Efficacy of second-line treatment for gemcitabine-refractory unresectable pancreatic cancer in a real-world setting

Abstract

Background

This study aimed to compare the benefits and identify the best second-line treatment regimen for gemcitabine-refractory unresectable pancreatic cancers.

Patients and methods

This retrospective analysis included 144 patients with unresectable pancreatic cancer who underwent a gemcitabine-based regimen as the first-line treatment. 57, 37, and 50 patients received oxaliplatin-, irinotecan-based, and modified FOLFIRINOX (mFFX) regimens, respectively. The primary endpoint of this study was progression-free survival (PFS) and the secondary endpoints were overall survival (OS), response rate, and treatment-related toxicity.

Results

There were no significant differences in median PFS (mPFS) (4.6 months vs. 2.9 months, P = 0.627, HR = 1.128, 95%CI 0.693–1.836) and median OS (mOS) (6.5 months vs. 10.2 months, P = 0.108, HR = 0.664, 95%CI 0.392–1.125) between irinotecan- and oxaliplatin-based groups. The mOS was significantly longer in the mFFX group than in the Iri/Oxa group (pooled the irinotecan- and oxaliplatin-based groups) (10.7 months vs. 8.8 months, P = 0.035, HR = 1.560, 95%CI 1.037–2.347), whereas no statistical difference was observed in mPFS between the two groups (4.4 months vs. 4.2 months, P = 0.222, HR = 1.247, 95%CI 0.866–1.797). However, after propensity score matching adjustment, no significant differences were found in mPFS (3.5 months vs. 4.2 months, P = 0.290, HR = 0.763, 95%CI 0.448–1.297) and mOS (8.5 months vs. 12.4 months, P = 0.464, HR = 1.262, 95%CI 0.673–2.367) between mFFX and Iri/Oxa groups. Survival analysis by performance status showed that patients with good performance status lived longer than those with poor performance status (10.8 months vs. 7.7 months, P = 0.000, HR = 2.194, 95%CI 1.408–3.420), suggesting that patient performance status, rather than the treatment regimen, was the primary factor affecting overall survival during second-line treatment.

Conclusions

In the second-line treatment of pancreatic cancer, the efficacy of common treatment regimens is not significantly different, while a good performance status is the key factor influencing survival. Thus, it is recommended that supportive care be enhanced concurrently with systemic therapy in patients with pancreatic cancer.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12885-025-14601-2.

Introduction

Pancreatic cancer remains one of the most aggressive malignancies, posing a formidable challenge to global oncology. By 2024, epidemiological projections indicate that this disease will surpass previous estimates to become the third leading cause of cancer-related mortality worldwide [1]. Clinical patterns reveal that approximately 80% of patients present with either metastatic dissemination or locally advanced disease at initial diagnosis [2, 3], significantly limiting therapeutic options. The prognosis remains dismal, with population-based studies demonstrating an aggregate 5-year survival rate of merely 6–10% [4]. Of note, patients with metastatic involvement exhibit particularly grave outcomes, with a 5-year survival probability of less than 2% [5].

Since 1997, when a pivotal study by Burris et al. reported improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreatic cancer, gemcitabine-based chemotherapies have become the first-line standard of care for metastatic pancreatic cancer over the past two decades [6–8]. Although prior studies have confirmed that FOLFIRINOX (FFX) confers a survival advantage over gemcitabine in metastatic pancreatic cancer, this is accompanied by increased toxicity, limiting its use to patients with good performance status (PS) [9]. The latest study also confirmed that the NALIRIFOX regimen as the first-line treatment can prolong the survival of patient compared to nab-paclitaxel plus gemcitabine, leading to its recommendation as the preferred regimen in the NCCN guidelines for metastatic pancreatic cancer [10]. Notwithstanding, gemcitabine-based chemotherapies remain the cornerstone of advanced pancreatic cancer, particularly for patients with intermediate PS, and nab-paclitaxel combined with gemcitabine or gemcitabine monotherapy are still the preferred regimens for first-line treatment.

