Sage Journals: Discover world-class research

Abstract

Background:

Nanoliposomal irinotecan combined with fluorouracil plus leucovorin (nal-IRI + 5-FU/LV) is a standard second-line treatment for patients with advanced pancreatic cancer. Despite its efficacy, the prognostic factors for treatment efficacy remain unclear in clinical practice.

Objectives:

To investigate prognostic factors for survival with nal-IRI + 5-FU/LV.

Design:

Single-centre retrospective cohort.

Methods:

We included 204 patients who were treated with nal-IRI + 5-FU/LV at our institution between July 2020 and March 2022. These patients had unresectable or recurrent pancreatic adenocarcinoma refractory to a gemcitabine-containing regimen. A Cox regression hazard model was used to explore prognostic factors for overall survival (OS).

Results:

Of the 204 eligible patients, 127 (64%) had received only one prior treatment. Most patients (90%) had metastatic disease, with 93, 61 and 55 patients having metastases to the liver, lungs and peritoneum, respectively. Among them, 18 patients had peritoneal metastasis without ascites. The median OS and progression-free survival (PFS) were 8.7 (95% confidence interval (CI), 7.5–9.8) and 3.6 (95% CI, 3.0–4.2) months, respectively. An Eastern Cooperative Oncology Group performance status (PS) of 0, serum albumin (Alb) level ⩾3.5 g/dL, C-reactive protein (CRP) level <0.5 mg/dL, carbohydrate antigen 19-9 (CA 19-9) level <1000 U/mL and peritoneum metastasis without ascites were independent prognostic factors for OS. The hazard ratios for these factors were 2.08, 1.96, 2.34, 2.22 and 1.92 with p-values of ⩽0.001, 0.001, <0.001, <0.001 and 0.043, respectively. Peritoneal metastasis, with or without ascites, was associated with 2-year OS rates compared to those without: 14.5% versus 6.0%, and 27.8% versus 6.5% (p-value = 0.053 and 0.010, respectively).

Conclusion:

A PS of 0, Alb >3.5 g/dL, CRP <0.5 mg/dL, CA 19-9 <1000 U/mL and the presence of peritoneal metastasis, especially without ascites, were favourable prognostic factors for survival in patients with advanced pancreatic cancer treated with nal-IRI + 5-FU/LV.

Plain language summary

Study identifying factors that may associate with survival in patients with advanced pancreatic cancer who received nanoliposomal irinotecan with fluorouracil and leucovorin (NAPOLI-1)

Why was the study done? Pancreatic cancer is often diagnosed late and is hard to treat and NAPOLI-1 is one of the treatments available for advanced stages; however, most patients do not survive for long. The researchers wanted to learn more about the factors, which could potentially improve survival outcomes for patients.

What did the researchers do? They reviewed medical records of 204 patients who were treated with NAPOLI-1 between July 2020 and March 2022. These patients had advanced pancreatic cancer that was either unresectable or metastatic and had progressed following prior treatments. The researchers examined whether the characteristics of patients associated with their survival time.

What did they find? Only 17 patients (8.3%) survived for more than two years. Some characteristics of patients were associated with longer survival: they had good physical function call Performance status (PS), low levels of a blood marker called C-reactive protein (CRP), low levels of another marker called carbohydrate antigen (CA) 19-9, and high levels of a blood marker called albumin. Additionally, patients with cancer that had spread to the peritoneum (the lining of the abdominal cavity) but without fluid collection in the abdominal cavity had better outcomes if they met these conditions.

What do the results mean? The findings suggest that certain factors, such as lower CRP and CA 19-9 levels, high Albumin, and disease spread to peritoneum, may improve the chances of surviving longer for patients on the NAPOLI-1 regimen. This information could help doctors identify which patients are more likely to benefit from this treatment.

Keywords

long survivor nanoliposomal irinotecan pancreatic cancer peritoneal metastasis predictive factor prognostic factor

Introduction

The incidence of pancreatic cancer amounted to approximately 510,000 cases worldwide in 2022 and has been increasing in recent years.¹ It is the seventh leading cause of cancer-related deaths worldwide, with an estimated 467,000 cases in 2022.¹ The prognosis for patients with pancreatic cancer remains poor. Adenocarcinoma is the most frequently encountered subtype of this cancer, with most studies focusing on pancreatic ductal adenocarcinoma (PDAC). Notably, the only curative treatment for PDAC is surgical resection; however, PDACs are generally diagnosed at an unresectable stage, and recurrence after surgery is common. Therefore, systemic chemotherapy remains the mainstay of treatment.

