Antitumor Antibiotics – Anthracyclines – Doxorubicin, Daunorubicin, Bleomycin, etc

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  • Group of antitumour drugs produced from the Streptomyces peucetius variation caesius
  • Active throughout the cell cycle, including the interphase
  • Rapidly proliferating tissues such as tumour tissues (but also bone marrow, gastrointestinal and oral mucosa, hair follicles) are the most sensitive to the antiproliferative effects

Classification

ANTHRACYCLINES

  • Daunorubicin
  • Doxorubicin (Adriamycin)
  • Idarubicin
  • Epirubicin

ANTHRACENIDIONES

  • Mitoxantrone

CHROMOMYCINS

  • Dactinomycin

MISCELLANEOUS

  • Bleomycin
  • Mitomycin

History

  • Use first established in the 1959
  • Farmitalia Research Laboratories in Milano and the Parisian group of the Rhone-Poulenc Laboratories
  • The Italian group – clinical studies with ‘daunomycin’ and subsequently its C-14 hydroxy derivative ‘adriamycin’
  • The French – clinical studies with ‘rubidomycin’
  • These drugs were soon renamed ‘daunorubicin’ and ‘doxorubicin’
  • Impressive activity was noted against acute leukemia and childhood solid tumors
  • Trials with doxorubicin, by the National Cancer Institute (NCI, U.S.A.) demonstrated impressive activity in breast cancer, ovarian cancer, lymphoma, small cell lung cancer, germ cell tumors and sarcomas in addition to the areas where daunorubicin were used
  • 2nd generation anthracyclines – epirubicin was first used in 1980 and idarubicin in 1991

Mechanism of Action

  • Transmembrane movement – free diffusion
  • All nucleated cells accumulate these drugs to an extraordinary degree (Intracellular to extracellular concentration – 30 to 1000-fold)
  • Drug binds to the 20S fraction of the proteasome
  • Following binding, dissociates from the proteasome and attaches to the DNA

DNA Intercalation

  • Anthracycline intercalates into the DNA double helix and cause protein-associated DNA breaks
  • The bulk of intracellular drug is in the nucleus and a portion of the anthracycline in the nucleus is intercalated into the DNA double helix .(intercalation- a reaction whereby the drug inserts itself between DNA base pairs and prevents DNA replication and mRNA production).

Topoisomerase II Interactions

  • Topoisomerases are enzymes that alter DNA topology by causing and resealing DNA strand breaks.
  • Topoisomerases bind to DNA and form transient cleavage complexes, where topoisomerases I and II create single- and double-stranded breaks, respectively.
  • Formation of cytotoxic oxygen free radicals results in single- and double stranded DNA breaks with inhibition of DNA synthesis and function.

Other Mechanisms of Action

  • DNA-anthracycline complexes – modify the ability of helicases (dissociate duplex DNA into DNA single strands in an ATP-dependent fashion) – limiting replication
  • Doxorubicin undergoes cycles of reduction and oxidation in essentially all intracellular compartments leading to the formation of reactive oxygen species
  • The ROS oxidise the DNA bases, inhibit both DNA polymerases and DNA repair systems , cause cell death
  • Iron-dependent production of formaldehyde from intracellular reactive oxygen metabolism of the anthracyclines can subsequently react to produce a drug-formaldehyde conjugate containing two anthracycline molecules
  • Conjugates form novel covalent DNA cross-links that enhance therapeutic activity
  • Anthracyclines induce cytochrome c release independent of DNA damage – apoptosis

Mechanism of Resistance

  • Increased expression of the multidrug-resistant gene with elevated P170 levels, which leads to increased drug efflux
  • Mutation in topoisomerase II with decreased binding affinity to drug
  • Increased expression of sulfhydryl proteins, including glutathione and glutathione-dependent enzymes
  • Overexpression of Bcl2 or mutation of p53

Drug Interactions

  • Co-administration of heparin and doxorubicin – increases rate of doxorubicin clearance
  • Phenobarbital has been shown to increase, and morphine decrease, doxorubicin disappearance
  • Doxorubicin is extensively metabolized by the liver – cytochrome P450 CYP3A4 and CYP2D6, and P-glycoprotein. Inducers and inhibitors would thus affect levels.
  • Doxorubicin and paclitaxel as short i.v infusion
  • Cremophor EL – the diluent is a substrate for the P- glycoprotein – affects the biliary excretion of doxorubicin
  • This interaction is not observed if paclitaxel is given over 24 hours (which lowers the concentration of the diluent in plasma) or if docetaxel is combined with doxorubicin, since the former taxane is not prepared in Cremophor EL.

