Chemotherapy with Renal and

Hepatic Insufficiency
Mason Assaf ,Pharm.D,RPh
Clinical pharmacist
King Faisal Specialist Hospital & Research Centre

Chemotherapy and Renal Insufficiency

Introduction: many chemotherapy agents are nephrotoxic, either acute or chronic renal
impairment (e.g., cisplatin) or specific renal lesions (e.g., ifosfamide). Some chemotherapy
agents are not usually nephrotoxic but may become so under certain circumstances (e.g.
methotrexate). In the presence of renal insufficiency other drugs or their metabolites excreted
by the kidney may accumulate and exert more significant systemic toxicities than usual (e.g.
cytarabine). Finally, any chemotherapy agent may induce renal failure, acid-base disorders or
electrolytes abnormalities as a result of a dramatic response to therapy, as characterized by
rapid tumor lysis syndrome or it is called acute uric acid nephropathy.
Clinical Presentation (1)
A. Acute renal failure is defined as a sudden decrease in GFR leading to an acute rise
in blood urea (BUN) and serum creatinine (SCr) levels.
1- Renal impairment in patients with malignant diseases is the major source of
morbidity and mortality, particularly in the elderly patients.
Patients may be under or over-dosed
B. Types of acute renal dysfunction (Please see the table below) (2)
1- Pre-renal sec to hypo perfusion, hypovolemia, increased Scr, BUN, and
decreased Na excretion
2- Intrinsic renal dysfunction, wasting electrolytes, renal tubules acidosis,
decrease in the rate of GFR, increasing excretion of uric acid (UA), amino
aciduria, glucosuria, small amount of protein and loss ability of concentrating
urine.
3- Fanconi syndrome differs from intrinsic renal dysfunction, it is common with
ifosfamide, and it is proximal tubular dysfunction, increase excretion of
amino acids (AA), bicarbonate, glucose, phosphates, K, Na, and UA.
4- Post-renal-mechanical obstruction of urine outflow (e.g. MTX)
5- Chronic RF, caused by chemotherapy such as nitrosoureas, patients may
present with slowly progressive elevation of SCr with or with out renal
tubular dysfunction syndrome.

A c u t e Renal Failure
Drugs

Pre-renal

ATN

Aminoglycosides
Amphotericin-B
CDDP
Cyclosporine

TTPHUS

Others

Obstructive

Cyclophosphamide
Foscarnet

Ifosfamide
Mannitol

Renal
Chronic RF
tubule
dysfunction

Mitomycin C

Methotrexate
FK-506

TTP-HUS =Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic syndrome

C. Risk factors developing renal impairment in Cancer patients. (3)

1- Tumor types such as multiple myeloma (MM)-(pre-renal), prostate (postrenal), high grade lymphoma, AML, ALL, and Wilms tumor are all have
the potential causing renal impairment.
2- Hypovolemia-poor intake, hypovolemia, N/V sec to chemotherapy
3- Age elderly and children with age 3-5 years of age high risk for renal
impairment. (Please see the tables 1 and 2 listed below). Older patients
with cancer are particularly at risk for adverse drug events because in
addition to chemotherapy, the patients may be taking supportive-care
medications ( anticholinergic, dexamethasone)
4- Febrile neutropenia with bactermia
5- Contrast agents used in cancer staging
6- Transplant patients increased risk for acute renal impairment.

Table-1: Physiologic changes and consequences of chemotherapy associated with aging in

Elderly patients with cancer (4)

Physiologic change
Slower repair of DNA damage
Reduced stem cell mass & hematopoiesis
Reduced functional reserve of organs
systems
Reduced GI absorptive surfaces, gastric
motility, and gastric secretion
Reduced fat-free mass
Greater anemia
Decreased liver mass
Decreased nephron mass (25-30%), GFR
by 0.75-1 ml/min per year after age of 40,
Cr stabilized due to loss of muscle mass

Consequence of chemotherapy
Prolonged toxicities (BM)
Slow recovery of blood and mucosal
Risk for organ failure
Reduced chemotherapy absorption
Altered drug distribution
Increased levels of circulating drugs
Reduced drug metabolism
Reduced drug excretion