Recently, several combination regimens have been proposed for advanced PDAC, including FOLFIRINOX (fluorouracil (5-FU), leucovorin (LV), irinotecan and oxaliplatin)² and gemcitabine (GEM) plus nab-paclitaxel (nab-PTX).³ However, despite its efficacy, FOLFIRINOX use is limited to young patients with a good performance status (PS) because of its toxic effects, such as anorexia and diarrhoea.⁴ Consequently, because of its wide indication, GEM plus nab-PTX is more likely to be administered in patients with unresectable PDAC. Nanoliposomal irinotecan (nal-IRI) plus 5-FU and LV (nal-IRI + 5-FU/LV) is recommended as a second-line treatment after GEM-containing regimens based on the results of the NAPOLI-1 phase III trial, which revealed its efficacy and safety compared with 5-FU plus LV in patients with GEM-refractory PDAC.⁵ In Japan, nal-IRI + 5-FU/LV was approved for treating unresectable pancreatic cancer based on the results of a domestic phase II trial published in 2020 as well as those of the NAPOLI-1 trial.⁶ Evidence supports its efficacy; however, the median progression-free survival (PFS) observed in the NAPOLI-1 and Japanese phase II trials was just 3.1 and 2.7 months, respectively.^5,6 Furthermore, only 29 patients (25%) were reported to have survived for >1 year in the NAPOLI-1 trial.⁷

Due to the limited efficacy of nal-IRI + 5-FU/LV, identifying prognostic factors for survival is necessary to help patients decide whether to receive the treatment. A post hoc analysis of the NAPOLI-1 trial reported some factors for long-term survival, which was defined as patients who survived for ⩾1 year⁷; however, patient characteristics are commonly different between clinical trials and the real world, and an overall survival (OS) of 1 year would be considered insufficient in recent years.^8,9 Therefore, this study investigated prognostic factors for survival among patients receiving nal-IRI + 5-FU/LV in our daily clinical practice and explored the factors associated with long-term survival >2 years.

Methods

Reporting guidelines

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines¹⁰ were used in this study to ensure the quality and transparency of the reported data (Supplemental File).

Patients

This single-centre retrospective study included 204 consecutive patients who received nal-IRI + 5-FU/LV at the Kanagawa Cancer Center between July 2020 and March 2022. Patients were considered eligible for nal-IRI + 5-FU/LV treatment if they met the following criteria: (1) they had experienced failure with GEM-containing regimens; (2) they had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1 and were ⩽85 years, or (3) they had an ECOG PS of 2 and were ⩽75 years; (4) they were capable of consuming at least half of their normal food intake and (5) they had normal liver and bone marrow functions, including serum bilirubin level <1.5 mg/dL, neutrophil count >1500/µL and platelet count >100,000/µL. However, this treatment was contraindicated in patients with watery diarrhoea or uncontrolled infection. The patients’ background data were retrospectively collected from their medical records, which included sex, age, ECOG PS, disease stage, sites of metastasis, initial dose reduction of the treatment and laboratory data such as the serum tumour markers: carcinoembryonic antigen and carbohydrate antigen 19-9 (CA 19-9). CA 19-9 values <2.0 ng/mL were excluded from the median calculations because patients with such low values were presumed to have no Lewis antigens. The presence of ascites was diagnosed by reviewing the imaging of computed tomography just before initiation of nal-IRI + 5-FU/LV treatment, and even a small amount of ascites was defined as the presence of ascites.

Treatment

The nal-IRI + 5-FU/LV comprised nal-IRI at a dose of 70 mg/m² delivered via a 90-min intravenous infusion, immediately followed by levo-leucovorin calcium at a dose of 200 mg/m² delivered via a 120-min intravenous infusion and 5-FU at a dose of 2400 mg/m² delivered via a 46-h continuous intravenous infusion. The dose of nal-IRI was reduced to 50 mg/m² when a patient was homozygous for uridine diphosphate glucuronosyltransferase (UGT)1A1 *28 or *6 or double heterozygous for UGT1A1 *28 and *6, based on the NAPOLI-1 and Japanese phase II trials.^5,6 Moreover, the initial dose was reduced at the discretion of the physician, such as in older patients, those with baseline anorexia or those with UGT1A1 status being unknown. Treatment was repeated every 2 weeks and continued until disease progression, unacceptable adverse events or patient refusal.

