Alkylating agents
Lihua Fang
Sun Yat-Sen Cancer Center
Outline
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概論 (Alkylating agents )
藥物機轉
藥物個論
臨床適應症
副作用的處理與預防
病人的藥物教育。
Pharmacology 藥理學

Same group drugs: indication is not related 相
同機轉或同類型藥物:沒有相同的適應症。
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Cytarabine and gemcitabine
Doxorubicin and daunorubicin
Cisplatin/carboplatin and oxaliplatin
Alkylating agents
MECHANISM OF ACTION
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
Via covalent binding and crosslinking of a variety of
macromolecules including DNA, RNA, and proteins.
Leading to either cell death or altered cellular
function.
The degree of inhibition of immune function is
dependent upon the dose and duration of therapy.
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Reductions in the number of B-cells as well as CD4+
and CD8+ T-cells, and an alteration in the ratio of
circulating T- and B-cells
To impair T-cell proliferative responses and other
measures of T-cell function.
ALKYLATING AGENTS
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Nitrogen mustards
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Chlorambucil (Leukaran )
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Cyclophosphamide (Cytoxan )
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Ifosfamide
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Melphalan ( Alkeran )
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Mechlorethamine (Mustargen®)
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Bendamustine (Treanda®)
Ethylenimines
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Thiotepa (Thioplex®)
Nitrosoureas
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Carmustine (BCNU, BiCNU )
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Lomustine (CCNU, CeeNU )
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Semustine (methyl‐CCNU)
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Streptozocin (Zanosar )
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Alkyl sulfonates
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Triazenes
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Busulfan
Dacarbazine
(DTIC‐DOME )
Temozolomide
(Temodar®)
Platinum analogues
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Cisplatin (Platinol )
Carboplatin (Paraplatin )
Oxaliplatin (Eloxatin®)
芥子毒氣（Mustard Gas，亦簡稱為芥子氣，學名二氯
二乙硫醚）是一種揮發性液體毒劑，中毒後無特效藥可
解其毒。


芥子氣主要通過皮膚或呼吸道侵入，
潛伏期2-12小時。直接損傷組織細胞
，具有糜爛刺激作用：皮膚燒傷，出
現紅腫、水皰、潰爛；呼吸道粘膜發
炎壞死，出現劇烈咳嗽和濃痰，甚至
阻礙呼吸；眼睛出現眼結膜炎，導致
紅腫甚至失明；對造血器官也有損傷
；多伴有繼發感染。吸入芥子氣會引
起嘔吐和腹瀉。有人認為芥子氣還會
導致人體發生癌病變。大約有1%的死
亡率。由於在戰史上使用量、普遍性
和殺傷最大，因此被稱作「毒劑之王
」。
芥子氣的含氮類似物稱為氮芥，毒性
比芥子氣小，其衍生物氮芥類物質被
作為腫瘤化療藥物使用。
PPO 7th editio
Alkylation Site
O6AT: O6-alkyltransferase
Alkylating agents
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Nitrogen mustards
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cyclophosphamide, ifosfamide,
melphalan, chlorambucil, bendamustine
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Alkyl sulfonates :busulfan
Nitrosoureas : lipophilicity. BCNU (bischloroethylnitrosourea), CCNU
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Triazines : temozolamide,
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Dacarbazine
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Platinum compounds( cisplatin,
carboplatin, oxaliplatin)
ADR
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Gonadal
 Female : premature amenorrhea (premature ovarian
failure), ovarian fibrosis, and permanent infertility.
 Male : reductions in sperm count. oligospermia or
azoospermia.
 Prevention: Gonadotropin-releasing hormone agonist
(GnRH-a) such as leuprolide to preserve ovarian
function)
Teratogenicity
Infection
Pulmonary toxicity (interstitial pneumonitis and fibrosis)

