PHARMACEUTICALS volume 100 A A review of humAn cArcinogens This publication represents the views and expert opinions of an IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, which met in Lyon, 14-21 October 2008 LYON, FRANCE - 2012 iArc monogrAphs on the evAluAtion of cArcinogenic risks to humAns ETOPOSIDE IN COMBINATION WITH CISPLATIN AND BLEOMYCIN Etoposide, cisplatin, and bleomycin were considered by a previous IARC Working Group in 1999 (IARC, 2000). Since that time, new data have become available, these have been incorporated into the Monograph, and taken into consideration in the present evaluation. 1. Exposure Data lotoxin; 4′-demethylepipodophyllotoxin 9-(4,6-O-ethylidene-β-d-glucopyranoside); 1.1 Identification of the agent 4′-demethylepipodophyllotoxin ethylidene- β-d-glucopyranoside; Toposar; Vepesid(e); 1.1.1 Etoposide pyrano[3,2-d]-1,3-dioxin, furo[3′,4′:6,7] naphtho[2,3-d]-1,3-dioxol-6(5aH)-one Chem. Abstr. Serv. Reg. No.: 33419-42-0 deriv. Chem. Abstr. Name: Furo[3′,4′:6,7] Description: White to yellow-brown crys- naphtho[2,3-d]-1,3-dioxol- talline powder; white to off-white crystal- 6(5aH)-one, 9-[4,6-O-(1R)- line powder [phosphate salt] (McEvoy, ethylidene-β-d-glucopyranosyl] 2007) oxy]-5,8,8a,9-tetrahydro-5-(4-hydroxy- 3,5-dimethoxyphenyl)-, (5R,5aR,8aR,9S)- (a) Structural and molecular formulae, and IUPAC Systematic Name: Furo[3′,4′:6,7] relative molecular mass naphtho[2,3-d]-1,3-dioxol-6(5aH)-one, O O 9-[(4,6-O-ethylidene-β-d-glucopyranosyl) oxy]-5,8,8a,9-tetrahydro-5-(4-hydroxy- O 3,5-dimethoxyphenyl) H 3C Synonyms: Celltop; Etopophos; HO O Eposin; furo[3′,4′:6,7]naphtho[2,3- O H H O d]-1,3-dioxol-6(5aH)-one, H 3C O O 9-[(4,6-O-ethylidene-β-d-glucopyranosyl) O HO O CH3 oxy]-5,8,8a,9-tetrahydro-5-(4-hy- OH droxy-3,5-dimethoxyphenyl)-, [5R-[5a,5ab,8aa,9b(R*)]]-; C29H32O13 4′-demethyl-1-O-[4,6-O-(ethylidene)- Relative molecular mass: 588.6 β-d-glucopyranosyl]epipodophyl- 91 IARC MONOGRAPHS – 100A 1.1.2 Cisplatin 1.2 Use of the agents Chem. Abstr. Serv. Reg. No.: 15663-27-1 Information for Section 1.2 is taken from Chem. Abstr. Name: Platinum, diam- McEvoy (2007), Royal Pharmaceutical Society of minedichloro-, (SP-4–2)- Great Britain (2007), and Sweetman (2008). IUPAC Systematic Name: Azane; dichloroplatinum 1.2.1 Etoposide Description: Yellow to orange crystalline powder (McEvoy, 2007) (a) Indications Etoposide is a semisynthetic derivative of (a) Structural and molecular formulae, and podophyllotoxin with antineoplastic properties; relative molecular mass it interferes with the activity of topoisomerase Cl NH3 II, thus inhibiting DNA synthesis, and is most Pt active against cells in the late S- and G2-phases of the cell cycle. It is used, usually in combina- Cl NH3 tion with other antineoplastics, in the treatment Cl2H6N2Pt of tumours of the testis, small cell cancer of the Relative molecular mass: 300.0 lung, and in acute leukaemias. (i) Testicular neoplasms 1.1.3 Bleomycin Etoposide or etoposide phosphate may be Chem. Abstr. Serv. Reg. No.: 11056-06-7 used intravenously as a component of various Chem. Abstr. Name: Bleomycin chemotherapeutic regimens for the treatment IUPAC Systematic Name: Bleomycin of refractory testicular tumours in patients Description: Cream-coloured, amorphous who have already received appropriate surgery, powder [sulfate salt] (McEvoy, 2007) chemotherapy, and radiation therapy. Etoposide alone can be used in the treatment of dissemi- (a) Structural and molecular formulae, and nated non-seminomatous testicular carcinoma relative molecular mass (Stage III), and in patients whose disease is NH2 refractory to cisplatin-containing combination H 2N O chemotherapy. Cisplatin-containing combina- HN tion chemotherapy regimens are used as initial N NH2 therapy in patients with Stage III or unresect- N able Stage II non-seminomatous testicular carci- H 2N O CH3 noma. For the initial treatment of advanced H 3C N HN O OH O OH H HN H H non-seminomatous testicular carcinoma, regi- N N S N HO H mens containing cisplatin and bleomycin, in O O O CH3 CH3 O N HO O combination with etoposide, are used. O S N OH O OH (ii) Cancer of the lung HO CH3 O OH S+ N O H 2N H Etoposide has been widely used for the H 3C treatment of lung cancer. Etoposide is used intravenously (either as etoposide or etopo- C H N O S 55 84 17 21 3 side phosphate) in combination chemotherapy Relative molecular mass: 1415.6 regimens for the treatment of small cell lung 92 Etoposide, cisplatin, and bleomycin carcinoma; etoposide also has been used orally, cell-cycle non-specific and are dependent upon its either alone or as a component of combination cis configuration; they appear to be related to its therapy for this cancer. Furthermore, etoposide hydrolysis in the body to form reactive hydrated has been used in conjunction with a platinum species. Although it causes immunosuppression, agent (i.e. cisplatin or