Doxorubicin (Adriamycin)

doxorubicin/adriamycin-anthracycline antitumor antibiotic

Mechanism of Action

  • DNA Intercalation
  • Topoisomerase II Inhibition

Indications

FDA-labeled indications for standard doxorubicin include-

Availability

  • It is available in a standard salt form and as a liposomal formulation.
  • Injection, powder: 10, 20, 50 mg
  • Injection, solution: 2 mg/mL (5, 10, 25, 100 mL)

Dose

  • 40 to 75 mg/m2 IV q 3 to 4 weeks
  • 20 to 30 mg/m2 IV for 2 to 3 days every 4 weeks
  • 20 mg/m2 IV once weekly
  • When doxorubicin is given by a low-dose weekly regimen (10 to 20 mg/m2/wk) or by slow continuous infusion over 96 hours, cumulative doses of more than 500 mg/m2 can be given.

Pharmacokinetics

  • Not absorbed orally.
  • IV infusion
  • Intravesical: superficial bladder cancer,30-50 mg in 25-50 ml saline instilled using a catheter and retained intravesically for 1-2 hours.
  • Intraarterial in hepatocellular carcinoma.
  • Distribution: Widely distributed to tissues. Does not cross the blood-brain barrier. About 75% of doxorubicin and its metabolites are bound to plasma proteins.
  • Metabolized extensively in the liver.

Dose Modification

  • Doxorubicin may be dose reduced by 50% for plasma bilirubin concentrations ranging from 1.2 to 3.0 mg/dL, by 75% for values of 3.1 to 5.0 mg/dL, and withheld for values greater than 5 mg/dL.
  • No dose adjustment required in renal failure.

Drug Interations

  • Amphotericin B (increases cellular toxicity to doxorubicin)
  • Verapamil (higher peak doxorubicin concentration in heart)
  • Streptozocin (higher doxorubicin levels)
  • Paclitaxel (Sequential administration of paclitaxel followed by doxorubicin in breast cancer patients is associated with cardiomyopathy at total doxorubicin doses above 340 to 380 mg/m2)
  • Phenytoin and fosphenytoin (levels are decreased with doxorubicin)
  • Trastuzumab (increases incidence of congestive heart failure if given together)
  • Cyclophosphamide—Increased risk of cardiotoxicity

Toxicity

  • Bone marrow: myelosuppression , leukopenia and thrombocytopenia
  • Nausea, vomiting, mucositis, stomatitis, diarrhea (rare)
  • Transient elevation of transaminases
  • Exanthema, urticaria, alopecia, delayed tissue reaction in a previously irradiated site (“radiation recall reaction”), nail changes, hyperpigmentation (rare)
  • Local toxicity causes severe necrosis
  • Other: infertility, peripheral neuropathy (rare), red urine
  • Secondary AML in 2%.Secondary leukemias are thought to be a result of balanced translocations that result from Top2 poisoning by the anthracyclines, albeit to lesser degree than other Top2 poisons, such as the epipodophyllotoxins.

Cardiotoxicity with Doxorubicin

Acute Cardiotoxicity

Acute doxorubicin cardiotoxicity is reversible, and clinical signs include tachycardia, hypotension, electrocardiogram changes, and arrhythmias. Acute toxicity develops during or within days of anthracycline infusion, the incidence of which has been significantly reduced by slowing doxorubicin infusion rates.

Chronic cardiotoxicity

It is the most common type of anthracycline damage and is irreversible. Chronic cardiotoxicity peaks at 1 to 3 months, but can occur even years after therapy. Congestive heart failure from congestive cardiomyopathy is more common.

Mechanism of Cardiotoxicity

  • Myocardial damage occurs by several mechanisms like, generation of reactive oxygen species, generation of hydrogen peroxide and the peroxidation of myocardial lipids contribute to myocardial damage.
  • Endomyocardial biopsy shows multifocal areas of patchy and interstitial fibrosis (stellate scars) and occasional vacuolated myocardial cells (Adria cells). Other characteristics are myocyte hypertrophy and degeneration, loss of cross-striations, and absence of myocarditis
  • Cumulative dose exceeds 450 mg/m2, at lower cumulative dose in pt. with other carditoxic drugs (TRASTUZUMAB), RT to mediastinum, cardiac dose >2000cGy, Age< 4,female, concurrent cyclophosphamide use.

Cumulative Dose and Cardiotoxicity

300 mg/m2 1-2 %
400 mg/m2 3-5 %
450 mg/m2 5-8 %
500 mg/m2 6-20 %

 

Role of Dexrazoxane in Doxorubicin Toxicity

  • Indicated for reducing the incidence and severity of cardiomyopathy associated with cumulative doxorubicin dose of 300 mg/m2 administration in women with metastatic breast cancer and who, in their physician’s opinion, would benefit from continuing therapy with doxorubicin. It is not recommended for use with the initiation of doxorubicin therapy. (Zinecard: 250, 500 mg single dose vial)
  • Indicated for the treatment of extravasation resulting from IV anthracycline chemotherapy. (Totect: 500 mg single dose vials)

  Mechanism of Action

  • Dexrazoxane is an iron-chelating agent .
  • The mechanisms by which dexrazoxane reduces tissue damage associated with anthracycline extravasation is not known.