Numerous second-line therapies have demonstrated survival benefits in patients with gemcitabine-refractory unresectable pancreatic cancer [11–13]. A randomized controlled trial (RCT) conducted by Helmut et al. confirmed that OFF (oxaliplatin, folinic acid, and fluorouracil) as a second-line treatment for gemcitabine-refractory unresectable pancreatic cancer could significantly extend the duration of overall survival [3]. Another RCT study, NAPOLI-1 which made a splash, suggested that nanoliposomal irinotecan in combination with fluorouracil and folinic acid as second-line therapy extends survival in patients with metastatic pancreatic cancer previously treated with gemcitabine-based regimens [11]. Consistent results were observed in the PAN-HEROIC-1 study, demonstrating the superior efficacy of nanoliposomal irinotecan as a second-line therapy for patients with pancreatic cancer [14]. Following the two RCTs, the clinical benefits of nanoliposomal irinotecan in significantly improving overall survival and progression-free survival have been further validated in a meta-analysis of both RCTs and real-world studies [15]. Notably, before 2023, nanoliposomal irinotecan was not commercially available in China, and despite being the standard second-line therapy after gemcitabine-based therapy, it is still not clinically available. Moreover, the high price of nanoliposomal irinotecan limits its clinical application. If nanoliposomal irinotecan is unavailable, irinotecan is a suitable alternative. So the choice of oxaliplatin-based (oxaliplatin, folinic acid, and fluorouracil or oxaliplatin and oral fluoropyrimidine) or irinotecan-based (irinotecan, folinic acid, and fluorouracil or irinotecan and oral fluoropyrimidine) regimens as second-line treatment remains difficult. Meanwhile, modified FOLFIRINOX (mFFX) remains a good option for patients with a good PS. Therefore, the preferred choice of second-line chemotherapy regimen for gemcitabine-refractory pancreatic cancer patients remains uncertain. Thus, we conducted a retrospective analysis of second-line treatment in patients with pancreatic cancer who had previously received gemcitabine-based therapy, aiming to compare the efficacy of different second-line treatment regimens in the real world and provide evidence for optimizing second-line treatment in advanced pancreatic cancer.

Patients and methods

Patients

This retrospective cohort study enrolled patients with advanced pancreatic cancer who received treatment at the First Affiliated Hospital of Nanjing Medical University Pancreas Center and BenQ Pancreas Center Affiliated of Nanjing Medical University. All patients with advanced pancreatic cancer were histologically confirmed and experienced progression during first-line gemcitabine-based chemotherapy. We systematically reviewed the electronic medical records of consecutive patients with metastatic or recurrent pancreatic cancer who began gemcitabine-based therapy as first-line chemotherapy between November 2020 and March 2024. Electronic medical records were consulted to extract the date of death and patient-specific information, including age, sex, date of diagnosis, extent of disease at the first visit, and tumor progression during first-line chemotherapy. In patients with generalized disease, the number of metastatic sites was assessed, and metastases to distant lymph nodes, liver, lung, and bone were regarded as different sites. The study was conducted in accordance with the Declaration of Helsinki, and all patients included in the study provided written informed consent before the initial treatment.

Treatment

All patients included in this study had previously received gemcitabine-based first-line chemotherapy, including nab-paclitaxel combined with gemcitabine, gemcitabine monotherapy, and gemcitabine combined with oxaliplatin therapy. In the case of confirmed disease recurrence or metastasis during adjuvant treatment or at the first follow-up 6 months postoperatively, the given regimen was regarded as first-line chemotherapy. Second-line treatment was initiated after disease progression was identified with gemcitabine-based first-line therapy, and patients included in this study received mFFX, oxaliplatin-based, or irinotecan-based second-line therapies. Oxaliplatin-based therapy regimens include SOX (oxaliplatin and S-1), CapeOx (oxaliplatin and capecitabine), and FOLFOX (oxaliplatin, fluorouracil and folinic acid), whereas irinotecan-based therapy regimens include FOLFIRI (irinotecan, fluorouracil and folinic acid) and S-1 combined with irinotecan. It is worth noting that in this study, irinotecan-based treatment did not include nanoliposomal irinotecan. Although nanoliposomal irinotecan has been marketed in the Chinese mainland since August 2023, and some patients with advanced pancreatic cancer have received nanoliposomal irinotecan treatment, to maintain consistency in the study, patients using nanoliposomal irinotecan as first-line or second-line therapy for advanced pancreatic cancer were excluded. After 6 months of chemotherapy, S-1, capecitabine, or FOLFIRI were administered as maintenance therapies. Treatment was continued until progressive disease (PD), unacceptable toxicity, or refusal of chemotherapy occurred.

