Liposomal irinotecan plus fluorouracil/leucovorin in older patients with advanced pancreatic cancer: a single-center retrospective study

doi:10.21203/rs.3.rs-2947171/v1

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Liposomal irinotecan plus fluorouracil/leucovorin in older patients with advanced pancreatic cancer: a single-center retrospective study

https://doi.org/10.21203/rs.3.rs-2947171/v1

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published 22 Nov, 2023

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Background: The global phase 3 NAPOLI -1 trial of patients with pancreatic ductal adenocarcinoma demonstrated an overall survival (OS) benefit from using liposomal irinotecan and 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) after treatment with gemcitabine when compared to 5-FU/LV alone. However, the efficacy and safety of this regimen in older patients are not well studied.

Methods: This single-center retrospective study compared results of nal-IRI+5FU/LV between older and younger patients.

Results: Of 115 patients, 54 (47.0%) and 24 (20.9%) were aged ≥70 and ≥75 years, respectively. The median OS and progression-free survival of the entire cohort were 8.5 and 3.6 months, respectively. There were no significant differences in OS and PFS hazard ratios using cutoffs of 70 years (P = 0.90 and 0.99, respectively) and 75 years (P = 0.90 and 0.76, respectively). There were also no significant differences in the incidence of treatment-related adverse events between patients aged ≥70 and <70 years, or those aged ≥75 and <75 years. Other than hematological toxicity, no treatment-related adverse events higher than Grade 4 were observed in either age group.

Conclusion: The efficacy and safety of nal-IRI+5-FU/LV for patients with pancreatic ductal adenocarcinoma are not significantly different for patients aged 70 years and older compared to younger patients.

liposomal irinotecan

fluorouracil/leucovorin

aging

pancreatic ductal adenocarcinoma

second-line treatment

NAPOLI-1 trial

Pancreatic ductal adenocarcinoma (PDAC) is one of the intractable cancers and ranks third and fourth for cancer-related mortality in the United States and Europe, respectively [1, 2]. More than 80% of PDAC cases are diagnosed with distant metastases; curative treatment is difficult for these patients, contributing to high mortality and low survival [3]. Systemic chemotherapy is the standard of care in the treatment of PDAC. For patients with metastatic PDAC, gemcitabine (GEM), nab-paclitaxel combination, and fluorouracil, leucovorin, irinotecan (IRI), and oxaliplatin combination have been established as standard first-line treatments [4, 5]. However, despite recent advances in chemotherapy, almost all cases of PDAC eventually progress after these first-line treatments. Accordingly, second-line treatments for these patients are essential.

In the NAPOLI-1 phase 3 trial of patients with PDAC, liposomal irinotecan (nal-IRI) in combination with 5-fluorouracil/leucovorin (5-FU/LV) increased overall survival (OS) compared with 5-FU/LV alone [6]. Consequently, nal-IRI + 5-FU/LV is considered standard treatment for patients with PDAC refractory to GEM-based regimens. Pancreatic cancer in older adults is increasing in Japan, with more than 50% of new cases occurring in people > 75 years [7]. Subgroup analysis of the NAPOLI-1 study reported that the risks of disease progression and mortality in the older patients were comparable to those in younger patients. However, the limited number of older participants (31 ≥ 70 years and 14 ≥ 70 years) did not allow a thorough assessment of the efficacy and safety of nal-IRI + 5-FU/LV in these patients [8]. Further, the report did not fully evaluate the usefulness of nal-IRI + 5-FU/LV for older patients in daily practice. Therefore, we aimed to evaluate the efficacy and safety of second-line nal-IRI + 5-FU/LV treatment for PDAC in older patients in our facility.

Overview

This single-center retrospective study was approved by the Kanagawa Cancer Center Institutional Review Board and conducted in accordance with the ethical principles of the Declaration of Helsinki. Although written or oral consent was not obtained from the research subjects, the opportunity to decline inclusion was provided.

