A Systematic Review of Neuropsychological Studies Confirms that
Adequate Folinic Acid Post Methotrexate Rescue Prevents Neurotoxicity
Sadeh Michelle,1 Toledano Helen,2,3 Cohen Ian Joseph,2,3
1.Israel Cancer Association, Tel Aviv, Israel.
2 . The Rina Zaizov Department of Pediatric Hematology-Oncology,
Schneider Children’s Medical Center of Israel, Petach Tikva, Israel
3. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Corresponding Author: Prof Ian Joseph Cohen, icohen@tauex.tau.ac.il
ORCID Numbers:
Sadeh M: 0000-0002-3312-6828
Toledano H: 0000-0002-1476-7937
Cohen IJ: 0000-0002-5364-3275
ABBREVIATIONS TABLE
FA Folinic acid
ALL Acute Lymphoblastic Leukaemia
MTX Methotrexate (MTX)
LD-IT-MTX Low-dose intrathecal methotrexate
HDMTX High-dose methotrexate
IT MTX Intrathecal MTX
CNS Central Nervous System
CSF Cerebrospinal fluid
WIPPSI Wechsler Preschool and Primary Scale of Intelligence
WISC-IV Wechsler Intelligence Scale for Children fourth edition
WAIS Wechsler Adult Intelligence Scale
IQ Intellectual Quotient
BFM Berlin Frankfurt Munster
POG Pediatric Oncology Group
GCI General cognitive index
WM Working memory
VIQ Verbal intelligence quotient
PIQ Performance intelligence quotient
PS Processing speed
WORD COUNT TEXT 5899 ABSTRACT 147
TABLES 4
RUNNING TITLE Adequate FA after MTX prevents cognitive damage .
Keywords:
Neuropsychological evaluation, high dose methotrexate, folinic acid
rescue therapy, neurocognitive damage
ABSTRACT
A comprehensive literature search was performed of all databases of the
Web of Science Citation Index, during 1990-2020, for the terms:
neuropsychological, neurocognitive, cognitive, acute lymphoblastic (and
lymphocytic) leukemia, and osteogenic sarcoma, to see if there was
evidence of a correlation between folinic acid (FA) rescue inadequacy
and long-term cognitive damage. All English language, peer-reviewed
articles of neuropsychological assessments of children who had been
treated with high-dose methotrexate without irradiation, and which
included details of methotrexate and FA schedules, were selected. Four
groups of studies were found and analyzed, Those with no evidence of
cognitive deterioration, Those with evidence of cognitive deterioration,
studies with more than one protocol grouped together, preventing
separate analysis of any protocols, and those with significant serious
methodical problems. In all studies, protocols without evidence of
cognitive deterioration reported adequate FA rescue, and those with
evidence of cognitive deterioration reported inadequate FA rescue.
.
INTRODUCTION
For over 50 years, our understanding of the pathophysiology of
treatment-related side effects following high dose MTX has been based on
several axioms, which require reassessment.
No evidence of the previous held belief of ”the folinic acid
methotrexate ratio” has been found. That concept suggested the effective
dose of folinic acid (FA) needed to rescue patient after MTX is linearly
correlated to the MTX dose [1]. Sirotnak [2] clearly
demonstrated that in a mouse model one can ”over rescue” and block the
efficiency of MTX by giving too much leucovorin after the MTX dose and
also that too little leucovorin or too prolonged starting of the rescue
can result in death from neurotoxicity. The question remains whether is
it possible to find a dose of FA that will prevent neurotoxicity without
reducing the chemotherapy effect. The answer can be found in the same
article showed that the appropriate, adequate, rescue dose of FA, after
doubling the MTX dose, needs to be 3-4 times higher that used for the
original MTX dose. ”On certain schedules with methotrexate, toxicity can
be virtually eliminated with no diminution in antitumor efficiency
[2]. It follows that when the previous dose of FA was barely
adequate for rescue, doubling both the MTX and FA doses will lead to
neurotoxicity. The previously not understood ” mysterious interaction”
[3] that high-dose MTX caused brain damage (leukoencephalopathy) if
given after, but not before, cranial irradiation, can now be explained,
since both irradiation and intra-arterial mannitol [4] disrupt the
blood brain barrier, and result in higher levels of both MTX and folinic
acid. The level of FA, however, may now be inadequate since for the
higher CSF level of MTX achieved, a much higher level of FA would be
needed for effective rescue [5]. It is therefore not surprising that
after low dose methotrexate, over rescue can occur after similar
milligram doses of FA. Such a finding was reported by Bowman who noted
that patients with head and neck cancer who received 40mg/m2 FA after
40mg/m2 MTX had a lower response rate than patients who received no FA
[6]. It will be expected that following high dose methotrexate, over
rescue will only be possible after ”Mega doses” of FA. This has too the
best of our knowledge only been reported to date, once, when by mistake,
such a dose of FA (1275mg ) was given after 12.5 grams of HDMTX[7].