Assessment of efficacy and adverse events

The primary endpoint of this retrospective study was progression-free survival (PFS), defined as the duration from the start of treatment to disease progression, death from any cause, or the last follow-up without disease progression. The secondary endpoints were overall survival (OS), response rate, and treatment-related toxicity. OS was defined as the time from the start of second-line treatment to death or the follow-up deadline, whichever occurred first. The tumor response rate was expressed as the objective response rate (ORR) and the disease control rate (DCR). RECIST 1.1 was used to evaluate the tumor response. Tumor response assessments were conducted through CT or MRI scans performed at 12-week intervals during chemotherapy, with additional imaging obtained when clinical symptoms or laboratory abnormalities suggested potential disease progression. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events of the National Cancer Institute (CTCAE 5.0) and were graded from 1 to 5.

Statistical analysis

The chi-squared test was used for comparisons of intergroups at a significance level of 5% (α = 0.05, two-sided). Survival probability was analyzed using the Kaplan-Meier method, and the log-rank test was utilized to compare the significance between groups. Global censoring rules were adopted in this study, patients without progression of the disease or death were censored at the last follow-up visit without the PFS event. The Cox proportional hazards model was used for multivariate survival analysis. All P-values were two-sided, and P-values < 0.05 (P < 0.05) were considered statistically significant. RStudio (Version 1.2.1335; RStudio, Inc.) and Adobe Illustrator 2020 were used for all statistical analyses and to create graphics.

Results

Patients and clinical characteristics

A total of 144 patients were retrospectively analyzed in this retrospective study (SFig 1). First, we included 94 patients with gemcitabine-refractory unresectable pancreatic cancer who were treated with irinotecan- and oxaliplatin-based regimens as a second-line treatment. Among them, 57 and 37 patients received oxaliplatin- and irinotecan-based regimens, respectively. The baseline information of the two groups of patients basically matched (Table 1). In addition to a slightly higher number of patients with peritoneal metastases in the Iri group than in the Oxa group, there were no significant differences in clinical characteristics, such as age, sex, ECOG (Eastern Cooperative Oncology Group) PS, and tumor location, between the two groups. Considering that patients with good PS following gemcitabine resistance often received mFFX as a subsequent therapy regimen, an additional 50 patients treated with mFFX as a second-line treatment were included in this study. Compared with the initial 94 patients, the mFFX cohort exhibited significantly better PS, and a higher proportion of men, and the difference was statistically significant. It is also understandable that only patients with good PS could tolerate mFFX treatment, and men tend to have better PS; these differences may introduce selection bias into subsequent analyses. More details are listed in Table 1.

Table 1.

Characteristics of all patients

	Oxaliplatin-based (n=57)	Irinotecan-based (n=37)	P	mFFX (n=50)	Oxaliplatin or Irinotecan-based (n=94)	P'	Total (n=144)
Age (years)			0.211			0.234
Median(range)	64 (39-77)	61 (45-77)		61 (47-70)	64 (39-77)		63 (39-77)
Sex			0.778			0.000
Male	26	18		41	44		85
Female	31	19		9	50		59
ECOG PSa			0.230			0.000
0-1	24	11		49	35		84
2	33	26		1	59		60
Tumor site
Head/uncinate	37	19	0.195	18	56	0.007	74
Neck/body/tail	19	16	0.337	32	35	0.002	67
Others	1	2	0.334	0	3	0.206	3
Recurrence/metastasis
Locally advanced	7	3	0.529	7	10	0.556	17
Recurrence	5	3	0.917	9	8	0.095	17
Metastasis	45	30	0.566	35	75	0.142	111
Site of metastasis lesions
Liver	36	19	0.261	28	54	0.774	83
Lung	5	3	0.917	2	8	0.315	10
Peritoneum	5	9	0.040	5	14	0.412	19
Bone	0	1	0.223	1	1	0.656	2
Distant lymph nodes	0	0	NA	2	0	0.053	2
Subcutaneous tubercle	1	0	0.433	1	1	0.656	2
Pleura	1	1	0.769	0	2	0.306	2
Duration of first-line therapy			0.537			0.021
<6 m	39	23		23	62		85
>=6 m	18	14		26	32		59
Regimen of first-line chemotherapy
AGb	57	36	0.223	48	93	0.089	141
GEMc	0	1	0.223	2	1	0.245	3
GEMOXd	0	0	NA	1	0	0.175	1
Median PFS in first-line therapy, months	4.700	5.067	0.626	6.050	4.867	0.092	5.083
Diabetes			0.168			0.990
Yes	33	16		26	49		75
No	24	21		24	45		69