Dose

Anthracycline cardiomyopathy prevention

Dose is based on doxorubicin dose and should be given as IV push or rapid drip infusion in 10:1 (dexrazoxane:doxorubicin) ratio with doxorubicin dose. Doxorubicin should be administered within 30 minutes of dexrazoxane infusion.

Anthracycline extravasation
  • 1,000 mg/m2 infused intravenously within 6 hours of anthracycline extravasation
  • 1,000 mg/m2 infused 24 hours after the first dose
  • 500 mg/m2 infused 48 hours after the first dose

Precautions while using Doxorubicin (Adriamycin)

  • Because doxorubicin is a vesicant, administer slowly over 60 minutes with a rapidly flowing IV. Careful administration of the drug, usually through a central venous catheter, is necessary as the drug is a strong vesicant(induce formation of blisters and ulcers and can cause tissue destruction). Close monitoring is necessary to avoid extravasation.
  • If extravasation is suspected, immediately stop infusion,withdraw fluid, elevate extremity, and apply ice to involved site. DMSO( dimethyl sulfoxide) 1 to 2 ml is applied topically and allowed to sun dry. May administer local steroids. In severe cases, consult a plastic surgeon.
  • Monitor cardiac function before (baseline) and periodically during therapy with either MUGA radionuclide scan or echocardiogram to assess left ventricular ejection fraction.
  • Use with caution in patients previously treated with radiation therapy as doxorubicin can cause a radiation recall skin reaction.
  • Patients should be cautioned to avoid sun exposure and to wear sun protection when outside.
  • Patients should be warned about the potential for red-orange discoloration of urine that may occur for 1–2 days after drug administration.
  • Pregnancy category D. Breast-feeding should be avoided.

Contraindications

  • Persistent myelosupression
  • Hypersensitivity to anthracycline
  • Severe hepatic impairment
  • Severe myocardial insufficiency
  • Recent MI

Liposomal Doxorubicin

Pharmacokinetics

  • Doxorubicin encapsulated in long-circulating microscopic vesicles composed of a phospholipid bilayer (liposomes), which protect it from being chemically or enzymatically degraded. The encapsulated drug penetrates through tumor neovasculature and into tumor tissue where the drug is released.
  • Liposomal encapsulation of doxorubicin results in reduced plasma protein binding, and decreased uptake in normal tissues. Equal efficacy but decreased cardiotoxicity.
  • In contrast to parent drug, doxorubicin, which has a large Vd (700–1, 100 L/m 2 ), liposomal doxorubicin has a small Vd(2 L/m 2 ). Does not cross the blood-brain barrier.

Metabolism

  • Plasma clearance of liposomal doxorubicin is slower than that of doxorubicin,resulting in AUCs that are significantly greater than an equivalent dose of doxorubicin. Prolonged terminal half-life of about 55 hours

Doses Available

  • Injection, solution: 2 mg/mL (10, 25 mL)

Indications and Dosage

  • AIDS-related Kaposi’s sarcoma—Used in patients with disease that has progressed on prior combination chemotherapy and/or in patients who are intolerant to such therapy. 20 mg/m 2 IV every 21 days.
  • Ovarian cancer—Metastatic disease refractory to both paclitaxel and platinum-based chemotherapy regimens. 50 mg/m 2 IV every 28 days
  • Multiple myeloma—FDA-approved in combination with bortezomib in patients who have not previously received bortezomib and who have received at least one prior therapy. 30 mg/m 2 IV on day 4 after bortezomib, which is administered at 1.3 mg/m 2 IV on days 1, 4, 8, and 11, every 21 days.

Dose Modification

  • Liposomal Doxorubicin may be dose reduced by 50% for plasma bilirubin concentrations ranging from 1.2 to 3.0 mg/dL, by 75% for values of 3.1 to 5.0 mg/dL, and withheld for values greater than 5 mg/dL.
  • No dose adjustment required in renal failure.

Side Effects

  • Liposomal doxorubicin is associated with less nausea and vomiting and relatively mild myelosuppression.
  • Liposomal doxorubicin can also cause hand-foot syndrome and an acute infusion reaction characterised by flushing, dyspnea, edema, fever, chills, rash, bronchospasm, and hypertension. These infusion-related events appear to be related to the rate of drug infusion.

Pegylated Liposomal Doxorubicin (Doxil)

Pharmacokinetics

Liposomes  are formulated by a process called pegylation (surface bound methoxypolyethylene glycol, MPE), to increase the blood circulation time by protecting liposomes from detection by the mononuclear phagocyte system. These molecules are also hypothesized to penetrate the vasculature of tumors.

The characteristic side effect called palmar plantar erythrodysesthesia (PPE) or hand foot syndrome is caused due to preferential concentration of the drug in the skin. Leakage of small amount of drug from capillaries in palms of hands and soles of feet may occur following administration. This leads to redness, tenderness, and uncomfortable and sometimes painful peeling of the skin.

