Hospital Pharmacy

Volume 42, Number 8, pp 702-711, 773

2007 Wolters Kluwer Health

Cancer Chemotherapy Update

Cisplatin, Doxorubicin, and High-dose
Methotrexate for Osteosarcoma
Carmen DeBellas, BSc,* Dominic A. Solimando , Jr, MA, FAPhA, FASHP, BCOP,
and J. Aubrey Waddell, PharmD, FAPhA, BCOP

The increasing complexity of cancer chemotherapy

increases the requirement that pharmacists be familiar with these highly toxic agents. This column will
review various issues related to preparation, dispensing, and administration of cancer chemotherapy, and
review various agents, both commercially available
and investigational, used to treat malignant diseases.
Questions or suggestions for topics should be
addressed to Dominic A. Solimando, Jr., President,
Oncology Pharmacy Services, Inc., 4201 Wilson Blvd
#110-545, Arlington, VA 22203, e-mail:
OncRxSvc@aol.com; or J. Aubrey Waddell, Associate
Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department,
Blount Memorial Hospital, 907 E. Lamar Alexander
Parkway,
Maryville, TN
37804,
e-mail:
waddfour@charter.net.
*Carmen DeBellas, Commander, US Public Health Service
is a pharmacist/project manager in the Division of AntiInfective and Ophthalmology Products, Center for Drug
Evaluation and Research at the Food and Drug Administration. At the time this review was written, he was a Doctor of Pharmacy candidate, School of Pharmacy and
Health Professions, Creighton University, Omaha, Neb.
The views expressed are those of the author and do not
necessarily reflect those of the FDA.

Regimen Name: Cisplatin, Doxorubicin, and Highdose Methotrexate for Osteosarcoma

Origen of Name: The regemin is named for the
three drugs it contains.
INDICATIONS
The cisplatin, doxorubicin, and methotrexate regimen has been used for adjuvant and neoadjuvant
therapy of localized and metastatic osteosarcoma.1-7
Current guidelines recommend a combination of at
least two of the following drugs as adjuvant therapy
of osteosarcoma: doxorubicin, cisplatin, ifosfamide,
and high-dose methotrexate.8

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Volume 42, August 2007

DRUG PREPARATION
A. Doxorubicin
1. Follow institutional policies for preparation of
hazardous medications when preparing doxorubicin.
2. Use doxorubicin injection 2 mg/mL or doxorubicin powder for injection.
3. If powder for injection is used, it should be
reconstituted to a concentration of 2 mg/mL
with 0.9% sodium chloride.
4. Dispense in a syringe, or in 50 to 100 mL
(bolus infusions), or 250 to 1,000 mL (24hour infusions) of 0.9% sodium chloride, 5%
dextrose in water, or a saline/dextrose solution
for infusion.
B. Methotrexate
1. Follow institutional policies for preparation of
hazardous medications when preparing
methotrexate.
2. Use methotrexate powder for injection, or
unpreserved methotrexate injection, 25
mg/mL.
3. Solutions preserved with benzyl alcohol
should be avoided due to potential neurotoxicity from the large amounts of the preservative.
4. Dilute in 250 to 1,000 mL of 0.9% sodium
chloride, 5% dextrose in water or a
saline/dextrose solution for infusion.
C. Cisplatin
1. Follow institutional policies for preparation of
hazardous medications when preparing cisplatin.
2. Use cisplatin injection 1 mg/mL.
3. Dilute in 100 to 1,000 mL of 0.9% sodium
chloride or a saline/dextrose solution.
4. To ensure the stability of cisplatin, the infusion
solution must have a final chloride concentration of at least 0.2%.
D. Leucovorin
1. Follow institutional policies for preparation of

Cancer Chemotherapy Update

Table 1. Cisplatin, Doxorubicin, and High-Dose Methotrexate

Drug

Dose

Route of
Administration

Administered
on Day(s)