^aECOG PS: Eastern Cooperative Oncology Group performance status

^bAG: gemcitabine plus nab-paclitaxel

^cGEM: gemcitabine

^dGEMOX: gemcitabine plus oxaliplatin 

Tumor response

After 12 weeks of treatment or laboratory abnormalities that suggested potential disease progression, the response rate was evaluated. Of the 54 patients receiving oxaliplatin-based treatment, 2 achieved partial response (PR), 23 had stable disease (SD), and 29 had PD, yielding an ORR of 3.70% and a DCR of 46.30%. Of the 37 patients treated with irinotecan-based regimens, 1 achieved PR, 13 had SD, and 16 had PD, with ORR and DCR of 3.33% and 46.67%, respectively. Of the 50 patients who received mFFX treatment, 2 achieved PR, 27 had SD, and 21 had PD, resulting in an ORR of 4.00% and a DCR of 58.00%. None of the 144 patients with unresectable pancreatic cancer achieved a complete response (CR) during second-line treatment (Table 2). As shown in Table 2, there were no significant intergroup differences in the tumor response.

Table 2.

Tumor response

	Total (n=134)	Oxaliplatin-based (n=54)	Irinotecan-based (n=30)	mFFX (n=50)	P
CR	0(0.00%)	0(0.00%)	0(0.00%)	0(0.00%)	NA
PR	5(3.73%)	2(3.70%)	1(3.33%)	2(4.00%)	0.989
SD	63(47.01%)	23(42.59%)	13(43.33%)	27(54.00%)	0.460
PD	66(49.25%)	29(53.70%)	16(53.33%)	21(42.00%)	0.434
ORR (CR+PR)	5(3.73%)	2(3.70%)	1(3.33%)	2(4.00%)	0.989
DCR (CR+PR+SD)	68(50.75%)	25(46.3%)	14(46.67%)	29(58.00%)	0.434

Survival analysis

As of January 2025, 116 patients (80.56%) had reached the endpoints of disease progression or death. Survival analysis in the irinotecan- and oxaliplatin-based groups revealed a median PFS (mPFS) of 4.6 months in the irinotecan-based group and 2.9 months in the oxaliplatin-based group, with no statistical difference between the two groups (P = 0.627, HR = 1.128, 95%CI 0.693–1.836) (Fig. 1A). The median OS (mOS) was 6.5 months in the irinotecan-based group and 10.2 months in the oxaliplatin-based group, and no difference in OS was identified at the time of this analysis (P = 0.108, HR = 0.664, 95%CI 0.392–1.125) (Fig. 1B).

Fig. 1.

Progression-free survival (A) and overall survival (B) in the oxaliplatin- and irinotecan-based groups. PFS, progression-free survival; OS, overall survival

As the lack of significant differences in mPFS and mOS between the irinotecan- and oxaliplatin-based groups, the two groups were pooled as the Iri/Oxa group for survival analysis against the mFFX group (Fig. 2). As shown in Fig. 2A, the mPFS was 4.4 months in the mFFX group and 4.2 months in the Iri/Oxa group, with no statistical difference between the two groups (P = 0.222, HR = 1.247, 95%CI 0.866–1.797). By contrast, overall survival analysis revealed that patients receiving mFFX as second-line therapy lived significantly longer than those in the Iri/Oxa group, and the difference was statistically significant (10.667 months vs. 8.767 months, P = 0.035, HR = 1.560, 95%CI 1.037–2.347) (Fig. 2B).

Fig. 2.

Progression-free survival (A) and overall survival (B) in the mFFX and Iri/Oxa groups. PFS, progression-free survival; OS, overall survival

We also performed survival analysis across the mFFX, irinotecan-based, and oxaliplatin-based groups. The results showed that in the comparison between the mFFX and irinotecan-based groups, mOS in the mFFX group was longer than that in the irinotecan-based group, and the difference was statistically significant (10.7 months vs. 6.5 months, P = 0.009, HR = 1.931, 95%CI 1.109–3.363) (SFig 2). However, no significant difference was observed in mPFS and mOS between the mFFX and oxaliplatin-based groups (SFig 3).

Propensity score matching analysis

Due to the imbalance in baseline data between the mFFX and Iri/Oxa groups, there is a potential selection bias in the survival outcomes. To adjust for the differences in baseline characteristics between the two groups, we performed 1:1 propensity score matching (PSM) to assess survival outcomes. Baseline characteristics including age, sex, ECOG performance status, tumor location, liver metastasis, duration of prior therapy, and diabetes were incorporated as categorical factors in a generalised linear model to generate the propensity scores. After PSM, the risk factors of the two groups of patients were relatively balanced (p > 0.05), and 31 patients were included in each group for the subsequent survival analysis (Table 3). Survival analysis was conducted in the PSM-adjusted mFFX and Iri/Oxa groups, and found that there were no significant differences in mPFS between the two groups (3.5 months vs. 4.2 months, P = 0.290, HR = 0.763, 95%CI 0.448–1.297) (Fig. 3A). Similar results were observed for mOS (8.5 months vs. 12.4 months, P = 0.464, HR = 1.262, 95%CI 0.673–2.367) (Fig. 3B). These findings suggest that the choice of a second-line treatment regimen did not significantly impact survival outcomes in patients with advanced pancreatic cancer.