The misleading advice that the FA rescue dose should be kept at a
minimum to prevent a reduction in cure rates by ”over rescue” has been
accepted without any evidence, and no reports of reduced prognosis with
increased FA rescue were found [8]. Reports that claimed increasing
the FA dose reduces prognosis did not stand up to close scrutiny and
have since been discredited [7], and many of the articles cited to
support this concept were recently shown to be problematic [10].
These reports have resulted in the use of low-dose (inadequate) FA
rescue after high dose MTX by certain groups, which was, as we
predicted, associated with significant neurological damage [11].
Previous studies examining adequacy of FA doses used and occurrence of
neurotoxicity were able to show correlations between neurotoxicity and
inadequate FA rescue [11], but were less helpful in defining a
critical FA dose, since they were hindered by the lack of a consensus
definition of what constitutes neurological damage. One group initially
limited reported neurotoxicity to the occurrence of strokes and seizures
[12] (Later this specific group published a neuropsychological
analysis of the same patients [13].) Current neuropsychological
studies can now demonstrate subtle brain damage that result in long-term
brain damage that should be assessed in order to prevent such damage. We
predict that the dose of FA needed to prevent subtle cognitive damage
found on neuropsychological assessment will be even higher than what is
found to be adequate for the prevention of gross neurological damage.
Peterson [14] performed a meta-analysis of neuropsychological
sequelae in children with ALL treated by different protocols without
cranial irradiation. The meta-analysis did not find any consistency in
the results with regard to visual-motor skills, visual memory, or verbal
fluency. But, in multiple domains of intelligence and academic
achievement (math and reading), processing speed, verbal memory, working
memory perceptual reasoning skills and some aspects of executive
functioning, worse functioning was found in ALL survivors. These
findings strengthen the understanding that chemotherapy as the sole CNS
relapse prevention protocol can cause cognitive and academic problems in
children.
Since the meaning of some of the terms used have changed over the years,
we define them as used in this manuscript.
1. High dose MTX refers to an intravenous infusion dose of
> 1gm/m2 MTX [15].
2. Adequate FA rescue is the term used to describe a dose of FA which,
when given after high-dose MTX, was not followed by any long-term
toxicity. It can be given intravenously or orally. An inadequate rescue
dose associated with toxicity could be due to an insufficient dose
and/or too long an interval between initiation of MTX and start of FA
rescue ”Too little too late”. The FA rescue after high dose MTX may be
delayed safely up to 36 hours after initiating MTX without neurotoxicity
[16]. However, the higher the dose of MTX and the longer the time to
rescue, the higher the rescue dose required. Thus, the doses of MTX and
FA, and time to rescue, both determine if a rescue protocol is adequate
or inadequate.
3. Comprehensive Neuropsychological studies refer to assessments that
include standard tests which address intelligence, learning and memory,
working memory, processing speed, linguistic abilities, executive
functions, problem solving – all differentiating between verbal and
non-verbal domains, attention, academic achievements, visual abilities
(perceptual, spatial) and fine motor functions. There are many tests
that examine each and every one of these cognitive abilities, but in
different research centres and countries researchers use different
tests, which make it harder to compare between the diverse studies done
in the world addressing cognitive abilities and impairments.
A sensitive issue when assessing any cognitive ability is related to
age. Depending on the childrens’ age, different assessment tools are
needed. For example, the WIPPSI vs. WISC-IV vs. WAIS, all standard tests
addressing the Intellectual Quotient (IQ) of the examinee, but are
appropriate for different age brackets.
Another issue important to consider when asking about any type of
cognitive ability affected by any intervention is the time of
assessment. Most neuropsychological tests allow repeating them after a
year, but if one asks about late effects of chemotherapy, one must state
what is considered late effect. If the question is chemotherapies’
detrimental effects on the childs’ ability to become a well-functioning
adult, then it is imperative that the effects of the oncological
treatment be assessed at least after being in school. The effect of the
oncological treatment on his or her reading, writing, comprehension and
math is crucial in answering such a question.
Furthermore, in an ideal world, it is best to do the 1st
neuropsychological testing before any intervention occurred. But that is
very difficult to achieve, thus it is best done as soon as possible.
When addressing the long-term effects of giving adequate or inadequate
FA, the assessments should be at least 2 or 3 years after the 1st
assessment, preferably using the same tests, asking about the same
cognitive abilities one studied to begin with.
METHODS
A comprehensive search of the literature during 1990-2020 was performed
in December 2020, of all the databases in the Web of Science Citation
Index using the terms neuropsychological, neurocognitive, and cognitive,
together with acute lymphoblastic (and lymphocytic) leukaemia and
osteogenic sarcoma. In addition, a personal data base of over 500
reprints of articles from over 130 journals on the subject of
methotrexate and FA and side effects was reviewed.