Treatment outcomes

OS, PFS and objective radiological responses were evaluated as efficacy endpoints. OS was calculated as the time from the date of initiation of nal-IRI + 5-FU/LV to that of death from any cause; PFS was calculated from the date of nal-IRI + 5-FU/LV initiation to that of documented disease progression or death from any cause. Patients were treated as censored if they did not show any events related to OS or PFS. The Response Evaluation Criteria in Solid Tumor version 1.1 was used to evaluate the objective radiological response, which was classified into complete response (CR), partial response (PR), stable disease (SD) and progressive disease.¹¹ The objective response and disease control rates were calculated using the number of patients with CR + PR and CR + PR + SD, respectively, divided by the total number of patients.

Statistical analysis

Categorical variables are presented as frequencies and percentages. Normally distributed continuous variables are reported as means and standard deviations, while non-normally distributed continuous variables are presented as medians with interquartile ranges. The median OS and PFS were estimated using the Kaplan–Meier method. Fisher’s exact test was used to conduct univariable analysis to compare categorical values; Student’s t test and the Mann–Whitney U test were used for continuous values of normal or non-normal distribution, respectively. To explore prognostic factors, a multivariable analysis was performed using a Cox regression hazard model with the backward elimination method. All statistical analyses were performed using the Statistical Package for Social Sciences version 23 (IBM Corp., Armonk, NY, USA), and statistical significance was set at a p-value <0.05.

Results

Patients

A total of 204 patients were included in this study. The median age of the entire cohort was 69 years, with 38 patients (19%) ≥75 years. In total, 127 patients (62%) had received only one prior treatment, and 38 (19%) had a history of irinotecan-containing regimens. Almost all patients had metastatic disease (n = 184 (90%)), with the most common metastatic site being the liver, followed by the lungs and peritoneum (n = 93, 61 and 55, respectively, although some patients had metastases in more than one site). Among the 55 patients who had peritoneal metastasis, 18 did not have malignant ascites. The dose of nal-IRI + 5-FU/LV was reduced in 83 patients (40.7%) due to unknown UGT1A1 status at the time treatment was initiated (n = 17), a poor general condition (n = 15), double hetero- or homozygous UGT1A1 status (n = 14), concomitant symptoms such as malaise and diarrhoea (n = 13) and older age (n = 9; with some observed duplicates). The detailed patient characteristics are shown in Table 1.’

Table 1.

Patients’ baseline characteristics (N = 204).

Factors	N (%)
Sex
Male	125 (61)
Female	79 (39)
Age (years)
Mean (SD)	67.0 (9.0)
⩾75 years	38 (19)
ECOG PS
0	95 (47)
1	104 (51)
2	5 (3)
Prior treatment
Number of regimens
1	127 (62)
⩾2	77 (36)
History of using irinotecan	38 (19)
Locally advanced	20 (10)
Metastatic disease	184 (90)
Liver	93 (46)
Lung	61 (30)
Peritoneum	55 (27)
Without ascites	18 (8.8)
UGT1A1
Wild type	100 (49)
Single heterozygous	84 (41)
Double heterozygous	20 (10)
Initial dose reduction
Yes	79 (39)
No	125 (61)
Albumin (g/dL)
Mean (SD)	3.67 (0.45)
⩾3.5 g/dL	140 (69)
CRP (mg/dL)
Median (IQR)	0.30 (0.10–1.25)
<0.50 mg/dL	129 (63)
CEA (ng/mL)
Median (IQR)	6.7 (3.5–17.2)
<5.0 ng/mL	76 (37)
CA 19-9^a (U/mL)
Median (IQR)	1105.2 (136.6–9499.3)
<1000 U/mL	95 (46.6)

Values <2.0 ng/mL were excluded from the calculation because patients with such low values were presumed to have no Lewis antigens.

CA 19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CRP, C-reactive protein; ECOG PS, Eastern Cooperative Oncology Group performance status; IQR, interquartile range; SD, standard deviation; UGT1A1, uridine diphosphate glucuronosyltransferase 1A1.