Table 3.

Propensity score matched population

	Oxaliplatin or Irinotecan-based (n=31)	mFFX (n=31)	P
Age (years)			0.729
Median(range)	62 (46-77)	59 (49-70)
Sex			0.761
Male	25	23
Female	6	8
ECOG PSa
0-1	30	30	1.000
2	1	1
Tumor site			1.000
Head/uncinate	14	15
Neck/body/tail	17	16
Liver metastasis			0.075
Yes	20	19
No	11	12
Duration of first-line therapy			0.444
<6 m	19	15
>=6 m	12	16
Diabetes			1.000
Yes	17	18
No	14	13

^aECOG PS Eastern Cooperative Oncology Group performance status

Fig. 3.

Progression-free survival (A) and overall survival (B) in the mFFX and Iri/Oxa groups after PSM. PFS, progression-free survival; OS, overall survival. PSM: propensity score matching

Subgroup analysis

Subgroup analysis was conducted to screen for the intended OS-benefited population. A Cox regression model was used to calculate the hazard ratios. Subgroup analysis between the irinotecan- and oxaliplatin-based groups revealed no significant differences, except in patients with a duration time of less than 6 months of first-line therapy (P = 0.015, HR = 0.46, 95%CI 0.24–0.86) or with poor PS (P = 0.043, HR = 0.54, 95%CI 0.29–0.98), who were more beneficial from oxaliplatin-based therapy (SFig 4 A). Subgroup analysis between the mFFX and Iri/Oxa groups demonstrated that patients in the mFFX group benefited more overall consistent in Fig. 2B, but surprisingly, no significant differences were detected (P > 0.05) (SFig 4B). Additional subgroup analyses were conducted between the irinotecan-based and mFFX groups and between the oxaliplatin-based and mFFX groups. SFig 4 C showed that most patients may obtain clinical benefits from the treatment of mFFX than irinotecan-based therapy, especially those younger than 65 years (P = 0.005, HR = 2.6, 95%CI 1.3-5), men (P = 0.045, HR = 2, 95%CI 1–4), and with metastatic pancreatic cancer at their first diagnosis (P = 0.047, HR = 1.8, 95%CI 1-3.3). No statistical differences were found in subgroup analysis between the oxaliplatin-based and mFFX groups (SFig 4D).

Multivariate analysis and subgroup survival analysis

As the significantly longer mOS in the mFFX group than versus the Iri/Oxa group (Fig. 2B), the lack of subgroup-specific advantage for mFFX (SFig 4B) and baseline imbalances between groups (Table 1) prompted us to suspect that patient PS or other factors, rather than treatment regimens, that affect overall survival during second-line treatment. To verify the suspicion, univariate and multivariate analysis were performed for sex, age, liver metastasis, tumor site, ECOG, and duration of prior therapy and found that ECOG and duration of first-line therapy were the independent prognostic factors (STable1). Due to the P < 0.001 of ECOG, we performed survival analysis of patients with different PS. As shown in Fig. 4A, there was no significant difference in mPFS between patients with good PS (ECOG = 1, mPFS = 4.3 m) and moderate PS (ECOG = 2, mPFS = 4.4 m) (P = 0.454, HR = 1.152, 95%CI 0.784–1.692), and the results were consistent with those described above. Notably, patients with good PS lived longer than those with poor PS, and the results were statistically different (10.8 months vs. 7.7 months, P = 0.000, HR = 2.194, 95%CI 1.408–3.420) (Fig. 4B).

Fig. 4.