Indications and Dose

  • Treatment of advanced ovarian carcinoma in women who have failed standard firstline therapy (platinum and paclitaxel based chemotherapy). 50 mg/m 2 IV every 28 days
  • Treatment of patients with AIDS related Kaposi’s sarcoma with CD4 counts < 200/mm3 and extensive mucocutaneous or visceral disease, who have failed or are intolerant of prior systemic combination chemotherapy (with at least 2 of vinca alkaloid, bleomycin, and doxorubicin or another anthracycline).
  • Monotherapy in metastatic breast cancer. 40 mg/m 2 IV every 28 days

Side Effects

  • The most common side effects reported are hand foot syndrome(3-5%), infusion reactions and mucositis.
  • During first infusion of pegylated liposomal doxorubicin, acute hypersensitivity reactions may occur, usually within first few minutes of starting infusion. It may cause symptoms like rash, flushing, facial swelling, shortness of breath, chills, headache, tightness in chest, back pain, hypotension, etc.
  • These are less likely to appear during subsequent cycles of chemotherapy if they didn’t occur during first cycle.
  • Infusion should be stopped immediately in case of signs and symptoms of an infusion reaction.

Recommended Clinical Monitoring

  • Cardiac function tests (Echo, or MUGA scans) for all patients with cardiac risk factors; baseline and regular intervals)
  • cumulative dose 450 mg/m2. (Cumulative dose lower for high risk patients)
  • CBC; baseline and regular
  • Liver function tests; baseline and regular
  • Clinical assessment of stomatitis, rash, hand foot syndrome, hypersensitivity

Daunorubicin

daunorubicin-anthracycline antitumor antibiotic

Mechanism of Action

  • DNA Intercalation
  • Topoisomerase II Inhibition

Indications

  • Acute myelogenous leukemia—Remission induction and relapse.
  • Acute lymphoblastic leukemia—Remission induction and relapse.

Doses Available

  • Injection, powder: 20, 50 mg
  • Injection, solution: 5 mg/mL

Dosage

  • AML: 60 mg/m 2 IV on days 1–3 of the first course of induction. Used in combination with continuous infusion ara-C.
  • ALL: 45 mg/m 2 IV in combination with vincristine, prednisone, and L-asparaginase.

Pharmacokinetics

  • Not absorbed orally. more lipid-soluble than doxorubicin. Widely distributed to tissues, does not cross the BBB. Extensively binds to plasma proteins (60%–70%).
  • Metabolism in the liver with formation of one of its primary metabolites-daunorubicinol, which has antitumor activity. Renal clearance accounts for only 10%–20% of drug elimination.
  • T1/2 parent drug is 20 hours, while T1/2 of the daunorubicinol metabolite is 30–40 hours. Daunorubicinol – a major part of the total AUC
  • Half -life – 40 minutes
  • Also has renal elimination (25%)

Drug Interactions

  • Use with caution in patients who have received previous anthracyclines as this can increase cardiotoxicity
  • Cyclophosphamide (increased cardiotoxicity)

Side Effects

  • Gastrointestinal: nausea and vomiting, mucositis, diarrhea
  • Hyperpigmentation of nails
  • Alopecia
  • Red-orange discoloration of urine
  • Cardiotoxicity
    • Acute: arrhythmias, conduction abnormalities, pericarditis or myocarditis during the first 2 to 3 days
    • Chronic: dose-dependent, dilated cardiomyopathy and heart failure. Risk increases with cumulative doses >550 mg/m2
  • Uncommon ;Radiation recall and sunlight hypersensitivity

Dose Modifications

  • Renal impairment: for patients with serum creatinine >3 mg/dL, reduce the dose by 50%
  • Hepatic impairment: Total bilirubin 1.2 to 3 mg/Dl- reduce recommended dose by 50%. Total bilirubin >3 to 5 mg/dL: reduce recommended dose by 75%

Liposomal Daunorubicin

  • First line cytotoxic therapy for advanced HIV-associated Kaposi’s sarcoma – approved in 1996
  • Administered i.v in 5%D over a 60 minute period at a dose of 40 mg/m2, every 2 weeks
  • LVEF should be measured at doses of 320 mg/m2, and every 160 mg/m2 thereafter
  • Myelosuppression , mild nausea, vomiting, alopecia
  • Serum bilirubin 1.2 to 3 mg/dL – ¾ the normal dose; serum bilirubin or creatinine > 3 mg/dL, give ½ the normal dose
  • Contraindications – hypersensitivity reaction, category D in pregnancy

Epirubicin

epirubicin-anthracycline antitumor antibiotic

Epirubicin is an epimer of doxorubicin with increased lipophilicity.