Treatment outcomes in the entire cohort

The median follow-up time was 7.6 months (range: 0.8–43.4), and we observed 158 (77%) and 181 (89%) events for OS and PFS, respectively. The median OS and PFS were 8.7 (95% confidence interval (CI), 7.5–9.8) and 3.6 (95% CI, 3.0–4.2) months, respectively (Figure 1). Seventeen patients (8.3%) survived >2 years and were considered long-term survivors. CR and PR were observed in 2 (1.0%) and 12 (5.9%) patients, respectively, with a corresponding response rate of 6.9%. A total of 106 patients had SD, with a disease control rate of 58.8%.

Figure 1.

Survival curves for the entire cohort. (a) Overall survival. (b) Progression-free survival.

Prognostic factors for survival

The multivariable analysis revealed that an ECOG PS of 0, albumin level ⩾3.5 g/dL, C-reactive protein (CRP) level <0.5 mg/dL, CA 19-9 level <1000 U/mL and the presence of peritoneum metastasis without ascites were favourable prognostic factors for OS; the hazard ratios were 2.08 (95% CI, 1.48–2.91; p < 0.001), 1.96 (95% CI, 1.34–2.86; p = 0.001), 2.34 (95% CI, 1.64–3.35; p < 0.001), 2.22 (95% CI, 1.57–3.15; p < 0.001) and 1.92 (95% CI, 1.02–3.63; p = 0.043), respectively (Table 2). Similarly, an ECOG PS of 0, CRP level <0.5 mg/dL, CA 19-9 level <1000 U/mL and the presence of peritoneal metastasis without ascites were significant prognostic factors for PFS; the hazard ratios were 1.60 (95% CI, 1.18–2.17; p = 0.003), 1.80 (95% CI, 1.29–2.50; p = 0.001), 2.00 (95% CI, 1.46–2.75; p < 0.001) and 1.90 (95% CI, 1.06–3.40; p = 0.031), respectively (Table 3). The median OS and PFS in patients with peritoneal metastasis without ascites versus all other patients were 11.7 months (95% CI, 10.2–13.2) versus 8.4 months (95% CI, 7.2–9.6) with p = 0.022 (Figure 2(a)), and 5.9 months (95% CI, 3.3–8.4) versus 3.5 months (95% CI, 3.0–4.0) with p = 0.016 (Figure 2(b)), respectively.

Table 2.

Multivariable analysis of prognostic factors for OS.

Factors	Median OS (months)	HR	95% CI	p-Value
ECOG PS
0	11.2
1–2	6.9	2.08	1.48–2.91	<0.001
Disease status
Peritoneum metastasis w/o ascites	11.7
The others	8.4	1.92	1.02–3.63	0.043
Albumin
⩾3.5 g/dL	9.6
<3.5 g/dL	6.0	1.96	1.34–2.86	0.001
CRP
<0.50 mg/dL	10.9
⩾0.50 mg/dL	5.5	2.34	1.64–3.35	<0.001
CA 19-9
<1000 U/mL	12.1
⩾1000 U/mL	7.3	2.22	1.57–3.15	<0.001

CA 19-9, carbohydrate antigen 19-9; CI, confidence interval; CRP, C-reactive protein; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; OS, overall survival.

Table 3.

Multivariable analysis of prognostic factors for PFS.

Factors	Median PFS (months)	HR	95% CI	p-Value
ECOG PS
0	4.9		1.18–2.17
1–2	2.6	1.60	1.18–2.17	0.003
Disease status
Peritoneum metastasis w/o ascites	5.9
The others	3.5	1.90	1.06–3.40	0.031
CRP
<0.50 mg/dL	4.7
⩾0.50 mg/dL	2.3	1.80	1.29–2.50	0.001
CA 19-9
<1000 U/mL	5.0
⩾1000 U/mL	2.8	2.00	1.46–2.75	<0.001

CA 19-9, carbohydrate antigen 19-9; CI, confidence interval; CRP, C-reactive protein; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; PFS, progression-free survival.

Figure 2.

Comparison between patients with peritoneal metastasis without ascites (dotted line) and all other patients (solid line). (a) Overall survival. (b) Progression-free survival.