Progression-free survival (a) and overall survival (b) in patients with different performance status. PFS, progression-free survival; OS, overall survival; ECOG, Eastern Cooperative Oncology Group

Adverse events

The details of the AEs are presented in Table 4. Overall, patients in the mFFX group experienced relatively high AE rates compared to other groups, including both hematological and non-hematological toxicities. Most AEs were grade 1 or 2. Hematological toxicity remained the most common adverse event, with leukopenia occurring in up to 45.19% of cases, followed by neutropenia (44.44%) and anemia (42.36%). Gastrointestinal toxicity, including anorexia (38.89%) and nausea (31.94%), also had high incidences. The incidence of diarrhea was similar between the mFFX and irinotecan-based groups, but lower in the oxaliplatin-based group. Other AEs included sensory neuropathy (21.53%) and increased ALT and AST levels (13.89%). During the treatment period, a total of 8 (16.0%) patients in the mFFX group experienced dose reduction, 11 (19.3%) in the oxaliplatin-based group, and 7 (18.9%) in the irinotecan-based group. No drug-related deaths were observed in this study, but treatment discontinuation occurred due to loss of follow-up or death. 1 patient in the oxaliplatin-based group and 7 in the irinotecan-based group discontinued treatment due to death. The causes of death included massive gastrointestinal bleeding (1), intestinal obstruction (3), massive ascites (2), and COVID-19 infection (2).

Table 4.

Adverse event

	Total (n=144)		Oxaliplatin-based (n=57)		Irinotecan-based (n=37)		mFFX (n=50)
	Any grade	≥3	Tatal	≥3	Tatal	≥3	Any grade	≥3
Leukopenia	65(45.19%)	4(2.78%)	21(36.84%)	1(1.75%)	11(29.73%)	1(2.70%)	33(66.00%)	2(4.00%)
Neutropenia	64(44.44%)	5(3.47%)	21(36.84%)	1(1.75%)	11(29.73%)	1(2.70%)	32(64.00%)	3(6.00%)
Anemia	61(42.36%)	1(0.69%)	22(38.60%)	0(0.00%)	9(24.32%)	0(0.00%)	30(60.00%)	1(2.00%)
Febrile neutropenia	3(2.08%)	3(2.08%)	1(1.75%)	1(1.75%)	1(2.70%)	1(2.70%)	1(2.00%)	1(2.00%)
Thrombocytopenia	52(36.11%)	5(3.47%)	22(38.60%)	3(5.26)	10(27.03%)	0(0.00%)	20(40.00%)	2(4.00%)
Anorexia	56(38.89%)	0(0.00%)	21(36.84%)	0(0.00%)	14(37.84%)	0(0.00%)	21(42.00%)	0(0.00%)
Nausea	46(31.94%)	0(0.00%)	17(29.82%)	0(0.00%)	10(27.03%)	0(0.00%)	19(38.00%)	0(0.00%)
Diarrhea	33(22.92%)	0(0.00%)	4(7.02%)	0(0.00%)	14(37.84%)	0(0.00%)	15(30.00%)	0(0.00%)
Sensory neuropathy	31(21.53%)	0(0.00%)	14(24.56%)	0(0.00%)	2(5.41%)	0(0.00%)	15(30.00%)	0(0.00%)
ALT/AST increase	20(13.89%)	0(0.00%)	7(12.28%)	0(0.00%)	6(16.22%)	0(0.00%)	7(14.00%)	0(0.00%)

Discussion

Gemcitabine plays an irreplaceable role in pancreatic cancer treatment. Currently, gemcitabine-based therapy is recommended for almost all patients, from postoperative adjuvant to advanced systemic therapy. As the cornerstone of adjuvant chemotherapy, gemcitabine-based therapy significantly delays recurrent disease after complete resection of pancreatic cancer compared with observation alone [16]. For patients with advanced pancreatic cancer, gemcitabine is more effective than fluorouracil and has been approved as a first-line treatment since 1997 [6, 17]. Subsequent studies exploring gemcitabine combinations have shown that adding nab-paclitaxel significantly improved OS, PFS, and response rate, establishing gemcitabine plus nab-paclitaxel as a recommended first-line treatment option [8]. This phase 3 study demonstrated that patients receiving gemcitabine plus nab-paclitaxel as first-line treatment had a median PFS of 5.5 months [8]. In our study, the duration of first-line therapy was 6.1 months in the mFFX group and 4.7 and 5.1 months in the oxaliplatin- and irinotecan-based groups, respectively, which were generally consistent with prior reports.