Alkylating agents, asparaginase, bleomycin, methotrexate.
ADR
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Malignancy : leukemia, skin cancer, and others
 chromosomal damage and decreased immune
surveillance. (2-3 yrs later )
 Myelodysplastic syndrome 8% with Wegener's
granulomatosis after cyclophosphamide, and 13% with a
cumulative dose over 100 grams
 Leukemia : Cholambucil> cyclophosphamide for sudies of
patients treated with alkylating agents for Hodgkin's
disease and ovarian cancer.
Bladder toxicity with cyclophosphamide /ifosfamide
 acrolein : cystitis, microscopic or gross hematuria
accompanied commonly, dysuria
 Mesna (sodium 2-mercaptoethane sulfonate)
ADR: Miscellaneous
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Nausea, Hair loss
Cardiac toxicity : Cyclophosphamide
SIADH: Cyclophoaphamide
Chlorambucil ( Nitrogen mustards)
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Chlorambucil was
synthesized in 1953. It is
an aromatic derivative of
mechlorethamine and is
closely related in
structure to melphalan.
slowest acting and
generally least toxic of
the alkylating agents.
Chlorambucil has been
used for over 40 years for
CLL, but is being
replaced by fludarabine
and rituximab
Indication
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Chronic lymphocytic leukemia
Non-Hodgkin's lymphomas
Hodgkin's disease, Multiple myeloma,
fungoides, Sezary syndrome
DOSAGE GUIDELINES:
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By white blood cell count.
Dosage may be reduced and/or delayed in
patients with bone marrow depression due to
cytotoxic/radiation therapy.
Note
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Cross-sensitivity between chlorambucil and melphalan
( rash).
Secondary malignancies
Reversible and permanent sterility in both sexes. Children
receiving chlorambucil before puberty generally have a
normal progression of puberty. In males, however, testicular
atrophy may occur and persist.
Pulmonary toxicity similar to bleomycin can occur.

Dyspnea, dry cough, fever, rales and tachypnea
developing over a 1-2 month period.
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Related with prolonged therapy (6-24 months) and a total
dose of >2 g. Partial recovery can occur within several
weeks after discontinuing therapy.
Children with nephrotic syndrome and patients receiving high
pulse doses may have an increased risk of seizures.
Which drug will replace chlorambucil
for CLL?
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Melphalan
Busulfan
Etoposide
Bendamustine
Ans: Bendamustine
Bendamustine Distinct Pattern
of Cytotoxicity

Activates DNA—
damage stress response
and apoptosis
ClH C
 Activates base
N
excision DNA
repair pathway
Inhibits mitotic
ClH C
checkpoints
Alkylating group
 Induces mitotic
catastrophe
2

Leoni L, et al. Clin Cancer Res. 2008;14:309-317.
Rummel M, et al. J Clin Oncol. 2005;23:3383-3389.
2
CH3
N
N
CO2H
Benzimidazole ring
Bendamustine vs Chlorambucil
in CLL: Phase III Results
Drug
Bendamustine
Chlorambucil
Patients, n
CR, %
ORR, %
139
125
29.5
2.0
68*
39
*P < .0001
Indolent B-cell non-Hodgkin lymphoma (NHL)
that progressed during or within six months of
treatment with rituximab or a rituximab-containing
regimen, CLL.(2008 FDA approved )
Knauf WU, et al. ASH 2007. Abstract 2043.
Median PFS,
Mos
21.2*
8.9
First-Line Bendamustine-R vs CHOP-R in
Indolent NHL and MCL: Phase III Results
Multicenter, Randomized Study
N = 463 (52% FL, 19% MCL, 26% other indolent lymphoma)
B-R
(n = 166)
CHOP-R
(n = 149)
Alopecia
0
94
Grade 3/4
leukocytopenia
16
41
Infection
23
41
100
Response Rate (%)
Adverse
Event, %
93
93
Bendamustine-R
CHOP-R
80
60
47
42
40
20
0
ORR
Rummel MJ, et al. ASH 2007. Abstract 385.
CR
Which drug is the best conditioning regimen for
multiple myeloma autotransplantation ?
Nature Reviews Clinical Oncology 2010 vol.7 no.9
Melphalan (phenylalanine mustard)
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Multiple myeloma ( autologous transplantation)
Available in both oral and intravenous
Transplantation
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Melphalan (穩定度); reconstituted and diluted
solution is unstable (<60 mins)
Cyclophosphamide

