Transcript 1428614088_1367

Antitumor 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Gsegment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
Anthracycline
Mechanism of toxicity
•
Dysrhythmias
– Sudden release catecholamines
•
Cardiomyopathy
– damage to mitochondrial DNA of heart
tissue
– free radical production
Anthracyclines
treatment
• 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
2-3 x ULN
> 3 x ULN
-
Bilirubin (mg/dl)
or
1.2-3
3-5
>5
Dose
75%
50%
25%
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 DNAprotein 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 Drugs
Antimotitic 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 - Chemistry
A
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 10desacetylbaccatin, 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 VP16 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 (Sphase).
•
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