Table 2: Relationship of age and the pharmacokinetics of common chemotherapy

drugs
Study
Lichtman et
al (5)
Smorenburg
et al. (6)

No. of
Patients
122
23

Age

Drug

Dose/schedule

results

Range 4686
Med 77

Paclitaxel

Not specific
Range 6580
Median 70,
range 66-81

Docetaxel
Docetaxel

175mg/m2 over
3h q 3 wk
80mg/m2 iv over
1 hour wkly for 3
wks
Not specific
75mg/m2 iv over
1 hour q3ks
30mg/m2 day1
and 8 q 3wks

AUC with in age,

clearance
with age clearance
of unbound and total
paclitaxel
Small clearance
No associations of age
with AUC or clearance
No age difference in
PK, no correlation
between age and drugtoxicity
No association of age
with 5-FU clearance,
female lower clearance
of 5-FU

Paclitaxel

Bruno et al
Ten Tije et
al (7)
Sorio et al
(8)

640
40

Milano et al

380

Med-62,
range 25-91

5-FU

1Gm/m2 CIV
infusion day 1-5+
CDDP 100
mg/m2 (1
mg/min)

Bressolle et
al (10)

62

MTX

7.5-15 mg IM
wkly

Age inversely
proportional to the
clearance of free and
total MTX

Toffoli et al
(11)

50

Cohort 1
38, range
65-83,
cohort 2
range 21-45
Range 5083

VP-16

100mg PO for 14
days q 3wks

Li et al (12)

56

Med 50,
range 12-74

Doxorubicin

Med 50mg/m2,
range 3075mg/m2

No age related
difference in
pharmacokinetics when
CrCl was accounted for
Older age associated
with lower early
clearance due to
decreased distribution
clearance and lower
total body clearance of
doxorubicin, patients
older than 65 yrs
experience greater risk
incidence of CHF.

Jen et al
(13)

445

Mean 50
range 1982

Temozolo
mide
Oral

Phase-II
150mg200mg/m2 for
5 days q28
days

10

Vinorelbine

(9)

No association
between age and PK
neutropenia &
thrombocytopenia
associated with age
and gender

D- Chemotherapy Agents Associated with Nephrotoxicity (03)

Aldesleukin
Aminoglutethimide
Asparaginase
Azacitidine
Bevacizumab

Carboplatin
Carmustine
Cetuximab
Cisplatin
Cyclophosphamide

Gemcitabine
Gefitinib
Ifosfamide
Imatinib
Lomustine

Methotrexate
Mitomycin
Nitrosoureas
Oxaliplatin
Plicamyicn

F- Clinical Presentation for Some Chemo-Nephrotoxic Agents (1, 14)

Chemotherapy
Azacytidine
Bevacizumab
Zoledronic Acid
CTX/VCR

Gemcitabine
Ifosfamide

Methotrexate
Mitomycin C
Nitrosoureas

Cisplatin

Renal Impairment/Complications
Proximal tubular dysfunction with acidosis
Proteinuria
Acute tubular necrosis (ATN)
Syndrome of inappropriate antidiuretic hormone(SIADH),this consists
of hyponatremia and an inappropriate urinary osmolality in the face of
a decreased serum osmolality, direct renal tubule damage, common
with HD-CTX,
Hemolytic-uremic syndrome (HUS), characterized by anemia,
thrombocytopenia and renal impairment.
Histologically: Fanconi syndrome (1-7%) in pediatric patients < 5
years or total cumulative ifosfamide , Clinically: renal excretion of
glucose, AA, PHOS, bicarbonate, UA, Na, K, Mg, and small MW
protein
Intra-renal obstruction uropathy in the distal tubules, direct tubular
toxicity and GFR, dysuria, uremia, and hematuria. .
Hemolytic-uremic syndrome (HUS), also referred as microangiopathic
hemolytic anemia (MAHA), (10%) in cancer patients, more frequent at
cumulative doses >50mg/m2.
Histologically: glomerular sclerosing, tubular atrophy, and interstitial
inflammatory changes. Clinically: progressive nephrotxoicity related to
cumulative drug exposure, Scr, uremia, proteinuria,
hypophosphatemia.
Histologically degeneration of the renal tubular epithelium (proximal,
distal) and mild interstitial fibrosis of the loop of Henle. Clinically:
SCr, UO, BUN, GFR (20-40%), electrolytes disturbances ( Mg,
Ca, K), avoid co-administration Aminoglycosides or Amphoteracin B. can be acute or chronic renal impairment.