Impact of peritoneal metastasis on long-term survival

Peritoneal metastasis was unexpected as a favourable prognostic factor for survival in patients with pancreatic cancer; therefore, the prognostic impact of peritoneal metastasis on long-term survival was additionally evaluated. Comparisons of patient characteristics and survival between patients with and without peritoneal metastasis, as well as between those with peritoneal metastasis without ascites and the others, are presented in Table 4. When comparing the 55 patients with peritoneal metastasis with the other 149 patients, the 1- and 2-year OS rates were 25.5% versus 24.8%, and 14.5% versus 6.0% (p = 0.531 and 0.053), respectively. The 1-year PFS rates were 12.7% versus 4.0%, respectively (p = 0.031). Moreover, when comparing the 18 patients with peritoneal metastasis without ascites with the other 186 patients, the prognostic impact was more significant, with 1- and 2-year OS rates of 33.3% versus 24.2% and 27.8% versus 6.5% (p = 0.276 and 0.010), respectively. The 1-year PFS rates were 22.2% versus 4.8% (p = 0.019), respectively. The response rate and disease control rate in patients with peritoneal metastasis versus all other patients were 5.4% versus 7.4% (p = 0.449) and 63.6% versus 57.0% (p = 0.246), respectively, whereas these rates in patients with peritoneal metastasis without ascites versus all other patients were 16.7% versus 5.9% (p = 0.113) and 83.3% versus 56.5% (p = 0.021), respectively.

Table 4.

Patient characteristics and survival based on the presence of peritoneal metastasis and ascites.

N (%)	Peritoneal metastasis			Peritoneal metastasis without ascites
N (%)	PresentN = 55	AbsentN = 149	p-Value	PresentN = 18	AbsentN = 186	p-Value
Sex: male	27 (49)	98 (66)	0.036	9 (50)	116 (62)	0.321
Age <75 years	48 (87)	118 (79)	0.227	16 (89)	150 (81)	0.536
ECOG PS: 0	20 (36)	75 (50)	0.084	12 (67)	83 (45)	0.086
No. prior treatment: 1	36 (65)	95 (64)	0.870	16 (89)	115 (62)	0.022
Locally advanced	0 (0)	20 (13)	0.002	0 (0)	166 (89)	0.226
Initial dose reduction	23 (42)	56 (38)	0.628	5 (28)	74 (40)	0.448
Albumin ⩾3.5 g/dL	37 (67)	103 (69)	0.865	15 (83)	125 (67)	0.192
CRP <0.10 mg/dL	37 (67)	92 (62)	0.413	15 (83)	114 (61)	0.077
CEA <5.0 ng/mL	23 (42)	53 (36)	0.420	9 (50)	67 (36)	0.308
CA 19-9 <1000 U/mL	26 (47)	69 (46)	0.872	8 (44)	87 (47)	0.808
1-Year OS	14 (26)	37 (25)	0.531	6 (33)	45 (24)	0.276
2-Year OS	8 (14.5)	9 (6.0)	0.053	5 (27.8)	12 (6.5)	0.010
1-Year PFS	7 (12.7)	6 (4.0)	0.031	4 (22.2)	9 (4.8)	0.019
Objective response	3 (5.4)	11 (7.4)	0.449	3 (16.7)	11 (5.9)	0.113
Disease control	35 (63.6)	85 (57.0)	0.246	15 (83.3)	105 (56.5)	0.021

CA 19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CRP, C-reactive protein; ECOG PS, Eastern Cooperative Oncology Group performance status; OS, overall survival; PFS, progression-free survival.

Discussion

Factors associated with OS in patients with advanced pancreatic cancer who received nal-IRI + 5-FU/LV were retrospectively explored. The results showed that an ECOG PS of 0, serum CRP level <0.5 mg/dL, CA 19-9 level <1000 U/mL and peritoneal metastasis without ascites were independent positive prognostic factors for OS and PFS. Furthermore, peritoneum metastasis was associated with long-term survival, and the results provide some insights for patients and physicians initiating second-line treatment.

The ancillary analysis of the NAPOLI study defined long-term survival as OS >1 year.⁷ In our study, we estimated the 2-year OS and 1-year PFS rates, in addition to the 1-year OS rate, as prognostic factors for long survival (OS >1 year) had already been evaluated in the NAPOLI-1 trial.⁷ Furthermore, in our study, the Kaplan–Meier curves for OS and PFS demonstrated fewer events beyond 2 and 1 year, respectively, indicating the presence of durable responders. Therefore, we included both the 2-year OS and 1-year PFS rates in our analysis. The most recent phase III study regarding first-line treatment revealed a median OS of 17 months and a median PFS of 6.7 months using the GEM plus nab-PTX treatment, indicating approximately 10 months of median survival after the failure of first-line treatment.¹² Moreover, patients with specific gene alterations can show a marked response to targeted therapy and a median PFS of approximately 1 year.¹³ We hope that further advancements in the treatment for advanced pancreatic cancer will redefine long-term survival, such as OS >2 years.

