Alkylating agents

Lihua Fang

Sun Yat-Sen Cancer Center

Outline 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。 Cytarabine and gemcitabine Doxorubicin and daunorubicin Cisplatin/carboplatin and oxaliplatin

Alkylating agents

MECHANISM OF ACTION

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. 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 Nitrogen mustards

Chlorambucil (Leukaran) Cyclophosphamide (Cytoxan) Ifosfamide Melphalan ( Alkeran) Mechlorethamine (Mustargen®) Bendamustine (Treanda®)

Ethylenimines Thiotepa (Thioplex®)

Nitrosoureas Carmustine (BCNU, BiCNU) Lomustine (CCNU, CeeNU) Semustine (methyl‐CCNU) Streptozocin (Zanosar)

Alkyl sulfonates Busulfan

Triazenes Dacarbazine (DTIC‐

DOME) Temozolomide

(Temodar®) Platinum analogues

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。

Alkylation Site

PPO 7th edition

O6AT: O6-alkyltransferase

Alkylating agents Nitrogen mustards

cyclophosphamide, ifosfamide, melphalan, chlorambucil, bendamustine

Alkyl sulfonates :busulfan Nitrosoureas : lipophilicity. BCNU (bis-

chloroethylnitrosourea), CCNU Triazines : temozolamide,

Dacarbazine Platinum compounds( cisplatin,

carboplatin, oxaliplatin)

ADR 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 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 Nausea, Hair loss Cardiac toxicity : Cyclophosphamide SIADH: Cyclophoaphamide

Chlorambucil  ( Nitrogen mustards) 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

Chronic lymphocytic leukemia       Non-Hodgkin's lymphomas Hodgkin's disease, Multiple myeloma,

fungoides, Sezary syndrome DOSAGE GUIDELINES:

By white blood cell count. Dosage may be reduced and/or delayed in

patients with bone marrow depression due to cytotoxic/radiation therapy.

Note 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. 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?

Melphalan Busulfan Etoposide Bendamustine

Ans: Bendamustine

Leoni L, et al. Clin Cancer Res. 2008;14:309-317.Rummel M, et al. J Clin Oncol. 2005;23:3383-3389.

Benzimidazole ring

Alkylating group

ClH2CN

N

N

CH3

CO2H

ClH2C

Bendamustine Distinct Pattern of Cytotoxicity

Activates DNA—damage stress response and apoptosis Activates base

excision DNA repair pathway

Inhibits mitotic checkpoints Induces mitotic

catastrophe

Drug Patients, n CR, % ORR, % Median PFS, Mos

Bendamustine 139 29.5 68* 21.2*

Chlorambucil 125 2.0 39 8.9

Knauf WU, et al. ASH 2007. Abstract 2043.

*P < .0001

Bendamustine vs Chlorambucil in CLL: Phase III Results

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 )

Multicenter, Randomized StudyN = 463 (52% FL, 19% MCL, 26% other indolent lymphoma)

Multicenter, Randomized StudyN = 463 (52% FL, 19% MCL, 26% other indolent lymphoma)

Rummel MJ, et al. ASH 2007. Abstract 385.

Adverse Event, %

B-R(n = 166)

CHOP-R(n = 149)

Alopecia 0 94

Grade 3/4 leukocytopenia

16 41

Infection 23 41

First-Line Bendamustine-R vs CHOP-R in Indolent NHL and MCL: Phase III Results

93

47 42

93

0

20

40

60

80

100

ORR CR

Res

pon

se R

ate

(%)

Bendamustine-R

CHOP-R

Which drug is the best conditioning regimen for

multiple myeloma autotransplantation ?

Nature Reviews Clinical Oncology 2010 vol.7 no.9

Melphalan (phenylalanine mustard) Multiple myeloma ( autologous transplantation) Available in both oral and intravenous Transplantation

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 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 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. 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 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 mucosa60%-200% mesna dosage of cyclophosphamide and

ifosfamideMesna shorter half-life Mesna can mix with ifosfamide.

Mesna dose for ifosphamide 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 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 Indication:  relapsed testicular cancer, soft‐

tissue sarcomas, lung, breast, and ovary  unilaterally nephrectomized patients

increased risk of neurotoxicity due to toxic metabolite chloroacetaldehyde.

Ifosfamide should not be given until 3 months after the nephrectomy. 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 CNS toxicity in children

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

A. cyclophosphamide B. carboplatin C. Docetaxel D. Busulfan All of the above are equally toxic

Ans: D

Busulfan 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 Indication

BMT and conditioning, CML 4-8mg/daily

Clinical application 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 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 (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. 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 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 Indication: brain tumor Oral: q6w: 130 mg/m2 po ADR : nausea and vomiting ( 54%)

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.

Myelosuppression is cumulative 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

Procarbazine and DTIC are triazines. DTIC : activated by cytochrome P450 microsomal

oxidoreductases, methylation of DNA at the O6 position of guanine.

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 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

Thrombocytopenia, neutropenia ( three times higher in females)

Pediatric patients appeared to tolerate higher plasma concentrations of temozolomide before reaching dose limiting toxicity.

Procarbazine

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. 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

fever, chills, nausea, vomiting, abdominal cramping, diarrhea, and hypotension occurred , 15 to 20 minutes after completion of oxaliplatin infusion

administration of oxaliplatin as a fixed-rate 48 hour continuous infusion.

Premedication of 5HT3, antihistamine, steroids are not effective.

Test name 連連看

Multiple myeloma autologus transplantation Temozolomide Glioma Ifosfamide Hogkins lymphoma (ABVD) Cisplatin AML allogeneic transplantation Melphalan CLL Cyclophosphamide Osteosarcoma Oxaliplatin Breast cancer Dacarbazine

Colon cancer Busulfan

Lung cancer Chlorambucil