INCLUSION CRITERIA
English language peer-reviewed articles of neuropsychological
assessments of children who had received treatment with high-dose
methotrexate without irradiation, which included details of methotrexate
and FA schedules, were selected. All articles found were examined and
reported irrespective of difficulties in separating subgroups who
received different therapy or those with methodological problems. Not
all of these studies had full details of the ITMTX (Intrathecal MTX)
doses These reports that could not be analysed were included to prevent
any suggestion of bias and to prevent challenge of the results of this
review in the future by citation of these problematic reports.
RESULTS
The selected literature was separated into four groups: (1) studies with
no evidence of cognitive deterioration, (2) studies with evidence of
cognitive deterioration, (3) studies of more than one protocol grouped
together, preventing analysis of each protocols, and (4) studies with
significant serious methodical problems. The results are presented
below, and include the treatment protocols, neuropsychological
assessments, and significance of the FA rescue regime used. It was found
that the studies without evidence of cognitive deterioration were those
in which the treatment protocol contained adequate FA rescue, while
those with evidence of cognitive deterioration had inadequate FA rescue.
1. Studies with no evidence of cognitive deterioration (Table 1)
Protocols used at the Hospital for Sick Children (Sick Kids Toronto
Canada) from1983-1996
Children aged 1-5 years were treated with three different Central
Nervous System (CNS) prophylaxis protocols with either cranial
irradiation, 3 doses of 8gm/m2 or 3 doses of 33.6 gm/m2 MTX. FA rescue
was started after 36 hours. Those who received MTX were initially given
100mg/m2 of FA followed by 12mg/m2 of FA every 3 hours x 6 then every 6
hours until the plasma levels were < 0.08 micromol /L. The
total dose was at least 172mg/m2. Patients who received 33.6gm/m2 MTX
were given 200mg/m2 FA followed by 12mg/m2 FA every 3 hours x6 then
every 6 hours until the serum levels were < 0.08 micromol/L.
The total FA dose was at least 272mg/m2 [17].
Spiegler et al. tested 79 of the 156 pediatric patients treated in these
studies: 22 after very high dose MTX, 32 after high dose MTX, and 25
after they received cranial irradiation. The patients were tested
10.5+2.7 years after diagnosis. Children in both the MTX groups had 17
of 18 measures of neurocognitive function, including intelligence,
attention, memory, and academics compatible with population norms.
Irradiated children had significantly lower results in 12
measures.[17]
This is an important group of studies that shows that adequate FA
rescue, even after very high dose MTX, prevents cognitive damage.
The Dutch (DCLSG) Protocol ALL-7
Four 2 weekly 24-hour infusions of 5g/m2 MTX were followed by 75mg/m2 FA
rescue at 36 hours from start of MTX, followed by twelve doses of 15
mg/m2 FA every 3 hours, for a total of 255mg/m2 (personal communication
with Dr. Annette Kingma).
Kingma et al. performed two studies of these patients. In the first
[18] they assessed 20 children < 7 years old at diagnosis,
after approximately 2 and 7 years follow up (median 7 years), using14
intelligence tests evaluating learning and memory, attention and speed,
visual motor integration, and fine motor function. No major cognitive
impairment was found, 12/14 tests showed no significantly lower test
score, and there were no differences in school achievement as compared
to siblings (p<0.004). In the second study, 17 children were
assessed 8 years after diagnosis with 12 psychometric measures [19].
Although they showed 16 defects on various test measures, all the
patients and their healthy siblings attained the mean level of education
for the current Dutch population of children 15 to 19 years of age.
Excluding fine motor measures, 10/17 lacked measures of poor function.
Although this is a protocol based on the ALL Berlin- Frankfurt –
Munster (BFM) 86 protocol without cranial irradiation, a significant
major difference is that they received a FA rescue protocol of 225mg/m2
initiated 36 hours after the start of the MTX, instead of an FA dose of
45mg/m2 initiated at 42 hours as in the BFM study. Groups that adopted
the rescue used by the BFM group have reported neurotoxicity [20].
Israel Osteosarcoma Group protocols
Three paediatric oncology units in Israel treated patients with
osteosarcoma with protocols including HDMTX and FA. All patients
received repeated doses of intravenous MTX (12-20 g/m2); however,
different doses of FA were used according to institutional
protocols.[21]
Bonda-Shkedi et al. examined long-term survivors without central nervous
system involvement who agreed to participate in the study, had not
received any other potentially neurotoxic therapy, and had no previous
neurological or psychiatric history. Twelve osteosarcoma patients aged
17-31 years were examined at least 4 years after completing therapy
(average time from completion of therapy to examination was 10-17+5.57
years (personal communication Bonda-Skedi E.) and had received 300-600
mg/m2 of FA after each treatment. They had statistically significant
(p<0.025) better results on 11 of 18 subtests (e.g.,
attention, visual perception, analysis and synthesis, verbal memory,
visual memory, executive functioning, and comprehension) than those who
received inadequate FA rescue (see below) [21].
The lack of cognitive damage after adequate FA rescue supports the
concept that adequate rescue prevents cognitive damage.
