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Plasmafiltration as an effective method in the removal of circulating pegylated liposomal doxorubicin (PLD) and the reduction of mucocutaneous toxicity during the treatment of advanced platinum-resistant ovarian cancer

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Abstract

Purpose

The present study evaluates the safety and efficacy of double-plasma filtration (PF) to remove the exceeding pegylated liposomal doxorubicin (PLD) in circulation, thus reducing mucocutaneous toxicity.

Methods

A total of 16 patients with platinum-resistant ovarian cancer were treated with 50 mg/m2 PLD applied in 1-h IV infusion every 28 days. PF was scheduled at 44–46 h post-infusion. The concentration of plasma PLD and non-liposomal doxorubicin (NLD) was monitored with high-performance liquid chromatography at 116 h post-infusion. A non-linear method for mixed-effects was used in the population pharmacokinetic model. The dose fraction of PLD eliminated by the patient prior to PF was compared with the fraction removed by PF. PLD-related toxicity was recorded according to CTCAE v4.0 criteria and compared to historical data. Anticancer effects were evaluated according to RECIST 1.1 criteria.

Results

The patients received a median of 3 (2–6) chemotherapy cycles. A total of 53 cycles with PF were evaluated, which removed 31% (10) of the dose; on the other hand, the fraction eliminated prior to PF was of 34% (7). Exposure to NLD reached only 10% of exposure to the parent PLD. PLD-related toxicity was low, finding only one case of grade 3 hand–foot syndrome (6.7%) and grade 1 mucositis (6.7%). Other adverse effects were also mild (grade 1–2). PF-related adverse effects were low (7%). Median progression-free survival (PFS) and overall survival (OS) was of 3.6 (1.5–8.1) and 7.5 (1.7–26.7) months, respectively. Furthermore, 33% of the patients achieved stable disease (SD), whereas that 67% progressed.

Conclusion

PF can be considered as safe and effective for the extracorporeal removal of PLD, resulting in a lower incidence of mucocutaneous toxicity.

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Abbreviations

AmPF :

Dose (%) eliminated during plasmafiltration

Amuntil PF :

Dose (%) eliminated before plasmafiltration

AUC:

Area under the concentration–time curve

AUC0−tlast :

Area under the concentration–time curve from zero until tlast

AUCtlast−∞ :

Area under the concentration–time curve tlast until infinity

CHT:

Chemotherapy

CLn :

Native (endogenous) clearance (CLuntilPF + CLpostPF)

CLPF :

Extracorporeal clearance

CLpostPF :

PLD clearance after PF termination up to the last plasma concentration at 117 h after PLD administration

CLuntilPF :

Estimated PLD clearance before PF at 45–47 h after PLD administration

C last :

Plasma concentration predicted for the last sampling interval

C max :

Maximum plasma concentration

CR:

Complete response

CT:

Computed tomography

C Tmax :

Peak (Cmax) plasma concentration in tumors

ECOG:

Eastern Cooperative Oncology Group

EOC:

Epithelial ovarian cancer

EPR:

Enhanced permeability and retention effect

HPLC:

High-performance liquid chromatography

IV:

Intravenous

LVEF:

Left ventricular ejection fraction

MRI:

Magnetic resonance imaging

NLD:

Non-liposomal doxorubicin

NP:

Nanoparticles

OS:

Overall survival

PD:

Progressive disease

PF:

Plasmafiltration

PFI:

Platinum-free interval

PFS:

Progression-free survival

PK:

Pharmacokinetic

PLD:

Pegylated liposomal doxorubicin

PPE:

Palmar–plantar erythrodysesthesia (hand–foot syndrome)

PR:

Partial response

PS:

Performance status

Q12:

Inter-compartmental clearance

QTc:

Corrected QT interval

RECIST:

Response Evaluation Criteria in Solid Tumors

SD:

Stable disease

SPC:

Summary of product characteristics

t 1/2 :

Elimination half-life

t last :

Last sampling interval

TD:

Toxicodynamics

V 1 :

Distribution volume of the central compartment

V 2 :

Distribution volume of the peripheral compartment

λ z :

Terminal slope on the loge (concentration)–time curve

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Acknowledgements

The authors thank Dr. Gerhard Pütz (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Freiburg) for his invaluable advice. The authors wish to thank Dr. Daniel Díaz, Ph.D. for his kind assistance in English language revision and proofreading.

Funding

The present study was supported by the Grant AZV 16-30366A from the Ministry of Health, CZ and PROGRES Q40/06.

Author information

Authors and Affiliations

  1. Department of Oncology and Radiotherapy, Faculty of Medicine, University Hospital in Hradec Králové, Charles University, Sokolská 581, 50005, Hradec Králové, Czech Republic

    Ondřej Kubeček, Miroslav Hodek & Stanislav Filip

  2. Department of Surgery, Faculty of Medicine, University Hospital in Hradec Králové, Charles University, Sokolská 581, 50005, Hradec Králové, Czech Republic

    Jiřina Martínková

  3. Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University, Šimkova 870, 50003, Hradec Králové, Czech Republic

    Jaroslav Chládek

  4. 4th Department of Internal Medicine-Hematology, Faculty of Medicine, University Hospital in Hradec Králové, Charles University, Sokolská 581, 50005, Hradec Králové, Czech Republic

    Milan Bláha

  5. Institute of Clinical Biochemistry and Diagnostics, Faculty of Medicine, University Hospital in Hradec Králové, Charles University, Sokolská 581, 50005, Hradec Králové, Czech Republic

    Jana Maláková

  6. Department of Obstetrics and Gynecology, Faculty of Medicine, University Hospital in Hradec Králové, Charles University, Sokolská 581, 50005, Hradec Králové, Czech Republic

    Jiří Špaček

Authors
  1. Ondřej Kubeček
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  4. Milan Bláha
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  8. Stanislav Filip
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Contributions

The authors SF, JM (Jiřina Martínková), MB, JS and OK developed the trial outline, protocols and applied for ethics committee approval; The authors OK, MH, and JS were responsible for patient information and obtaining written consent; OK, MH, and SF were responsible for chemotherapy administration and patient care at the Department of Gynecology, University Hospital in Hradec Králové, while MB was responsible for the extracorporeal treatment at the Apheresis Center, 4th Department of Internal Medicine, University Hospital in Hradec Králové. JM (Jana Maláková) performed the analysis of serum PLD and NLD concentrations; JC was responsible for the model calculations of population pharmacokinetics and statistic evaluation, while JM (Jiřina Martínková) performed data analysis and interpretation of pharmacokinetic parameters; The manuscript was drafted by OK, while the authors JM (Jiřina Martínková), JC, MB, and SF made major contributions and improvements. All authors read and approved the final manuscript.

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Correspondence to Stanislav Filip.

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Kubeček, O., Martínková, J., Chládek, J. et al. Plasmafiltration as an effective method in the removal of circulating pegylated liposomal doxorubicin (PLD) and the reduction of mucocutaneous toxicity during the treatment of advanced platinum-resistant ovarian cancer. Cancer Chemother Pharmacol 85, 353–365 (2020). https://doi.org/10.1007/s00280-019-03976-2

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