Intraperitoneal chemotherapy for ovarian cancer using sustained-release implantable devices

ABSTRACT

Introduction: Epithelial ovarian cancer (EOC) remains to be the most lethal of all gynecological malignancies mainly due to its asymptomatic nature. The late stages are manifested with predominant metastases confined to the peritoneal cavity. Although there has been a substantial progress in the treatment avenue with different therapeutic interventions, the overall survival rate of patients remain poor due to relapse and drug resistance.

Areas covered: The pharmacokinetic advantages offered by intraperitoneal (IP) chemotherapy due to peritoneal–plasma barrier can be potentially exploited for EOC relapse treatment. The ability to retain high concentrations of chemo-drugs with high AUC peritoneum/plasma for prolonged durations in the peritoneal cavity can be utilized effectively through the clinical adoption of drug delivery systems (DDSs) which obviates the need for indwelling catheters. The metronomic dosing strategy could enhance anti-tumor efficacy with a continuous, low dose of chemo-drugs providing minimal systemic toxicity.

Expert opinion: The development of a feasible, non-catheter based, IP DDS, retaining the peritoneal-drug levels, with less systemic levels could offer significant survival advantages as a patient-compliant therapeutic strategy. Suturable-implantable devices based on metronomic dosing, eluting drug in a sustained manner at low doses, could be implanted surgically post-debulking for treatment of refractory EOC patients.

KEYWORDS:

• Intraperitoneal therapy
• ovarian cancer
• localized drug delivery
• sustained release
• peritoneum
• metronomic dosing

Article Highlights

• EOC is the most lethal of all gynecological malignancies mainly due to the asymptomatic nature of the disease as well as the lack of early detection techniques. Despite the treatment strategies, the overall survival rate is poor due to relapse as well as drug resistance issues.

• The principal site for the spread of ovarian cancer at late stages is the peritoneum. Intraperitoneal administration of drugs exclusively into the peritoneal cavity is pharmacokinetically advantageous due to the presence of peritoneal–plasma barrier and delayed peritoneal clearance of the drug which helps to retain its concentrations in the cavity.

• The frequent dosing of chemotherapy drugs with indwelling catheters into the abdomen creates toxicity issues and catheter-associated complications, making them highly non-compliant for patient use.

• Metronomic dosing could ensure better anti-tumor activity by providing continuous low drug levels for sustained periods and reduced systemic toxicity.

• Although micro/nano particulate DDS, injectable depots, implantable devices etc have been explored as IP DDS for exploiting the pharmacokinetic advantages of IP therapy, none of them have been clinically approved for IP therapy.

• An ideal IP DDS would be an implantable depot that can be fixed within the abdomen, eluting the chemotherapy drug metronomically, retaining therapeutic drug levels in the peritoneum with less systemic drug levels, and providing enhanced anti-tumor activity with less toxicity.

This box summarizes key points contained in the article.

Acknowledgments

The authors would like to acknowledge Northeastern University, Boston, MA and Amrita Vishwa Vidyapeetham, Kochi for all infrastructural support and for carrying out the research work.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The authors would like to acknowledge the financial support from Department of Biotechnology, Government of India through the project grant-in-aid 6242-P74/RGCB/PMD/DBT/DPMN/2015. One of the authors SP acknowledges the Department of Science & Technology, Government of India for the Inspire Senior Research Fellowship.