Sir Kenneth was Chief Medical Officer for Scotland andfor England, and is now the Vice-Chancellor of theUniversity of Durham Get big cell kill from fluorouracil, be a medicine man with melphalan, keep things pristine with vincristine, shout with glee with 6MP… but, and this is important for today, you can flatten ’em, with platinum Witness Seminar held by the Wellcome Trust Centre for the History of Medicine at UCL, London, on 4 April 2006
History of Cisplatin The compound cis-PtCl2(NH3)2 was first described by M.Peyrone in 1845, and known for a long time as Peyrones salt.The structure was deduced by Alfred Werner in 1893. In 1965, Barnett Rosenberg, van Camp et al. of Michigan StateUniversity discovered that electrolysis of platinum electrodesgenerated a soluble platinum complex which inhibited binaryfission in Escherichia coli (E. coli) bacteria. Although bacterialcell growth continued, cell division was arrested, the bacteriagrowing as filaments up to 300 times their normal length.Cisplatin was approved for use in testicular and ovarian cancersby the U.S. Food and Drug Administration on December 19,1978.
PROPRIETÀ CHIMICHE CHE GOVERNANO L’ATTIVITÀ CLINICA DEI COMPLESSI DEL PLATINOcarrier ligands leaving groups 1. Configurazione 2. Stato di ossidazione 3.Natura dei gruppi uscenti (leaving groups) 4. Natura dei carrier ligands
Chimica del cisplatino in soluzione acquosa Cl Cl OH 2 H 3N Pt Cl H 3N Pt OH 2 H 3N Pt OH 2 NH 3 NH 3 NH 3 reattivo nella cellua m ajor groov e m ajor groove m a jo r g ro o v e Cl G Cl G H 3N GH 3N Pt OH 2 + G Pt G Pt H 3N NH 3 H 3N G NH 3
Action of Cisplatin Cisplatin coordinates to DNA and that this coordination complex not only inhibits replication and transcription of DNA, but also leads to programmed cell death (called apoptosis)
• In vitro studies on both prokaryotic and eukaryotic cells revealed that DNA adducts of both cisplatin and trans-DDP blocked the action of DNA polymerase• In vivo studies showed that cisplatin and trans-DDP inhibited replication equally well• DNA replication is not the only factor important for the clinical activity of cisplatin
The cytotoxic activity of cisplatin mayarise from the cell’s inability to repairDNA damage caused by cisplatin.
• The cell detects DNA damage by the action of damage recognition proteins• HMG-domain proteins bind cisplatin– DNA adducts in vitro• In vivo assays on yeast shown that HMG- domain proteins are important for the activity of cisplatin:• These effects may also be in operation in mammalian cells
Role of HMG domain proteins1. HMG domain containing transcription factors bind preferentially to the cisplatin–DNA adducts, they could wreak havoc with the transcriptional machinery2. When HMG domain proteins bind to the cisplatin–DNA adducts, the adducts would not be recognized by the repair machinery
Cisplatin Administration • Mixed in 250 - 1000 ml NS • Mixed with 2 – 4 grams magnesium sulfate in same bag • Infused over atleast 2 hours • Pre-hydration of 250 – 1000 mL NS depending on dose – ensure adequate UOP (> 200 cc/2 hours) – Caution in patients with HF or CRI who cannot tolerate this amount of fluids – May require furosemide IVP • Post-hydration with 1 Liter NS – instruct patient to drink 6 – 8 full glasses of water/day (1.5 – 2 Liters/day) at home
CISPLATIN TOXICITY• Nausea and vomiting – acute or delayed – highly emetogenic if use doses than 50 mg/m2 – moderately emetogenic if use doses 50 mg/m2 – severe if not adequately prevented with appropriate medications – typical anti-emetic regimen • aprepitant 125 mg po day 1 then 80 mg po days 2 – 3 • dexamethasone 12 mg po day 1 then 8 mg po daily x 3 days • palonosetron 0.25 mg IVP day 1 • metoclopramide 10 mg every 4 hours prn N/V
CISPLATIN TOXICITY• HEMATOLOGIC TOXICITY – can affect all 3 blood lineages – minor neutropenia, thrombocytopenia, and ANEMIA – its mild hematologic toxicity has allowed its combination with highly myelosuppressive chemotherapy• OTOTOXICITY – audiograms show bilateral and symmetrical high frequency hearing loss – usually irreversible – caution with other drugs (aminoglycosides)