G- Chemotherapy Agents excreted by the kidney, in renal insufficiency may

accumulate to cause enhanced toxicity. (03)
Bleomycin
Carboplatin
Cisplatin
Cytarabine (High-Dose)
Topotecan

Dacarbazine
Etoposide
Hydroxyurea
Ifosfamide

Melphalan
Methotrexate (High-Dose)
Nitrosoureas
Pentostatin

H- Chemotherapies agents may cause renal failure, acid/base disturbances or electrolytes

abnormalities as a result of dramatic response to therapy (tumor lysis syndrome).
This topic will be covered by other Clinical Pharmacists under the oncologicemergencies sections.

I- Prevention of Nephrotoxicity (3,15)

1- Cisplatin
Eliminated primarily (>90%) in the urine and it self highly nephrotoxic. It is
mandatory to evaluate renal function either calculated Cr or urine collection to
calculate CrCl. Hydration with NS, hypertonic saline infusion and mannitol to keep
UO 125ml/hr. There are various hydration regimens but no evidence to recommend
one over others. Vigorous hydration reduces but does not eliminate the risk of renal
damage caused by cisplatin. The risk factors for cisplatin toxicity are hyperuricemia,
Hypoalbuminemia, and inadequate pre-hydration. Patients with older than 70 years of
age with out significant co-morbidity and a good performance status should able to
tolerate approximately 60mg/m2 of cisplatin without significant toxicity. Amifostine
may provide some protection against cisplatin-induced nephrotoxicity, neurotoxicity,
and Ototoxicity, which may improve the therapeutic index in the elderly patients.
2- Ifosfamide
The toxicity seen more in children may be due to chloroacetaldehyde, a metabolite of
ifosfamide. The risk factor include high doses > 60mg/m2, the recommended
cumulative dose 80mg/m2, the young age < 5 years, previous or concurrent
Carboplatin or cisplatin, previous renal irradiation, single kidney, and history of
surgical nephrectomy.
3- Methotrexate
The ant metabolite methotrexate is not normally toxic to the kidney, although 90% of
the drug is excreted unchanged in the urine. Nephrotoxicity observed high dose of
methotrexate can delay methotrexate clearance and markedly intensify the drugs
other toxic effects. The renal damage related may be related to precipitation of
methotrexate or 7-hydroxy-methotrexate in acidic urine or to direct effects on the
renal tubules. Drug precipitation can be prevented by vigorous IV hydration and
alkalinization of the urine. The risk factors include inadequate pre and post
hydration, urine pH< 7. Impaired renal function will predispose patients to renal
6

toxicity. The dose of methotrexate should be adjusted based on patient's renal

function. Patients with pleural effusions or ascites are at risk for prolonged drug
elimination and toxicity
4- Nitrosoureas (Carmustine, Lomustine, sesmustine, streptozocin)
The cumulative doses of nitrosoureas more than 1500mg/m2 associated with
progressive renal atrophy, this complication in children has been seen with
sesmustine (methyl-CCNU). The renal tubule disease frequently occurs after the
completion of chemotherapy and can be unfortunately irreversible toxicities.
5- Carboplatin
The nephrotoxic potential of Carboplatin appear to be less than that of Cisplatin,
hyponatremia secondary to increased urinary loss can occur but it is reported rarely.
Renal tubules damage has occurred followed treatment with Carboplatin. The
Carboplatin dosage should be routinely calculated according the Calvert formula in
adult cancer patients. The dose of Carboplatin should always be always based on
GFR rather than BSA. Vigorous hydration (3L/m2) should be used with high dose
regimens.
6- Cyclophosphamide and Vincristine
The incidence of SIADH may be decreased with careful monitoring of serum Na,
weight, and urine output with rapid diuresis if necessary.
7- Cytarabine (Ara-C)
Reduction in the dose of high-dose Ara-C is highly recommended in patients with
renal impairment will decrease the incidence of Neurotoxicity, the alteration in renal
function in elderly patients contribute to the increased toxicity of HD-Ara-C and its
metabolites Ara-U.
Summary Specific Measures to Prevent Renal Toxicities from Potential Nephrotoxic
Agents Listed above. (16)
1- Hydration status should be optimized and renal function evaluated to establish
possible need for dose adjustment, serum Cr is not sufficient in assessing renal
function.
2- Cockcroft-Gault and Jelliffe equations are available to calculate CrCl in younger
patients with normal renal function. However, in older patients, these equations
are not accurate.
3- Within each group class, preference may be given to agents that are less likely to
be influenced by renal clearance.
4- Or, within each drug class, preference may be given to agents that are less toxic
to the kidneys or for which there are ways to prevent renal toxicity.
5- Co administration of known nephrotoxic drugs, such as NSAIDS, Cox-2
inhibitors, or penicillin antibiotics Bactrim or Septra with HD-MTX should be
avoided, high risk for delay excretion of MTX, leads to developing mucositis.