Total Dose/
Cycle

Before Surgery
MTX
8 g/m2
IV
1
8 g/m2
a
Leucovorin
15 mg every 6 h for 12 doses
IV
2,3
180 mg
Cisplatin
40 mg/m2
CIVI
6-8
120 mg/m2
Doxorubicin
60 mg/m2
IV
8
60 mg/m2
Cycle repeats: every 4 weeks for two cycles1,2
After Surgery
MTX
8 g/m2
IV
21
8 g/m2
a
Leucovorin
15 mg every 6 h for 12 doses
IV
22,23
180 mg
Cisplatin
40 mg/m2
CIVI
27-29
120 mg/m2
Doxorubicin
45 mg/m2
IV
1,2
90 mg/m2
1,2
Cycle repeats: every 7 weeks for three cycles
Before Surgery
MTX
8 g/m2
IV
0,32
16 g/m2
Leucovorina
12 mg/m2 every 6 h for 12 doses
IV
1,2,33,34
288 mg/m2
Cisplatin
100 mg/m2
CIVI
10,42
200 mg/m2
2
Doxorubicin
25 mg/m
IV
10-12,42-44
150 mg/m2
Cycle does not repeat4
After Surgery
MTX
8 g/m2
IV
77,109
16 g/m2
a
2
Leucovorin
12 mg/m every 6 h for 12 doses
IV
78,79,110,111
288 mg/m2
Cisplatin
100 mg/m2
CIVI
87,119
200 mg/m2
Doxorubicin
25 mg/m2
IV
87-89,119-121
150 mg/m2
4
Cycle does not repeat
Before Surgery
MTX
10 g/m2
IV
1
10 g/m2
Leucovorina
Dose, route, frequency, and duration of therapy not specified
Cisplatin
40 mg/m2
CIVI or CIAI
9-11
120 mg/m2
2
Doxorubicin
60 mg/m
IV
11
60 mg/m2
Cycle repeats: every 4 weeks for two cycles5
After Surgery
MTX
10 g/m2
IV
21
10 g/m2
a
Leucovorin
Dose, route, frequency, and duration of therapy not specified
Cisplatin
40 mg/m2
CIVI or CIAI
27-29
120 mg/m2
Doxorubicin
45 mg/m2
IV
1,2,27,28
180 mg/m2
5
Cycle repeats: every 7 weeks for two cycles
MTX
12 g/m2 (Max = 20 g)
IV
1
12 g/m (max = 20 g)
Leucovorina
15 mg/m2
PO
Duration of therapy
not specified
Cisplatin
120 mg/m2
IV
1
120 mg/m2
2
Doxorubicin
45 mg/m
IV
1,2
90 mg/m2
6
Cycle repeats : Doxorubicin: weeks 1, 11, 20, and 29; Cisplatin: weeks 5, 8, 15, and 24; MTX/leucovorin: weeks 3, 4, 13, 18, 19, 22, 23,
27, 28, 31, and 32
MTX
12 g/m2 (max = 20 g)
IV
1
12 g/m2 (max = 20 g)
Leucovorin
10 mg every 6 h
until MTX level
< 0.1 mcmol/L
IV
2,3
Cisplatin
120 mg/m2
IV
1
120 mg/m2
2
Doxorubicin
25 mg/m
CIVI
1-3
75 mg/m2
Cycle repeats7: Doxorubicin: weeks 0,5,12,17,22,27; Cisplatin: weeks 0,5,12,17; MTX: weeks 3,4,8,9,15,16,20,21,25,26,30,31
a

Unless otherwise specified, leucovorin should be given at a dose of 10 to 15 mg/m2 IV or PO until the methotrexate level is 0.01 to 0.1
micromole/L (1 x 10-8 to 1 x 10-7 M).
CIAI = continuous intra-arterial infusion; CIVI = continuous (24 h) intravenous infusion; IA = intra-arterial; IV = intravenous; max =
maximum; MTX = methotrexate; PO = oral.

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Cancer Chemotherapy Update

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Cancer Chemotherapy Update

hazardous
medications
when preparing leucovorin.
2. Use leucovorin solution for
injection, 10 mg/mL, or
powder for reconstitution.
3. Leucovorin is also available
as 5, 10, 15, and 25 mg
tablets for oral use.
4. Dispense in a syringe, or in
50 to 100 mL (bolus infusions) of 0.9% sodium
chloride, 5% dextrose in
water or a saline/dextrose
solution for infusion; or as
tablets for oral administration.
DRUG ADMINISTRATION
A. Doxorubicin: In the trials
reviewed, doxorubicin was
given as an 8- or 24-hour infusion following the cisplatin. It
may also be given as a slow (1
to 10 minutes) IV push, or a
bolus (15 minutes to 6 hours)
infusion.
B. Methotrexate: In the trials
reviewed, methotrexate was
given as a 4- to 6-hour infusion. It may also be given as a
24- to 42-hour infusion.
C. Cisplatin: In the trials
reviewed, cisplatin was given
as a 24-hour continuous infusion. It can also be given as a
30-minute to 6-hour bolus
infusion.
D. Leucovorin:
1. Leucovorin may be administered
intramuscularly,
orally, or intravenously
(IV), as an IV push or a
short (5 to 15 minutes)
infusion.
2. It is usually given every 6
hours, beginning 24 hours
after the start of the
methotrexate
infusion.
Many high-dose methotrexate regimens give a
minimum of eight doses.
3. Leucovorin should be