Pharmacokinetics

  • Half life – 18.3 hours
  • Metabolism– glucuronides of parent and 13-ol
  • Excretion – Primarily parent compound, 13-ol, and glucuronides, renal-30%
  • No drug interactions, except cimetidine increases AUC by 50%

Indications

  • Breast cancer
  • Gastric cancer
  • Ovarian cancer
  • Small cell lung cancer
  • Lymphoma (non-Hodgkin’s lymphoma)
  • Metastatic soft tissue sarcoma
  • Superficial bladder cancer (Tis; Ta)

Dose

  • Available as 10, 20, 50, 200 mg vials as a red solution
  • Given iv or intravesically only
  • Typical doses of epirubicin are 60 to 120 mg/m2, given as an i.v infusion in NS or 5%D, in not less than 3-4 min , every 3-4 weeks

Intravesical Administration

In Transitional cell carcinoma of bladder 

  • 8 weekly instillations of 50 mg, with local toxicity – 30 mg
  • In Tis, the dose may be increased up to 80 mg

Prophylaxis after transurethral resection of superficial tumours

  • Weekly administrations of 50 mg for a month followed by 11 monthly instillations at the same dose

Adverse Effects

The incidence of nausea and vomiting, alopecia, and cardiac toxicity is less with epirubicin compared to doxorubicin (cumulative dose > 900 mg/m2). However, similar to doxorubicin, severe myelosuppression can occur.

Side effects can be summarized as follows-

  • Leukopenia , thrombocytopenia
  • Cardiotoxicity (1-2%) at doses >900mg per m2 , dexrazoxane given at dose >550 mg per m2
  • Severe vesicant
  • AML (1-2%)
  • Epirubicin is also a vesicant.

Dose modifications

  • Dose adjustments are recommended for hepatic dysfunction: 50% dose reduction for serum bilirubin 1.2 to 3 mg/dL or aspartate aminotransferase (AST) two to four times the upper limit of normal, and 75% dose reduction for bilirubin greater than 3 mg/dL or AST greater than four times the upper limit of normal.
  • No dose adjustment for serum creatinine below 5 mg/dl. If serum creatinine above 5 mg/dl, 50 % dose reduction is needed.

Contraindications

  • Severe myocardial insufficiency, recent myocardial infarction or severe arrhythmias
  • Previous treatment with maximum cumulative dose of anthracyclines
  • Hypersensitivity reaction to epirubicin , other anthracyclines, or anthracenediones

Idarubicin

idarubicin-anthracycline antitumor antibiotic

Synthetic derivative of daunorubicin, lacking the 4-methoxy group

Mechanism of Action

  • DNA strand breakage mediated by topoisomerase II
  • Free radical induced injury
  • Induction of apoptosis

Pharmacokinetics

  • Multidrug resistance – mediated by MDR1, Topoisomerase II mutations, Altered apoptotic response
  • Half life – 22 hr , oral availability 30%
  • Metabolism – in liver
  • Primary metabolite is 13-epirubicinol, half life 45 hours
  • Excretion – 80% excreted in urine as 13-ol

Availability

  • Injection, solution: 1 mg/mL (5, 10, 20 mL)
  • Orange-red lyophilised powder

Indications

  • AML and ALL (FLAG-IDA regimen) – It is FDA-approved as part of combination chemotherapy for acute myeloid leukemia and is also active in acute lymphoid leukemia. It is given intravenously at a dose of 12 mg/m2 for 3 consecutive days.
  • IDA-FLAG regimen – Idarubicin (days 2-4, 12 mg/m2/d), fludarabine (days 1-4, 30 mg/m2/d), cytarabine (days 1-4, 2000mg/ m2/d) and G-CSF (day 0 up to ANC > 1 x 10(9)/l, 400 microg/m2/d).

Dosage and Administration

  • 12 mg/m2 for 3 days
  • 20 mg vials should be reconstituted with 20 mL of water for injection to give a concentration of 1 mg/mL, administered via a freely flowing iv infusion
  • Given oral, in metastatic breast cancer, 30-45 mg/m2 over 1,3 or 5 days

Dose Modification

Renal impairment

  • CrCl 10 to 50 mL/min: give 75% of dose
  • CrCl < 10 mL/min: give 50% of dose

Hepatic impairment

  • Total bilirubin 2 to 5 mg/dL: give 50% of dose
  • Total bilirubin > 5 mg/dL: do not give

Side Effects

Idarubicin has similar toxicities as daunorubicin, including myelosuppression, nausea, vomiting, alopecia, cardiac toxicity, and tissue necrosis in cases of extravasation.

  • Myelosuppression – Leukopenia , thrombocytopenia
  • Vomiting, diarrhoea, abdominal pain
  • Cardiac toxicity – Less than that of doxorubixin – cumulative doses of >150 mg/m2 have been associated with decreased LVEF
  • Dermatological -generalized rash, urticaria and a bullous erythrodermatous rash of the palms and soles
  • Radiation recall
  • Category D drug in pregnancy , discontinue during lactation

Mitoxantrone

mitoxantrone-anthracycline antitumor antibiotic

  • An anthracenedione.
  • Synthesized by chemists at American Cyanamid Laboratories in the late 1970s.
  • Narrow spectrum of antitumor activity – breast, prostate cancer, leukemias and lymphomas.
  • It was originally synthesized in the 1970s in a search for anthracycline analogs with less cardiac toxicity.
  • Mitoxantrone is a DNA intercalator and stabilizes the Top2-DNA complex, leading to double-strand DNA breaks.
  • Relative to anthracyclines, mitoxantrone is less likely to undergo oxidation-reduction reactions and form free radicals, thereby decreasing its cardiac toxicity.

