Pediatr Blood Cancer 2010;55:1296–1299
Ambulatory High-Dose Methotrexate Administration Among Pediatric
Osteosarcoma Patients in an Urban, Underserved Setting is Feasible, Safe, and
Cost-Effective
Kris M. Mahadeo, MD, MPH,* Ruth Santizo, BA, Lindsay Baker, BA, MBA, Joan O’Hanlon Curry, MS, RN, CPNP, CPON,
Richard Gorlick, MD, and Adam S. Levy, MD
Background. We describe the safety, feasibility, and provide a
cost-estimate of outpatient high-dose methotrexate administration
(HDMTX) among an urban, underserved population. Procedure. A
retrospective analysis of ambulatory HDMTX administration among
osteosarcoma patients, at Montefiore Medical Center’s Children’s
Hospital (Bronx, NY) was performed. HDMTX (12 g/m2 ) was given
intravenously (IV) over 4 hr after urine alkalinization. Patients were
discharged home to continue IV hydration and alkalinization deliv-
ered via a home infusion pump. Families were instructed to monitor
urine pH overnight and management was adjusted according to our
institution’s treatment algorithm until MTX level ≤0.1 ␮mol/L. A cost
estimate was performed to assess the difference in costs for outpa-
tient versus hypothetical inpatient administrations. Results. Of the 97
ambulatory HDMTX administrations, 99% were successfully com-
Key words: chemotherapy; cost-effective; methotrexate; osteosarcoma; pediatric oncology; underserved
INTRODUCTION
High-dose methotrexate (HDMTX) administration is used for
a variety of pediatric cancers including osteosarcoma, acute
lymphoblastic leukemia, and non-Hodgkin’s lymphoma. While
administration has proven to be an effective treatment modal-
ity, there are significant toxicities associated with therapy. Renal
toxicity, hematologic as well as gastrointestinal toxicity have all
contributed to historical mortality rates as high as 5–6% [1]. Clin-
ical monitoring, hydration, and urine alkalinization have helped to
reduce the mortality rate associated with HDMTX therapy to <0.1%
[1]. Monitoring the serum concentrations of methotrexate (MTX)
is a well-accepted method to identify patients who are at high risk
for severe toxic effects of the drug [1]. Because of the risks associ-
ated with HDMTX, most institutions still require a minimum 72-hr
inpatient admission for administration. One cancer center recently
described their institution’s experience with outpatient adminis-
tration of HDMTX [2]. They provided evidence that outpatient
administration represents a safe modality among their patient pop-
ulation [2]. Their experience, however, may not be generalizable to
more urban, underserved populations [2]. Various socioeconomic
variables among underserved populations may lead to the perception
that outpatient HDMTX administration is neither safe nor practical,
and thus, preclude its implementation among these populations. In
addition, the lack of economic incentive regarding outpatient admin-
istration may serve as a barrier given the scarce resources available
to urban hospitals, despite the growing need for available inpatient
hospital beds among many centers.
Although the association between ambulatory chemotherapy and
improved quality of life (QOL) has not yet been rigorously estab-
lished, HDMTX administered in the pediatric outpatient setting
could conceivably contribute to improved quality-of-life for our
pediatric patients and their families [3]. Several studies have exam-
ined the possibilities and limits of outpatient supportive measures in
© 2010 Wiley-Liss, Inc.
DOI 10.1002/pbc.22772
Published online 15 October 2010 in Wiley Online Library
(wileyonlinelibrary.com).
pleted. One patient failed outpatient administration secondary to
home infusion pump malfunction. This patient successfully com-
pleted subsequent courses as an outpatient. Most patients (72%)
had a MTX level of <10 ␮mol/L at 24 hr post-HDMTX. No patients
were found to have a MTX level of >50 ␮mol/L at 24 hr. About
26% of courses were associated with grade III or IV neutropenia,
4% were associated with grade III or IV thrombocytopenia and
1% were associated with grade III/IV leukopenia. Compared to a
hypothetical hospital inpatient stay, the hospital costs for ambula-
tory HDMTX were an average of $1400 less per cycle. Conclusion.
Ambulatory HDMTX administration among an underserved, urban
population is safe, feasible, and cost-effective. Pediatr Blood Cancer.
2010;55:1296–1299. © 2010 Wiley-Liss, Inc.
pediatric oncology. However, questions often remain as to whether
results of such studies are generalizable to urban, under-served pop-
ulations and may result in delays in the application of such measures
among these patient populations.
Montefiore Medical Center’s Children’s Hospital primarily
serves residents of the Bronx, New York. More than 40% of children
under the age of 18 are below the poverty level, making the Bronx,
one of the most economically distressed communities in the United
States. We describe our institution’s experience with ambulatory
HDMTX administration among an urban, underserved population
and provide a cost estimate of such administration.
METHODS
A retrospective analysis of all ambulatory HDMTX adminis-
tration among osteosarcoma patients, between January 2005 and
December 2008 at Montefiore Medical Center’s Children’s Hos-
pital was performed. This study was approved by the Institutional
Review Board.
Several demographic and clinical variables were extracted from
the electronic medical record. Demographics, such as sex, age,
ethnicity, and insurance were examined to determine the socioeco-
nomic profile of our sample population. New York State Medicaid,
a health program in the United States for persons with low income
Abbreviations: HDMTX, high-dose methotrexate; MTX, methotrexate..
Division of Pediatric Hematology/Oncology, Children’s Hospital at
Montefiore, Bronx, New York
Conflict of interest: nothing to declare.
*Correspondence to: Kris M. Mahadeo, Division of Pediatric Hematol-
ogy/Oncology, Children’s Hospital at Montefiore, Bronx, NY 10467.
E-mail: krismd03@hotmail.com
Received 8 May 2010; Accepted 7 July 2010
 Ambulatory High-Dose Methotrexate 1297
TABLE I. Treatment Algorithm at Montefiore Medical Center’s Children’s Hospital

