Antitumor antibiotics and PLANT ALKALOIDS Antitumor antibiotics and PLANT ALKALOIDS Plant Alkaloids Vinca alkaloids : periwinkle plant (catharanthus rosea)

Antitumor antibiotics and PLANT ALKALOIDSAntitumor antibiotics and PLANT ALKALOIDS

• Plant Alkaloids• Vinca alkaloids : periwinkle plant (catharanthus rosea)

Vincristine, Vinblastine and Vinorelbine• Taxanes : Pacific Yew tree (taxus) Paclitaxel and

Docetaxel• Podophyllotoxins:  Etoposide and Tenisopide• Camptothecan analogs: Irinotecan and Topotecan.

• Antitumor Antibiotics• By soil fungus Streptomyces.  (multiple phases of the cell

cycle )• Anthracyclines:  Doxorubicin, Daunorubicin,

Epirubicin, Mitoxantrone, and Idarubicin.• Chromomycins:  Dactinomycin and Plicamycin.• Miscellaneous:  Mitomycin and Bleomycin.

第一股 DNA G-segment﹝ ﹞結合到 A’ subunits後，緊接著 ATP便結合在 ATPase domain上，伴隨著第二股 DNA T-segment﹝ ﹞加入整個反應機構。位於 A’ subunits上的一對 tyrosine 的 phenolic oxygens便會以共價方式結合到 G-segment 5’端的磷酸基團上，而放出同股 DNA 3’端的 OH group，另一 monomer上的 tyrosine也是以同樣方式作用在此 DNA的另一股，而這兩個 tyrosine作用的位置彼此相距 4 個 base pairs，整個作用是一個 transesterification的過程。接下來，第二股 DNA T-segment﹝ ﹞ 與 ATP也同時加入來參與反應；當 ATP水解產生能量、切斷 G-segment 被 tyrosine作用的兩端之間 4 個 base pairs，並將已切斷的兩段 G-segment彼此拉開遠離而形成一〝 gate〞，使 T-segment通過此閘口，之後兩個 A’ subunits間的 interface便會打開，放出 T-segment，同時已被切開的 G-segment再度以 transesterification的作用將〝 gate〞再度連合，回覆到原先的狀態，之後再進行下一個相同的反應，形成一循環。

Antitumor Antibiotics

• Anthracyclines:  Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone, and Idarubicin.

• Chromomycins:  Dactinomycin and Plicamycin.

• Miscellaneous:  Mitomycin and Bleomycin.

ANTHRACYCLINE

ANTHRACYCLINE• Cardiotoxicity : is cumulative across members of

the anthracycline (daunorubicin, doxorubicin, epirubicin, idarubicin) and anthracenedione (mitoxantrone) class of drugs.– Acute (within 24 hrs, nonspecific ST-T wave change, sinus

tachycardia, dysrhythmias, 40% ), Transient reduction in the ejection fraction can also occur acutely with pericarditis-myocarditis syndrome.

– Subacute (weeks to months after last dose, CHF with low cardiac output)

– Late effects (>5 yrs, incidence high 65% 4-10 yrs after receiving anthracyclines )

Anthracyclines Risk factors

• Dose (< 450-550mg/m2 , 1-10% CHF , 270 mg/m2 less cardiotoxicity )

• 900 to 1000mg/m2

– CHF refractory to medical therapy.– Cardiac irradiation or the administration of

Cyclophosphamide may increase the risk of cardiotoxicity.

• Bolus • Extreme young, advanced old• Previous mediastinal radiation• Malnutrition• Pre-existing cardiac disease

AnthracyclineMechanism of toxicity

• Dysrhythmias – Sudden release catecholamines

• Cardiomyopathy– damage to mitochondrial DNA of heart

tissue– free radical production

Anthracyclinestreatment

• Arrhythmia– Monitor, no need treatment

• Cardiomyopathy– Discontinuation of the drug and standard

treatment of CHF. – ACEI, carvedilol, drugs to decrease pre and

after load.– The cardioprotective agent dexrazoxane

(Zinecard) recommended to be started at a doxorubicin cumulative dose greater than 350mg/m2.

