AQUPLA（Nedaplatin）Nedaplatin: A Radiosensitizing Agent for Patients with Cervical CancerAbstractDespite the recent advances in the management of cervical cancer using cisplatin-based concurrent chemoradiotherapy, substantial treatment failure still occurs, especially in advanced-stage patients and early-stage cervical cancer patients with high-risk prognostic factors.Therefore, efforts to further improve the survival and quality of life of these patients are necessary.Nedaplatin (cis-diammine-glycoplatinum), a derivative of cisplatin, was developed with the aim of producing a treatment with a similar effectiveness to cisplatin but decreased renal and gastrointestinal toxicities. Based on the promising results of preclinical studies, the clinical efficacy of nedaplatin as a radiosensitizing agent was eva luated in patients with cervical cancer.Retrospective analysis of nedaplatin-based concurrent chemoradiotherapy (CCRT) against cervical cancer suggested that nedaplatin-based CCRT can be considered as an alternative to cisplatin-based CCRT in both early-stage and advanced-stage cervical cancer patients.However, due to the lack of a randomized controlled study, nedaplatin-based CCRT has not been convincingly proven to be clinically effective in patients with cervical cancer.Further investigations in randomized controlled trials are therefore needed.IntroductionNedaplatin (cis-diammine-glycoplatinum), a derivative of cisplatin, was developed in 1983 by Shionogi Pharmaceutical Company in Japan with the aim of producing a treatment with a similar effectiveness to cisplatin but decreased renal and gastrointestinal toxicities, nedaplatin has a novel chemical structure involving a five-membered ring structure in which glycolate is bound to the platinum ion as abidentate ligand.In a preclinical eva luation of cervical cancer, nedaplatin demonstrated similar antitumor activity to cisplatin. Its lower incidence of nephrotoxicity in comparison to cisplatin has been demonstrated to be associated with differences in the kidney distribution of these drugs.When the two agents were administered at the same dose, the accumulation of nedaplatin in the rat kidney was approximately 40% of that of cisplatin, which explains why nedaplatin is associated with less nephrotoxicity than cisplatin.Clinically, previous phase II studies conducted in Japan suggested that nedaplatin has a particularly favorable clinical efficacy towards squamous cell carcinoma (SCC) of the lung, head and neck, esophagus, and uterine cervix.According to a clinical study of nedaplatin in nonsmall cell lung cancer patients, the response rate in patients with SCC histology was 57.1%, which is significantly higher than 5.5% observed in patients with nonSCC histology.In the area of uterine cervical cancer, in a phase II clinical trial, nedaplatin demonstrated a response rate of 46% in patients with recurrent cervical cancer, which was slightly superior to that obtained with cisplatin (39%).Moreover, since nedaplatin does not require hydration, nedaplatin treatment can be managed in an outpatient setting. On the basis of these advantages, nedaplatin has been used clinically in Japan as an alternative to cisplatin for patients with recurrent cervical cancer.The radiosensitizing properties of nedaplatin have been demonstrated in several preclinical studies. An in vitro investigation demonstrated that nedaplatin in combination with irradiation is highly effective for cervical cancer.Although the preliminary data from clinical studies of the use of nedaplatin-based CCRT in patients with head and neck or esophageal cancer has been reported, however, the clinical experience with this agent in the setting of CCRT for cervical cancer patients is limited.As shown in Table 1, the use of concurrent weekly nedaplatin in patients with invasive cervical cancer in the setting of definitive radiotherapy was investigated in two Phase I, two Phase II studies, and one retrospective study; however, in the setting of adjuvant radiotherapy, nedaplatin-based CCRT has only been eva luated in one Phase I and two retrospective studies. Thus, it remains unclear whether nedaplatin-based CCRT is superior to RT alone in patients with cervical cancer.Concurrent chemoradiotherapy, usually involving 40mg/m2 of weekly cisplatin, is accepted as the standard first-line treatment for cervical cancer. However, its nephrotoxicity and gastrointestinal toxicity may limit its use.In a previous Japanese Phase I study, which determined the recommended dose of weekly cisplatin in the setting of CCRT after radical hysterectomy, dose-limiting toxicity(DLT) was observed at 40mg/m2, indicating that a weekly dose of 40mg/m2 of cisplatin may be too high for Japanese patients with cervical cancer.As nedaplatin exhibits minimal nephrotoxicity, it can be used in patients with marginal renal function. Moreover, since nedaplatin does not require hydration and shows minimal gastrointestinal toxicity, nedaplatin treatment can be managed in anoutpatient setting.Thus, the substitution of nedaplatin for cisplatin as a concurrent chemotherapy for patients with cervical cancer may be beneficial.Recently, we investigated the efficacy of nedaplatin-based CCRT in the settings of adjuvant treatment after radical hysterectomy and definitive radiotherapy. Although they were retrospective in nature, to the best of our knowledge, these are the only reports that have demonstrated a significant improvement in the survival of cervical cancer patients treated with nedaplatin-based CCRT.In this review, we show the results of these retrospective analyses and provideinformation on the results of other clinical studies that investigated the efficacy of nedaplatin-based CCRT in patients with cervical cancer.