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Volume 42, August 2007

administered until the

serum methotrexate level is
in the nontoxic range [0.01
to 0.1 mcmol/L (1 x 10-8 to
1 x 10-7 M)].
SUPPORTIVE CARE
A. Acute Emesis Prophylaxis: The
cisplatin/doxorubicin/methotrexate regimen is predicted to
cause acute emesis in greater
than 90% of patients on the
days when the cisplatin and
doxorubicin are given. On
days when only methotrexate
is given, the incidence of nausea or vomiting is much lower,
but can be severe if it does
occur.9 The studies reviewed
reported nausea or vomiting in
5% to 96% of patients but did
not differentiate between the
cisplatin/doxorubicin and the
methotrexate portions of the
cycles.4 Appropriate acute emesis prophylaxis for the cisplatin/doxorubicin
portion
includes a serotonin antagonist, corticosteroid, and neurokinin (NK1) antagonist.10-12
One of the following regimens
is suggested:
1. Ondansetron 16 to 24 mg
orally, dexamethasone 12
mg orally, and aprepitant
125 mg orally, given 30
minutes before cisplatin/
doxorubicin.
2. Granisetron 2 mg orally,
dexamethasone 12 mg orally, and aprepitant 125 mg
orally given 30 minutes
before cisplatin/doxorubicin.
3. Dolasetron 100 to 200 mg
orally, dexamethasone 12
mg orally, and aprepitant
125 mg orally given 30
minutes before cisplatin/
doxorubicin.
4. Palonosetron 0.25 mg IV,
dexamethasone 12 mg oral-

ly, and aprepitant 125 mg

orally given 30 minutes
before cisplatin/doxorubicin on day 1 only.
The antiemetic therapy should
continue for at least 3 days. A
meta-analysis of several trials
of serotonin antagonists recommends against prolonged
(greater than 24 hours) use of
these agents; making a steroid,
or steroid and dopamine
antagonist combination, most
appropriate for follow-up therapy.13 One of the following regimens is suggested:
1. Dexamethasone 4 mg orally twice a day for 3 days,
aprepitant 80 mg orally
every morning for 2 days
metoclopramide 0.5 to 2
mg/kg orally every 4 to 6
hours diphenhydramine
25 to 50 mg orally every 6
hours if needed starting on
day 2 of cisplatin/doxorubicin.
2. Dexamethasone 4 mg orally twice a day for 3 days,
aprepitant 80 mg orally
every morning for 2 days
prochlorperazine 10 mg
orally every 4 to 6 hours
diphenhydramine 25 to 50
mg orally every 6 hours if
needed, starting on day 2 of
cisplatin/doxorubicin.
3. Dexamethasone 4 mg orally twice a day for 3 days,
aprepitant 80 mg orally
every morning for 2 days
promethazine 25 to 50 mg
orally every 4 to 6 hours
diphenhydramine 25 to 50
mg orally every 6 hours if
needed starting on day 2 of
cisplatin/doxorubicin.
Patients who experience significant nausea or vomiting with
one of these regimens should
receive an agent from a different pharmacologic category.10-12

Cancer Chemotherapy Update

A few small studies suggest

substituting granisetron for
ondansetron in subsequent
treatment cycles; however,
none of these reports found the
improvement to be statistically
significant.14-18
High-dose methotrexate alone
is predicted to cause acute emesis in 30% to 60% of patients.9
The studies reviewed only list
an overall incidence of nausea
and do not mention the incidence in the different phases of
Although
the
regimen.1-7
accepted guidelines recommend prophylactic antiemetic
therapy with a serotonin
antagonist and steroid for regimens with an anticipated incidence of nausea or vomiting of
30% to 60%, some patients
may not require such aggressive therapy.10-12 If a serotonin/corticosteroid combination is used, one of the following regimens may be given 30
minutes prior to therapy:
1. Ondansetron 8 to 16 mg
orally dexamethasone 20
mg orally given 30 minutes
before methotrexate.
2. Granisetron 1 to 2 mg orally dexamethasone 20 mg
orally given 30 minutes
before methotrexate.
3. Dolasetron 100 mg orally
dexamethasone 20 mg orally given 30 minutes before
methotrexate.
4. Palonosetron 0.25 mg IV
and dexamethasone 20 mg
orally or IV given 30 minutes before methotrexate
on day 1 only.
The antiemetic therapy should
continue for at least 3 days. A
meta-analysis of several trials
of serotonin antagonists recommends against prolonged
(greater than 24 hours) use of
these agents; making a steroid,