This study’s results are consistent with the ancillary analysis of the NAPOLI-1 study^7,14 and several studies evaluating prognostic factors for survival.^15–18 Notably, one consistent prognostic factor for survival in the NAPOLI-1 ancillary analyses and the present study was a low CA 19-9 level.⁷ Age, Karnofsky performance status (KPS) and neutrophil-to-lymphocyte ratio (NLR) were also included in the NAPOLI-1 study; although these factors were not evaluated as covariates in the present study, albumin and CRP levels were included as covariates instead of NLR, and ECOG PS instead of KPS. Low levels of albumin and high levels of CRP are a result of increased levels of inflammatory cytokines such as interleukin-6 and tissue necrosis factor-alpha, which are reflected by a high NLR.¹⁹ Therefore, low albumin and high CRP levels may be considered almost equivalent to a high NLR. Regarding PS, KPS is known to evaluate the general conditions of patients more precisely than ECOG PS; we speculate that this is the reason KPS was previously identified as an independent prognostic factor. However, KPS is too complex to implement in daily clinical practice, and we were able to show that ECOG PS was also a prognostic factor for OS. Therefore, we believe that ECOG PS is more useful in daily clinical practice.

Considering peritoneal metastasis as a prognostic factor, a similar tendency was observed between the present study and the NAPOLI-1 trial. Although this factor was not statistically significant in the ancillary analysis of the NAPOLI-1 study, where patients with peritoneal metastasis comprised 38% of long-term survivors and 24% of all patients in the nal-IRI + 5-FU/LV arm,⁷ another subgroup analysis of the NAPOLI-1 study that evaluated prognosis based on the metastatic sites showed better OS in patients with peritoneal metastasis than in those without (median, 9.0 vs. 6.1 months).¹⁴ Therefore, we believe that our findings are consistent with those of the NAPOLI-1 study because patients with peritoneal metastasis were more likely to have a better prognosis and to be long-term survivors. By contrast, patients with massive ascites that are accompanied by peritoneal metastasis will have bowel dysfunction and difficulty in defecation, which may lead to reabsorption of SN-38, the active metabolite of irinotecan, from the intestine. Consequently, they will have high serum concentrations of SN-38 and develop severe adverse events caused by its cytotoxicity. Additionally, ascites accumulation with peritoneal metastasis may depend on whether or not vascular permeability increases. Increased vascular permeability is mainly caused by an excess serum concentration of VEGF, and VEGF production is considered proportional to tumour progression.²⁰ Therefore, we speculate that the prognosis may differ between patients with peritoneal dissemination who do not accumulate ascites and those who do. Thus, we suppose the prognostic significance of peritoneal metastasis was clearer when patients with ascites were excluded from the analysis than when all patients with peritoneal metastasis were included.

The subgroup analysis of metastatic sites in the NAPOLI-1 study revealed that among those who received nal-IRI + 5-FU/LV, the OS of patients with peritoneal metastasis was better than that in those without, whereas it was comparable in patients with and without peritoneal metastasis in the 5-FU/LV arm.¹³ It suggests peritoneal metastasis is not only a favourable prognostic factor in patients receiving nal-IRI + 5-FU/LV but also a favourable predictive factor. The underlying mechanism of better efficacy in the presence of peritoneal metastasis may result from the nanoliposomal form of the drug; hence, nal-IRI remains in the peritoneal cavity longer than non-liposomal irinotecan.²¹ Liposomal or albumin-bound drug formulations, other than nal-IRI, include pegylated liposomal doxorubicin (PLD) and nab-paclitaxel. Approximately 80% of PLD remains localized within the peritoneal tissue 24 h after direct instillation into the peritoneal cavity.²² Gangannapalle et al.²³ reported that nab-paclitaxel was more effective than solvent-based paclitaxel in patients with gastric cancer with peritoneal metastasis, although no difference was observed between the two paclitaxel formulations in those without peritoneal metastasis. The authors suggested that the superior efficacy of nab-paclitaxel for peritoneal metastasis could be attributed to its enhanced penetration through the peritoneum, a conclusion based on preclinical studies using a rabbit model.²⁴ Accordingly, we speculate that the nanoliposomal formulation may enhance the efficacy of nal-IRI in patients with peritoneal metastasis of pancreatic cancer. Our study did not include patients receiving treatments other than nal-IRI + 5-FU/LV, and we could not evaluate the interaction between peritoneal metastasis and nal-IRI-containing treatment. Nevertheless, the use of nal-IRI + 5-FU/LV treatment in patients with peritoneal metastasis should be considered, although it should be used with caution in those with malignant ascites.