Mechanism of Action

  • Binds to nucleic acids and inhibits DNA and RNA synthesis
  • Causes single and double strand breaks by formation of an enzyme cleavable complex
  • Has the basic quinone structure – lesser generation of  free radicals
  • Stimulates apoptosis

Pharmacokinetics

  • Preliminary t1/2 10 min and 1.1 to 1.6 hours, terminal t1/2 – 23-42 hours
  • >75% protein bound, does not cross the BBB
  • Metabolism – hepatic, no active metabolites
  • 25% fecal and 10% renal excretion
  • Prolonged terminal half-life >60 hours with liver impairment
  • Mitoxantrone is rapidly cleared from the plasma and is highly concentrated in tissues. A small amount is cleared via the kidney, and most of the drug is excreted in the feces.
  • Dose reduction needed in hepatic dysfunction.

Mechanism of Resistance

  • Amplification of the P170 glycoprotein
  • Alterations in topoisomerase II function
  • A novel member of the ATP-binding cassette superfamily of transporters that encodes an amino acid protein – breast cancer resistance protein – efflux
  • Altered intracellular pH
  • Modifications in apoptosis
  • Shares cross-resistance with vinca alkaloids and doxorubicin

Availability and Dose

  • Available as 2mg per ml (10 mg)
  • Sterile, nonpyrogenic, dark blue aqueous solution
  • Dosage for bolus intravenous
    • 12 mg/m2 per day for 3 days for treatment of AML
    • 12 to 14 mg/m2 per day once every 3 weeks in solid tumors

Indications

  • Prostate cancer
  • AML
  • Breast cancer
  • Ovarian cancer
  • Non hodgkin’s lymphoma
  • ALL
  • Hepatoma

Administration

  • Diluted to 50 mL, given in 0.9% NS or 5% D
  • 30-minute infusion, via a free flowing line
  • Never subcutaneously, intramuscularly
  • Should not be administered in solutions containing heparin

Alternate Routes of Administration

  • Intra arterial
  • Intraperitoneal – Local concentrations >> systemic. Used in ovarian or colon cancer. Dose is 12 to 38 mg/m2 as a single dose every 4 weeks in 2 L of dialysate. Toxicity includes higher incidence of leukopenia, abdominal discomfort, tenderness, catheter dysfunction

How is it different from Doxorubicin?

  • Lesser cardiac toxicity – reduced potential to undergo one-electron reduction
  • Diminished potential for extravasation injury
  • Lesser nausea and vomiting or alopecia

Drug Interactions

  • Used in combination with arabinosyl cytosine – biochemical synergy of the two agents
  • Mitoxantrone sensitizes cells to both hyperthermia and ionizing radiation

Side Effects/Toxicity

Dose-limiting toxicities involve myelosuppression. Nausea, vomiting, alopecia, and mucositis are less common compared to doxorubicin. Cardiac toxicity(5%) is generally seen at cumulative doses greater than 160 mg/m2.

  • Congestive heart failure , incidence < 5%
  • The risk of symptomatic CHF – 2.6% for a cumulative dose of 140 mg/m2 & 5% for 160 mg/m2
  • Leukopenia, mild thrombocytopenia
  • Nausea and vomiting; and rarely abnormal liver enzymes
  • AML and MDS (1-2%)
  • Rarely, bluish discoloration of the sclera, fingernails, urine

Contraindications

  • Hypersensitivity reaction to anthracyclines or mitoxantrone
  • Severe hepatic impairment; safety with hepatic impairment has not been established, reduced dosage has been used
  • Pregnancy ( category D ) and lactation

Bleomycin

bleomycin-antitumor antibiotic

  • Umezawa and colleagues isolated small glycopeptides from culture broths of the fungus Streptomyces verticillus in 1966 in Japan
  • Bleomycin A2, the predominant peptide
  • Molecular weight is 1,500 KDa
  • The clinical mixture is a white to cream sulfate salt
  • Potency measured in units (U) of antimicrobial activity
  • Each unit contains 1.2 to 1.7 mg of polypeptide protein

Mechanism of Action

  • Uptake is via a bleomycin-binding membrane protein, translocates to the nucleus
  • Progression of G2 into mitosis is blocked, S phase is lengthened
  • The drug forms an unstable ternary complex with iron and oxygen
  • Results in generation of superoxide radicals – scission of DNA strands
  • DNA damage
    • Direct
    • Chromosomal breaks and deletions and both single-strand and (less frequently) double-strand breaks

Mechanism of Resistance

  • Intracellular factors : drug inactivation, decreased accumulation, and increased repair of DNA damage
  • Increased bleomycin hydrolase activity
  • Bleomycin is not affected by P-glycoprotein

Pharmacokinetics

Absorption

  • Poor gastrointestinal absorption so must be given parenterally

Metabolism

  • Degraded by specific intracellular cysteine proteinase called bleomycin hydrolase
  • Enzyme found throughout the body in normal and malignant cells, except lungs and skin

Elimination

  • Renal elimination
  • 2/3 of bleomycin cleared by kidneys within first 24 hours
  • Half life in normal renal function = 2 – 4 hours
  • Half life creatinine clearance less than 25 to 35 mL/min – variably increased
  • Given as intravenous bolus.
  • Continous intravenous infusion causes more side effects.