is a cyclic phosphamide
ester of
mechlorethamine. It is
transformed via hepatic
and intracellular
enzymes to active
alkylating metabolites,
acrolein and
phosphoramide
mustard.
Indication
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ALL, AML
Breast cancer
Chronic lymphocytic leukemia, Chronic myelogenous
leukemia, Ewing's sarcoma, Hodgkin's disease
Lung cancer, small cell
Multiple myeloma
Mycosis fungoides
Neuroblastoma, Non-Hodgkin's lymphoma
Osteogenic sarcoma
Retinoblastoma, Rhabdomyosarcoma,
Soft tissue sarcoma
Cyclophosphamide
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Cyclophosphamide is metabolically activated by
cytochrome P450 mixed function oxidases in the
liver to 4-hydroxycyclophosphamide by P450 in
the liver.
Bioavailability of IV and oral is quite similar.
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Doses as little as 50 to 100 mg/day orally
Solid tumor : bolus doses of 400 to 700 mg/m2
Stem cell transplantation : 60 mg/kg daily for 2 days
Bladder toxicity
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hemorrhagic cystitis
cyclophosphamide and ifosfamide
Intravesical chemotherapy: BCG, mitomycin,
high > low cumulative dose
children > adults
acrolein (inactive metabolite)
 bind to thiol compounds in the bladder mucosa
 60%-200% mesna dosage of cyclophosphamide and
ifosfamide
 Mesna shorter half-life
 Mesna can mix with ifosfamide.
Mesna dose for ifosphamide
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hydration with 1.5‐2 L NS pre‐ and post hydration.
oral fluid intake to 2‐3 liters of fluid per dashould be with
mesna
ASCO guideline
- use with ifosfamide (< 2.5 g/m2/d)
1. Ifosfamide given as short infusion:
mesna bolus (20% ifosfamide) given 15 min before and 4 and 8
hour after ifosfamide
Ifosfamide continuous infusion:
mesna bolus (20% ifosfamide) +
mesna continuous infusion (40% of ifosfamide) for 12 to 24
hours after ifosfamide infusion
Management of hemorrhage cystitis
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Symptoms of dysuria and urinary frequency for up
to 9 days after treatment ( parallel hematuria)
Occurs months and years
Mesna is not useful in this delay-onset.
Saline irrigation remove clots.
Silver nitrate (astringents): local vasoconstriction
Hemostatic agents: aminocaporic acid), protaglandin E2 or
F2.
Formalin or phenol: hydrolyze protein and coagulate tissue.
Remove bladder.
Ifosfamide
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Indication: relapsed testicular cancer, soft‐tissue sarcomas, lu
ng, breast, and ovary
unilaterally nephrectomized patients
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Ifosfamide should not be given until 3 months after the
nephrectomy.
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increased risk of neurotoxicity due to toxic metabolite
chloroacetaldehyde.
Glomerular, proximal or distal tubular impairment
Proximal tubular damage (ireversible)
 Fanconi syndrome (hypophosphatemic rickets, growth
failure), renal tubular acidosis or diabetes insipidus).
 Lab: low P, low bicarbonate, glucosuria, aminoaciduria
and hypochloremic metabolic acidosis.
 Risk factors : < 5 years old (for proximal tubular damage;
this appears to be the only age-related nephrotoxicity);
prior treatment with cisplatin; concurrent use of
nephrotoxic drugs, unilateral nephrectomy; and total dose
(increased risk with increased cumulative dose)
Ifosfamide
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CNS toxicity in children
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somnolence, disorientation, lethargy,
cerebellar dysfunction, transient weakness,
cranial nerve dysfunction or seizure activity.
This toxicity appears to be transient and
reversible, resolving within 4 days.
( chloroacetaldehyde, which is structurally
similar to chloral hydrate).
Nausea and vomiting are dose-related