K- Chemotherapeutics Drugs do not require Dose Modifications in Renal Failure

Patients (03)
Actinomycin D
Amsacrine
Busulfan
Docetaxel
5-FU

Gemcitabine
Idarubicin
Melphalan PO
6-MP (???)
Mitoxantrone

Paclitaxel
Procarbazine
Teniposide
6-TG
Vinblastine/ VCR/Vinorelbine

L- Chemotherapy Agents Requiring Dose Modifications in Renal Failure (03, 17)

Drug

>60ml/min

30-60ml/min

10-30ml/min

Bleomycin
Carboplatin
Cisplatin
CTX
Ara-C
DTIC
VP-16
Fludarabine
Hydroxyurea
Ifosfamide
Melphalan (IV)
MTX
Mithramycin
Mitomycin C
Nitrosoureas
Pentostatin
Topotecan

NC
Use Calvert
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC

50%
Formula to
50
NC
50
75
NC
75
75
75
75
50
75
75
Omit
50
75

Omit
Calculate the
Omit
NC
Omit
50
NC
50
75
50
75
Omit
50
50
Omit
Omit
50

<10ml/min
Omit
Dose
Omit
50
Omit
Omit
50
Omit
50
Omit
50
Omit
Omit
Omit
Omit
Omit
Omit

The chemotherapy agents requiring dose modifications in renal impairment patients

according to the British Royal College of Radiologist. Please see the table on below;
they are slightly different from above table. (18)

M- Measurement of Renal Function

It is typically has been on the basis of SCr levels, Cr endogenous compound produced
mainly from muscle catabolism and released into blood, the amount is relatively stable in a
given person. The rate of SCr production is affected by body mass muscle, muscle mass,
diet, drugs, age, and fluid status of patients. SCr should be interpreted with caution in clinical
practice. It should not be used as a "standalone" marker of renal function but should be only
be used in conjunction with other parameters.
Degree of GFR Rate Decrease (16)
Stage
1
2
3
4
5

Description
Kidney damage with normal or increased GFR
Mild decrease in GFR
Moderate decrease in GFR
Severe decrease in GFR
Kidney failure

GFR(ml/min/1.73m2)
>90
>60-89
30-59
15-29
<15 or dialysis

Cr Clearance (16)
1- Estimating of CrCl by measurement of Urine Cr over-24h period.
It is lengthy and most of time inaccurate and overestimate of GFR because Cr is
secreted as well as filtered.
9

2- Formula to estimate CrCl

A- Cockcroft-Gault (C-G Formula) method was derived from a dataset of 249
non-cancer men, all of whom were inpatients in a veteran's hospital. From 19
up to 92 (mean 57). The C-G formula was not derived in an elderly cancerspecific population, significant underestimation of GFR for decreasing renal
function. The formula is not considered to be reliable for obese or edematous
patients. The C-G formula approximation underestimates GFR for normal and
moderately reduced levels of renal function. For patients with significantly
impaired renal function, the C-G overestimates renal function. In the elderly,
the C-G formula was shown to produce a consistently low estimate of GFR.
B- The Jelliffe Formula
The Jelliffe formula was derived in a group of male and female patients
without cancer who had undergone renal transplantation and assumes a 10%
reduction in CrCl for female patients. The inaccuracy of the Jelliffe formula is
similar to the C-G formula.
C- The Wright formula and Martin formula.
The population pharmacokinetics approach was used in the development of
Wright or Martin formula; the data were derived from patients with cancer
A retrospective analysis of a larger cohort of elderly cancer patients
demonstrated the Wright formula to be the most precise and least biased
formula over a range of GFR levels