Hours pre-/post-HDMTX MTX level Leucovorin (LV)

administration (␮mol/L) rescue dose Clinical intervention

−0 Until urine alkalinization IV sodium bicarbonate bolus of 1 mEq/kg (maximum

dose of 100 mEq) over 15 min. Repeat bolus until
the urine is alkalinized to a pH ≥ 7
0 (urine pH > 7) Infuse MTX 12 g/m2 over 4 hr. (maximum dose of
20 g) IV hydration 3 L/m2 /day
<10 10 mg po q6h IV hydration 3 L/m2 /day
10–20 20 mg po q6h IV hydration 3L/m2 /day
20–30 30 mg po q6h Increase IV hydration
30–50 50 mg po q6h Increase IV hydration
24 ≥50 1G IV over 24 hr Admit to hospital. Increase IV hydration. Close
monitoring and lab work
48 ≤1 Continue prior dose Continue IV hydration at current rate
>1 Consider dose escalation Continue IV hydration at current rate
72 ≤0.1 Discontinue Discontinue IV hydration
>0.1 Continue prior dose Continue IV hydration at current rate. Repeat MTX
level q24h. Discontinue LV and IV hydration when
MTX level ≤0.1 ␮mol/L

and resources, was used as an indicator of economic disadvantage.
In addition, family income in comparison to United States fed-
eral poverty guidelines was assessed. Clinical variables, such as
diagnosis, number of treatment cycles, number of completed/failed
outpatient administrations, and laboratory parameters such as serum
MTX levels, serum creatinine, alanine transferase, bilirubin levels,
white blood cell count, absolute neutrophil count, platelet count,
and hemoglobin were also examined.
HDMTX (12 g/m2 ) was given intravenously (IV) over 4 hr fol-
lowing urine alkalinization [MTX supplied as 1 g of lyophilized
powder (Lederele, Inc., Pearl River, NY) reconstituted with SWFI,
USP (Sterile Water for Injection, United States Pharmacopeia)].
Urine alkalinization was achieved by repeated administrations of
an intravenous sodium bicarbonate bolus of 1 mEq/kg (maximum
dose 100 mEq) over 15 min, until the urine pH was ≥7. Patients
were discharged home to continue IV hydration and alkalinization
delivered via a home infusion pump. IV hydration consisted of D5W
admixed with 50 mEq/L of NaHCO3 at a rate of 3 L/m2 /day. Fam-
ilies were instructed to monitor urine pH overnight using a urine
dipstick. Sodium bicarbonate tablets were prescribed to maintain a
urine pH > 7. Patients returned daily to clinic to monitor urine pH,
serum electrolytes, MTX level, and received continued hydration.
History and physical examinations were performed daily.
Leucovorin was started at 24 hr following MTX administra-
tion at 10 mg by mouth every 6 hr and management was adjusted
according to our institution’s treatment algorithm until MTX level
≤0.1 ␮mol/L (see Table I).
Guidelines requiring hospitalization included severe mucositis,
MTX levels ≥50 mol/L at 24 hr, fever (temperature >38◦ C), infec-
tion requiring intravenous antibiotics, pump malfunction occurring
during off-hours for the clinic (pump malfunction which occurred
during clinic hours would be addressed in the clinic), encephalopa-
thy, nephrotoxicity, and dehydration.
A cost estimate was performed to assess the economic impact
of ambulatory HDMTX administration from the perspective of the
hospital. Charges for care were entered into the Montefiore Medi-
cal Center billing system and extracted from the daily transaction
report by hospital number and service code date (date the charge
was incurred). Charges were linked by patient registration number
and analyzed confidentially. A cost-to-charge ratio of 0.5 was used
for our analysis. The institutional cost (based upon facility charges)
of an outpatient cycle was compared to the estimated cost of room
and board care associated with an avoided admission during a simi-
lar time period. Costs related to chemotherapy, laboratory tests, and
physician and other ancillary services were excluded from the anal-
ysis, as the actual cost to our hospital would be the same regardless
of whether administration was performed as an inpatient or out-
patient. A one sample t-test was used to compare the mean cost
of outpatient cycles to that of theoretical inpatient cycles of equal
length.
RESULTS
Our patient sample consisted of 12 patients with high grade
osteosarcoma. No patients with osteosarcoma were excluded from
receiving ambulatory HDMTX during the study period. Their ages
ranged from 7 to 22 years with a mean age of 15 years. Males
comprised 58% of our patient sample. One half of our patients
(n = 6) were African-American, 42% (n = 5) were Caucasian, and
8% (n = 1) were Asian. New York State Medicaid was the insurer
for all patients in our sample, with approximately half qualifying for
this entitlement solely based upon low family incomes as compared
to United States federal poverty guidelines.
There were a total of 97 ambulatory HDMTX administrations.
The median number of cycles completed was 9. Of the 97 ambula-
tory HDMTX administrations, 99% were successfully completed.
One patient failed outpatient administration secondary to home
infusion pump malfunction. This patient successfully completed
subsequent courses as an outpatient. About 72% of patients had
a MTX level of <10 ␮mol/L at 24 hr post-HDMTX. No patients
were found to have a MTX level of >50 ␮mol/L at 24 hr. Toxicity
was assessed using the National Cancer Institute Common Toxi-
city Criteria (NCI CTC-Version 2.0, June 1999). There were no
significant elevations in creatinine levels associated with any of
the cycles. Approximately, 26% of courses were associated with
grade III or IV neutropenia, 4% were associated with grade III or