150 mg/kg (6000 mg/m2), 95% of patients
experience very severe nausea and vomiting.
Which of the following agents produce the greatest
inhibition of myelocytic bone marrow cell proliferation
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A. cyclophosphamide
B. carboplatin
C. Docetaxel
D. Busulfan
All of the above are equally toxic
Ans: D
Busulfan
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Busulfan is alkylsulfonate, at the N7 position of
guanine and produces an N7-N7 biguanyl DNA
cross-link.
Busulfan is a potent stem cell toxin, killing both
early and late hematopoietic progenitor cells
and damaging the bone marrow stroma.
Busulfan
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Indication
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BMT and conditioning, CML 4-8mg/daily
Clinical application
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Low emetogenic
High dose: seizure (generalized tonic-clonic
prophylaxis by lorazepam 1mg q6h )
Hepatic veno-occlusive disease
Lung fibrosis > 3 yrs exposure, pulmonary interstitial
and intra-alveolar edema, leading to fibrosis
Busulfan IV or Oral
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Steady-state busulfan concentration of 917 ng/ml had a significantly
lower relapse rate and better survival than < 917 ng/ml.
Ensure a "targeted" steady-state concentration (Css= AUC/dosing
interval) of 900 ng/mL.
VOD: Css > 925 to 1025ng/ml
>600ng/ml, favor engraftment
>900ng/ml associated lower relapse in adult CML, without unaceptable
rate of VOD
IV Busulfex: 0.8mg /kg q6hrs 16 doses.
Mean concentration at steady sate: 800-900ng/ml
Adjusted dose (mg) = Actual dose (mg) x [target AUC
µmol(min) / actual AUC µmol(min)] (busulfan
molecular weight=246

Blood. 1997;89: 3055-3060, Bone Marrow Transplantation (2002) 29, 963–965
Nitrosoureas: Carmustine (BCNU),
Lomustine (CCNU)
Nitrosoureas
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(2-chloroethyl)-N-nitrosourea BCNU (Carmustine)
N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea (CCNU)
LOMUSTINE, is used predominantly as an oral nitrosourea
in children with brain tumors
High hydrophobicity, actively penetrating the blood-brain
barrier. Short half-life (18 minutes-BCNU, 2hrs- CCNU )
Association between the AUC of BCNU and pulmonary
toxicity has been observed.
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High-dose treatment of recurrent lymphomas.
Sustained complete remission rates of approximately 40%–60%.
Doses of between 600 and 1000 mg/m2 have been safely
administered.
BCNU cause profound and cumulative bone marrow suppression
at conventional doses of 120 to 150 mg/m2, limiting treatment to 3
to 5 cycles at 6-week intervals.
BCNU
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Primary brain cancer: I.V. 150-200 mg/m2 every 6 weeks
Autologous BMT : I.V.
Combination therapy: Up to 300-900 mg/m2
Single-agent therapy: Up to 1200 mg/m2 (fatal necrosis is associated with
doses >2 g/m2)
ADMINISTRATION : Significant absorption to PVC (in glass over 1-2 hours.
Rate of infusion of < 3 mg/m2/minute to avoid excessive flushing, agitation,
and hypotension
Glioblastoma multiforme (recurrent), malignant glioma: Implantation (wafer):
8 wafers may be placed in the resection cavity (total dose 62.6 mg)
ADR
>10%: CV: Hypotension (alcohol content of the diluent)
CNS: Dizziness, ataxia; Wafers: Seizures 54%
Gastrointestinal: Severe nausea and vomiting (2-6 hrs)
Hematologic: Myelosuppression, delayed thrombocytopenia (3 wks)
Complications

Interstitial fibrosis: 50% cumulative dose >1400 mg/m2, may
be delayed up to 3 years. Forced vital capacity (FVC) or
carbon monoxide diffusing capacity of the lungs (DLCO) <70%
of predicted are at higher risk.
 steroids during the inflammatory but not fibrotic phase
 Fibrosis is associated with an early interstitial infiltrate
followed by evidence of hyaline membrane formation and
replacement of the chronic inflammatory cells by fibrosis
over a 4- to 6-week period.
 Interstitial nephritis with glomerulosclerosis, interstitial
fibrosis, and dropout of tubules have been reported with
BCNU or CCNU.
Lomustine
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
Indication: brain tumor Oral: q6w: 130 mg/m2 po
ADR : nausea and vomiting ( 54%)

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Myelosuppression is cumulative


45 minutes to 6 hours after dose and usually abates within
24 hours. If the patient vomits after 30-45 minutes, do not
repeat the dose.
after repeated courses of treatment, recovery of blood cell
count is slower and bone marrow hypoplasia may persist.
Pulmonary toxicity

> 1,100 mg/m2 or pulmonary toxicity at a cumulative dose
of only 600 mg. The onset of toxicity : from months to as
late as 15 years after.
Methylating Agents: procarbazine,
dacarbazine (DTIC), streptozotocin, and
temozolomide
Methylating Agents: procarbazine,
dacarbazine (DTIC), streptozotocin, and
temozolomide

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Procarbazine and DTIC are triazines.
DTIC : activated by cytochrome P450 microsomal
oxidoreductases, methylation of DNA at the O6 position
of guanine.