carboplatin) and ifosfa- stimulation of the host immune response against mide with mesna. the tumour has been suggested as contributing to Etoposide is also used as part of first- or cisplatin’s antineoplastic action. second-line combination chemotherapy regi- Cisplatin is used in the treatment of tumours mens for the treatment of non-Hodgkin of the testis, usually as a major component lymphoma, Hodgkin lymphoma, acute myeloid of combination chemotherapy regimens, and leukaemia, a variety of paediatric solid tumours, particularly with bleomycin and etoposide acute lymphocytic leukaemia, and in high-dose (BEP), or with bleomycin and a vinca alkaloid. It conditioning programmes before haematopoi- is also used to treat metastatic ovarian tumours, etic stem-cell transplantation. cervical tumours, lung cancer, advanced bladder cancer, and squamous cell carcinoma of the head (b) Dosage and neck. Etoposide is administered orally and by slow (b) Dosage intravenous infusion. Etoposide phosphate is administered by intravenous infusion. Lower doses are generally used for combina- The usual intravenous dose of etoposide tion chemotherapy regimens than in single agent ranges from 50–120 mg/m2 daily for 5 days. therapy; 20 mg/m2 or more is given once every Alternatively, 100 mg/m2 has been given on alter- 3–4 weeks. A dose of 20 mg/m2 daily for 5 days nate days to a total of 300 mg/m2. The usual oral every 3–4 weeks has been used in combination dose of etoposide is 100–240 mg/m2 daily for 5 chemotherapy for the treatment of testicular consecutive days. Courses may be repeated after tumours. 3–4 weeks. Various analogues of cisplatin have been Etoposide is available as a 50 mg liquid-filled developed or investigated including those with capsule and as 100, 150, 200, 250, 500 mg and 1 g fewer adverse effects (e.g. carboplatin, neda- (20 mg/mL) solutions for injection concentrates platin), an altered spectrum of activity (oxali- and for intravenous infusion. Etoposide phos- platin), or activity on oral dosage (satraplatin). phate is available as 500 mg and 1 g (of etoposide) Various adjustments to the administration solutions for injection, and 100 mg (of etoposide) of cisplatin have been suggested in an attempt solutions for injection and intravenous infusion. to improve its effectiveness while reducing its toxicity. (c) Trends in use Toxicity is reported to be reduced when No information was available to the Working cisplatin is given by continuous intra-arterial or Group. intravenous infusion. It has also been suggested that giving cisplatin in the evening rather than 1.2.2 Cisplatin in the morning results in less damage to renal function, apparently because of circadian vari- (a) Indications ations in urine production. However, another The antineoplastic cisplatin is a platinum- study found that morning, rather than evening, containing complex that may act similarly to the doses of cisplatin resulted in less renal damage. alkylating agents. Its antineoplastic actions are 93 IARC MONOGRAPHS – 100A (c) Trends in use than those previously in use, or than those in No information was available to the Working use in the Unites States of America, and care is Group. recommended in evaluating the literature. In the United Kingdom, the licensed dose 1.2.3 Bleomycin as a single agent for squamous cell or testicular tumours is 15000 international units (15 USP (a) Indications units) three times a week, or 30000 international Bleomycin is an antineoplastic antibiotic that units twice a week, by intramuscular or intrave- binds to DNA and causes strand scissions, and is nous injection, although in practice, treatment of malignancy will generally be with combination probably most effective in the 2G - and M-phases of the cell cycle. It is used to treat malignant regimens. This may be repeated, at usual inter- disease particularly squamous cell carcinomas, vals of 3–4 weeks, up to a total cumulative dose including those of the cervix and external geni- of 500000 international units. The dose and total talia, oesophagus, skin, and head and neck; cumulative dose should be reduced in those over Hodgkin lymphoma and other lymphomas; 60 years of age (see below). Continuous intra- malignant neoplasms of the testis and malignant venous infusion at a rate of 15000 international effusions. It has also been tried in other malig- units per 24 hours for up to 10 days or 30000 nancies, including carcinoma of the bladder, international units per 24 hours for up to 5 days lung, and thyroid, and some sarcomas, including may also be used. In patients with lymphoma, a Kaposi sarcoma. dose of 15000 international units once or twice Bleomycin is often used with other anti- weekly by intramuscular injection has been neoplastics, with etoposide and cisplatin (BEP) suggested, to a total dose of 225000 international in testicular tumours, and with doxorubicin, units.