Anthracyclines• GI: Nausea/vomiting, mucositis• Hematologic : leukopenia • Radiation recall• AML: 0.2% at 3 yrs.• The tissue necrosis that occurs with extravasation may

happen days to weeks after the treatment.

• Dose adjustment (ex: doxorubicin)– liver function/bilirubin

ALT/AST Bilirubin (mg/dl) Dose 2-3 x ULN - 75% > 3 x ULN or 1.2-3 50% - 3 - 5 25% - > 5 Do not administer

Doxorubicin (Adriamycin)• Stabilizing DNA-topoisomerase II complexes, DNA intercalation, and

free radical formation.• Absorption, Fate, and Excretion: • T1/2= 30 hrs, metabolized in the liver. Adjust by liver dysfunction• Preparation and Administration: • IV bolus/ infusion, powerful vesicant. • ADR • Continuous infusion can decrease the risk of cardiotoxicity• Therapeutic Indications in Hematology:

– Solid tumors, Hematologic malignancies : Hodgkin's disease (ABVD regimen), NHLs (CHOP, MACOP-B), and multiple myeloma (VBAP, VAD).

Epirubicin

• CHF (0.9%, 1.6%, 3.3% at a cumulative dose of 550 mg/m(2), 700 mg/m(2), 900 mg/m(2)

• CHF increases rapidly with increasing total cumulative doses of epirubicin in excess of 900 mg/m(2)

• ADR– Cardiac toxicity – Secondary acute myelogenous leukemia (AML)

MDS (0.27% at 3 years, 0.46% at 5 years and 0.55% at 8 years.

Daunorubicin

• Biliary excretion accounts for approximately 75% of the drug and metabolite elimination. Patients with significant hepatic dysfunction should receive an attenuated dose of daunorubicin.

• Preparation and Administration: • Red color to the urine for up to 72 hours after

administration.• Therapeutic Indications in Hematology:

– in combination with other drugs in the treatment of AML and ALL (45mg/m2/daily for 3 days)

Idarubicin • Acute lymphocytic leukemia • Adult Acute myeloid leukemia

– induction, 12 mg/m(2) IV daily for 3 days in combination with cytarabine (dosed as 100 mg/m(2) every day by continuous infusion for 5-7 days every day.

• ADR– less cardiac toxicity than doxorubicin or daunorubicin. There is no

currently recommended maximum cumulative lifetime dose for idarubicin.

• Local erythematous streaking along the vein and facial flushing may result from too rapid administration.

• Radiation recall reactions, the timing of the radiation may be before, concurrent with or even after the administration of the idarubicin. – Recurrent injury to a previously irradiated site may occur weeks to

months following radiation.

Mitoxantrone• AML, ALL

– 12 mg/m2/day IV x 5 days for 1-2 cycles • Maximum lifetime dose: 140 mg/m2 (no prior anthracycline,

normal cardiac function, less in children) • 120 mg/m2 (in combination with previous anthracycline,

thoracic radiation or cyclophosphamide) • 100 mg/m2 (previous maximum dose anthracyline, if cardiac

assessment acceptable) • Bone marrow transplant: much higher doses are used for

tumour ablation prior to marrow transplant than for standard treatment regimens; eg, 12 mg/m2/day IV x 3 days or 60-75 mg/m2 IV in multiday, divided doses; in combination with other cytotoxic chemotherapy

• Dosage in myelosuppression: modify according to protocol by which patient is being treated.

• Dosage in hepatic failure: decrease dose by 50% if bilirubin >3mg/dl

Mitoxantrone• SPECIAL PRECAUTIONS: • Cardiac monitoring is recommended

– prior anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin) or mediastinal radiotherapy and/or patients with pre-existing cardiac disease.

– Cardiac monitoring (echocardiogram, ejection fraction) is advisable every 2-3 cycles, and before every cycle in patients who have received a total cumulative dose of 140 mg/m2 (approximately 10 courses).

– The cumulative dose is lower in children and in patients who have received radiation to the mediastinal area or concomitant therapy with other cardiotoxic agents such as cyclophosphamide.

• Stomatitis is dose-limiting with the 5 day schedule and with the high doses used for bone marrow transplantation (eg, high grade mucositis in nearly 70% of BMT patients in one study).