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DTIC is used in combination with doxorubicin,
vinblastine, and bleomycin (ABVD) in Hodgkin's
disease
Maximum tolerated doses of DTIC : 1000 mg/m2
Common side effects: myelosuppression and
gastrointestinal toxicity (including severe watery
diarrhea)
DTIC
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Indication : Hodgkin's disease, * Malignant melanoma,
Neuroblastoma, Soft tissue sarcomas
Dose: q15d: 375 mg/m2 , q3-4w: 850 mg/m2
q3-4w: 250 mg/m2/day x 5 days
Dilute in 250-500 mL D5W over 15-60 minutes.
administration over 1 hour to minimize pain. If painful,
slow the infusion rate( icepack), protect from light
ADR: Nausea and vomiting (severe on the first day)
flu-like syndrome
Hepatic : hepatic vein thrombosis and hepatocellular necrosis
(Budd-Chiari Syndrome)
Temozolomide


undergoes rapid chemical
conversion at physiologic pH
to the active compound,
monomethyl triazeno
imidazole carboxamide
(MTIC). The cytotoxicity of
MTIC is thought to be due
primarily to methylation of
DNA at the O6 position of
guanine.
Temozolomide and
dacarbazine are prodrugs of
MTIC.
Temozolomide

Indication : Astrocytoma, Glioblastoma, Melanoma

4 weeks: 150 mg/m2 (range 100-200 mg/m2) PO qd
for 5 days starting on day 1
Administer with food or on an empty stomach.
Hematologic toxicities

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
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Thrombocytopenia, neutropenia ( three times higher in
females)
Pediatric patients appeared to tolerate higher plasma
concentrations of temozolomide before reaching dose
limiting toxicity.
Procarbazine




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Less serious side effects.
Hodgkin's disease.
not cross-resistant with other alkylating
agents.
Round dose to the nearest 50 mg.
Oral: q3w: 100 mg/m2/day po x 2 days
q4w: 100 mg/m2/day po x 7-14 days
 q6w: 60 mg/m2/day po x 14 days

Procarbazine

Procarbazine may be responsible for the
infertility seen in males treated with MOPP
(mechlorethamine, ONCOVIN®, procarbazine,
prednisone) for Hodgkin's disease.


azoospermia, which is often irreversible; and
amenorrhea in females.
ADR

Hypersensitivity pneumonitis: within hours by
nausea, fever, nonproductive cough and dyspnea.
On chest radiographs, bilateral interstitial infiltrates
and pleural effusion can be observed.
ADR: Procarbazine

is a weak MAOI that crosses the blood-brain
barrier rapidly.

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
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Neurotoxic effects: depression, insomnia,
nervousness and hallucinations (10-30%).
Peripheral neuropathy (10-20%): paresthesia in
hands and feet, decreased deep tendon reflexes
and myalgia.
Bleeding tendencies (petechiae, nosebleeds,
vomiting of blood) occur frequently.
Radiation recall
Cisplatin, carboplatin, oxaliplatin


One of most frequently used
anticancer drugs
Mechanism
 similar to alkylating
agents


chlorine atoms are
leaving groups which
bind to N7 guanine
inter-strand cross-links
and interstrand adducts
- kill proliferating cells
Cisplatin (indication and Pk)





Head and neck,breast, testicular, ovarian, hodgkin’s
and non-hodglin’s, lymphoma, neuroblastoma, sarcoma,
bladder, gastric, lung, esophagus, cervical, prostate,
myeloma, melanoma, mesothelioma, osteosarcoma ,
small cell lung cancer (carboplatin same as )
Distribution: high concentration in kidney, liver, ovaries,
uterus, lungs, spleen, gallbladder, GI tract.T1/2 :20-30
minutes, secondary:44-73 mins.
Metabolism: by binging glutahione and thiosulfate in cell
and blood stream.
Excretion: >90% excreted by kidney
CCr 10-50ml/min: 50% CCr<10ml/mm: do not
administer
Renal toxicity (cisplatin)


acute (1-2 days):
 inadequate hydration
 focal acute proximal
tubular necrosis
chronic:
 glomerular filtration rate
progressively decreased
 Distal tubular damage
 serum creatinine may
be elevated
 electrolyte
abnormalities
Renal toxicity (cisplatin) Prevention