The CCG-107 study
This study treated babies aged 1-12 months diagnosed with ALL with a
protocol that included a CNS -directed therapy consisting of four
24-hour infusions of 33.6 gm/m2 MTX. Thirty six hours after the start of
the MTX they received 200mg/m2 FA then six 12mg/m2 doses of FA every 3
hours, and 12mg/m2 FA every 6 hours until serum MTX level was
< 8x10-8M. The total dose was at least 284 mg/m2.[22]
Thomas A. Kaleita assessed the neurodevelopmental effects of the intense
chemotherapy treatment given to these children by testing them using the
McCarthy Scales of Children’s Abilities (27 children received this test,
3 received IQ tests). This assessment tool has 18 cognitive and motor
subtests which provide six scales: general cognitive (GCI), verbal,
perceptual-performance, quantitative, memory, and motor. The results on
all scales were close to the normal population norm; though the range
was wide (one child had a GCI more than two standard deviations above
the mean, and two children a GCI between one and two standard deviations
below the mean). They were tested aged 62.1+ 17.2 months [23].
Although this study was performed more than 2 years after the treatment
with HDMTX, most of the 30 children participating in this study were
assessed prior to entering school, which may have been too early to pick
up many of the late deleterious cognitive and scholastic effects. The
lack of cognitive damage at this very young age is certainly
encouraging.
2. Studies with evidence of cognitive deterioration (table 2)
The ACL0131 STUDY [24] examined children who were treated in the POG
9201 and POG 9605 studies without cranial irradiation. Those on the POG
2901 protocol received six courses of 200mg/m2 MTX over an hour,
followed by 800mg/m2 MTX over 23 hours together with (intrathecal
methotrexate) ITMTX, every three weeks. FA rescue was started at 42
hours after the start of MTX. 5 doses of 10 mg/m2 FA was given every 6
hours, (total 50 mg/m2). Children on the POG9605 protocol received
additional MTX at 2 of 3 weeks, either intravenous or
intrathecal.[24]
Duffner et al. reported the results of neurocognitive studies in 52
patients aged 1-10 years at diagnosis who were tested more than 2.6
years after completion of therapy with Paediatric Oncology Group (POG)
9605 and POG 9201 protocols. Twenty subgroups of tests were assessed in
seven functional areas: global intellectual function, verbal abilities,
perceptual and spatial abilities, spatial planning, attention and
concentration, processing speed, and memory. Forty percent of patients
scored < 85 on either verbal IQ (VIQ) or performance IQ (PIQ).
Note the average IQ is 100 with a standard score of +/- 15. Children in
both studies had significant attention problems, but P9605 children
scored below average on more neurocognitive measures than P9201 children
(14/17 (82%) vs. 4/17 (24%) measures, respectively).[24]
The reason why the children on the P9605 did worse than those on the
P9605 is unclear from the discussion by Duffner[24] who presents
three different possible suggestions. We would suggest a more convincing
reason is that the patients on both these protocols received only
50mg/m2 FA initiated after 42 hours, although 60mg/m2 initiated after 36
hours was the dose of FA shown to prevent neurological damage when this
dose of MTX was given without ITMTX [25]. This dose was clearly
inadequate to prevent cognitive damage especially since both protocols
also included ITMTX. This inadequacy was more marked in the POG 9605
study patients who received more, inadequately rescued, MTX.
The POG AALL0232 protocol study
Children received four courses of 5gm/m2 MTX and IT MTX followed by FA
rescue of 15mg/m2 at 42,48, and 54 hours. When MTX levels were higher
than 1micromol/L at 42 hours or 0.4 micromole at 48 hours, FA rescue was
continued. Another group received five doses of escalating dose MTX with
PEG asparaginase but without FA rescue [13].
The COG AALL06N1 study assessed children who were treated with the COG
AALL0232 protocol. Hardy reported the neurocognitive impact of this
treatment in 192 children, aged 1-18 years, at diagnosis 8-24 months
after completion of chemotherapy (average age 14.4+4.0 months). They
were evaluated by a > 4-hour comprehensive
neuropsychological battery or a screening battery (approximately 1 hour)
by a psychometrist for IQ, working memory (WM), and processing speed
(PS). Patients in both groups together demonstrated impairment in IQ of
21.4% and 28.6% had impaired processing speed as defined by scores of
equal or less than 1 standard deviation below the mean-versus 15.9% of
individuals in the normative samples for each Wechsler measure
(two-sided P=2.04 and <.01 respectively). Cognitive outcome
correlated with age and insurance status which in the US is a proxy for
socioeconomic status. They found that children < 10 years old
at diagnosis were at risk of deficits in IQ and PS. [13]
Thus the folinic acid dose that was given to the children after IVMTX
was inadequate to prevent the damage seen to the children who received
IV MTX (with L asparaginase) without any FA. Others who used this
protocol with these rescue doses have reported considerable
neurotoxicity [26].