• The majority of extravasations of mitoxantrone result in a blue discolouration of the skin which slowly fades.

Dactinomycin• Mechanism

– At low concentrations, dactinomycin inhibits DNA-primed RNA synthesis by intercalating with guanine residues of DNA.

– At higher concentrations, it also inhibits DNA synthesis. Interstrand and DNA-protein cross-links may also occur. (cell cycle phase-nonspecific)

• The tissue necrosis that occurs with extravasation may happen days to weeks after the treatment.

• Radiation recall reactions, the timing of the radiation may be before, concurrent with or even after the administration of the dactinomycin. Recurrent injury to a previously radiated site may occur weeks to months following radiation.

• Hepatotoxicity – Wilm's tumour : increased AST (SGOT) and bilirubin levels, ascites and liver

enlargement. (thrombocytopenia may accompany hepatotoxicity ). – Factors: concurrent other hepatotoxic agents, especially halogenated

anesthetics; using single-dose dactinomycin as opposed to a 5 day regimen; doses of dactinomycin ≥60 mcg/kg; and radiation.

• Adults: – Direct intravenous: q2w: 1.25 mg/m2, q3-4w: 1-2 mg/m2 (25-50 mcg/kg) – q4-6w: 400-600 mcg/m2/day (max :500mcg) x 5 days

Bleomycin• MECHANISM OF ACTION:

– Bleomycin causes DNA strand scission through formation of an intermediate metal complex requiring a metal ion cofactor such as copper or iron. This action results in inhibition of DNA synthesis, and to a lesser degree, in inhibition of RNA and protein synthesis. The drug is cell-cycle specific for G phase, M-phase and S phase

• Indication : Malignant pleural effusion, Soft tissue sarcoma, Testicular cancer.

• Use with caution in patients– with compromised pulmonary function, with compromised renal

function, > 40 years, receiving concomitant chest radiation, receiving concomitant administration of cisplatin, cyclophosphamide, methotrexate or doxorubicin, receiving positive fluid balance during prolonged surgical procedures and who smoke. These are all risk factors that can predispose the patient to bleomycin pulmonary toxicity (BPT), which can be severe and life threatening.

• A cumulative dose > 450 units known risk factor ( BPT).

Bleomycin• Dermatologic effects

– The most frequent adverse effects of bleomycin (50%) usually occurring 2-4 weeks after initiation of therapy.

– Adverse mucocutaneous effects including erythema, rash, striae, vesiculation, hyperpigmentation, and tenderness of skin usually develop in the second or third week of bleomycin therapy. Mucocutaneous effects appear to be dose related, usually occurring after 150-200 units of bleomycin.

• Febrile reactions : 50% given IV and in 25% given IM. This reaction can be prevented by hydrocortisone premedication. Pre-treatment with antipyretics or antihistamines can also be used, but have not produced uniform results.

Mitomycin• MECHANISM OF ACTION

– activated in vivo to a bifunctional and trifunctional alkylating agent. Binding to DNA leads to cross-linking and inhibition of DNA synthesis and function. (cell cycle phase-nonspecific).

• Indication: Bladder cancer, Gastric cancer, Colorectal cancer • Myelosuppression : delayed (onset: 3 weeks, Nadir: 4-6 weeks)• The tissue necrosis that happens with extravasation may happen

days to weeks after the treatment. • Pulmonary toxicity consisting of dyspnea, non-productive cough for

weeks to months, and basilar rales : 2.8-12%. 40% develop pulmonary toxicity will die of progressive pulmonary dysfunction. Threshold dose : 50-60 mg/m2. Steroids may be of some benefit.

• A syndrome of renal failure and microangiopathic hemolytic anemia– 10%. Threshold of 50-60 mg/m2 and usually appears after 6 months of

therapy. • Genitourinary irritation following intravesical (bladder) administration

includes dysuria, cystitis, nocturia, increased micturition and hematuria. Myelosuppression has not been noted with intravesical administration.