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Volume 42, August 2007

or steroid and dopamine

antagonist combination, most
appropriate for follow-up therapy.13 One of the following regimens is suggested:
1. Dexamethasone 4 mg orally twice a day for 3 days
metoclopramide 0.5 to 2
mg/kg orally every 4 to 6
hours diphenhydramine
25 to 50 mg orally every 6
hours if needed starting on
day 2 of methotrexate.
2. Dexamethasone 4 mg orally twice a day for 3 days
prochlorperazine 10 mg
orally every 4 to 6 hours
diphenhydramine 25 to 50
mg orally every 6 hours if
needed starting on day 2 of
methotrexate.
3. Dexamethasone 4 mg orally twice a day for 3 days
promethazine 25 to 50 mg
orally every 4 to 6 hours
diphenhydramine 25 to 50
mg orally every 6 hours if
needed starting on day 2 of
methotrexate.
If a less aggressive antiemetic
regimen is believed to be
appropriate for a particular
patient, one of the following
regimens may be given 30 minutes prior to therapy:
1. Dexamethasone 8 to 20 mg
orally given 30 minutes
before methotrexate.
2. Prochlorperazine 10 mg
orally or IV diphenhydramine 25 to 50 mg orally
if needed given 30 minutes
before methotrexate.
3. Metoclopramide 0.5 to 2
mg/kg orally or IV
diphenhydramine 25 to 50
mg orally if needed given
30
minutes
before
methotrexate.
4. Promethazine 25 to 50 mg
orally or 12.5 to 25 mg IV
diphenhydramine 25 to

50 mg orally if needed
given 30 minutes before
methotrexate.
Patients who do experience significant nausea or vomiting
with one of these regimens
should receive a serotonin
antagonist and steroid combination
as
prophylactic
antiemetic therapy for subsequent cycles of methotrexate.
B. Delayed Nausea and Vomiting:
Cisplatin in doses of more than
50 mg/m2 (either as a single
dose or cumulative over consecutive days) is reported to
cause delayed nausea in 78%
of patients and delayed emesis
in 61% of patients. Delayed
nausea or emesis may begin as
soon as 16 hours after cisplatin
administration, reach peak of
severity at 48 to 72 hours after
cisplatin administration, and
usually abate between 96 to
168 hours after cisplatin
administration.19 Prophylactic
therapy should continue for at
least 3 days after the last cisplatin dose of each cycle. A
meta-analysis of several trials
of serotonin antagonists recommends against prolonged
(greater than 24 hours) use of
these agents; making a steroid,
or steroid and dopamine
antagonist combination most
appropriate for follow-up therapy.13 One of the following regimens is suggested:
1. Metoclopramide 0.5 to 2
mg/kg orally every 4 to 6
hours diphenhydramine
25 to 50 mg orally every 6
hours if needed, dexamethasone 4 or 8 mg orally
twice a day for 3 days, and
aprepitant 80 mg orally
once a day for 2 days starting
on
day
2
of
cisplatin/doxorubicin.
2. Prochlorperazine 10 mg

Cancer Chemotherapy Update

orally every 4 to 6 hours

diphenhydramine 25 to 50
mg orally every 6 hours if
needed, dexamethasone 4
or 8 mg orally twice a day
for 3 days, and aprepitant
80 mg orally once a day for
2 days, starting on day 2 of
cisplatin/doxorubicin.
3. Promethazine 25 to 50 mg
orally every 4 to 6 hours
diphenhydramine 25 to 50
mg orally every 6 hours if
needed, dexamethasone 4
or 8 mg orally twice a day
for 3 days, and aprepitant
80 mg orally once a day for
2 days starting on day 2 of
cisplatin/doxorubicin.
If an NK1 antagonist (eg,
aprepitant) was used on day 1,
the day 2 and 3 regimens suggested for prophylaxis against
acute nausea would be expected to prevent delayed nausea
also.
C. Breakthrough Nausea and
Vomiting:10-14 Patients should
receive an antiemetic prescription to treat breakthrough nausea. One of the following regimens is suggested:
1. Metoclopramide 0.5 to 2
mg/kg orally every 4 to 6
hours if needed diphenhydramine 25 to 50 mg orally
every 6 hours if needed.
2. Prochlorperazine 10 mg
orally every 4 to 6 hours if
needed diphenhydramine
25 to 50 mg orally every 6
hours if needed.
3. Prochlorperazine 25 mg
rectally every 4 to 6 hours if
needed diphenhydramine
25 to 50 mg orally every 4
to 6 hours if needed.
4. Promethazine 25 to 50 mg
orally every 4 to 6 hours if
needed diphenhydramine
25 to 50 mg orally every 4
to 6 hours if needed.