Patient eligibility

Patients were identified from records extracted from our institution’s electronic records system. Eligible patients met the following criteria: an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2, no documentation in their medical records of massive ascites, watery diarrhea, and paralytic ileus, pathologically proven PDAC, unresectable disease, prior history of one or more GEM-based regimens, and initiation of nal-IRI + 5-FU/LV between June 2020 and January 2021.

Treatment

Patients received Nal-IRI, 70 mg/m² over 90 min; LV, 400 mg/m² over 30 min; and 5-FU, 2400 mg/m² over 46 h every two weeks, as possible [6, 9]. The initial dose was reduced in a small number of patients at the physician's discretion, based on the patient's condition. Treatment was continued until disease progression, intolerable toxicity, or patient refusal occurred; subsequent treatment was based on the physician's discretion and the patient's condition.

Outcomes and analyses

The observation period lasted until March 31, 2022. The study outcomes were progression-free survival (PFS), OS, disease control rate (DCR), objective response rate (ORR), and treatment-related adverse events (trAEs). PFS was defined as the interval from the initial date of nal-IRI + 5-FU/LV treatment to the date of documented disease progression, death from any cause, or last follow-up. OS was calculated from the initial date of nal-IRI + 5-FU/LV treatment to the date of death from any cause or last follow-up. Objective response was evaluated according to Response Evaluation Criteria in Solid Tumor version 1.1 [10], and ORR was calculated as the number of patients whose best response was complete (CR) or partial (PR), divided by the total number of patients. DCR was calculated as the number of patients whose best response was CR, PR, or stable, divided by the number of patients whose radiological response was available. TrAEs were evaluated using the Common Terminology Criteria for Adverse Events, version 5.0 [11].

Statistical analyses

We compared the efficacy and safety between the ≥ 70 and < 70 years patient groups and between the ≥ 75 and < 75 years groups. The Kaplan-Meier method was used to obtain the median OS and PFS, and the log-rank test was used to compare OS and PFS between the groups. Hazard ratios (HR) were calculated using the Cox proportional hazards model. Multi- and univariate analyses were performed using the Cox proportional hazard model to disclose the prognostic factors for survival. Fisher's exact test and Mann-Whitney U test were used to compare nominal and continuous variables between groups, respectively. Statistical significance was considered as a P-value < 0.05.

Patient's background

One hundred and fifteen patients were eligible for the study. Patient characteristics are shown in Table 1. Patients aged 70 years or older accounted for 47.0% of the total, while those aged 75 years or older represented 20.9%. The proportion of patients with an ECOG Performance Status of 0 increased with age: 39.3%, 48.1% and 50% in patients aged < 70, ≥70 and ≥ 75 years, respectively. Over 50% of patients in each age group had a history of receiving two or more regimens of chemotherapy.

Table 1

Patient demographics, by age group
	< 70 years	≥ 70 years	< 75 years	≥ 75 years
Number of patients	61	54	91	24
Gender
Male	38 (62.3)	34 (63.0)	56 (61.5)	16 (66.7)
Female	23 (37.7)	20 (37.0)	35 (38.5)	8 (33.3)
UICC^†Stage
Stage III	7 (11.5)	4 (7.4)	9 (9.9)	2 (8.3)
Stage IV	54 (88.5)	50 (92.6)	82 (90.1)	22 (91.7)
ECOG^‡Performance status
0	24 (39.3)	26 (48.1)	38 (41.8)	12 (50.0)
1	35 (57.4)	27 (50.0)	50 (54.9)	12 (50.0)
2	2 (3.3)	1 (1.9)	3 (3.3)	0 (0.0)
Number of prior treatments
1	27 (44.3)	25 (46.3)	44 (48.4)	8 (33.3)
2	34 (55.7)	29 (53.7)	47 (51.6)	16 (66.7)
History of IRI-containing^∫regimen	19 (31.1)	8 (14.8)	23 (25.3)	4 (16.7)
Albumin (g/dL), median (range)	3.7 (2.4–4.4)	3.5 (2.5–4.8)	3.6 (2.4–4.4)	3.4 (2.7–4.8)
CEA^§(ng/mL), median (range)	9.0 (1.0-957.2)	7.1 (1.1-458.6)	8.0 (1.0-957.2)	7.7 (1.8-150.9)
CA19-9^¶(U/mL), median (range)	1073.6 (2.0-513560.0)	479.3 (2.0-333420.0)	952.2 (2.0-513560.0)	658.4 (2.0-275630.0)
^†UICC, Union for International Cancer Control; ^‡ECOG, Eastern Cooperative Oncology Group;^∫IRI, irinotecan; ^§CEA, carcinoembryonic antigen; ^¶CA 19 − 9, carbohydrate antigen 19 − 9.