• Radiation recall reactions

Antimitotic DrugsAntimotitic agents block (arrest) cells in mitosis by

interfering with microtubule dynamics

Two of the most clinically useful classes of antimitotic drugs are the vinca alkaloids and the taxanes

Vinca alkaloids block cells at the metaphase/anaphase junction of mitosis by destabilizing microtubules

Taxanes arrest cells in mitosis, but promote the polymerization of purified tubulin, causing stabilization and bundling of microtubules

Microtubules

Vinca Alkaloids – History and Use• Natural products isolated from the periwinkle

長春花 plant Catharanthus roseus

• During the past 30 years, vincristine and vinblastine have been used extensively in the treatment of leukemias, lymphomas and testicular cancer

• By modifying the velbanamine or 'upper' portion of the vinblastine structure, vinorelbine was the first new second generation vinca alkaloid to emerge

•Vinorelbrine is now used both as a single agent and in combination therapy for cancers as diverse as lung (non small cell), breast and ovarian

Vinca Alkaloids - ChemistryA

B

Vinca Alkaloids Aggregate Tubulin Dimers (depolymerization) - Leads to Microtubule

Depolymerization

Vinblastine

• Indication: Breast cancer, Hodgkin's disease, Kaposi's sarcoma,Testicular cancer

• SPECIAL PRECAUTIONS – may be lethal if injected intrathecally.– The tissue necrosis : extravasation (days to weeks ) – Neurotoxicity  is qualitatively similar but quantitatively

different (vincristine>vindesine>vinblastine). • Numbness, paresthesia, mental depression, loss of deep tendon

reflex, headache, malaise, dizziness, seizures or psychosis. • Cranial nerve neuropathy : vocal cord paresis or paralysis,

oculomotor nerve dysfunction and bilateral facial nerve palsies. Reversible when treatment with vinblastine is discontinued.

• Severe jaw pain or parotid gland : within a few hours of the first dose of vinblastine. No need to stop or modify the dose; treat with analgesics.

• Autonomic neuropathy : constipation, abdominal pain, urinary retention and paralytic ileus. (Dose > 20 mg)

Vincristine

• Indication: Solid tumors, lymphoma,Leukemia, Multiple myeloma, Retinoblastoma, Kaposi’s sarcoma, Waldenstrom’s macroglobulinemia, small cell lung cancer

• Dose: 0.4-1.4mg/m2 • SPECIAL PRECAUTIONS:

– is nearly always fatal if administered by the intrathecal (IT) route.

• Contraindicated – Neurological disorders including hereditary motor and sensory

neuropathy type 1, demyelinating Charcot-Marie-Tooth Syndrome (腓骨肌萎縮症 )and childhood poliomyelitis,

– Vincristine has produced severe hepatic toxicity when given in conjunction with abdominal radiation therapy.

Vincristine• Use with caution in: using other neurotoxic drugs and other ototoxic drugs

including amino glycosides, carboplatin, cisplatin and furosemide. • Neurotoxicity :

– Peripheral, autonomic and central neuropathy– Dose-limiting toxicity of vincristine. Dose related and reversible– Neurotoxicity can persist for months after discontinuation. – Infants are at a higher risk for experiencing vincristine-related neurotoxicity.

• Peripheral neuropathy is the most common – Loss of deep tendon reflexes, peripheral paresthesias, pain and tingling can occur. If

therapy is prolonged or high doses are administered, wrist and foot drop, ataxia, a slapping gait and difficulty in walking can occur.

– Cranial nerve toxicities may lead to vocal cord paresis or paralysis (hoarseness, weak voice), ocular motor nerve dysfunction (ptosis, strabismus), bilateral facial nerve palsies, or jaw pain. Severe jaw pain can occur within a few hours of the first dose of vincristine.

• Autonomic neuropathy – constipation (which can be severe, impaction of stool in the upper colon), abdominal

pain, urinary retention and paralytic ileus. Stool softeners and laxatives should be given prophylactically to prevent constipation.

• Central neuropathy : headache, malaise, dizziness, seizures, mental depression, psychosis and SIADH.

Vinorelbine

• MECHANISM OF ACTION:– Vinorelbine inhibits cell growth by binding to the tubulin of the

mitotic microtubules.– Microtubules are present in mitotic spindles, neuronal axons, and

other cells. Inhibition of mitotic microtubules appears to correlate with antitumour activity, while inhibition of axonal microtubules seems to correlate with neurotoxicity.