Indications

  • Germ cell tumours
  • Hodgkin’s lymphoma
  • Squamous cell cancer- Head and neck cancer, penis, cervix and vulva
  • Kaposi’s sarcoma
  • Sclerosing agent for malignant pleural effusion and ascites. Response equivalent to tetracycline in malignant pleural effusion with minimal side effects ( fever and pleuritis). Respone poor in ascites.

Dose and Availability

  • Available as 15 and 30 units per vial
  • Dose – 10-20 units per metre2 intravenously
  • 15 or 30 units reconstituted in 5 or 10 ml 0.9% NS, given over 10 min, not in 5% Dextrose

Dose Adjustment

Hepatic Impairment

  • No need for dose adjustment

Renal Impairment

  • CrCl 40 – 50 mL/min. Give 70% of dose
  • CrCl 30 – 40 mL/min. Give 60% of dose
  • CrCl 20 – 30 mL/min. Give 55% of dose
  • CrCl 10 – 20 mL/min. Give 45% of dose
  • CrCl 5 – 10 mL/min. Give 40% of dose

Bleomycin Regimens

BEP regimen for Testicular Cancer

Repeat every 21 days for 3 – 4 cycles

  • Bleomycin 30 Units IV Day 1, 8, 15
  • Etoposide 100 mg/m2 Day 1 to 5
  • Cisplatin 20 mg/m2 Day 1 to 5

ABVD regimen for Hodgkin’s Disease

Repeat every 28 days for 6 – 8 cycles

  • Doxorubicin 25 mg/m2 IV Days 1 and 15
  • Bleomycin 10 units/m2 IV Days 1 and 15
  • Vinblastine 6 mg/m2 IV Days 1 and 15
  • Dacarbazine 375 mg/m2 IV Days 1 and 15

Intracavitary instillation into pleural space: 60 units/m2 in 100ml ns, administer via thoracostomy tube, which is clamped for 8hrs and then removed by suction.

Drug Interactions

  • Concurrent renal toxic medications may increase risk for pulmonary toxicity. Cyclosporine, cisplatin, aminoglycosides, amphotericin B, foscarnet, tacrolimus, vancomycin.
  • Oxygen – High concentrations of oxygen may enhance the pulmonary toxicity of bleomycin. FIO2 should be maintained at no higher than 25% when possible
  • Vinca alkaloids -Pretreatment with vinca alkaloids (6 to 8 hours before bleomycin) arrest cells in the mitosis phase increasing the proportion of susceptible cell populations Synergistic effect
  • Radiation therapy enhances the pulmonary toxicity of bleomycin.

Routes of Administration

  • Parenteral – i.v, intramuscular and subcutaneous
  • Intraarterial infusion – carcinoma of the cervix and head and neck. 30-60 units once or twice a week, until a total dose of 300 units
  • Topical – 3.5% ointment – Paget’s disease of vulva, 2 weeks
  • Intrapleural – malignant effusions
      • 40 U/m2 is dissolved in 100 mL normal saline and instilled through a thoracostomy tube, after effusion is drained ( less than 100 ml drained in 24 hours) and lung expansion is confirmed
      • Clamped for 8 hours and then returned to suction
      • Toxic reactions – fever and pleuritis, resolve in 24 to 48 hours
  • Intraperitoneal – ovarian cancer, mesothelioma, malignancy confined to the peritoneum
      • 60 mg/m2 was dissolved in 2 L of saline, 4- to 8-hour dwell time in the peritoneal cavity
      • Side effects – abdominal pain, fever, rash, mucositis
  • Intravesical – transitional cell carcinoma of bladder
      • 60 U in 30 mL of sterile water
      • Primary toxicity – cystitis

Adverse Effects/Toxicity

  • The most important – lungs and skin
  • Mild myelosuppression in severely compromised marrow function.
  • Fever may be seen 48 hours after administration in 25% of cases.
  • Fatal allergic reaction possible