Treatment

The proportion of patients who initiated with a reduced dosage was significantly higher in older than in younger patients: 18% of patients aged < 70 years vs. 37% of patients aged ≥ 70 years (P = 0.03), and 23% of patients aged < 75 years vs. 42% of patients aged ≥ 75 years (P = 0.08). Reasons for initiating with a reduced dose are shown in Online Resource 1. There were no significant differences in the median number of doses between the age groups: six cycles in both patients aged < 70 years and those aged ≥ 70 years (P = 0.70), and seven cycles in patients < 75 years vs. five cycles in patients aged ≥ 75 years (P = 0.67). There was no significant difference in the proportion of patients who experienced one or more treatment delays due to adverse events: 38% of patients aged < 70 years vs. 35% of patients aged ≥ 70 years (P = 0.85), and 34.0% of patients aged < 75 years vs. 45.8% of patients aged ≥ 75 years (P = 0.08). Reasons for treatment delays are described in Online Resource 2. There were no significant differences in the percentage of patients who received reduced dosages during treatment; the reasons for dose reductions during treatment are described in Online Resource 3.

Efficacy

With a median follow-up time of 10.6 months, the median OS and PFS in the entire cohort were 8.5 and 3.6 months (95% confidence interval [CI], 6.7–10.5 and 3.1–4.6), respectively (Online Resource 4).Comparing patients < 70 vs. ≥70 years old, the median OS were 8.4 months (95% CI, 6.4–11.0) and 7.9 months (95% CI, 5.8–11.0), respectively, with an HR of 1.03 (95% CI, 0.67–1.56; P = 0.90) (Fig. 1-A). The median PFS were 3.6 months (95% CI, 3.1–5.0) and 3.4 months (95% CI, 2.8–5.4), respectively with an HR of 1.00 (95% CI, 0.67–1.49; P = 0.99) (Fig. 1-B). The ORR for patients < 70 and ≥ 70 years old was 3.4% and 2.0%, respectively (P = 1.00), and their DCR was 63.7% and 61.2%, respectively (P = 1.00).

Using 75 years as the cutoff, there were no significant differences in OS and PFS between younger and older patients (Figs. <link rid="fig1">1</link>-C and 1-D).

Safety

TrAEs observed in patients aged < 70 years and ≥ 70 years are shown in Table 2. The most common adverse events were neutropenia, nausea, anorexia and leukopenia in patients aged < 70 years, and anemia, neutropenia, leukopenia and anorexia in patients aged ≥ 70 years. Regarding to Grade 3 and Grade 4 trAEs, neutropenia was the most common in both patients aged < 70 years (33%) and ≥ 70 years (36%), while all non-hematological adverse events were less than 10%. In patients < 70 years old, nausea in all grades was significantly higher than in those ≥ 70 years (P = 0.0002). The results of safety comparison between patients aged < 75 and ≥ 75 years were similar to those observed in the group using 70 years as the cutoff. (Online Resource 5).