– is more selective against mitotic than axonal microtubules in vitro, which may account for its decreased neurotoxicity.

– Vinorelbine is a radiation-sensitizing agent.• Dose

– 25mg/m2 or oral 60-80mg/m2– Adjust by liver bilirubin and neurotoxicity

Vinorelbine• Injection site reactions (Picc line or central line )

– moderate vesicant and can produce extravasation injury ( irritation, local tissue necrosis and/or thrombophlebitis).

– Injection site reactions occur 1/3 , 2% were severe. Reactions include erythema, pain at injection site, vein discoloration, localized rash and urticaria.

– Chemical phlebitis (Hydrocortisone 100 mg IV) may be given prior to vinorelbine if the patient experiences pain on administration.

• Acute dyspnea and severe bronchospasm – occur infrequently and respond to bronchodilators. – Risk factor : concurrent use of mitomycin, Subacute pulmonary

reactions occur within one hour after drug administration and may be characterized by cough, dyspnea, hypoxemia and interstitial infiltration. Subacute pulmonary reactions : corticosteroid therapy and oxygen.

• Neuropathy: Mild to moderate peripheral neuropathy (paresthesia, hypesthesia) is the most frequently reported neurologic toxicity– reversible on discontinuation of vinorelbine– Cisplatin does not appear to increase the neurotoxic effects. – Paclitaxel may result in cumulative neurotoxicity.

Vinorelbine• Alopecia : hair loss is uncommon.• Chest pain: history of cardiovascular disease or

tumour within the chest. • Pain in tumour-containing tissue: within 30 minutes

after the first dose of vinorelbine. The pain usually lasts for one hour or less, but can continue for two days. – Risk factors:

• locoregional relapse of head and neck cancer. The theory is that prior surgery and/or radiation cause a nervous lesion, and that subsequent vinorelbine causes a neuralgic pain.

• The pain can be managed with NSAID or corticosteroids and may sometimes require narcotic analgesics.

Taxanes – History and Use

• First isolated from the bark of the Pacific yew tree (Taxus spp.) in 1971 • Paclitaxel (Taxol®) now obtained for commercial purposes by semisynthesis from 10-

desacetylbaccatin, a precursor

• Paclitaxel: role in the combination therapy of ovarian, breast, lung, esophagus, bladder, and head and neck cancers

• Paclitaxel is a diterpenoid compound that contains a complex taxane ring as its nucleus. The side chain linked to the taxane ring at C 13 is essential for antitumor activity

• Modification of the side chain has led to identification of a more potent analogue, Docetaxel (Taxotere®), which has clinical activity against breast and ovarian cancers

Taxanes – Chemistry : It promotes the assembly of tubulin into stable microtubules and inhibits their

disassembly.

Paclitaxel• Elderly patients : arthralgia, myalgia, neutropenia, neuropathy• Hypersensitivity reactions (HSR):

– Either the Cremophor EL in the paclitaxel injection or from the paclitaxel itself.

– HSR most often occur in the first hour of an infusion (75% occur within the first 10 mins)

– The frequency and severity HSR are not affected by the dose or schedule

– Delayed onset of urticarial rash, 7-10 days following completion of a course of treatment, has been seen in some Kaposi’s sarcoma patients.

– Incidence of HSR are significantly reduced by premedication. Corticosteroids (e.g., dexamethasone), histamine H1-antagonists (e.g., diphenhydramine) and H2-antagonists (e.g., ranitidine) should be administered prior to paclitaxel administration

• 45 minutes before paclitaxel, dexamethasone 20 mg IV • 30 minutes before paclitaxel, diphenhydramine 50 mg IV and

ranitidine 50 mg IV.

Paclitaxel • A more protracted premedication scheme, which may be more effective

– 12 hours and 6 hours before paclitaxel, dexamethasone 20 mg po and then following the above premedication regime.