Pediatr Blood Cancer DOI 10.1002/pbc

1298 Mahadeo et al.
TABLE II. Results of Cost Estimate
Variable Outpatient
Average cost per treatment cycle $968
Average cost per patient $8,712
The institutional cost (based upon facility charges) of an outpatient cycle was compared to the estimated cost of room and board care associated
with an avoided admission during a similar time period.
IV thrombocytopenia, and 1% were associated with grade III/IV
leukopenia. No patients had severe or irreversible hepatotoxicity.
Table II summarizes the results of our cost estimate. The hospital
costs for ambulatory HDMTX cost an average of $1407 less than a
hypothetical inpatient hospital stay (P < 0.001). Over the course of
multiple cycles (median of nine cycles per patient) this represented
approximately $12,663 in cost savings per patient.
DISCUSSION
While MTX has proven to be effective in a variety of childhood
malignancies, HDMTX (>1 g/m2 ) has been particularly useful in the
treatment of osteosarcoma [4,5]. The dose utilized in the treatment
of osteosarcoma (10–12.5 g/m2 ) is many fold higher than that of
conventional doses and it is believed that the mechanism of action
may be different at these higher doses [6].
While the precise mechanism by which HDMTX works remains
an enigma, there is sufficient evidence that it is effective [7]. Rosen
et al. [8] reported improved response rates in children <12 years
of age with osteosarcoma who received HDMTX (≥12 g/m2 ) [7].
Non-MTX based therapy has been reported as a major poor prog-
nostic factor for osteosarcoma [9]. In addition, HDMTX is effective
in eliminating overt pulmonary metastases, enhances the effect of
radiation therapy for palliation and results in better rates of limb
salvage [10].
Prior to the adoption of adequate monitoring and supportive
measures, HDMTX was associated with high rates of toxicity and
mortality [1,3]. Deaths were mainly related to myelosuppression and
renal failure [11]. Contemporary supportive measures have proven
HDMTX to be relatively safe, especially among pediatric patients
[12]. The most common side effect is mild gastrointestinal toxi-
city, such as mucositis and diarrhea [12]. Renal toxicity and life
threatening infections secondary to myelosuppression are now seen
at relatively low rates [2]. Adequate hydration and urinary alki-
nalization, pharmacodynamic monitoring, avoidance of drug–drug
interactions and use in patients with significant third space fluids
(MTX accumulates in third space fluids and contributes to delayed
clearance and toxicity) have all led to the dramatic improvements
in rates of toxicity seen with HDMTX [5].
One cancer center recently reported their experience with
HDMTX on an ambulatory basis and showed that this was safe
among their patient population [2]. While they saw an unexpected
5% of courses complicated by 24-hr MTX levels ≥50 mol/L, none
of their patients experienced life-threatening toxicity nor suffered
from renal toxicity [2]. Likewise, we saw no life threatening or sig-
nificant renal toxicity in our current study. In addition, none of our
patients were found to have 24-hr MTX levels ≥50 mol/L. Given the
historical mortality rates associated with HDMTX, the ambulatory
mode of administration has yet to be more universally implemented,
despite reassuring evidence that it is safe. Successful ambulatory
Pediatr Blood Cancer DOI 10.1002/pbc
Inpatient Difference P-value
$2,375 $1,407 <0.0001
$21,375 $12,663 <0.0001
HDMTX requires the patient and family to become more active
participants in the treatment regimen. While this can be empow-
ering, some may question whether such administration is feasible
among underserved populations, where numerous barriers have his-