The St Jude X protocol
This protocol compared the efficacy of two CNS prophylaxis protocols in
ALL. One group received 1gm/m2 MTX over 24 hours (together with ITMTX
12mg/m2). FA rescue was given at 36 and 42 hours from the start of the
HDMTX by 2 doses of 30 mg/m2 FA then 3mg/m2 FA at hours 54, 66 and 78
(total 69 mg/m2). This element of therapy was given once a week for 3
weeks then every 6 weeks for up to 75 weeks. The other group received
cranial irradiation and ITMTX. (12mg/m2 x5 over 2.5 weeks then every 12
weeks for 30 months) [27].
Ochs et al. examined 26 children who received HDMTX and 23 who received
cranial radiation. The aim of the study was to determine if different
protocols resulted in differences in cognition at 6 years post
diagnosis. One of the main findings, when comparing abilities at the
beginning of the treatment vs. 6 years later, was that both treatment
paradigms caused a decrease in the children’s full-scale IQ, VIQ, and
arithmetic and reading abilities. In addition, they found that 20% of
those receiving parenteral MTX had white matter hypodensity and 58%
abnormal electroencephalogram. The repeated inadequate FA rescue caused
neuropsychological damage similar to that caused by cranial irradiation
[3].
St Jude protocol Total Therapy XV
Patients in the low risk group received four courses of (approximately)
2.5gm/m2 MTX followed by a FA dose of 10mg/m2 at 44 hours, repeated four
times every 6 hours (total = 50mg/m2), and the standard risk/high risk
groups received (approximately) 5 gm/m2 MTX over 24 hours followed by a
FA dose of 15mg/m2 initiated at 42 hours and repeated four times every 6
hours (total = 75mg/m2). Age-dependant intrathecal triple therapy of
MTX, hydrocortisone and cytarabine was given with each infusion
[28].
Three analyses [29, 30, 31] have been published showing the
neuropsychological outcome of patients treated with the St Jude protocol
Total Therapy XV.
The study reported by Krull reported 218 children treated with low-risk
and standard/high risk arms. Executive functions were assessed, among
them cognitive flexibility, verbal fluency, WM, organization, and
problem-solving abilities. Additional cognitive abilities included IQ,
processing speed, attention, memory, and fine motor dexterity. These
children who were at least 5-years post diagnosis and older than 8 years
of age, showed their full-scale intelligence was within normal limits,
but scored significantly lower than the population mean on six measures
of executive function (flexibility, fluency, WM, organization/planning,
and abstract reasoning), as well on measures of perceptual reasoning,
attention, memory, and processing speed. Younger age at diagnosis and
higher MTX dose were associated with lower activation in areas related
to response inhibition, shifting of attention, language, executive
functions and decision-related processes. The study concluded that
“this study demonstrates that, at more than 5-years post diagnosis, a
substantial proportion of survivors experience neurocognitive
dysfunction” [29].
The 2012 study by Conklin tested 243 children with ALL, between the ages
of 1-18 years old, who underwent a very extensive neuropsychological
evaluation 120 weeks after the end of therapy, stratified by age, which
also included academic achievement tests. Their conclusion was that
“treatment with chemotherapy alone is not without risks”. The negative
cognitive effects seen in these children were: (1) when given more
chemotherapy, there were more detrimental cognitive outcomes in
processing speed and academic achievement, with parents reporting more
learning problems; and (2) younger age at the beginning of treatment
caused worse results in sustained attention and memory. The fact that
these children were assessed around 2 years old, after cessation of
treatment, in a group of children aged 1.02-18.73 years, raises
significant concerns. An important subgroup of children who, when
assessed, had not yet entered school, could potentially conceal
cognitive, learning, and real-life future problems [30].
Sherief et al. in their study compared 50 patients treated with this St.
Jude protocol to 50 who received a low-dose intrathecal methotrexate
protocol (LD-IT-MTX ONLY CCG1991 PROTOCOL). The children were
cognitively assessed using the Arabic version of Wechsler Intelligence
Scale test (WISC-III), looking at the full-scale IQ as well as all
subtests within the verbal and performance subtests. In the study each
subject was tested once in a cross sectional design at one to seven
years after completing therapy and the statistical design does not allow
any attempt to control for age at diagnosis or any other known risk
factors. Although both groups were negatively affected compared to
controls, the total XV protocol treated children were negatively
affected more than those receiving the LD-IT-MTX ONLY CCG1991 PROTOCOL.
Furthermore, there was a negative correlation between duration from end
of therapy to the verbal and performance abilities of these children.
Thus, the more time that passed from end of therapy to the assessment,
the worse the VIQ and PIQ became. In the first year after cessation of
treatment the average VIQ was 90, while seven years later it decreased
to 70 (the same trend was seen in PIQ, from 100 to 90). In terms of age
and gender, the younger the patients were at diagnosis and treatment,
the worse they performed specifically on the full scale IQ and PIQ.
Female patients seemed to be more effected than males with regard to
full-scale IQ, PIQ, and VIQ. It should be noted that this type of study
cannot demonstrate a deterioration in neurocognitive function over time
[31]
Not only was the FA rescue clearly inadequate, but it is relevant to
mention the study by Fellah et al. [32] who tested 165 of the
children reported by Krull [29] 6.7 years after diagnosis, and
reported high rate of leukoencephalopathy with both the low-risk and
high-risk protocols (67% and 86%, respectively).