3- Calculations CrCl in Pediatric Patients

A-Swartz Creatinine Clearance Equation

CLCR = (k x Ht) / SCr

. . . where Ht is height (length) in cm
. . . SCr is the most recent serum Cr
. . . k = 0.45 if age < 1 year
. . . k = 0.55 if age 1-12 years
. . . BSA is body surface area
B-Traub's equation:
CrCl=0.48 x Ht x BSA/ Scr X (0.0113) X 1.73
CrCl = creatinine clearance in ml/min/1.73 m2
Ht = height in cm
SCr = serum creatinine in mg/dl
This equation can be used for children ages 1 - 18 years.
It is less accurate with heights < 107 cm.
An equal number of CrCl are over and under estimated
with this equation.
Traub et al. Amer J Hosp Pharm 1983; 40:107-10
10

Formulas for Calculating CrCl in Adult Patients (16)

Dialysis of Chemotherapy (19)

Agent
Aminoglutethimide
Bleomycin
Carboplatin
Carmustine
Cisplatin
CTX
Cytarabine
Doxorubicin
Etposide
5-FU
Lomustine
MTX
Teniposide
Topotecan

Hemodialysis
Yes
No
Yes
No
Yes
Yes
Unknown
No
No
May be
No
Yes
No
Yes

Peritoneal dialysis
Unknown
Unknown
No
Unknown
Unknown
Unknown
No
No info
No info
NO
No
Known

11

Patients Cases
Case #1
MC is 1.5 yrs Saudi male diagnosed with testicular germ cell, which
Revealed advanced disease. He has received 2 cycles
BEP and now due to 3rd cycle he returns to CCC clinic prior admission
and is found to have the Following WBC=4, Poly=60%, mono=20%,
eosinophils =2%, band=5%, BUN=16.5, SCr=115, Na=136 , K=2.9, Mg=0.65,
CL=104, CO2=22
A- proceed with hydration and hold chemo
B-proceed with hydration+ Mannitol + and chemo full dose
C-proceed with hydration+ Mannitol+ and modified Chemo
D-proceed with chemo as written previously during cycle 1 &2

Case #2
NS is 11 yrs Saudi F diagnosed with left tibia OS, she is to begin today Ifosfamide (5
days) + doxorubicin (3 days) , the patient recently completed two weeks of
Gentamicin, Vancomycin, and Tazocin to treat polymicrobial bactermia, her
chemistry Na= 138, K=3.8, Glucose= 3.6, Scr= 150, ALT=40, Tot Bili=40.
A- NS should have her dose of Doxo and Ifos decreased
B- NS should have her dose of Ifos decrease only
C- NS should receive the recommended dose per chemo protocol
D- NS should receive decreased dose of doxorubicin

Case #3
13.5 y/o with RMS who will be receiving IFOS 1.8gm/m2
Daily x 5 days, BSA=1.89m2. What is the correct dose of
Mesna to be administered to this patient.
A- 680mg IV prior to Ifos followed up by 680mg @ 4 and 8 hrs post Ifos infusion.
B- 680mg prior to Ifos followed by CIV of 1360mg for 12-24hrs after
completion Ifos Infusion
C- 1360mg PO prior to Ifos followed up by 680mgIV @ 2h and 1360mg
PO @ 8hrs
D-680mg IV prior to Ifos followed by 680mg po at 4 and 8hrs