– Premedicated patients, symptoms of HSR 41%, severe HSR < 2% • The occurrence of HSR, can rechallenge again, further premedication

with close monitoring.– Prolonging the infusion to > 6 hours, decreased HSR with increased

infusion times.• Moderate HSR: moderate rash, flushing, pruritus, mild dyspnea, chest

discomfort, abdominal discomfort, lower back pain, mild hypotension • Stop infusion. • Give diphenhydramine 25-50 mg IV and/or hydrocortisone 100 mg • Resuming at 25% of previous rate for at least 5 minutes, 50% for at least 5

minutes, 75% for at least 5 minutes and then full rate if no reaction. • Depending on severity of reaction, may increase to full rate. • Premedication for all future cycles. Initiate infusion at slower rate (consider 50%

of full rate).

Paclitaxel• Severe (potentially life threatening) : One more of

respiratory distress requiring treatment, angioedema, hypotension requiring therapy) – Stop infusion and do not restart.– Give diphenhydramine 50 mg IV push and/or

hydrocortisone 100 mg IV push and oxygen if needed for dyspnea

– Normal saline if needed for hypotension – Epinephrine or bronchodilators if indicated – Either permanently discontinue the drug or attempt to

retreat on another occasion after premedication and using slower infusion rate.

– True anaphylactic reaction: won’t respond to premedication and a slow initial infusion rate .

– Docetaxel has been successfully substituted in some patients who experienced severe HSR with paclitaxel; cross-sensitivity has also been reported.

Paclitaxel • Arthralgia/myalgia is dose and schedule dependent; worse with higher

doses and shorter infusions.– usually transient, occur within 2-3 days after paclitaxel, and resolve after a few

days.– If arthralgia/myalgia is grade 2 (moderate) or higher and is not relieved by

adequate doses of NSAIDS or acetaminophen with codeine, a suggested symptomatic treatment includes

• gabapentin 300 mg po on day prior to paclitaxel, 300 mg po tid x 7-10 days • prednisone 10 mg po bid x 5 days starting 24 hours post-paclitaxel • Dose reduction may be considered

• Peripheral neuropathy – mild paresthesia characterized by numbness and tingling in a stocking-and-glove

distribution.– Onset may be rapid, occurring within a few days of an infusion.– Frequency and severity are related to cumulative doses– Sensory manifestations usually improve or resolve several months after

discontinuing paclitaxel.– Pre-existing neuropathies resulting from prior therapies are not a contraindication

for treatment with paclitaxel. • Bradycardia and hypotension : asymptomatic and generally does not

require treatment. • Ethanol is contained in the paclitaxel formulation at a concentration of 396

mg/mL.

Docetaxel• Patients with prior severe hypersensitivity reactions should generally

not be rechallenged with docetaxel.– With objective tumour responses and without other options to docetaxel

therapy, re-treatment may be attempted with extreme caution and aggressive premedication by experienced practitioners.

• Preexisting effusions: – Closely monitored from the first dose for the possible exacerbation of the

effusions. • Liver impairment

– > docetaxel 100 mg/m2 are at a higher risk of developing severe adverse reactions if they have elevated transaminase (ALT and/or AST greater than 1.5 times the upper limit of normal [ULN]) and alkaline phosphatase (greater than 2.5 times ULN).

– Liver impairment reduces clearance and increases systemic exposure to docetaxel. Adverse reactions include life-threatening sepsis and gastrointestinal hemorrhage, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia.

• Alcohol abuse: When docetaxel is used in patients who abuse alcohol,, the risk of severe neurotoxic reactions may be increased.

Docetaxel• Peritreatment administration of dexamethasone

– is recommended to decrease the frequency and severity, and to delay the onset of docetaxel-induced fluid retention. Dexamethasone also reduces the severity of docetaxel-induced hypersensitivity reactions and cutaneous toxicity.

– 3-weekly regimen: dexamethasone 8 mg PO twice a day for 3 days starting one day prior to each docetaxel infusion. ( minimum of 3 doses of dexamethasone prior to docetaxel treatment. If dexamethasone has not been taken prior to treatment, it should be started and the docetaxel infusion delayed until the following day.) If treatment delay is not possible, diphenhydramine 50 mg IV and dexamethasone 10 mg IV may be given 30 minutes before starting docetaxel. Note that this premedication regimen has not been shown to reduce the incidence and severity of fluid retention, but is only an attempt to ameliorate hypersensitivity reactions. The patient should then be instructed to take dexamethasone 8 mg PO twice a day for two days.