Despite notable advances in survival improvements afforded by the current first-line treatment regimens, there are still great challenges in treatment owing to drug resistance and the limited effective therapeutic options [18]. While clinical trial enrollment is a good option following first-line failure, second-line chemotherapy treatment represents the only option to extend survival for patients ineligible for trials or unable to participate for various reasons. For most pancreatic cancer patients, there is no doubt that second-line chemotherapy was associated with significantly higher survival than best supportive care (BSC) [19, 20]. The global randomized open-label phase 3 NAPOLI-1 trial demonstrated that nanoliposomal irinotecan combined with fluorouracil and folinic acid prolongs survival with manageable toxicity in patients with metastatic PDAC previously received gemcitabine-based therapy [11]. This study reported mOS and mPFS of 6.1 months and 3.1 months, respectively, for patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid as second-line treatment. A real-world study in Spain showed that this combination as second or third-line therapy achieved an mPFS of 3.7 months, slightly better than NAPOLI-1 [21]. Other investigations have also further validated the clinical efficacy of this combination regimen in advanced pancreatic cancer [15, 22, 23]. Findings from NAPOLI-1 and subsequent real-world evidence led to international approval and guideline recommendation of nanoliposomal irinotecan plus fluorouracil and folinic acid as the standard second-line regimen after gemcitabine failure. However, the inaccessibility of nanoliposomal irinotecan in mainland China poses significant challenges for treatment selection following gemcitabine failure, and potentially compromising patient survival outcomes.

Prior to the approval of nanoliposomal irinotecan, there was no consensus regarding second-line treatment after gemcitabine treatment failure. The CONKO-003 randomized phase III trial demonstrated that second-line OFF (oxaliplatin plus folinic acid and fluorouracil) significantly extended the duration of overall survival when compared with FF (folinic acid and fluorouracil) alone in gemcitabine-refractory advanced pancreatic cancer [3]. According to the results of CONKO-003, OFF used as the second-line therapy achieved a mOS of 5.9 months and mPFS of 2.9 months, which were comparable to the nanoliposomal irinotecan plus fluorouracil and folinic acid regimen in NAPOLI-1. It seems that OFF could serve as an alternative to the nanoliposomal irinotecan plus fluorouracil and folinic acid regimen as the second-line treatment. However, the PANCREOX trial showed no survival benefit with the addition of oxaliplatin, administered as mFOLFOX6, versus infusional FU/LV in patients with advanced pancreatic cancer previously treated with first-line gemcitabine [24]. Meanwhile, the PANTHEON trial aimed to compare the efficacy of second-line therapy with FOLFIRI (irinotecan plus folinic acid and fluorouracil) vs. OFF, suggested similar efficacy and toxicity profiles between regimens in PDAC after the failure of gemcitabine/nab-paclitaxel [25]. In our study, the mOS of Iri/Oxa-based regimens as the second-line therapy was 8.8 months, and the mPFS was 4.2 months, which was comparable to or even slightly better than nanoliposomal irinotecan plus fluorouracil and folinic acid regimen in NAPOLI-1 and other real-world studies [11, 21, 22].

The PRODIGE 4/ACCORD 11 was the first to confirm that for patients with metastatic pancreatic cancer and good PS, FFX was associated with a survival advantage compared with gemcitabine [9]. Subsequent researchers confirmed that mFFX has an improved safety profile with maintained efficacy of the original FFX [26, 27]. These studies thus established FFX or mFFX as standards for advanced or metastatic pancreatic cancer. However, studies on FFX/mFFX as a second-line treatment are few and may be largely limited to significant toxicity. Nevertheless, mFFX may be a viable option for carefully selected patients with a good PS following gemcitabine/nab-paclitaxel failure [17]. A retrospective study found that mFFX as second-line therapy was efficient and tolerable for metastatic pancreatic cancer [28]. In this study, mFFX as second-line therapy achieved a mOS of 10.7 months and mPFS of 4.4 months. These outcomes surpass both the Iri/Oxa regimens in our study and the nanoliposomal irinotecan plus fluorouracil and folinic acid in prior studies [11, 21, 22]. These findings are consistent with the results reported by Tezuka et al. [29]. Notably, while mFFX confers significant survival benefits, it is associated with higher rates of adverse events.

However, it is not difficult to find from Table 1 that the patients using the mFFX regimen were mostly male patients with good PS, so we speculate that this may be the reason for the longer survival of patients in the mFFX group. Subgroup survival analysis by PS scores revealed no significant difference in survival between patients treated with different second-line regiments. These results were unexpected and reasonable. This finding is consistent with the results of another retrospective study by our team, showing that patients receiving enhanced supportive care combined with systemic therapy had better overall survival compared with other patients at the same time. Such enhanced supportive care and systemic therapy included additional medical, endoscopic, and surgical management for symptom relief, complication control, and quality of life (QoL) improvement. Previous studies have found that poor PS and hypoalbuminemia were negative prognostic factors for survival in second-line palliative treatment for patients with advanced pancreatic cancer [30]. The APACaP GERCOR randomized trial further confirmed that adapted physical activity had significant benefits for global health status and could improve several dimensions of health-related quality of life (HRQoL) in patients with advanced pancreatic cancer [31]. Overall, there has been little attention and research on strengthening supportive care and systemic therapy to improve physical strength in pancreatic cancer patients. These findings suggest that more attention should be paid to enhancing supportive care and strengthening the physical strength of patients during systemic chemotherapy to ensure timely chemotherapy and prolong the survival of patients with advanced pancreatic cancer.