THE UKALL X1 protocol [31]
This protocol compared different CNS prophylaxis protocols. Patients
received HDMTX and ITMTX (6 gm/m2 for children at least 4 years of age,
and 8 gm/m2 for infants) followed by FA rescue at hour 36; 15 mg/m2 FA
was given every 3 hours until 48 hours, then every 6 hours until the MTX
level was < 10-7 micromol/L (since we would expect the MTX
level to reach 10-7 micromol/L by 72 hours, the total FA dose would be
expected to be 120-135 mg/m2) [33].
Halsey [34] reported the full-scale VIQ and PIQ scores in 555
children on this protocol compared with 311 controls; 202 low-risk
children who received HDMTX and ITMTX were compared with 197 similar
patients treated with ITMTX; 79 high-risk patients who received HDMTX
and ITMTX were compared with 77 who received cranial irradiation. They
were tested at 5 months, 3 years, and 5 years from start of therapy. At
5 months, no significant difference was seen in IQ scores between the
randomised groups, but at 3 and 5 years all treatment groups showed a
significant reduction (p<0.002) in all three IQ scores of 3.6
and 7.3 points, respectively, compared with controls [34].
This contrasts with the report by Rodgers on a small number of patients
on this protocol tested >2 years after completing therapy.
They reported that patients did not exhibit the deficits witnessed in
previous cohorts and were performing at comparable levels on all
measures of attention [35]. However, when this study was included in
the mega-analysis by Iyer, who found diminished function in working
memory, attention /concentration, and information processing speed
[36].
The rescue dose we calculated to be between 120-135mg/m2 were much less
than the 225mg/m2 dose used after similar doses of MTX in a study with
no reported major toxicity [37].
Treatment protocol Israel Osteosarcoma Group – also see above
Bonda-Shkedi found that 11 osteosarcoma patients, aged 17-31 years, who
were examined at least 6 months after completing therapy (average time
from completion of therapy to examination was 6.18+ 4.07 years, personal
communication Bonda-Skedi) and had received 120-250 mg/m2 FA after each
treatment with 12-20gm/m2 MTX, had statistically significant (p=0.025)
worse results on 11 of 18 subtests of attention, visual perception,
verbal memory, VM, executive functioning, and comprehension compared
with the 12 who received adequate FA rescue (300-600mg/m2 FA).[21]
3. Studies of more than one protocol grouped together preventing
analysis of each protocols (Table 3)
In the NOPHO-ALL- 86 Protocol, standard-risk patients received 1gm/m2
MTX rescued at 24 and 36 hours by 30mg/m2 FA (total 60 mg/m2) as given
in the BFM-86 protocol. The high-risk NORPHO 1990 protocol patients
received 8 gm/m2 MTX rescued at 36 hours by 50mg/m2, followed by 6 doses
of 12mg/m2FA every 3 hours (total 112mg/m2) [39-41].
The NOPHO-ALL-1992 SR and intermediate-risk (IR) patients received
5gm/m2 MTX followed by 15mg/m2 FA at 42,48, and 52 hours, than every 6
hours until plasma MTX level was < 0.08 micromole/L (the total
dose was at least 45mg/m2) (personal communication Dr Arja Harila
–Saari). High-risk patients were given 8gm/m2 MTX rescued with 140mg/m2
FA, started at 36 hours.
Harila et al. [38] reported on neuropsychological outcomes seen in
64 survivors treated on several of these different protocols during
1972-1992, 20 of them without radiotherapy.
Nofstad et al. [39,40] and Reinfjell [41] looked at the
NOPHO-ALL-1992 protocol survivors. Some received 5gm/m2 and others 8
gm/m2 MTX, nevertheless, they were analysed together. The FA rescue
protocol was also different, preventing analysis of the significance of
the FA protocols.
The dose of FA rescue 45mg/m 2 given 42 hours after the start of MTX was
clearly inadequate, while 140 mg/m2 FA given after 8 gm/m2 HDMTX seems
to be a more realistic dose. Analysis of the cognitive damage with such
a mix of FA rescue doses was not possible.
4. Studies with significant serious methodical problems (Table 4)
ALL BFM 95 protocol [40-42]
Children < 18years received 4 courses of HD-MTX 5gm/m2 over 24
hours followed by 15mg/m2 FA at 42,48, and 54 hours (total 45mg/m2) [
42-44].
COALL 06-09 protocol
Children received eight courses of 1gm/m2 MTX followed by two doses of
15mg/m2 FA rescue starting at 48 hours (total dose 30mg/m2) (personal
communication Dr Gritta Janke).
Krapmann et al. [45] examined 57 children on protocol ALL BFM 95 and
nine children on protocol COALL-0609. The study did not differentiate
between patients treated with two very different protocols.