CDDP-INDUCED ORGAN TOXICITY* Nephrotoxicity* Neurotoxicity* Cardiomyopathy
CDDP CARDIOMYOPATHY1- Electrocardiographic changes2- Myocarditis3- Arrythmia4- Congestive heart failure5- Bradycardia6- Lethal cardiomyopathy when CDDP is given in combination chemotherapy protocols containing MTX, 5-FU, BLM, and DOX
CISPLATIN TOXICITY• Neurotoxicity – dose-limiting toxicity – most common symptoms are peripheral neuropathy and hearing loss – less common include Lhermitte’s sign (electric shock-like sensation transmitted down the spine upon neck flexion) – autonomic neuropathy, seizures, encephalitic symptoms, and vestibular disturbances – cumulative doses > 300 mg/m2 – first signs are loss of vibration sensation, loss of ankle jerks and painful paresthesias in hands and feet – proximal progression and deficits in proprioception, light touch and pain – recovery is typically incomplete
CISPLATIN TOXICITY• Nephrotoxicity – dose-limiting toxicity – renal damage is usually reversible but rarely can be irreversible and require dialysis – platinum concentrations are higher in the kidney than in the plasma or other tissues – initiating event is proximal tubular lesion – secondary events such as disturbances in distal tubular reabsorption, renal vascular resistance, renal blood flow, and glomerular filtration, and polyuria seen 2 to 3 days later – hypomagnesemia develops in about 75% of patients, beginning 3 to 12 weeks after therapy and persisting for months to years
CISPLATIN NEPHROTOXICITY • Preventive Measures – aggressive saline hydration (enhance urinary excretion) – lower doses may require less hydration – infuse over 24 hours – pretreatment with amifostine – avoid other nephrotoxic agents – magnesium supplementation – predisposing factors to developing nephrotoxicity include age 60 years or older, higher doses, pretreatment GFR < 75 ml/min, cumulative dose, low albumin, single dose compared with daily x 5 administration schedules
Drug Interactions DRUG INTERACTIONS• Phenytoin ... decreased epilepsy control• Frusomide, hydralazine, diazoxide &propranolol increased nephrotoxicity• Dose adjustment of Allopurinol & colchicine doses needed due to hyperuricemia of Cisplatin• Antihistamines mask ototoxicity of cisplatin• Cephalosporins Abs e.g. Cephalexin & Aminoglycosides Abs e.g. Gentamycin increased nephrotoxicity• Live attenuated vaccines are contraindicated 57
CLINICAL PHARMACOLOGY OFCARBOPLATIN•Both carboplatin and cisplatin exert theirtherapeutic effects primarily by forming intrastrandDNA adducts with adjacent guanine residues intumor-cell DNA .• Although the platinum-containing moieties ofcarboplatin and cisplatin are identical , it is theunique leaving groups of each that ultimatelyfacilitate DNA binding.• In the case of carboplatin,the carboxylate groupsare much more stable adducts than the chloridegroups of cisplatin. This decreases the chemicalreactivity of carboplatin relative to cisplatin andsignificantly lengthens the time required for itsaquation and subsequent DNA-adduct formation .
CARBOPLATIN• IV NORMAL SALINE.• DOSING-mg/m2×min(AUC).• DOSE-4,5,or6mg/m2×min,in 250ml NS, 3-4 weeks.• INFUSION TIME- 1hr-4hr.• LESS NEPHROTOXIC, MORE MYELOTOXIC
•Carboplatin is excreted almost exclusivelyby the kidneys.•The total body clearances of ultrafiltrableplatinum and that of the parent carboplatinmolecule are roughly equivalent andcorrelate linearly with the pretreatmentglomerular filtration rate (GFR).•Approximately 65%-70% of the totalplatinum dose is eliminated as intactcarboplatin in the urine during the first 12-16hours after administration, while theremaining 30%-35% of the dose, which isprotein-bound and inactive, is eliminatedslowly over the next five days
CALVERT’ S FORMULATotal dose (mg) = target AUC (mg/ml ´ min)´ (GFR [ml/min] + 25) The value of 25 ml/min is a constant that used to correct for the nonrenal clearance of irreversibly tissue-bound carboplatin .