A few small studies suggest

that
higher
doses
of
granisetron (3 mg IV or 40 to
240 mcg/kg)14-18 may be effective in treating breakthrough
nausea; however, none of these
reports found the improvement
to be statistically significant.
D. Hydration: Cisplatin can cause
irreversible kidney damage by
acute tubular necrosis. Maintenance of a urine output of at
least 75 to 100 mL/h for several hours before and after each
cisplatin dose is the best prophylaxis for cisplatin-induced
nephrotoxicity. A wide variety
of hydration and diuretic regimens for this purpose have
been reported. Cornelison and
Reed (1993) reported that,
with the possible exception of
the first treatment cycle, diuretics add nothing to vigorous
hydration for prevention of cisplatin nephrotoxicity.20 Kintzel
(2001) noted the mechanism of
action of diuretics intuitively
supports their use to prevent
cisplatin-induced nephrotoxicity; but there is no evidence to
recommend them over vigorous hydration.21
A suggested hydration regimen
is 5% dextrose/0.9% sodium
chloride injection or 0.9%
sodium chloride injection
infused at 250 mL/h for 2 to 4
hours before and after each cisplatin dose. Oral hydration
regimens are also used, but the
increased chloride from IV
sodium chloride injections may
offer better renal protection.20
The methotrexate dose used in
the
cisplatin/doxorubicin/
methotrexate regimen may
cause renal damage by precipitation of the drug in renal
tubules. This can result in
delayed
clearance
of
methotrexate, which increases

the risk of severe toxicities

such as mucositis and bone
marrow suppression. Aggressive hydration and urine alkalinization before administration of the methotrexate are
recommended to minimize the
risk of nephrotoxicity:21,22
1. The patients creatinine
clearance (CrCl) should be
at least 60 mL/min.
2. Adequate hydration
a. Oral or IV hydration
with greater than 3,000
mL/24 h, beginning 12
to 24 hours before
methotrexate administration.
b. Urine output greater
than 75 to 100 mL/h.
3. Alkalinization of the urine
to a pH greater than 7. One
of the following regimens,
beginning 12 hours before
methotrexate administration and continuing for 48
hours after completion of
the methotrexate infusion,
is recommended.
a. Sodium bicarbonate
(1) Oral - 3 g every 3
hours, AND/OR
(2) IV - 50 to 100 mEq
added to each 1,000
mL of hydration fluid.
b. Polycitrate solution 1 to
1.5 mmol/kg/24 h.21
E. Hypersensitivity Precautions:
Doxorubicin can induce acute
hypersensitivity
reactions.
However, such reactions are
very rare and require no specific precautions. Doxorubicin
may also cause a flare reaction, manifested by erythema,
pruritus, and urticaria surrounding the injection site or
extending along the vein being
infused. Although sometimes
confused with an extravasation
or allergic reaction, generally it
is self-limiting and resolves at

Hospital Pharmacy

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Cancer Chemotherapy Update

the end of the infusion. Additional doses of the drug can be

administered without concern.23
F. Hematopoietic Growth Factors: Accepted practice guidelines and pharmacoeconomic
analysis suggest that an antineoplastic regimen have a
greater than 20% incidence of
febrile neutropenia before prophylactic use of colony-stimulating factors is warranted. For
regimens with an incidence of
febrile neutropenia between
10% and 20%, use of colonystimulating factors should be
considered. For regimens with
an incidence of febrile neutropenia less than 10%, routine prophylactic use of
colony-stimulating factors is
not recommended.24,25
Since febrile neutropenia was
reported in 3% to 49% of
patients, and grade 4 neutropenia was reported in 32% of
patients in the trials reviewed,
prophylactic use of colonystimulating factors is recommended.4,5
G. Extravasation: Doxorubicin is
a potent vesicant, and extravasation should be avoided. If
extravasation occurs, stop the
infusion immediately, and aspirate as much of the extravasated solution as possible before
withdrawing the needle. The
limb should be elevated and
cooled intermittently (ice packs
for 15 to 20 minutes four times
a day for 3 days).26-28
21,22
H. Leucovorin Rescue:
a. Leucovorin 10 to 15 mg/m2
every 6 hours for 48 hours.
b. Monitor serum methotrexate levels every 24 hours,
beginning 24 hours after
the start of the methotrexate administration.
c. Continue leucovorin until

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Volume 42, August 2007

the methotrexate level is

less than 0.01 to 0.1
mcmol/L (1 x 10-8 to 1 x
1 0 - 7 M).
d. If the methotrexate level is
above 0.05 mcmol/L 48
hours after the start of the
methotrexate infusion, the
leucovorin
may
be
increased to 20 to 30 mg/m2
until the methotrexate level
is less than 0.01 to 0.1
mcmol/L (1 x 10-8 to 1 x
10-7 M).

