–1.621; P < 0.001), distant metastasis (yes vs. no: HR = 1.533, 95% CI = 1.240–1.895; P < 0.001), liver metastasis (yes vs. no: HR = 1.235, 95% CI = 1.085–1.406; P = 0.001), and CA19-9 (> 200 U/mL vs. ≤ 200 U/mL: HR = 1.304, 95% CI = 1.151–1.477; P < 0.001) were shown to be independent risk factors for OS. Second-line chemotherapy (receiving chemotherapy vs. supportive care only: HR = 0.232, 95% CI = 0.149–0.361; P < 0.001) was an independent protective factor for OS. Therefore, our data suggested that even though patients treated with different first-line regimens had differences in clinical baseline levels, the treatment pattern of 5-FU-based first-line therapy followed by Gem-based second-line therapy significantly improved OS.

Figure 5
Figure 5

Forest plot of PFS (A) and OS (B).

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Table 3

Univariate and multivariate Cox regression analyses for OS in the entire cohort

Discussion

Patients with APC encounter challenges in treatment due to the limited availability of effective therapeutic options. Despite notable advances in survival rates using the current first-line treatment regimens (FOLFIRINOX and AG), as recommended by the NCCN guidelines, approximately 50% of patients still have PD within 6 months. This finding is attributed to primary and secondary drug resistance to chemotherapy. Given the constrained treatment alternatives, enrollment in clinical trials is highly recommended for patients with APC. However, first-line chemotherapy remains the only available option for patients residing in centers unable to conduct or participate in clinical trials, as well as patients who are ineligible for clinical trials. Nonetheless, considerable controversy exists regarding the selection of second-line treatment for patients who progress after first-line therapy or discontinue first-line chemotherapy for other reasons. For patients who do not meet the enrollment criteria for clinical trials, the implementation of a rational second-line chemotherapy regimen represents the only option to extend survival. Based on real-world data from our center, we concluded regardless of the chemotherapy regimen used, patients can achieve a survival benefit compared to patients receiving supportive are. Indeed, a significant number of patients benefit from chemotherapy as second-line treatment. In contrast, patients who receive life support only and have a lower ECOG performance status at the start of treatment understandably have a poor prognosis. Therefore, when patients receive first-line treatment, clinicians who have difficulty in ensuring that the current treatment is effective should focus on maintaining the patients’ physical status and reducing treatment-related adverse reactions to ensure that the patients receive subsequent treatment. For patients treated with Gem-based chemotherapy as first-line regimen, 5-FU-based chemotherapy is often preferred as a second-line regimen. For patients who received a 5-FU-based chemotherapy regimen as first-line regimen, Gem and its combination regimens are the main options for second-line chemotherapy. Patients treated with chemotherapy as a second-line intervention may derive benefits from this approach. However, patients receiving life support only have lower ECOG performance status initially, which could contribute to an unfavorable prognosis. Consequently, when administering first-line treatment, clinicians who encounter challenges in ensuring treatment efficacy should prioritize maintaining a patients’ physical condition and minimizing treatment-related adverse events to preserve the option for subsequent therapies.