12

Case #4
TT 40 y/o F AML admitted to receive cycle #1 (day 0) of chemotherapy Consolidation
high dose Ara-C 3gm/m2 q12h x 4 doses, patient's renal profile and hepatic enzymes
function as follow: Na= 138, K=3.8, Cl =102, Scr= 75M/L, ALT= 45, Tot bilirubin=
22, ALP= 160, another patient SS 55 y/o M diagnosed with AML was admitted in the
next room is scheduled to receive cycle #2 (day 7) high dose Ara-C 3gm/m2 q12h x 4
doses , his labs as follow: Na= 136, K= 3.6, Cl =101, CO2=23, Cr=65 , ALT=85,
AlP=150, tot bilirubin = 35. Prior receiving the 4th dose of Ara-C, TTs repeated labs
results as follow: Na=136, K=3.5, Cl =100, Scr =280M/L 5, ALT= 120, Tot
bilirubin=45, ALP=165, for SSs repeated results labs as follow: Na=135, K=3.4,
Cl =99, Scr = 90M/L, ALT =250, ALP=350.
Which patient has the potential to be transferred to ICU and why?
A- TT and SS should be transferred to ICU
B- SS should go and TT should stay
C- TT should go and SS should stay
D- SS and TT should receive the 4th dose Ara-C without Dose modifications.

Hepatic Function and Chemotherapy (22)

The liver has a central role in the metabolism and detoxification of many chemotherapeutics
agents and is therefore a target for drug toxicity. It is important to distinguish drug causes
from viral hepatitis or tumor-related effects of hepatic abnormality. Further more, agents that
depends on the liver for metabolism. Thus, to reduce toxicity it becomes necessary to modify
therapy with therapeutic agents with liver dependent metabolism. The chemotherapyinduced liver toxicity is variable. Some agents cause reversible toxicity while others are
associated with a progressive course that can lead to chronic liver impairment (e.g. fibrosis
or cirrhosis) despite drug discontinuation. There are insufficient data to make rational
validated dose modifications for most cytotoxic drugs in patients with liver dysfunction.
Clinical trials are needed specifically to address the issue of dose modifications in the
presence of hepatic impairment.
Risk factors for Hepatotoxicity
1- Altered clearance resulting from decreased hepatocyte uptake or impaired liver blood
flow.
2- Altered biliary excretion
3- Altered metabolic capacity
4- Decreased albumin production resulting in increased free drugs.

13

Pathophysiology (3)
1- Primary or metastatic tumor ( paraneoplastic associated with cholestasis)
involvement of the liver- Please see Table below
2- Hepatotoxic drugs(e.g. cytotoxic, hormones, antiemetics ( phenothiaznes),
antibiotics (INH, rifampin)
3- Infections (e.g. hepatic candidiasis, viral hepatitis)
4- Total parenteral nutrition (TPN)
5- Allopurinol
Hepatotoxicity from chemotherapy (23)
Drug Agent
Asparaginase

Dosage Regimens
3 -5 times/week

Prevalence
Frequent

Carmustine

Wkly bolus, or
daily
High dose q12h x4
Daily x 5
High dose (BMT)
DAILY (ALLmaintenance)
Daily (PO)
Weekly
HD-MTX
HD
Daily ( ALL)

Common

Type of toxicity
Hepatocellular liver
steatosis, decreased
lipoprotein synthesis
Hepatocellular

Rare
Infrequent
Common
Common??

Cholestatic
Hepatocellular
Hepatocellular
Cholestatic

Common
Rare
uncommon
Uncommon
Uncommon

Hepatocellular,
fibrosis/cirrhosis with
chronic oral
VOD
VOD

Cytarabine
DTIC
VP-16
6-MP
MTX

Mitomycin C
6-TG

Tumors Associated with Paraneoplastic Cholestasis

Renal cell carcinoma
NHL
prostate carcinoma
Medullary thyroid cancer
HL
Schwannoma
Wilms' tumor
GI carcinoma
LCH
Cytotoxic where specific dose modifications should be considered (22)
Total drug exposure and toxicity are increased in patients with liver dysfunction treated with
anthracyclines, vinca alkaloids, taxoids and irinotecan. Dose should be considered. Most
studies do not distinguish between liver dysfunction caused by cancer (e.g. breast, germ cell,
lymphoma, Langerhans Cell Histiocyctosis)

