Dose Intensification of Platinum Compounds with Glutathione Protection as Induction Chemotherapy for Advanced Ovarian Carcinoma

Abstract

Based on previous clinical experience indicating the tolerability and efficacy of high-dose cisplatin with glutathione protection in the treatment of advanced ovarian cancer, this study was undertaken to explore the efficacy and feasibility of an alternative high-dose, platinum-based approach including a combination of high-dose cisplatin plus carboplatin as induction chemotherapy of advanced ovarian carcinoma and intervention surgery. Fifty consecutive eligible patients with untreated stage III or IV epithelial ovarian cancer received 40 mg/m² cisplatin daily on days 1–4 and 160 mg/m² carboplatin on day 5. The cycle was repeated after 28 days. Patients received glutathione (2,500 mg) before each cisplatin or carboplatin administration and standard intravenous hydration. After 2 courses of induction chemotherapy, the patients underwent surgical reevaluation with debulking, when possible, followed by a further 3 cycles of 120 mg/m² cisplatin (i.e. 40 mg/m² daily for 3 consecutive days plus 600 mg/m² cyclophosphamide on day 3) except in instances of lack of response. All eligible patients were assessed for response and toxicity. The toxicity was moderate with lack of significant nephrotoxicity. Neurotoxicity and ototoxicity were acceptable and in no patient was treatment discontinued for those toxic effects. Myelotoxicity was somewhat more severe than that observed with our previous study with high-dose cisplatin and probably related to the addition of carboplatin. Of the 40 responsive patients, 23 (46%) had a pathological complete response and 4 (8%) had a clinical complete response (without second-look laparotomy). The efficacy of the present protocol was also documented by overall survival (median survival >48 months), which appeared to be better than expected with the current therapy in this group with advanced/bulky disease. The impressive efficacy suggests a possible contribution of reduced glutathione itself in improving the outcome, as supported by preclinical studies. The results of this study should be placed in context with current platinum-based therapy including paclitaxel.

The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear

“…These patients present with tinnitus and/ or hearing loss in high frequencies; but cisplatin can also affect the speech frequencies (Nagy et al, 1999). Although the dose of cisplatin given is an important factor in achieving optimal antineoplastic effects (Bohm et al, 1999), high doses can cause serious side effects, for example, peripheral neuropathies, renal insufficiency and sensorineural hearing loss. Hearing impairment is dose related, cumulative, bilateral and usually permanent.…”

Dose Response of Carboplatin‐Induced Nephrotoxicity in Rats

“…It is suggested that maintenance of high reduced to oxidized glutathione ratio is an important intracellular event for proper renal functions. Other studies have also shown the importance of intracellular glutathione in protecting against toxicity induced by platinum containing anticancer agents (Fontanelli et al 1992;Hamers et al 1993;Babu et al 1995;Bohm et al 1999;Hu et al 1999). Moreover, carboplatin at higher doses significantly increased renal glutathione-Stransferase activity indicating that the renal system is compensated in response to high doses of carboplatin to conjugate it with glutathione and thereby detoxified and excreted out through the kidney.…”

“…Earlier studies had shown that carboplatin is toxic at a dose of (100-200 mg/kg, intraperitoneally) to rats (Kimura et al 1989;Nonclercq et al 1989;Haragsim & Zima, 1992;Blommaert et al 1996;Husain et al 2001). These doses are equivalent to the clinical therapeutic doses of carboplatin in cancer patients (Bishop 1992;Bohm et al 1999;Wandt et al 1999;Maldoon et al 2000). However, administration of high and/or cumulative doses of carboplatin produced renal toxicity in humans (Agraharkar et al 1998;English et al 1999) and experimental animals (Ueda et al 1991;Martinez et al 1993).…”

“…Since carboplatin has a less toxic adverse effect profile than cisplatin, it is being tried as a replacement for cisplatin in many cancer therapy regimens (Mckeage 1995;English et al 1999). In order to achieve optimal antitumour effects, administration of increased doses of carboplatin is required in the clinic (Bohm et al 1999;Wandt et al 1999). The predominant dose-limiting toxicities of carboplatin are bone marrow suppression and ototoxicity (Mckeage 1995;Cavaletti et al 1998;Husain et al 2001).…”

Should Patients Undergoing Chemotherapy and Radiotherapy Be Prescribed Antioxidants?

“…61 There have been several other phase 2 trials showing the same positive result. [62][63][64] Although the latter were nonrandomized phase 2 trials, there have also been randomized trials of the same concept. In one study, 151 patients received cisplatin for ovarian cancer.…”