D.

E.

F.
MAJOR TOXICITIES
Most of the toxicities listed
below are presented according to
their degree of severity. Higher
grades represent more severe toxicities. Although there are several
grading systems for cancer
chemotherapy toxicities, all are
similar. One of the frequently used
systems is the National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events
(http:/ctep.info.nih.gov). Oncologists generally do not adjust doses
or change therapy for grade 1 or 2
toxicities; but make, or consider,
dosage reductions or therapy
changes for grade 3 or 4 toxicities.
Incidence values are rounded to the
nearest whole percent unless incidence was less than or equal to
0.5%.
A. Cardiovascular4: Cardiotoxicity, unspecified (grade 1) 6%,
(grade 2) 1%, (grade 3) 1%;
phlebitis (grade 1) 10%, (grade
2) 3%.
Alopecia
B. Dermatologic4:
(grade 1) 3%, (grade 2) 22%,
(grade 3) 53%, (grade 4) 7%;
skin reactions (grade 1) 7%,
(grade 2) 5%.
Diarrhea
C. Gastrointestinal4:
(grade 1) 11%, (grade 2) 8%,
(grade 3) 3%, (grade 4) 1%;
nausea and vomiting (grade 1)
5%, (grade 2) 27%, (grade 3)

G.
H.
J.
K.
L.

55%, (grade 4) 9%; oral

(grade 1) 22%, (grade 2) 23%,
(grade 3) 6%, (grade 4) 5%.
Hematologic:
Hemorrhage
(grade 1) 7%,4 (grade 2) 4%,4
(grade 3) 1%,4 (grade 4) 1%4;
leukopenia (grade 4) 12% to
32%2,5; neutropenia (grade 1
or 2) 12%2; thrombocytopenia
(grade 4) 1%.2
Hepatic4: Changes in liver
enzymes (grade 1) 11%, (grade
2) 6%, (grade 3) 4%, (grade 4)
4%.
Neurologic4: Peripheral neuropathies (grade 1) 3%.
Renal4: Unspecified toxicity
(grade 1) 6 %, (grade 2) 3%,
(grade 3) 2%.
Pulmonary4: Unspecified toxicity (grade 1) 5%.
Allergy4: Allergic reactions
(grade 1) 6%, (grade 2) 1%.
Infection4: Infection (grade 1)
10%, (grade 2) 18%, (grade 3)
8%, (grade 4) 2%.
Treatment Related Mortality5:
Sepsis 1%.

PRETREATMENT LABORATORY
STUDIES NEEDED
A. Baseline
1. Aspartame
aminotransferase/alanine aminotransferase (AST/ALT)
2. Total bilirubin
3. Serum creatinine
4. CrCl (estimated)
5. Complete blood (cell) count
(CBC) with differential
B. Prior to each treatment
1. AST/ALT
2. Total bilirubin
3. Serum creatinine
4. CrCl (estimated)
5. Serum electrolytes (magnesium, potassium)
6. CBC with differential
C. Recommended pretreatment
values: The minimally acceptable pretreatment CBC values
required to begin a cycle with

Cancer Chemotherapy Update

full-dose therapy in the protocols reviewed were:

1. Initial cycle:
a. Total bilirubin
(1) Less than or equal
to 1.2 mg/dL.4
(2) Less than or equal
to 1.5 times the upper
limit of normal (ULN).7
b. ALT or AST less than
2.5 times the ULN.7
c. Serum creatinine
(1) Less than or equal
to 1.45 mg/dL.4
(2) Less than or equal
to 1.5 times the ULN.7
d. CrCl (estimated) greater than 40 mL/min, or
70 mL/min/1.73 m2.7
e. WBC greater than or
equal to 4,000 cells/
mcL.4
f. Platelets greater than or
equal to 100,000 cells/
mcL.4
g. Fraction shortening on
echocardiogram greater
than or equal to 29%
or ejection fraction
greater than or equal to
50%.7
2. Subsequent cycles:
a. White blood cell count
(WBC)
(1) Leukocyte
count
greater than or equal to
1,500 cells/mcL and
absolute
neutrophil
count (ANC) greater
than 500 cells/mcL.1
(2) ANC
(a) Greater
than
1,000 cells/ mcL for cisplatin and
doxorubicin.2
(b) Greater
than
800 cells/mcL - for
methotrexate.2
(3) WBC greater than
or equal to 3,000
cells/mcL and granulocyte count great-