14

Drug Class of
Chemotherapy
Anthracyclines

Vinca-alkaloids

Epipodophyllotoxins

Dose Modifications (17)

Doxorubicin/Daunorubicin-Greater toxicities (pancytopenia,
painful mucositis) in patients with liver dysfunction (bilirubin
>50M/L). dose modifications recommended in patients with
elevated Direct-Bilirubin or AST/ALT >3 x ULN
Idarubicin: dose modification in patients with mild-moderate
hepatic impairment, the data is insufficient in severe hepatic
impairment.
Epirubicin: AST is a more sensitive and reliable marker of
Epirubicin clearance than bilirubin.
VCR & Vinblastine metabolized by hepatic microsomes with
drugs and metabolites, and then excreted into bile. The biliary
system is the main elimination rout. Greater neurotoxicity in
patients with liver dysfunction. Dose modifications highly
recommended in patients with elevated tot bilirubin.
VP-16 partially metabolized into inactive forms in the liver
and cleared by both liver and the kidneys. No dose
modification needed in patients with mild-to-moderate liver
dysfunction (25-80M/L), severe hepatic impairment can
contribute to greater toxicity (myelosuppression, mucositis),
patients with low serum albumin more free fraction of VP-16
leads to greater hematological toxicities.

Camptothecins

Irinotecan is primarily metabolized into active metabolite SN38 and eliminated hepatically; the drug and its metabolites are
partially excreted renally. Patients with liver dysfunction, high
tot bilirubin leads to slower excretion of irinotecan and higher
drug exposure, more febrile neutropenia and diarrhea. Dose
modifications in elevated tot bilirubin and AST highly
recommended.
Topotecan, no dose adjustment is recommended in patients
with impaired liver function.

Taxanes

Paclitaxel: dose reductions recommended in patients with

elevated AST/bilirubin
Docetaxel: dose reduction in patients with elevated AST/ALT
(>1.5x ULN) /bilirubin (>1x ULN)/ALP (>2.5 x ULN)

Antimetabolites

5-FU primarily metabolized in the liver by the enzyme

dihydropyrimidine dehydrogenase (DPD). It is predominately
in the liver, patients with DPD deficiency leads to severe
toxicities. Patients with mild to moderate renal dysfunction
(130-260M/L), mild to-moderate hepatic dysfunction (tot
bilirubin 25-85M/L), severe hepatic dysfunction (tot bilirubin
>85 M/L) safely treated with weekly CI over 24h without
adjustment. Female patients experience more toxicities
15

comparing to male patients. Patients over the age 70

experience more grade3-4 toxicities.
Cytarabine (Ara-C): no definite evidence of hepatotoxicity
could be found. Leukemia patient were give high-dose of AraC given by CI over 72hr developed abnormal liver tests, the
effects are reversible.
6-MP used mainly in the maintenance phase therapy of ALL
patients. Hepatotoxicity induced by 6-MP may occur with
doses exceeds 2mg/kg, may present either Hepatocellular or
Cholestatic liver.
6-TG has been implicated in the production of hepatic venoocclusive disease (HVOD).
Methotrexate: is an antifolate and it is used for the
maintenance therapy in children with ALL, it led to the
development of hepatic cirrhosis and fibrosis. Fatty change,
focal hepatitis, or portal fibrosis. The tot MTX clearance for
tot and free MTX is inversely proportional to age.
Elevations of ALT/LDH are common following high-dose
MTX, the abnormalities resolve within 2 weeks.
Chronic low dose MTX leads to fibrosis/cirrhosis, while highdose MTX cause altered liver function tests.

Case # 5
14 years old Saudi male diagnosed stage IV with B syndrome, highly suspicious bone
marrow involvement, patients lab results prior starting chemotherapy. Renal profile as
follow Na= 138, K= 3.8, Cl = 104, SCr= 160 (H), ALT= 185, Tot bilirubin 95 (H), Direct
bilirubin 60(H). Patient is due to first cycle ABVD.
What recommend to this patient?
A) Proceed with ABVD
B) Modify ABVD dose
C) Hold chemotherapy
D) Seek another chemotherapy treatment on this patient

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Dose Modifications in Hepatic Impairment (17)

