Localized Delivery of Cisplatin to Cervical Cancer Improves Its Therapeutic Efficacy and Minimizes Its Side Effect Profile

• Published in: International journal of radiation oncology, biology, physics Vol. 109; no. 5; pp. 1483 - 1494
• Main Authors: Federico, Cinzia, Sun, Jennifer, Muz, Barbara, Alhallak, Kinan, Cosper, Pippa F., Muhammad, Naoshad, Jeske, Amanda, Hinger, Amanda, Markovina, Stephanie, Grigsby, Perry, Schwarz, Julie K., Azab, Abdel Kareem
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2021
• Subjects: Adult; Aged; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Biopsy; Cell Line, Tumor; Chemoradiotherapy - methods; Cisplatin - administration & dosage; Cisplatin - adverse effects; Cisplatin - analysis; Cisplatin - pharmacokinetics; DRUG DELIVERY; Drug Implants; Female; Humans; Injections, Intralesional - methods; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; MORTALITY; NEOPLASMS; PATIENTS; Polymers - administration & dosage; RADIATION DOSES; Radiation-Sensitizing Agents - administration & dosage; Radiation-Sensitizing Agents - adverse effects; Radiation-Sensitizing Agents - pharmacokinetics; RADIOLOGY AND NUCLEAR MEDICINE; RADIOTHERAPY; SIDE EFFECTS; Tissue Distribution; TOXICITY; Tumor Burden; Uterine Cervical Neoplasms - chemistry; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; WOMEN
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/j.ijrobp.2020.11.052

Cervical cancer represents the fourth most frequent malignancy in the world among women, and mortality has remained stable for the past 4 decades. Intravenous cisplatin with concurrent radiation therapy is the standard-of-care for patients with local and regional cervical cancer. However, cisplatin induces serious dose-limiting systemic toxicities and recurrence frequently occurs. In this study, we aimed to develop an intracervical drug delivery system that allows cisplatin release directly into the tumor and minimize systemic side effects. Twenty patient biopsies and 5 cell lines treated with cisplatin were analyzed for platinum content using inductively coupled plasma mass spectrometry. Polymeric implants loaded with cisplatin were developed and evaluated for degradation and drug release. The effect of local or systemic cisplatin delivery on drug biodistribution as well as tumor burden were evaluated in vivo, in combination with radiation therapy. Platinum levels in patient biopsies were 6-fold lower than the levels needed for efficacy and radiosensitization in vitro. Cisplatin local delivery implant remarkably improved drug specificity to the tumor and significantly decreased accumulation in the blood, kidney, and other distant normal organs, compared with traditional systemic delivery. The localized treatment further resulted in complete inhibition of tumor growth. The current standard-of-care systemic administration of cisplatin provides a subtherapeutic dose. We developed a polymeric drug delivery system that delivered high doses of cisplatin directly into the cervical tumor, while lowering drug accumulation and consequent side effects in normal tissues. Moving forward, these data will be used as the basis of a future first-in-human clinical trial to test the efficacy of localized cisplatin as adjuvant or neoadjuvant chemotherapy in local and regional cervical cancer.