– Weekly regimen: dexamethasone 8 mg PO for 3 doses starting the night before, morning of and evening after treatment (total dose, 24 mg/week). Alternatively, a single 8 mg dexamethasone dose 1 hour prior to docetaxel administration may be used.

Docetaxel• Dexamethasone dose for children: dose of 3 mg/m² PO or IV for two doses 12

hours and 6 hours prior to the dose of docetaxel • Hypersensitivity reactions

– during the first two cycles of docetaxel treatment, generally within the first few minutes after the infusion is started.

– Signs and symptoms usually abate within 15 minutes after the infusion is stopped.

– Flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever or chills. If minor reactions occur, continued. For severe reactions such as hypotension requiring treatment, bronchospasm, and generalized rash/erythema; stop the docetaxel.

• Rechallenge after severe hypersensitivity reaction– Severe hypersensitivity reactions: not be rechallenged– Tumour responder without other options to docetaxel therapy

• slower rate of infusion• corticosteroid and a histamine H1 blocking antagonist. Treatment was

continued without further difficulty after sodium cromoglycate (400 mg PO four times a day, starting immediately after the second cycle) was added to the prophylactic regimen.

Docetaxel• Fluid retention ( 82%: 52% with dexamethasone premedication)

– begins at the lower extremities and may become generalized with a weight gain of 3 kg or more.

– due to increased capillary permeability rather than hypoalbuminemia or cardiac, hepatic or renal damage.

– It is slowly reversible after treatment is discontinued (median 29 weeks). • Neuropathy: moderate to severe neuropathy, leading to decreased

dexterity and/or disturbances in gait ( 600 mg/m2 ) • Rash/pruritus: rash, including localized eruptions mainly on feet and

hands, but also on arms, face or thorax. ( 48%) resolve before the next infusion, and are not disabling.

• Severe nail changes occur in 2% of patients and are characterized by discoloration of fingernails or toenails.

• Hand-foot skin reaction that occurs despite dexamethasone prophylaxis may respond to administration of pyridoxine 50 mg orally three times a day.

• Tearing/watery eyes: An unexpected toxicity with the weekly schedule is excessive tearing. Dose related median of 400 mg/m² (range, 120-960 mg/m²). Treatment with artifical tears or other ocular moisturizers ameliorated symptoms in some patients.

Etoposide (Vepesid)• Etoposide (VP-16), etoposide phosphate, and teniposide (VM-26) are

semisynthetic derivatives of epipodophyllotoxin.• Mechanism : to stabilize a topoisomerase II-DNA cleavable complex, which

acts as a replication fork barrier and leads to the generation of irreversible DNA damage and cell death in proliferating cells.

• Absorption, Fate, and Excretion: • Etoposide has an oral bioavailability of 25% to 75%.(T1/2 is 6 to 8 hrs)• Etoposide phosphate is rapidly and completely converted in vivo to VP-16

by the activity of phosphatase, and has been shown to have the same pharmacokinetics as VP-16. Due to its increased water solubility, etoposide phosphate can be given intravenously in much less volume. In addition, the metabolic acidosis and hypotension seen with the infusion of VP-16 are not seen with this prodrug.

• Teniposide has a multiphasic pattern of clearance from plasma with a terminal half-life of 9.5 to 21 hours. Unlike those of etoposide, metabolites of teniposide account for greater than 80% of the drug excreted in the urine.

Derivatives of epipodophyllotoxin• Preparation and Administration: • Etoposide : PO: 50-mg capsules, vials 50-100 ( 20mg/Ml).

Concentration : 0.2 or 0.4mg/mL (stable for 96 or 48 hrs), respectively. Etoposide must be administered slowly over more than 30 minutes to prevent hypotension. ADR:

• Myelosuppression, especially leukopenia, (dose-limited) • Nausea and vomiting are usually mild and easily prevented with

antiemetics.• Rapid infusion of etoposide (<30 minutes) may cause hypotension.

Anaphylactoid reactions (e.g., bronchospasm) occur in less than 2% of patients and may be related to the cremaphor vehicle.

