Integration of liposomal irinotecan in the first-line treatment of metastatic pancreatic cancer: try to do not think about the white bear

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Abstract

The approval of novel therapeutic agents remains widely reliant on evidence derived from large phase III randomized controlled trials. Liposomal irinotecan (ONIVYDE ^®) stands out as the only drug that has demonstrated improved survival both as a first-line therapy in combination with oxaliplatin and 5-fluorouracil/leucovorin (5FU/LV) (NALIRIFOX) compared to the standard gemcitabine plus nab-paclitaxel in the NAPOLI3 trial, and as a second-line treatment in combination with 5FU/LV compared to the standard 5FU/LV in the NAPOLI1 trial. However, just as the white bear of the Dostoevsky’s paradox, the judgment of these results is invariably distracted by the intrusive thought of how different they might be if compared to similar regimens containing standard-free irinotecan as FOLFIRINOX or FOLFIRI, respectively. Here, we present and thoroughly discuss the evidence encompassing the pharmacologic, preclinical, and clinical development of liposomal irinotecan that can dispel any intrusive thoughts and foster a rational and well-considered judgment of this agent and its potential integration into the therapeutic strategies for pancreatic ductal adenocarcinoma.

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Cancer statistics, 2023

Rebecca L Siegel, Kimberly D Miller, Nikita Sandeep Wagle … (2023)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes using incidence data collected by central cancer registries and mortality data collected by the National Center for Health Statistics. In 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States. Cancer incidence increased for prostate cancer by 3% annually from 2014 through 2019 after two decades of decline, translating to an additional 99,000 new cases; otherwise, however, incidence trends were more favorable in men compared to women. For example, lung cancer in women decreased at one half the pace of men (1.1% vs. 2.6% annually) from 2015 through 2019, and breast and uterine corpus cancers continued to increase, as did liver cancer and melanoma, both of which stabilized in men aged 50 years and older and declined in younger men. However, a 65% drop in cervical cancer incidence during 2012 through 2019 among women in their early 20s, the first cohort to receive the human papillomavirus vaccine, foreshadows steep reductions in the burden of human papillomavirus-associated cancers, the majority of which occur in women. Despite the pandemic, and in contrast with other leading causes of death, the cancer death rate continued to decline from 2019 to 2020 (by 1.5%), contributing to a 33% overall reduction since 1991 and an estimated 3.8 million deaths averted. This progress increasingly reflects advances in treatment, which are particularly evident in the rapid declines in mortality (approximately 2% annually during 2016 through 2020) for leukemia, melanoma, and kidney cancer, despite stable/increasing incidence, and accelerated declines for lung cancer. In summary, although cancer mortality rates continue to decline, future progress may be attenuated by rising incidence for breast, prostate, and uterine corpus cancers, which also happen to have the largest racial disparities in mortality.

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FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.

Thierry Conroy, Françoise Desseigne, Marc Ychou … (2011)

Data are lacking on the efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer. We randomly assigned 342 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival. The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001). As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. (Funded by the French government and others; ClinicalTrials.gov number, NCT00112658.).

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Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.

Daniel Von Hoff, Thomas Ervin, Francis Arena … (2013)

In a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel-gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.).

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Author and article information

Contributors

Davide Melisi:

ORCID: https://orcid.org/0000-0002-4031-7585

Role: ConceptualizationRole: Funding acquisitionRole: Writing – original draftRole: Writing – review & editing

Simona Casalino: Role: Writing – review & editing

Silvia Pietrobono: Role: Writing – review & editing

Alberto Quinzii: Role: Writing – review & editing

Camilla Zecchetto: Role: Writing – review & editing

Valeria Merz:

ORCID: https://orcid.org/0000-0002-2120-1923

Role: ResourcesRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Journal

Journal ID (nlm-ta): Ther Adv Med Oncol

Journal ID (iso-abbrev): Ther Adv Med Oncol

Journal ID (publisher-id): TAM

Journal ID (hwp): sptam

Title: Therapeutic Advances in Medical Oncology

Publisher: SAGE Publications (Sage UK: London, England )

ISSN (Print): 1758-8340

ISSN (Electronic): 1758-8359

Publication date (Electronic): 4 April 2024

Publication date Collection: 2024

Volume: 16

Electronic Location Identifier: 17588359241234487

Affiliations

[1-17588359241234487]Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy

[2-17588359241234487]Digestive Molecular Clinical Oncology Research Unit, University of Verona, Piazzale L.A. Scuro, 10, Verona 37134, Italy

[3-17588359241234487]Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy

[4-17588359241234487]Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy

[5-17588359241234487]Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy

[6-17588359241234487]Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy

[7-17588359241234487]Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy

[8-17588359241234487]Medical Oncology Unit, Santa Chiara Hospital, Trento, Italy

Author notes

[*] davide.melisi@ 123456univr.it

Author information

Davide Melisi https://orcid.org/0000-0002-4031-7585

Valeria Merz https://orcid.org/0000-0002-2120-1923

Article

Publisher ID: 10.1177_17588359241234487

DOI: 10.1177/17588359241234487

PMC ID: 10996353

PubMed ID: 38584763

SO-VID: fae20705-4b7e-4689-aa3f-42b54763a4ca

License:

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

History

Date received : 9 August 2023

Date accepted : 5 February 2024

Funding

Funded by: Associazione Italiana per la Ricerca sul Cancro, FundRef https://doi.org/10.13039/501100005010;

Award ID: 23719

Funded by: Ministero dell'Istruzione e del Merito, FundRef https://doi.org/10.13039/501100024370;

Award ID: PNRR -M4C2- I1.3 763 Project PE_00000019

Funded by: Ministero della Salute, FundRef https://doi.org/10.13039/501100003196;

Award ID: GR-2016-02361134

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cover-date January-December 2024

typesetter ts1

Keywords: liposomal irinotecan,nalirifox,pancreatic ductal adenocarcinoma

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Keywords: liposomal irinotecan, nalirifox, pancreatic ductal adenocarcinoma

Integration of liposomal irinotecan in the first-line treatment of metastatic pancreatic cancer: try to do not think about the white bear

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Most cited references 65

Cancer statistics, 2023

FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.

Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.

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