er
than
1,500
cells/mcL.4
b. Platelet count
(1) Greater than 80,000
cells/mcL.1
(2) Greater than 80,000
cells/mcL - for methotrexate.2
(3) Greater than 100,000
cells/mcL - for cisplatin
and doxorubicin.2
(4) Greater than 100,000
cells/mcL.4
In clinical practice, a pretreatment ANC of 1,000 cells/mcL and
platelets of 75,000 cells/mcL are
usually considered acceptable.
DOSAGE MODIFICATIONS
A. Renal
1. Cisplatin
a. Serum creatinine less
than or equal to 1.45
mg/dL - do not give
drug.4
b. CrCl
(1) Less
than
60
mL/min but greater
than or equal to 45
mL/min reduce cisplatin dose 25%.29
(2) Less
than
45
mL/min but greater
than or equal to 30
mL/min reduce cisplatin dose 50%.29
2. Doxorubicin - no adjustment recommended.29
3. Methotrexate:
a. Less than or equal to
1.45 mg/dL.4
b. CrCl
(1) Less
than
60
mL/min and greater
than or equal to 45
mL/min reduce dose
35%.29
(2) Less
than
45
mL/min and greater
than or equal to 30
mL/min reduce dose
50%.29

(3) Less
than
30
mL/min do not give
drug.29
B. Liver30
1. Cisplatin - no adjustment
required.
2. Doxorubicin:
a. AST or ALT two to
three times ULN reduce dose 25%.
b. Total bilirubin 1.2 to 3
mg/dL or AST or ALT
greater than three times
ULN - reduce dose
50%.
c. Total bilirubin 3 to 5
mg/dL - reduce dose
75%.
d. Total bilirubin greater
than 5 mg/dL do not
give drug.
3. Methotrexate
a. Bilirubin
(1) Greater than 3.1
mg/dL and less than 5
mg/dL reduce dose
25%.
(2) Greater than 5
mg/dL do not give
drug.
b. ALT/AST: Greater than
three times the ULN
reduce dose 25%.
C. Myelosuppression
1. Cisplatin
a. WBC
(1) Nadir WBC greater
than 1,000 cells/mcL
and less than or equal
to 2,000 cells/mcL reduce dose 15%.4
(2) Nadir WBC less
than 1,000 cells/mcLreduce dose 30%.4
b. Platelet count
(1) Greater than 25,000
cells/mcL and less than
or equal to 50,000
cells/mcL - reduce dose
15%.4
(2) Less than 25,000
cells/mcL - reduce dose

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30%.4
2. Doxorubicin
a. WBC
(1) Nadir WBC greater
than 1,000 cells/mcL
and less than or equal
to 2,000 cells/mcL reduce dose 15%.4
(2) Nadir WBC less
than 1,000 cells/mcLreduce dose 30%.4
b. Platelet count
(1) Greater than 25,000
cells/mcL and less than
or equal to 50,000
cells/mcL - reduce dose
15%.4
(2) Less than 25,000
cells/mcL - reduce dose
30%.4
D. Mucositis: Grade 3 or 4 reduce doxorubicin dose 20%.
REFERENCES
1. Bacci G, Picci P, Ferrari S. et al. Primary
chemotherapy and delayed surgery for nonmetastatic osteosarcoma of the extremities.
Cancer. 1993;72:3227-3238.
2. Bacci G, Ferrari S, Bertoni F, et al. Longterm outcome for patients with nonmetastatic osteosarcoma of the extremity treated at
the instituto ortopedico rizzoli according to
the instituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report. J Clin
Oncol. 2000;18:4016-4027.
3. Hudson M, Jaffe MR, Jaffe N, et al.
Pediatric osteosarcoma: therapeutic strategies, results, and prognostic factors derived
from a 10-year experience. J Clin Oncol.
1990;8:1988-1997.
4. Bramwell V, Burgers M, Sneath R, et al.
A comparison of two short intensive adjuvant chemotherapy regimens in operable
osteosarcoma of limbs in children and
young adults: the first study of the European
osteosarcoma intergroup. J Clin Oncol.
1992;10:1579-1591.
5. Bacci G, Ruggieri P, Picci P, et al. Intraarterial versus intravenous cisplatinum (in
addition to systemic Adriamycin and high
dose methotrexate) in the treatment of
osteosarcoma of the extremities. results of a
randomized
study.
J
Chemother.
1996;8:70-81.
6. Fuchs N, Bielack SS, Epler D, et al.
Long-term results of the co-operative Ger-

710

Volume 42, August 2007

man-Austrian-Swiss osteosarcoma study

groups protocol COSS-86 of intensive multidrug chemotherapy and surgery for
osteosarcoma of the limbs. Ann Oncol.
1998;9:893-899.