Although immunotherapy has achieved significant breakthroughs in various solid tumors, pancreatic cancer responds poorly to immunotherapy, attributed to its poor immunogenic properties, low number of neoantigens, and immunosuppressive tumor microenvironment [17, 32]. Monotherapy with immune checkpoint inhibitors has thus far proven clinically ineffective, and combined with chemotherapy has not proven effective in advanced pancreatic cancer, except in patients with microsatellite instability-high (MSI-H) tumors [33–35]. Consequently, patients who received immunotherapy were excluded from this study. The POLO trial proved that olaparib as a maintenance therapy can prolong PFS in patients with a germline BRCA mutation, indicating that molecular-targeted therapy has made a breakthrough in the treatment of pancreatic cancer [36]. In addition, previous studies have confirmed that larotrectinib was effective in TRK fusions, sotorasib was effective in KRAS p.G12C-mutated, and selpercatinib had exceptional responses to RET fusion-driven metastatic pancreatic cancer [37–39]. While these data validate the effectiveness of molecular-targeted therapy, the low incidence of such mutations or fusions in pancreatic cancers necessitated their exclusion from our analysis.

This study evaluated the efficacy and safety of second-line treatment for gemcitabine failure in patients with good PS of advanced pancreatic cancer and found that mFFX could prolong survival compared to oxaliplatin- and irinotecan-based regimens. Additionally, we investigated the impact of performance status on patient survival and found that performance status rather than different treatment regimens was the primary determinant of overall survival. Last but not least, this study was retrospective in a real-world setting, and the results obtained were more in line with the actual clinical situation and are real world. These results have several important clinical implications. However, this real-life analysis has several limitations. First, imperfect baseline characteristics matching may have introduced partial bias into the results. Second, as a retrospective study, it lacks the rigorous monitoring of a randomized controlled trial. Finally, the small sample size, retrospective nature, and heterogeneity of the treatment regimens were also limitations of our study.

In conclusion, there was no significant difference between oxaliplatin- or irinotecan-based second-line treatment regimens for patients with advanced pancreatic cancer. The choice of the mFFX regimen as a second-line treatment can prolong the survival of patients because of their favorable performance status. Therefore, it is recommended that supportive care be enhanced concurrently with systemic therapy in patients with pancreatic cancer.

Abbreviations

mFFX

Modified FOLFIRINOX

PFS

Progression-free survival

OS

Overall survival

PS

Performance status

RCT

Randomized controlled trial

OFF

Oxaliplatin, folinic acid, and fluorouracil

PD

Progressive disease

ORR

Objective response rate

DCR

Disease control rate

AE

Adverse events

ECOG

Eastern Cooperative Oncology Group

CTCAE

Criteria for Adverse Events of the National Cancer Institute

CR

Complete response

PR

Partial response

SD

Stable disease

PD

Progressive disease

FOLFIRI

Irinotecan plus folinic acid and fluorouracil

QoL

Quality of life

MSI-H

Microsatellite instability-high

Authors’ contributions

Study concept and design: M.T., R.J. Acquisition, analysis or interpretation of data: D.X., Y.W. Drafting of the paper: Q.W., N.L. Critical revision of the paper for important intellectual content: J.W., W.G., J.W., B.X. All authors have read and approved the manuscript.

Funding

This work was supported by Young Scholars Fostering Fund of the First Affiliated Hospital of Nanjing Medical University (PY202424); Jangsu Province Hlospital (the First Affiliated Hospital with Nanjing Medical University) Clinical Capacity Enhancement Project (JSPH-MB-2023-12); and Development Cancer for Medical Science & Technology National Health Commission of the People’s Republic of China “Innovative Drug post-marketing Clinical Research Research Project” (WKZX2024CX102203). The grants had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Data availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The study was approved by the First Affiliated Hospital of Nanjing Medical University Ethics Committee and complied with the ethical standards of the Declaration of Helsinki. All participants gave their written informed consent at registry inclusion.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.