The prognostic significance of peritoneal metastasis without ascites warrants further validation. A previous report identified peritoneal metastasis as a poor prognostic factor in patients with advanced pancreatic cancer treated with nal-IRI + 5-FU/LV; however, that study did not differentiate between patients with and without ascites.²⁵ Furthermore, an ongoing clinical trial (NCT05277766) is investigating the pharmacokinetics and pharmacodynamics of intraperitoneal chemotherapy using nal-IRI, including drug concentrations in plasma, tumour tissue and the peritoneal cavity. The results of this study are expected to provide valuable insights into the therapeutic effects of nal-IRI on peritoneal metastasis.

This study has some limitations due to its retrospective nature. First, the multiplicity of analyses without declaring a significant difference in advance could lead to misleading results and interpretations. Second, the limited number of patients, especially those with peritoneal metastasis, raises the possibility that the statistically significant factors observed in this study were coincidental. Third, treatment modification was based on the physician’s discretion, which could vary for each patient. Although a report showed that early dose reduction and treatment delays do not significantly affect the treatment’s efficacy,²⁶ we could not rule out the possibility that such modifications may influence outcomes, as our study did not evaluate these factors beyond initial dose reductions. Despite these limitations, this study is the first to report prognostic factors focused on the site of metastasis, and the findings suggest that peritoneal metastasis may predict the efficacy of nal-IRI + 5-FU/LV treatment.

Conclusion

Good PS, low levels of CRP and CA 19-9 and peritoneal metastasis without ascites were favourable prognostic factors for survival in patients with unresectable pancreatic cancer who received nal-IRI + 5-FU/LV treatment. These prognostic and predictive factors for survival will be crucial for guiding clinicians’ decisions regarding second-line treatment selection for patients with advanced pancreatic cancer, particularly when choosing between nal-IRI + 5-FU/LV and alternative regimens.

Supplemental Material

sj-docx-1-tam-10.1177_17588359251351540 – Supplemental material for Peritoneum carcinomatosis as a favourable prognostic factor for treatment with nanoliposomal irinotecan and fluorouracil plus leucovorin in advanced pancreatic cancer

Supplemental material, sj-docx-1-tam-10.1177_17588359251351540 for Peritoneum carcinomatosis as a favourable prognostic factor for treatment with nanoliposomal irinotecan and fluorouracil plus leucovorin in advanced pancreatic cancer by Satoshi Kobayashi, Taito Fukushima, Shun Tezuka, Kazumasa Shiraishi, Masato Enomoto, Shotaro Tsunoda, Tomomi Hamaguchi, Ritsuko Ohishi, Yuichiro Tozuka, Masaaki Murakawa, Naoto Yamamoto, Makoto Ueno, Junji Furuse and Shin Maeda in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Satoshi Kobayashi

Supplemental material

Supplemental material for this article is available online.

References

International Agency for Research on Cancer. GLOBOCAN, https://gco.iarc.fr/ (accessed 28 August 2024).

Conroy

Desseigne

Ychou

, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364: 1817–1825.

Von Hoff

Ervin

Arena

, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369: 1691–1703.

NCCN Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma. Version 3.2024, https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf (accessed 28 August 2024).

Wang-Gillam

Bodoky

, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet 2016; 387: 545–557.

Ueno

Nakamori

Sugimori

, et al. Nal-IRI + 5-FU/LV versus 5-FU/LV in post-gemcitabine metastatic pancreatic cancer: randomized phase 2 trial in Japanese patients. Cancer Med 2020; 9: 9396–9408.

Wang-Gillam

Hubner

Siveke

, et al. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: final overall survival analysis and characteristics of long-term survivors. Eur J Cancer 2019; 108: 78–87.