Hydration 2-3 L normal saline before, during, after cisplatin
administration, maintain urine output>100ml/hr.
Electrolytes supplement (Mg, K)
Diuretics
Amifostine
 binds to and inactivates oxygen free radicals
 Prevent the formation of platinum-DNA adducts
 Vomiting and nausea, hypocalcemia
Cisplatin




Caution : with pre-existing renal impairment,
myelosuppression or hearing impairment.
Fertility : at least temporary infertility. Among males receiving
cisplatin for testicular cancer, almost all became azospermic
within the first two cycles of therapy, but recovery of normal
sperm morphology, motility, and sperm count occurred in 40%
within 1.5-2 years.
Hydration
 Pre-hydration with 1 or 2 L of fluid 8-12 hours prior
cisplatin dose.
 Hydration with NS, hypertonic saline infusion, and
mannitol, or furosemide-induced diuresis, to effectively
decrease cisplatin-induced nephrotoxicity.
 Lower doses of cisplatin are given with less intensive
hydration. ( 35 mg/m2 / 500 mL NS over 1 hour, with no
post-hydration. 25 mg/m2 - oral hydration (600-900 mL)
Daily < 100mg/m2
Hydration regimen for adults
BC Cancer Agency; 8 June 2000
Cisplatin ADR




Anemia :
 Decrease in erythropoietin or erythroid stem cells.
 Direct Coombs’ positive hemolytic anemia.
Electrolyte disturbances
 Hhypomagnesemia, hypocalcemia and hypokalemia.
Hypophosphatemia and hyponatremia. (renal tubular
damage)
 Hypomagnesemia and or hypocalcemia may become
symptomatic, with muscle irritability or cramps, clonus,
tremor, carpopedal spasm and/or tetany.
Emetogenic effects :

Acute nausea and vomiting (usually 2-3 hours after
administration of cisplatin. 5HT3

Delayed nausea and vomiting : after 24 hours
chemotherapy (dexamethsone, aprepitant)
Nephrotoxicity
ADR

Nervous system effects
Peripheral neuropathies and sensory in nature (e.g., parethesias of
the upper and lower extremities). Cumulative and reversible

Motor difficulties (especially gait); reduced or absent deep-tendon
reflexes and leg weakness

Lhermitte’s sign (a sensation during neck flexion resembling electric
shock)
Otic effects ( cumulative and irreversible , damage to the inner ear.

Tinnitus, with or without clinical hearing loss, Vestibular ototoxicity

Audiograms be performed prior to initiating therapy (Loss of high
frequency acuity (4000 to 8000 Hz)



Sensitivity reactions




Anaphylactoid reactions: facial edema, flushing, wheezing or
respiratory difficulties, tachycardia, and hypotension.
A few minutes after IV cisplatin; diaphoresis, nasal stuffiness,
rhinorrhea, conjunctivitis, generalized erythema, apprehension, and
sensation of chest constriction.
After multiple cycles of cisplatin (e.g., at least 5 doses)
Prophylaxis is not uniformly effective in preventing recurrence.
Carboplatin

is an analog of cisplatin.
More stable and has less nephrotoxicity,
neurotoxicity, ototoxicity and emetogenesis.

Carboplatin is a radiation-sensitizing agent.


Indication

Same as cisplatin

ADR
Myelosuppression : dose-limiting.
Thrombocytopenia and less commonly as leukopenia, neutropenia
and anemia.

Risk factors: prior cytotoxic therapy (especially cisplatin), poor
performance status, old age, impaired renal function .

Myelosuppression, closely related to the renal clearance of carboplatin,
and minimized by using the Calvert AUC-based dosing formula.

Anemia is more common with increased carboplatin exposure
Nausea /vomiting : begin within 6-12 hours after administration and may
persist up to 24 hours or longer.

Can be reduced when carboplatin is given as a 24-hour continuous IV
infusion or in divided doses over 5 consecutive days.
Neurotoxicity

Peripheral sensory neuropathy (eg, paresthesia) is less frequent or
severe than with cisplatin.