torically led to disproportionate health outcomes [13]. Public health
studies have recognized the need to improve the validity and gen-
eralizability of studies with regard to underserved populations [14].
As such, novel and beneficial therapeutic modalities may some-
times remain elusive to underserved populations secondary to lack
of data. Our results demonstrate that ambulatory HDMTX is a safe
and feasible mode of administration among an underserved popu-
lation. We hope that our data will encourage other providers among
underserved populations to explore ambulatory HDMTX strategies.
Prior studies have documented the negative impact of occupied
inpatient hospital beds on emergency room outcomes in urban hos-
pitals [15,16]. Hence, ambulatory HDMTX administration would
alleviate this problem by way of making inpatient hospital beds
available. Ambulatory HDMTX is a less costly mode of adminis-
tration, with a direct cost saving of approximately $1400 per cycle
to the hospital.
Changes in reimbursement for outpatient chemotherapy sec-
ondary to the Medicare Modernization Act of 2003 were feared to
negatively affect access to outpatient chemotherapy. This remains to
be seen. In one study, the authors discuss whether sudden changes
to a practice are often limited by high fixed costs [17]. While ambu-
latory HDMTX is cost-effective to the payor, there will be some
upfront costs associated with organizational changes needed for
implementation, such as purchase of infusion pumps and costs asso-
ciated with ambulatory staffing and training. Payors must develop
adequate compensation mechanisms in order to encourage more
patient focused ambulatory care. The cost effectiveness of ambula-
tory care has been documented among other disease models [18–21].
A randomized study published in 1988 of inpatient versus outpatient
continuous infusion chemotherapy for adult patients with locally
advanced head and neck cancer demonstrated the cost-effectiveness
of outpatient chemotherapy [21]. Adequate payor incentives for
ambulatory care have not yet been developed [20]. In this study,
outpatient reimbursement rates more than $1400 per treatment cycle
lower than comparable inpatient reimbursement rates would serve
as a disincentive to provide such care on an outpatient basis.
Studies have shown improved QOL parameters when patients
are offered ambulatory and home chemotherapy [3,22,23]. Further
studies may be needed to confirm this assumption among patients
from underserved communities. Improved QOL for childhood can-
cer patients serve as an additional impetus for more widespread
implementation of ambulatory HDMTX.
There are limitations to our current study. While we provide
information on 97 HDMTX cycles, we were limited by a relatively
small patient sample. The analysis was limited to osteosarcoma
patients and thus, care must be taken in extrapolating results to

patients with other diagnoses. As a retrospective chart review, we
were limited in the factors analyzed. For example, information
regarding mucositis was not included in our analysis because of
the lack of consistency in its documentation. In terms of our cost-
estimate, we did not separately compare reimbursement rates, as
local differences in Medicaid reimbursement would complicate the
generalizability of any conclusions.
Our study indicates that ambulatory HMDTX with adequate sup-
portive measures is safe, feasible and cost-effective in an urban,
underserved population. Adoption of ambulatory HDMTX could
result in significant healthcare savings and would make more inpa-
tient hospital beds available, which is especially important among
urban, underserved populations.
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