Table 2

Incidence of treatment related adverse events, by patient age group
	Tatal		All grade	Grade 2	Grade 3	Grade 4
Fatigue	33 (28%)	≥ 70 years	15 (28%)	10 (19%)	1 (2%)	0 (0%)
Fatigue	33 (28%)	< 70 years	17 (28%)	12 (20%)	0 (0%)	0 (0%)
Nausea	40 (34%)	≥ 70 years	9 (17%)	1 (2%)	0 (0%)	0 (0%)
Nausea	40 (34%)	< 70 years	31 (51%)	18 (30%)	2 (3%)	0 (0%)
Anorexia	48 (41%)	≥ 70 years	19 (35%)	6 (11%)	2 (4%)	0 (0%)
Anorexia	48 (41%)	< 70 years	29 (48%)	17 (28%)	2 (3%)	0 (0%)
Vomiting	8 (7%)	≥ 70 years	1 (2%)	0 (0%)	0 (0%)	0 (0%)
Vomiting	8 (7%)	< 70 years	7 (12%)	1 (2%)	1 (2%)	0 (0%)
Diarrhea	30 (26%)	≥ 70 years	15 (28%)	7 (13%)	3 (6%)	0 (0%)
Diarrhea	30 (26%)	< 70 years	15 (25%)	3 (3%)	5 (4%)	0 (0%)
Constriction	14 (12%)	≥ 70 years	5 (9%)	2 (4%)	1 (2%)	0 (0%)
Constriction	14 (12%)	< 70 years	9 (8%)	5 (4%)	0 (0%)	0 (0%)
Leukopenia	44 (38%)	≥ 70 years	20 (37%)	7 (13%)	10 (19%)	0 (0%)
Leukopenia	44 (38%)	< 70 years	24 (39%)	12 (19%)	7 (11%)	0 (0%)
Neutropenia	68 (59%)	≥ 70 years	32 (59%)	9 (17%)	12 (22%)	6 (11%)
Neutropenia	68 (59%)	< 70 years	36 (56%)	8 (13%)	19 (30%)	4 (6%)
Thrombocytopenia	14 (12%)	≥ 70 years	6 (11%)	6 (11%)	0 (0%)	0 (0%)
Thrombocytopenia	14 (12%)	< 70 years	8 (7%)	10 (2%)	2 (3%)	0 (0%)
Anemia	66 (58%)	≥ 70 years	35 (65%)	23 (43%)	7 (13%)	0 (0%)
Anemia	66 (58%)	< 70 years	31 (27%)	9 (8%)	8 (7%)	0 (0%)

Analysis of prognostic factors

In the multivariate analysis, only serum levels of albumin < 3.5 g/dL, PS of 1–2, and carbohydrate antigen 19 − 9 ≥ 1000 U/mL were independent prognostic factors for OS (Table 3 and Online Resource 6).

Table 3

Multivariate analysis of prognostic factors for overall survival by patient age group, using an age cut-off of 70 years
	univariate analysis	multivariate analysis
	P-value	Hazard ratio (HR)	95% Confidence Interval [CI]	P-value
< 70 years (vs. ≥ 70 years)	0.90	1.04	0.66–1.64	0.86
UICC^†Stage III (vs. Stage IV)	0.34	1.48	0.71–3.07	0.29
Albumin ≤ 3.5 g/dl (vs. >3.5 g/dl)	0.05	2.18	1.37–3.48	0.001
ECOG PS^‡0 (vs. 1–2)	< 0.001	0.40	0.25–0.62	< 0.001
History of IRI^∫-containing regimen: no (vs. yes)	0.52	0.89	0.53–1.47	0.64
CA 19 − 9^§<1000 U/ml (vs. ≥1000 U/ml)	0.004	0.42	0.27–0.67	< 0.001
^†UICC, Union for international cancer control; ^‡ECOG PS, Eastern Cooperative Oncology Group performance status;^∫IRI, irinotecan; ^§CA 19 − 9, carbohydrate antigen 19 − 9.

We conducted a single-center retrospective study to evaluate the efficacy and safety of nal-IRI + 5-FU/LV in 115 Japanese patients with advanced PDAC, including 54 patients ≥ 70 years and 24 patients ≥ 75 years. In this study, the efficacy and safety of nal-IRI + 5-FU/LV in older patients were comparable with those in younger patients. Age was not a significant prognostic factor for OS using a cutoff age of either 70 or 75 years.