• In bone marrow transplantation doses, mucositis and diarrhea are prominent and may be dose limiting.

• Secondary leukemia AML/APL : <2000mg/m2 , 0.37-8.1 9 to 68 months after diagnosis of the first cancer; treatment responses have been poor in most patients.

Derivatives of epipodophyllotoxin

• Potential Drug Interactions: – Synergistic cytotoxic effects: VP-16 is given after a

topoisomerase I inhibitor, which appears to upregulate the amount of topoisomerase II enzyme.

– Antagonistic effects : topoisomerase II inhibitor is given before a topoisomerase I inhibitor.

• Therapeutic Indications: • NHLs and as a second-line treatment for Hodgkin's disease. • Bladder cancer, Ewings’s sarcoma, Kaposi’s sarcoma,

Ependyoma, AML, Germ cell tumor, Rhabdomyosarcoma, small cell lung cancer

• Bone marrow transplantation of refractory lymphomas and acute leukemia.

Etoposide • Allergic reactions are rare but can be life threatening.

– occur within 5-10 minutes of the infusions with complete recovery once the infusion is discontinued. ( pressor agents, corticosteroids, antihistamines, or volume expanders. )

– To omit etoposide from the chemotherapy regimen.– Higher rates of anaphylactoid reactions in children

• Congestive heart failure and myocardial infarction– continuous IV infusion over 5 days. Some of these patients had pre-existing

cardiovascular disease, and these cardiovascular side effects were attributed to the large volumes of NS used as the diluent for administration of the drug.

• Hypotension– following rapid IV administration.– over at least 30 minutes (usually 30-60 minutes).– usually responds to stopping the infusion, and administration of IV fluids or

other supportive therapy as needed. • Acute reactions to products containing polysorbate 80 have been

reported. In premature infants, a life threatening syndrome of liver and renal failure, pulmonary deterioration, thrombocytopenia and ascites has been associated with injectable vitamin E product containing polysorbate 80.

Diluted etoposide solution for infusion

• Etoposide injection is lipid soluble – surfactant polysorbate 80 leaches the plasticizer

diethylhexyl phthalate [DEHP] from polyvinyl chloride [PVC] containers and tubing into etoposide IV solution. ( IV infusions in nonPVC containers )

• Dilute in NS or D5W at concentrations of 0.2 mg/mL to 0.4 mg/mL.

• Filtration of etoposide solutions of 0.1-0.4 mg/mL in D5W or NS have been filtered through several commercially available filters ( 0.22 μm ) without filter decomposition.

Irinotecan ( CPT-11)

• Mechanism of Action: • CPT-11 is a prodrug, is cleaved in vivo by carboxylesterase converting

enzyme to generate SN-38. SN-38 is approximately 1000-fold more potent a topoisomerase I inhibitor than CPT-11.

• Absorption, Fate, and Excretion: • T1/2: 14.7 hrs.• SN-38 is excreted into the bile and can undergo glucuronidation. • ADR • Early diarrhea : cramping, vomiting, flushing, and diaphoresis.

– cholinergic effects of CPT-11 and can be managed with atropine. • Severe later onset diarrhea

– treated with high-dose loperamide, which has been found to decrease the incidence of grade 4 diarrhea from 20% to 2%.

Camptothecan analogs: Topotecan

• MECHANISM OF ACTION: • Topotecan is a semisynthetic, water-soluble derivative of

camptothecin– inhibits the action of topoisomerase I, an enzyme that produces

reversible single-strand breaks in DNA during DNA replication. These single-strand breaks relieve torsional strain and allow DNA replication to proceed.

– binds to the topoisomerase I-DNA complex and prevents religation of the DNA strand, resulting in double strand DNA breakage and cell death.

– a radiation-sensitizing agent.5 It is cell cycle phase-specific (S-phase).

• Indication: ovarian cancer, small cell lung cancer

Topotecan• SPECIAL PRECAUTIONS: • Renal dysfunction• Adults: • Intravenous: 3 weeks: 1.5 mg/m2 (range 0.75-2 mg/m2) IV once daily

for 5 consecutive days starting on day 1