Risk factors: > 65, receiving prolonged carboplatin therapy or with
prior cisplatin therapy.
Nephrotoxicity: is less common or severe than with cisplatin; No need IV
hydration and diuresis.




ADR Hypersensitivity








2% carboplatin alone
9-30% with other cytotoxic drugs.
Same as other platinum agents (eg, cisplatin) and include
anaphylaxis and anaphylactoid reactions.
Symptoms: pruritus, rash, palmar erythema, fever, chills,
rigors, swelling (face, tongue, infusion arm), GI upset,
dyspnea, wheezing, tachycardia, and hypertension or
hypotension.
Onset : During or several hours to days after carboplatin.
The risk of reactions increases with repeated exposure to
platinum agents. (after 7 courses ) or receiving the second
course of carboplatin after prior platinum therapy.
IgE-mediated type I immediate reaction but may also
involve direct histamine release.
Management :
 prophylactic corticosteroid and antihistamine and/or
desensitization.
Dose

Intravenous: AUC-based carboplatin dose IV for one dose on day 1

Calculate carboplatin dose with Calvert formula:
Dose (mg) = AUC x (GFR + 25)
where AUC = 4-7, GFR obtained from nuclear renogram (preferred) or
approximated by CrCl calculated from serum creatinine using the
Cockcroft-Gault formula:
GFR (mL/min) = N x (140 – Age) x weight (kg)/
serum creatinine (μmol/L)
where N = 1.04 for females and 1.23 for males
Note that the Cockcroft-Gault formula overpredicts CrCl in certain
conditions (eg, muscle wasting, obesity, ascites). Lean or ideal body weight
may be used to correct for excess fat or fluid. Repeat renogram to modify
dose if > 20% increase in serum creatinine during treatment.
Calvert AUC-based dosing formula is not recommended with GFR or CrCl
< 20 mL/min.






Oxaliplatin


Indication: be synergistic with fluorouracil to colorectal
cancer.
Oxaliplatin is a radiation-sensitizing agent.
Oxaliplatin Peripheral sensory neuropathy


is cumulative, dose-related and reversible a few months after stopping
treatment.
Symptoms

sensory ataxia and dysesthesia of the limbs, mouth, throat and
larynx, and may be exacerbated by exposure to cold (eg, touching
cold surface, drinking cold liquid).

grade 2 neuropathy is :10% after ( 3 cycles ), 50% (10 cycles).
Grade 3 : 10% (after 9 cycles) and 50% (14 cycles), is reversible in
74% of the cases, and begins to recover after 13 weeks.

Paresthesia 16% (eg, buttoning clothing, holding objects, writing)
after 4 months of treatment

Oxaliplatin neuropathy is related to injury to small sensory fibres.

Preliminary evidence : infusion of 1 g calcium gluconate and 1 g
MgSO4 prior to oxaliplatin may reduce the incidence and severity
peripheral neuropathy.

Gabapentin PO 1000 mg bid maybe effective in some patients.
alpha-lipoic acid IV 600 mg weekly for 3-5 weeks, then followed by
oral 600 mg three times daily.
ADR

Pharyngolaryngeal dysesthesia with
sporadic reduced sensitivity of the larynx
and pharynx





1-2% shortly after drug infusion. Symptoms
usually resolve within hours of onset
Feeling of difficulty in breathing or swallowing
Treatment is usually not needed
To prevent recurrence, infusion time should
be extended to 6 hours.
Elderly patients over 65 may be at higher
risk of severe (grades 3-4) diarrhea.
Hypersensitivity reaction




Steroid prophylaxis did not prevent
hypersensitivity reactions.
During 7-9 cycles
Cough, nausea, dyspnea, and flush and
erythema of the trunk 1 hour after the start
infusion.
Hydrocortisone (100 mg IV) and produced
resolution of symptoms within 20 minutes.
Complication of infusion

Infusion reaction

administration of oxaliplatin as a fixed-rate
48 hour continuous infusion.
Premedication of 5HT3, antihistamine, steroids
are not effective.


fever, chills, nausea, vomiting, abdominal cramping,
diarrhea, and hypotension occurred , 15 to 20 minutes
after completion of oxaliplatin infusion
Test

name
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