Previous studies have demonstrated that combination chemotherapy regimen improves the survival benefit among patients with APC30,31. The findings of the Metastatic Pancreatic Cancer Trial (MPACT) revealed an median OS advantage of Gem combined with nab-paclitaxel compared to single Gem (8.5 months vs. 6.7 months: HR = 0.72, 95% CI = 0.62–0.83; P < 0.001)31. Similarly, in the PRODIGE trial, which involved 342 patients with untreated metastatic pancreatic ductal adenocarcinoma (PDAC), concluded that the FOLFIRINOX regimen yielded superior mean survival outcomes compared with Gem (11.1 months vs. 6.8 months: HR = 0.57, 95% CI = 0.45–0.73; P < 0.001)30. In a subset of 417 patients with metastatic PDAC who were initially treated with Gem and had PD, the NAPOLI-1 trial revealed that the combination of nano-nal-IRI, 5-FU, and LV resulted in a more favorable OS compared to the combination of 5-FU and LV, with a median OS of 6.1 months. This finding was notably superior to the median OS of 4.2 months achieved with a 5-FU and LV combination (HR = 0.67, 95% CI = 0.49–0.92; P = 0.012)32. Previous studies have demonstrated a survival advantage resulting from the utilization of AG as a secondary treatment following initial treatment with FOLFIRINOX11,33-35. Moreover, (m)FOLFIRINOX can serve as a second-line regimen for PD after AG therapy36-38. However, based on real-world data from our center, no significant differences in PFS or OS were observed between patients treated with single Gem or 5-FU and patients treated with other chemotherapy agents. First, in the real world, many patients face challenges in achieving the performance status of patients enrolled in clinical trials. Consequently, numerous patients receiving combination therapy in second-line treatment discontinue treatment due to treatment-related adverse events and poor performance status. In contrast, patients undergoing single-agent maintenance therapy tend to maintain treatment for longer periods, which might be the primary reason for the lack of survival benefit in patients treated with combination therapy. Second, the current combination regimens are not optimally effective for patients receiving second-line therapy. It is difficult to achieve a survival benefit in patients with advanced disease treated with combination therapy given the challenges in controlling tumor progression with the existing regimens. Finally, the results in the real world may vary from the conclusions drawn from clinical trials due to the stringent inclusion and exclusion criteria of clinical trials. In the current study the second-line chemotherapy group had superior OS compared to the supportive care only group (5.6 months vs. 1.9 months: HR = 0.766, 95% CI = 0.677–0.867; P < 0.001), which is consistent with the findings of the German CONKO study39. Several studies have shown no significant difference in the efficacy of AG and (m)FOLFIRINOX regimens as first-line regimens for APC30,31. Shi et al.40 reported that a high strain ratio (SR) obtained by endoscopic ultrasound elastography is associated with poor prognosis in resected pancreatic cancer but predicted improved survival in patients treated with the AG regimen. Pijnappel et al.41 showed that Gem combined with nab-paclitaxel treatment led to a significantly inferior OS compared to FOLFIRINOX as first-line therapy (4.7 months vs. 6.6 months: HR = 1.20, 95% CI = 1.02–1.41; P < 0.001) based on the Netherlands Cancer Registry (NCR). The results from our center showed that OS was significantly longer in patients treated with a 5-FU-based regimen than patients treated with a Gem-based regimen as first-line therapy and are consistent with previous findings41,42. This phenomenon is mainly due to differences in the tolerability of second-line regimens. Patients who progress after a 5-FU first-line regimen and are treated with Gem and its combination regimen as second-line therapy often receive longer maintenance therapy cycles. However, patients who progress after first-line treatment with Gem had poor tolerance to 5-FU and its combination. This phenomenon is associated with poor ECOG performance status after first-line treatment. Therefore, patients should be preferentially treated with (m)FOLFIRINOX or NALIRIFOX at the start of first-line therapy to provide more options for later lines of therapy unless there is evidence regarding the survival benefit from Gem or albumin-bound paclitaxel, or if 5-FU toxicity is intolerable. Liang et al.43 proposed that Ki-67 is a valuable prognostic indicator for PDAC and inclusion of the grade of malignancy (GOM) in the TNM staging system may potentially enhance prognostic accuracy for PDAC, which should be useful in choosing the optimal chemotherapy regimen. In addition, Zhou et al.44 proposed a new model of immune-CD8+ T lymphocytes, CD133+ cancer stem cells, and tumor budding (CSC-TB) for accurately predicting prognosis for patients with PDAC. Patients are treated with immune checkpoint inhibitor combined chemotherapy regimen in our center but the sample size was small. An immunotherapy regimen can remodel the tumor microenvironment by tumor infiltration of the accumulated effector CD8+T cells45. However, a single immunotherapy regimen failure in the clinical trial46 may have been due to an immunomodulatory effect by chemotherapy such that Gem-based chemotherapy depleted immunosuppressive Tregs47 and myeloid-derived suppressor cells (MDSCs). Another study48 showed that the combination of chemotherapy and immunotherapy had similar advert effects to chemotherapy alone and that some patients had a durable overall response rate. Orsi et al.49 reported that patients with PDAC with germline BRCA1-2 pathogenic variants treated with a platinum-based regimen second-line therapy had prolonged survival. Unfortunately, it was shown that MUC5AC antibody (NPC-1C) as targeted therapy administered with second-line Gem and nab-paclitaxel compared with Gem and nab-paclitaxel alone did not improve survival in patients with advanced PDAC who failed first-line FOLFIRINOX50, although the preclinical evidence is promising51,52. The combination of chemotherapy, immunotherapy, and targeted therapy will be expected to prolong OS for patients in the future53,54.

Conclusions

The findings from our center, which are based on real-world data, demonstrated no significant difference in PFS and OS between single Gem or 5-FU or combined therapies in the second-line treatment for patients with APC. We recommend enrolling such patients in a clinical trial upon progression after first-line therapy. Single-agent maintenance chemotherapy is advised for individuals for whom treatment discontinuation may result from the inability to mitigate the toxic effects of a combination regimen.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Author contributions

Conceived and designed the analysis: Jihui Hao, Song Gao.

Collected the data: Yuxiao Liu, Xiaofan Guo, Yuning Song, Jing huang, Xingyun Chen.

Contributed data or analysis tools: Yuxiao Liu, Xiaofan Guo, Wenbo Zhu.

Performed the analysis: Yuxiao Liu, Xiaofan Guo, Yuning Song.

Wrote the paper: Yuxiao Liu, Xiaofan Guo, Peijun Xu.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Footnotes

  • ↵*These authors contributed equally to this work.

  • Received January 19, 2024.
  • Accepted April 2, 2024.
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