The dose of MTX given in the COALL 06-09 protocol has not been reported
to cause neurotoxicity, even without any FA rescue, and the rescue
regime would not be expected to have any effect when started after 48
hours [16], while the 57 children on protocol ALL BFM 95 received
inadequate FA rescue [16].
The findings as reported in the study by Krappmann et al. [45] of
“almost normal cognitive function during therapy” have several serious
methodical problems. The title of the article suggests that the authors
presented what they intended to show and not what they found. The report
does not differentiate between the 57 children who received protocol ALL
BFM 95 and the nine children on protocol COALL 06-09. Although
“Implications for follow up” appears in the title, the study examined
performance at diagnosis and after 21-31 weeks of chemotherapy.
Furthermore, the IQ measured at this early stage of follow up used the
German version of the K-ABC for kids (2.5 – 12 years) and adolescent
and adult version (the K-Tim in German), which are not standard tests
used to measure intelligence. Nonetheless, they showed a significant
reduction (p=0.035) especially in girls (p=0.004) and younger children
(p=0.001). Other neuropsychological parameters were not addressed except
for visual–motor function, known not to be affected in ALL patients,
and concentration [14], which was not affected. An examination
utilizing standard IQ tests with a verbal and nonverbal component was
not performed. The analysis does not report the cognitive damage by
comparison with a control group, but only compares the results at
diagnosis (T1) with end of reinduction therapy (T2), 21-31 weeks after
diagnosis when the children were 10 months older, which does not entitle
it to be called a longitudinal study.
While 2- and 5-years post treatment would have been an acceptable time
frame to look for cognitive difficulties, no report or publication of
the promised results of re-examination after maintenance therapy were
found. It would seem that following the publication of this article the
BFM group accepted the premise that since this protocol resulted in
“almost normal cognitive function during therapy”, and thus they
stopped doing any evaluations of neurotoxicity in subsequent studies.
Other groups such as the Italian AIEO group with a similar protocol
noted 5.8% acute neurotoxicity when 5gm/m2 MTX and intrathecal MTX was
rescued by a FA dose higher than the 45mg/m2 used by the BFM group. They
used the equivalent of 75mg/m2 FA (37.5mg/m2 l-folinic acid) [20].
Unfortunately, since this group combined with the BFM group study in the
AIEOP-BFM ALL 2000 study, their neurotoxicity data is no longer
reported. Not only has the BFM group decided that cognitive damage does
not exist after treatment with high dose MTX whatever the FA rescue dose
used, but they also convinced others to accept this fallacy. Some have
used “the same dosing and leucovorin rescue as reported by the BFM for
thousands of patients, without an increase in neurotoxicity or
neurocognitive dysfunction” [46]. Even more worrying is the fact
that the NOPHO 2008 protocol for all risk groups are ”rescued” with a 15
mg/m2 FA dose started 42 hours after 5gm/m2 MTX and repeated every 6
hours until MTX is less than 0.2 micromoles/l (personal communication
Dr. Arja Harila Saari). Thus, some may only receive a rescue dose of
30mg/m2 FA [9].
The Berlin-Frankfurt-Munster (BFM) Group has treated 6609 children
< 18 years of age in 82 centers in Germany, Austria, and
Switzerland in five consecutive trials during 1981-2000. Since the
ALL-BFM 86 study, all patients have received 4 courses of HD-MTX 5gm/m2
over24 hours. In the ALL-BFM 86 study, the FA rescue dose was originally
75mg/m2 at 36 hours and 15mg/m2 5 times every 3 hours then 4 doses every
6 hours (total 210mg/m2). This was reduced in 1988 to six 15mg/m2 doses
of FA from 36 hours every 6 hours (total 90mg/m2). Later the ALL-BFM- 90
study started FA 30mg/m2 at 42 hours, and 15mg at 48 and 54 hours (total
75mg/m2). The ALL-BFM 95 subsequently have used 15mg/m2 at 42, 48, and
54 hours (total 45mg/M2) [42-44].
Studies comparing different FA rescue protocols
The above study by Bonda-Shkedi et al. [21] seems to be the only
report, to date, to examine the cognitive function according to the
adequacy of the FA rescue dose.
Eleven of 18 subtests of full neuropsychological assessment showed
significantly favourable results (p=0.025) in the group who received the
higher dose of FA, compared to the low FA group in attention, WM, verbal
and visual memory, and in executive functions. It was however a
retrospective report of osteogenic survivors who were treated in three
centres who used different treatment protocols.
DISCUSSION
Different diseases will require different dose regimes of MTX. There is
clear evidence to support the use of a 24 hour infusion of least 6 g/m2
IV MTX [47] or 5g/ m2 with 12mg/m IT MTX [48] in the treatment
of acute lymphoblastic leukemia to achieve a 24 hour serum MTX level of
1 molar. This level was achieved in only some of the children when 5g/m2
IV MTX was given alone [48,49]. A study that attempted CNS
intensification /consolidation of four weekly courses of MIX(25mg/m
q6hrs x4 and triple intrathecal therapy weekly x6 and oral folinic acid
rescue) resulted in 21/239 patients developing a CNS relapse. In
Pediatric Brain Tumors patients a 24 hour CSF MTX of 1 molar was
achieved with 10g/m2 IV MTX or 5gm/m2 MTX following radiotherapy and in
Osteogenic Sarcoma patients adjusting MTX levels to 2x10-5 M at 24 hours
and 1x10-6 M at 48 hours followed by high dose FA rescue led to some of
the best results reported to date (high cure rate and absence of
neurotoxicity on neuropsychological testing) [50].