Pulmonary Toxicity

  • Subacute or chronic interstitial pneumonitis complicated by progressive interstitial fibrosis, hypoxia, and death
  • Various forms of ILD – nonspecific interstitial pneumonia, diffuse alveolar damage, organizing pneumonia, hypersensitivity pneumonia
  • Incidence
      • 3 to 5% with dose of < 450 Units
      • 10% with higher doses
      • Mortality is around 1%
Risk Factors for Pulmonary Toxicity
  • Age > 70 years
  • Renal insufficiency
  • Underlying pulmonary disease and extent of lung metastases
  • Prior chest irradiation
  • Oxygen during surgery
  • Cumulative dose >400U
  • Bolus drug delivery
  • Combination with other drugs e.g. cisplatin, growth factors
  • Single dose>25 units per m2
  • Cigarette smoking
Mechanism
  • Not entirely clear
  • Oxidative damage, relative deficiency of the deactivating enzyme bleomycin hydrolase, genetic susceptibility, and elaboration of inflammatory cytokines
Molecular Basis
  • Bleomycin forms a complex with Fe2+, induces generation of reactive oxygen radicals
      • ROS cause fatty acid oxidation, lead to membrane instability
      • Oxidants induce inflammatory reactions
  • Alveolar macrophages and endothelial cells release cytokines – interleukin-1, MIP -1, PDGF and TGF-B
  • Proliferation of myofibroblasts + secretion of extracellular matrix lead to fibrosis
  • The mechanism by which alveolar macrophages activated is unknown
  • Bleomycin receptors have been identified on the surfaces of rat alveolar macrophages, suggesting that macrophage activation may occur via a second messenger
Clinical Features
  • Nonproductive cough, dyspnea, occasionally fever and pleuritic pain
  • Minimal auscultatory evidence
  • CXR – patchy reticulonodular infiltrate, lower ones- subpleural
  • Arterial oxygen desaturation and an abnormal carbon monoxide diffusion capacity
  • D/D – interstitial lung disease and carinii pneumonia
  • Open lung biopsy is required for definitive diagnosis
Histological Findings
  • Main abnormalities seen in endothelial and epithelial cells
  • Necrosis of type I alveolar cells, acute inflammatory infiltrate in the alveoli, interstitial and intraalveolar edema, pulmonary hyaline membrane formation, and intraalveolar and later, interstitial fibrosis
  • Squamous metaplasia of type II alveolar lining cells – characteristic

Precautions during Surgery and Anaesthesia

  • Greater risk of respiratory failure in the postoperative period
  • Current safeguards for anesthesia –
      • Use of the minimum tolerated concentration of inspired oxygen (<25%)
      • Modest fluid replacement to prevent pulmonary edema
Treatment
  • No specific therapy
  • Discontinuation of the drug
  • Corticosteroids remains controversial

Newer Therapies

  • Sirolimus
  • Geftinib – inhibits proliferation of mesenchymal cells and targets tyrosine kinase receptors
  • Montelukast – reduces the fibrotic area and hydroxyproline content, inhibits overexpression of IL-6, IL-10, IL-13 and TGF-𝛽1
  • Imatinib, nilotinib – inhibits tyrosine kinase activity of PDGFR
  • 2C4 – monoclonal antibody against HER2HER3 – reduced collagen deposition
  • ACE inhibitors – ACE2, a homolog of ACE inhibits RAS and counterbalances the action of ACE
  • Pravastatin
  • Human amniotic epithelial cells – possess multipotent differentiation ability, low immunogenicity, and anti-inflammatory properties- reduces fibrosis

Skin Toxicity

  • More common , at doses of 150-200U
  • Occurs in 2nd or 3rd week
  • Areas affected – digits, hands, joints, and areas of previous irradiation
Clinical Features
  • Erythema, induration, hyperkeratosis, peeling of skin – may progress to ulceration
  • Hyperpigmentation, alopecia, nail changes
  • Raynaud’s phenomenon & hypersensitivity reactions
  • Flagellate Erythema
    • Incidence – 8% to 20%
    • Drug specific, independent of the dose, route or disease
    • Onset – 1 day to 9 weeks
    • Prodrome – generalized pruritus and erythema, ameliorates and lesions develop into papules and nodules
    • Physical examination
      • Linear intermingled streaks formed by rows of adjoining firm papules, which can have punctuate hemorrhages or be pustular – Later hyperpigmentation for 6 months
      • No characteristic distribution
    • Mechanism – skin reaction to localized toxic levels
    • Biopsy – spectrum including inflammatory oncotaxis, urticarial hypersensitivity reaction, lymphocytic vasculitis, drug-induced toxic skin reaction, and a fixed drug eruption-like reaction
    • No specific treatment
    • Self-limited course
Radiation and Bleomycin
  • Administration within 3 hours of irradiation, either before or after, produces greater than additive effects, due to free-radical damage to DNA by both
  • Seen in lymphomas , squamous carcinomas of the esophagus and head and neck

Monitoring

  • Pulmonary Function Tests with special focus on DLCO and vital capacity should be obtained at baseline and before each cycle of therapy. A decrease of >15% in PFTs should mandate the immediate discontinuation of bleomycin, even in the absence of clinical symptoms.
  • Chest X-ray should be obtained at baseline and before each cycle of therapy to monitor for evidence of infiltrates and/or interstitial lung findings.
  • Monitor for clinical signs of pulmonary dysfunction.
  • Doses should be reduced in the presence of renal dysfunction, renal status should be monitored before each cycle.
  • Patients with lymphoma may be at increased risk for developing an anaphylactic reaction.

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