Ozaka

Nakachi

Kobayashi

, et al. A randomised phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel for locally advanced pancreatic cancer (JCOG1407). Eur J Cancer 2023; 181: 135–144.

Sudo

Nakamura

Ueno

, et al. Clinical utility of BRCA and ATM mutation status in circulating tumour DNA for treatment selection in advanced pancreatic cancer. Br J Cancer 2024; 131: 1237–1245.

10.

The Strengthening the Reporting of Observatinal Studies in Epidemiology (STORBE) Statement. Equator Network, https://www.equator-network.org/reporting-guidelines/strobe/ (accessed 5 April 2025).

11.

Eisenhauer

Therasse

Bogaerts

, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–247.

12.

Ohba

Ozaka

Ogawa

, et al. 1616O Nab-paclitaxel plus gemcitabine versus modified FOLFIRINOX or S-IROX in metastatic or recurrent pancreatic cancer (JCOG1611, GENERATE): a multicentred, randomized, open-label, three-arm, phase II/III trial. Ann Oncol 2023; 34: S894.

13.

Pishvaian

Blais

Brody

, et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol 2020; 21: 508–518.

14.

Macarulla Mercadé

Chen

, et al. Liposomal irinotecan + 5-FU/LV in metastatic pancreatic cancer: subgroup analyses of patient, tumor, and previous treatment characteristics in the pivotal NAPOLI-1 trial. Pancreas 2020; 49: 62–75.

15.

Boeck

Hinke

Wilkowski

, et al. Importance of performance status for treatment outcome in advanced pancreatic cancer. World J Gastroenterol 2007; 13: 224–227.

16.

Stotz

Gerger

Eisner

, et al. Increased neutrophil-lymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer. Br J Cancer 2013; 109: 416–421.

17.

Maisey

Norman

Hill

, et al. CA19-9 as a prognostic factor in inoperable pancreatic cancer: the implication for clinical trials. Br J Cancer 2005; 93: 740–743.

18.

Levine

Rompen

Franco

, et al. The impact of metastatic sites on survival rates and predictors of extended survival in patients with metastatic pancreatic cancer. Pancreatology 2024; 24: 887–893.

19.

Wattenberg

Herrera

Giannone

, et al. Systemic inflammation is a determinant of outcomes of CD40 agonist-based therapy in pancreatic cancer patients. JCI Insight 2021; 6: e145389.

20.

Jacob

Sangeerthana

Razack

, et al. Malignancy of malignant ascites: a comprehensive review of interplay between biochemical variables, tumor microenvironment and growth factors. Asian Pac J Cancer Prev 2024; 25: 3413–3420.

21.

Choi

Harper

Pandalai

, et al. A multicenter phase 1 trial evaluating nanoliposomal irinotecan for heated intraperitoneal chemotherapy combined with cytoreductive surgery for patients with peritoneal surface disease. Ann Surg Oncol 2023; 30: 804–813.

22.

Sugarbaker

Stuart

OA.

Pharmacokinetics of the intraperitoneal nanoparticle pegylated liposomal doxorubicin in patients with peritoneal metastases. Eur J Surg Oncol 2021; 47: 108–114.

23.

Gangannapalle

Shahnoor

Sattar

, et al. Nanoparticle albumin‑bound paclitaxel and solvent-based paclitaxel as chemotherapy options for patients with advanced gastric cancer: a systematic review and meta-analysis. Cureus 2023; 15: e41711.

24.

Coccolini

Acocella

Morosi

, et al. High penetration of paclitaxel in abdominal wall of rabbits after hyperthermic intraperitoneal administration of nab-paclitaxel compared to standard paclitaxel formulation. Pharm Res 2017; 34: 1180–1186.

25.

Yang

Huang

Chiu

, et al. Improved survival with adding-on strategy after failure of nanoliposomal irinotecan plus 5-fluorouracil and leucovorin in metastatic pancreatic adenocarcinoma. J Formos Med Assoc. Epub ahead of print March 2025. DOI: 10.1016/j.jfma.2025.02.035.

26.

Chen

Macarulla

Blanc

, et al. Early dose reduction/delay and the efficacy of liposomal irinotecan with fluorouracil and leucovorin in metastatic pancreatic ductal adenocarcinoma (mPDAC): a post hoc analysis of NAPOLI-1. Pancreatology 2021; 21: 192–199.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.03 MB