Patients with PDAC aged ≥ 70 and ≥ 75 years have been reported to account for 50% and 36–39% of all pancreatic cancer patients, respectively [1, 2, 12]. Our study included more older patients with advanced pancreatic cancer than did the NAPOLI − 1 clinical trial. Therefore, we were able to investigate the outcomes of older patients who received nal-IRI + 5-FU/LV in daily clinical practice. Our findings revealed that PFS did not differ between older and younger patients, and that OS was not lower in older patients. Importantly, the OS and PFS obtained in our study were comparable to those of the older subgroups of the NAPOLI-1 trial [8].

Although safety is an issue for older patients, the results of our study showed no significant difference in the incidence of trAEs of nal-IRI + 5-FU/LV between older and younger patients, which is consistent with NAPOLI-1 subanalyse [8]. We speculate two reasons for our results. First, the mechanism of action of nal-IRI may contribute to its safety results. In general, older patients have a decreased ability to metabolize drugs owing to lower muscle mass, leading to increased blood levels of antineoplastic drugs and an increased incidence of trAEs [13, 14]. In contrast, nal-IRI is designed to be distributed to tumors rather than to normal organs [15], and may be safer to use in older people with typically low muscle volume. Second, more physicians prescribed initial dose reduction in older patients than in younger patients – 37% and 42% for patients aged ≥ 70 and ≥ 75 years compared with about 18% and 23% of those aged < 70 and < 75 years. This may have resulted in the comparable results of dose reduction and delays during treatment between the older and younger patients. Nevertheless, we note that the efficacy in older patients was comparable to that in young patients even when the older patients had lower intensity of the treatment. This finding is supported by a previous study that concluded neither early dose reduction nor treatment delay affected the efficacy of nal-IRI + 5-FU/LV [16]. Therefore, in older patients, we recommend taking into account their condition before determining or adjusting treatment doses.

The 2017 Life Tables of the United States reported that the lowest 25th percentile of life expectancy at age 80 was also more than four to five years [17]. The median OS of the patients enrolled in our study was only 8–9 months, and pancreatic cancer was a significant prognosticator, even in patients aged 80 years. Therefore, effective chemotherapy is essential for prolonging health in older patients, and a regimen containing nal-IRI, considered safe, should be proposed for this population.

There were several limitations to this study. First, the number of older patients was small. However, the number of patients aged ≥ 70 was higher than in previously reported studies. Second, our comparisons of older and younger patients may have been affected by bias due to background factors, such as a higher proportion of patients with ECOG Performance Status of 0 in the older patients than in the younger ones. This would imply that our older patients receiving nal-IRI + 5-FU/LV were in better health than the younger patients. Moreover, the proportion of patients with prior history of IRI-containing regimens was higher in the younger group. Therefore, we think general conditions, such as a performance status of 0, should be considered before administering nal-IRI + 5-FU/LV in older patients. Third, the study design was retrospective, and mild trAEs, such as Grades 1–2, may not have been picked up at the time of data collection. Despite these limitations, we believe our study will help older patients and physicians in considering the use of nal-IRI + 5-FU/LV as a treatment for advanced pancreatic cancer.

Our study of patients with PDAC found that Nal-IRI + 5-FU/LV is a feasible, safe, and effective second-line treatment in older as well as younger patients. These results should be further evaluated through a larger, prospective study.

Conflict of Interest

All authors declare that: (i) no support, financial or otherwise, has been received from any organization that may have an interest in the submitted work; and (ii) there are no other relationships or activities that could appear to have influenced the submitted work.

Acknowledgments

None

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You are reading this latest preprint version

Liposomal irinotecan plus fluorouracil/leucovorin in older patients with advanced pancreatic cancer: a single-center retrospective study

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Abstract

Figures

Introduction

Patients and Methods

Overview

Patient eligibility

Treatment

Outcomes and analyses

Statistical analyses

Results

Patient's background

Treatment

Efficacy

Safety

Analysis of prognostic factors

Discussion

Conclusion

Declarations

References

Supplementary Files

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