CARBOPLATIN TOXICITY• Moderately emetogenic• Renal impairment is rare – because it is excreted primarily in the kidneys as an unchanged drug, it is not directly toxic to the renal tubules• Neurotoxicity is rare• Myelosuppression – especially THROMBOCYTOPENIA – dose-limiting toxicity – cumulative• Hypersensitivity reaction – thought to be due to type I hypersensitivity (IgE mediated) – incidence of hypersensitivity seems to be correlated with increased number of cycles of carboplatin administered – risk of hypersensitivity due to carboplatin exposure significantly increases during the sixth cycle, and it continues to increase up to cycle 8
•Oxaliplatin differs from cisplatin in that theamine groups of cisplatin are replaced bydiaminocyclohexane (DACH).• The molecular weight of oxaliplatin is397.3.• It is slightly soluble in water, less so in methanol, and almost insoluble in ethanoland acetone .• Its full chemical name, oxalato(trans L- 1,2diaminocyclohexane)platinum, refers to thepresence of an oxalate “leaving group” andthe DACH carrier ligand, which areresponsible, at least in part, for its uniqueproperties
OXALIPLATIN• IV IN 5%DEXTROSE.DOSING IN mg/m2• DOSE-85-130mg/m2 ,2-3weeks• INFUSION TIME-6hr, but 2hr and 4 hr is used.• COLORECTAL CANCER
Oxaliplatin Toxicity• Gastrointestinal – Moderate emetogenicity – diarrhea• Minimal hematologic toxicity – Thrombocytopenia is dose-related (doses > 135 mg/m2) – mild neutropenia – mild anemia• No nephrotoxicity• Hypersensitivity reaction – mild – generally subside upon discontinuation – slowing down infusion rate and giving an antihistamine and/or steroid – desensitization protocol• Peripheral neuropathy – Prevention: Stop and Go Strategy, Ca and Mg infusions (may compromise efficacy)
Clinical characteristics of oxaliplatin neurotoxicity Acute symptoms Chronic symptoms• Common (90% of patients) • 10% to 15% moderate• May appear at first treatment cycle neuropathy after a cumulative• Generally mild dose of 780 to 850 mg/m2• Onset during or within hours of • Does not seem to be infusion schedule-dependent• Transient, short lived • Dysesthesias and• Cold-triggered or cold-aggravated paresthesias persisting• Dysesthesias and paresthesias between cycles• Manifesting as stiffness of the • Progressively evolving to hands or feet, inability to release functional impairment: grip, and sometimes affecting the difficulties in activities legs or causing contractions of the requiring fine sensorimotor jaw coordination, sensory ataxia• Distal extremeties, perioral, oral, • Tends to improve/recover and pharyngolaryngeal areas after treatment is stopped• Depending on dosing schedule • Spares motor neurons (like (infusion rate) cisplatin)
OXALIPLATIN NEUROPATHY Supportive care for prevention of oxaliplatin induced neuropathy avoid cold temperatures if exposure to cold temperatures cannot be avoided, such as use of the refrigerator, wear gloves during the exposure use scarves and face masks in cold weather prolonging the infusion time use cotton socks, pot holders, rubber gloves for dish washing assess the water temperature in the home use moisturizer
Satraplatin and Prednisone Against Refractory Cancer SPARC Trial (n=912) R A Satraplatin 80 mg/m2/d x 5 po q5wksProgressive N + Prednisone 5 mg x 2/daily Q 35 days HRPC D O 1 prior M chemo Placebo + Prednisone I 5 mg x 2/daily Q 35 days Z E 2:1 1° Endpoint: 30% increase in TTP with 85% power 2° Endpoints: OS, time to pain progression J.Bellmunt 09/2008