17

18

19

Specific Dose Modifications of Chemotherapy Agents with Liver-Dependent

Metabolism According to Supportive Care of Children with Cancer, Current Therapy
and Guidelines from the Childrens Cancer Group (CCG). (21)
Drug
VCR/VBL
VP-16
Doxo/Dauno/Ida
Actinomycin-D
MTX/CTX
CCNU/BCNU/5FU/Ara-C/DTIC
Procarbazine

Bilirubin <25
ALT<70

Bilirubin 2550
ALT 60-180

100%
100%
100%
100%
100%
100%

50%
50%
50%
50%
50%
100%

Bilirubin >50
ALT>180

Bilirubin
>50-85
ALT>85

Bilirubin >85
ALT>180

HOLD
HOLD
100%

----25%
25%
25%
100%

-------HOLD
HOLD
HOLD
HOLD

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Answers for patients Cases

Case #1
B is the answer, the patient is obviously exhibits signs of renal dysfunction secondary to
CDDP therapy (BUN= 16.5, Cr= 115). His chemotherapy regimens is a curative regimen for
testicular cancer even in advanced stages. Holding the chemotherapy or reducing doses of
any drugs would not be an option for this patient. Something should be done to assist the
patient with elimination of these chemotherapy agents by giving the patient vigorous
hydration with mannitol diuresis is an effective means of doing this. A recent study showed
increased toxicity in patients receiving mannitol.

Case#2
A is the answer, patient having elevated serum Cr, Ifos should be adjusted accoding to
patients calculated CrCl, also the patiet having high total bilirubin, should order
fractionation of tot bilirubin, if direct bilirubin high then doxorubicin dose be adjusted.

Case #3
A is the answer, the recommended dose of mesna 60% of the ifos dose divided into 3 doses
at 0 prior Ifos infusion and at 4 and 8 hours post ifos infusion., the CIV of mesna only for
patients with persistent +3 RBC and above in the urine. Oral Mesna is twice of the iv mesna,
if this patient tolerate oral mesna the correct dose of oral mesna at 4 and 8 hours will be
1360mg.

Case #4
C is the answer, Patient TT has the potential to go to ICU because the patient is very high
risk developing cerebellar toxicities leads to impaired balance, TT having elevated serum Cr
and Ara-C metabolized into Ara-U and eliminated renally. Ara-U accumulates in the CNS
of patients with poor renal function resulting in higher CNS levels of the Ara-CTP that is
believed to be the neurotoxic agent. (20)

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Case # 5
D is the correct answer
ABVD regimen has the potential to be highly toxic for this patient (17)
Chemotherapy Toxicities with hepatic impairment
Giving doxorubcin to patients with elevated tot bili/high direct bili
Doxorubicin
greater toxicities (pancytopenia, paiful mucositis, possible death)
This patients having compromized renal function, dose limiting
Bleomycin
toxicities for bleomycin is interstitial pneumonitis with a 1-2% fetal
lung damage, this patient will have higher risk for pulmonary toxities,
dose modification highly recommended.
Biliary system is the main elimination route for Vinblastine, this
Vinblastine
patient will have greater toxicities (e.g. pancytopenia and
Neurotoxicity)
No dose modifications in hepatic impairment, dose modification with
DTIC
renal impairmet.
Alternative regimen for this patient will be COPP (CTX, VCR, Procarbazine, and
Prednisone)
Chemotherapy Toxicities with hepatic impairment
No dose adjustment needed, dose adjusted in patient with renal
CTX
impairment only with large doses.
Biliary system is the main elimination route for VCR, this patient will
VCR
have greater toxicities (e.g. SIADH and Neurotoxicity), and Clinical
judgment is needed to give minimal dose 25% of the VCR dose.
Dose adjustment needed only in patient with severe renal or hepatic
Procarbazine
impairment.
Would switch to prednisolone if there is a concern for the inadequate
Prednisone
conversion of prednisone to prednisolone occurs.
Third alternative will be APPE (Ara-C, Cisplatin, Prednisone, and Etoposide) , this the
third line of chemotherapy in patients with Hodgkins lymphoma. This combination is very
myelosuppressive and it is highly recommended to discharge patient GCSF therapy.

22

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