17. Smith IE. A dose-finding study of

granisetron, a novel antiemetic, in patients
receiving cytostatic chemotherapy. The
Granisetron Study Group. J Cancer Res Clin
Oncol. 1993;119:350-354.

7. Meyers PA, Schwartz CL, Krailo M, et

al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or
muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin
Oncol. 2005;23:2004-2011.

18. Soukop M. A dose-finding study of

granisetron, a novel antiemetic, in patients
receiving high-dose cisplatin. Granisetron
Study Group. Support Care Cancer.
1994;2:177-183.

8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in

Oncology Bone Cancer. V.1.2007.
http://www.nccn.org/professionals/physician_gls/PDF/bone.pdf. Accessed June 28,
2007.
9. Hesketh PJ, Kris MG, Grunberg SM et
al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin
Oncol. 1997;15:103-109.
10. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in
Oncology - Antiemesis. V.1.2007. http://
www.nccn.org/professionals/physician_gls/P
DF/antiemesis.pdf. Accessed June 28, 2007.
11. Kris MG, Hesketh PJ, Somerfield MR,
et al. American Society of Clinical Oncology
guideline for antiemetics in oncology:
update 2006. J Clin Oncol. 2006;24:29322947.
12. Multinational Association for Supportive Care in Cancer. Antiemetic guidelines.
2007.
http://www.mascc.org/media/
Resource_centers/MASCC_Guidelines_Up
date.pdf. Accessed June 28, 2007.
13. Geling O, Eichler HG. Should 5hydroxytryptamine-3 receptor antagonists
be administered beyond 24 hours after
chemotherapy to prevent delayed emesis?
Systematic re-evaluation of clinical evidence
and drug cost implications. J Clin Oncol.
2005;23:1289-1294.
14. Terrey JP, Aapro MS. The activity of
granisetron in patients who had previously
failed ondansetronantiemetic therapy. Eur J
Clin Res. 1996;8:281-288.
15. Carmichael J, Keizer HJ, Cupissol D,
Milliez J, Scheidel P, Schindler AE. Use of
granisetron in patients refractory to previous treatment with antiemetics. Anticancer
Drugs. 1998;9:381-385.
16. de Wit R, de Boer AC, vd Linden GH,
Stoter G, Sparreboom A, Verweij J. Effective
cross-over to granisetron after failure to
ondansetron, a randomized double blind
study in patients failing ondansetron plus
dexamethasone during the first 24 hours following highly emetogenic chemotherapy. Br
J Cancer. 2001;19;85:1099-1101.

19. Kris MG, Gralla RJ, Clark RA, et al.

Incidence, course, and severity of delayed
nausea and vomiting following the administration of high-dose cisplatin. J Clin Oncol.
1985; 3:1379-1384.
20. Cornelison TL, Reed E. Nephrotoxicity
and hydration management for cisplatin,
carboplatin, and ormaplatin. Gynecol
Oncol. 1993;50:147-158.
21. Kintzel PE. Anticancer drug-induced
kidney disorders. Drug Saf. 2001;24:19-38.
22. Pitman SW, Frei E 3rd. Weekly
methotrexate-calcium leucovorin rescue:
effect of alkalinization on nephrotoxicity;
pharmacokinetics in the CNS; and use in
CNS non-Hodgkins lymphoma. Cancer
Treat Rep. 1977;61:695-701.
23. Weiss RB. Hypersensitivity reactions.
Semin Oncol. 1992;19:458-477.
24. Smith TJ, Khatcheressian J, Lyman GH,
et al. 2006 update of recommendations for
the use of white blood cell growth factors:
an evidence-based clinical practice guideline.
J Clin Oncol. 2006;24:3187-3205.
25. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in
Oncology - Myeloid Growth Factors.
V.1.2007. http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf.
Accessed June 28, 2007.
26. Larson DL. Treatment of tissue extravasation by antitumor agents. Cancer.
1982;49:1796-1799.
27. Larson DL. What is the appropriate
management of tissue extravasation by antitumor agents? Plast Reconstr Surg.
1985;75:397-405.
28. Mullin S, Beckwith MC, Tyler LS. Prevention and management of antineoplastic
extravasation injury. Hosp Pharm.
2000;35(1):57-74.
29. Kintzel PE, Dorr RT. Anticancer drug
renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treat
Rev. 1995;21:33-64.
30. Floyd J, Mirza I, Sachs, Perry MC.
Hepatotoxicity of chemotherapy. Semin
Oncol. 2006;33:50-67.