Abstract
Intraperitoneal (IP) delivery of cisplatin was developed in the 1970s based on a strong pharmacologic rationale and rodent models. Its advantage over intravenous (IV) administration was supported initially by observational studies in treating recurrent ovarian cancer and eventually by better outcomes from IP vs. IV cisplatin in randomized studies in patients undergoing optimal surgical debulking at diagnosis. In the past two decades, with the introduction of novel anticancer interventions (such as taxanes, bevacizumab, inhibitors of DNA repair, and immune check point inhibitors), advantages of IP drug delivery are less clear and concerns are raised on cisplatin's therapeutic index. The discovery of BRCA genes and their key role in DNA repair, on the other hand, have strengthened the rationale for IP drug delivery: high grade serous cancers arising in the Mullerian epithelium in association with hereditary or somatic BRCA function inactivation are linked to peritoneal spread of cells that - while initially sensitive - are prone to emergence of platinum resistance. Therefore, selection of patients based on genomic features and focusing on the better tolerated IP carboplatin are ongoing. Recent examples of leveraging the peritoneal route include (1) targeting the cell membrane copper transport receptor - that is shared by platinums - by the combination of the proteasome inhibitor bortezomib and IP carboplatin; and (2) enhancing IP 5-fluoro-2-deoxyuridine cytotoxicity when coupled with PARP inhibition.
Highlights
Platinum resistance is the central issue in the treatment of most ovarian cancers
In its clinical development, cisplatin showed unprecedented activity against ovarian cancer - a disease that is usually diagnosed at advanced stages, with surgery most often playing an ancillary role in its treatment
Even “platinum sensitive” recurrences may reflect some degree of platinum resistance, as suggested by retrospective analysis of 176 women receiving two or more platinum-based regimens for recurrent ovarian cancer, with “the length of a prior response highly predictive of the upper limit of the duration of response achieved to a subsequent platinum program”[4]
Summary
Platinum resistance is the central issue in the treatment of most ovarian cancers. The development of cisplatin as an anticancer agent was reviewed by us at the 50th anniversary of the discovery of its potential anticancer properties[1]. In its clinical development, cisplatin showed unprecedented activity against ovarian cancer - a disease that is usually diagnosed at advanced stages, with surgery most often playing an ancillary role in its treatment.
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