The appropriate dose of folinic acid for rescue will also depend on the
time interval from the start of the MTX to the start of the FA as well
as the dose of MTX being used. This can be critical. One study in which
2.5g/m2 MTX given over 24 hours had 16 cases of severe toxicity and 5
deaths when FA rescue was started after 48 hours reported no toxicity at
all, when the rescue was started after 36 hours [51]. We have shown
that it is safe to postpone the start of FA rescue until 36 hours from
the start of the MTX [16].
Based on the data presented in this review we can support the use of FA
rescue started 36 hours after the start of MTX
5g/m2 MTX FA 75mg/m2 +12mg/m2 q3hrs x12 (total 255mg/M2) [18,19]
8 g/m2 MTX FA 100 mg +12mg/m2 q3hs x6, then q6hr to 0.8x10-8 micromol /L
[17]
12-20g/m2 MTX FA 50mg/m2 x8 then 45mg/m2 x8q6hrs (total 760mg/m2)
[21,50]
33.3 g/m2 MTX FA 200 mg/2 +12mg/m2 q3hrs x6, then q6hrs to 0.8 x10-8
micromol/L[17] 33.6 g/m2 MTX FA 200 mg/2 +12mg/m2 q3hrs x6, then
q6hrs to 0.8 x10-8 micromol/L[23]
The neuropsychological studies reviewed here show a clear correlation
between inadequate FA rescue and cognitive damage. This analysis and the
results being generated by ongoing studies such as the Ponte di Legno
toxicity working group neurotoxicity analysis of the NOPHO-ALL- 2008
protocol and the neurotoxicity sub-study of the UKALL2011 protocol will,
we hope, result in an improvement in the way FA rescue is used after
high dose MTX.
DECLARATIONS
Funding: This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Conflicts of interest/Competing interests: The authors have no conflicts
of interest relevant to this article to disclose.
Acknowledgements: We would like to thank Ms. Debby Mir for expert
editorial help.
References
1. Bernard S, Etienne MC, Fischel JL, Formento P, Milano G (1991)
Critical factors for the reversal of methotrexate cytotoxicity by
folinic acid. Brit J Cancer 63;303-307. doi: 10.1038/bjc.1991.70
2. Sirotnak FM, Moccio DM, Dorick DM (1978) Optimization of high-dose
methotrexate with leucovorin rescue therapy in the L1210 leukemia and
sarcoma 180 murine tumor models. Cancer Res. 38:345-353.
3. Ochs J, Mulhern R, Fairclogh D, et al. (1991) Comparison of
neuropsychologic functioning and clinical indicators of neurotoxicity in
long-term survivors of childhood leukemia given cranial radiation or
parenteral methotrexate: a prospective study. J Clin Oncol. 9:145-151.
doi: 10.1200/JCO.1991.9.1.145
4. McAllister LD, Doolittle ND, Guastandisegni PE, et al. (2000)
Cognitive outcome and long term follow - up after enhanced chemotherapy
delivery for primary central nervous system lymphoma. Neurosurgery
46;51-60.
5. Cohen IJ (2007) Prevention of high-dose-methotrexate neurotoxicity by
adequate folinic acid rescue is possible even after central nervous
system irradiation. Med Hypotheses. 68:1147-1153. doi:
10.1016/j.mehy.2006.04.074
6. Bowman GP, Goodyear MDE, Levine MN, Russell R, Archibald SD, Young
JEM.(1990) Modulation of the antitumor effect of methotrexate by low
doseleucovorin in squamous cell head and neck cancer:a randomized
placebo controlled clinical trial J Clin Oncol 8:203-8.
7. Cohen IJ (2003) Progression of osteosarcoma after high dose
methotrexate:Over rescue by folinic acid Ped Hematol and Oncol
20:579-581.
8. Cohen IJ (2008) The importance of adequate methotrexate and adequate
folinic acid rescue in the treatment of primary brain lymphoma. J
Neurooncol. 140: 757. doi: 10.1007/s11060-018-2999-x
9. Cohen IJ (2013) Challenging the relevance of folinic acid over rescue
after high dose methotrexate (HDMTX). Medical Hypothesis. 81;942-947.
10. Cohen IJ (2021) Folinic acid over rescue of high dose Methotrexate:
how problematic citations conserve discredited concepts. Med Hypotheses.
146;110467.
11. Cohen IJ (2017) Neurotoxicity after high -dose methotrexate (MTX) is
adequately explained by insufficient folinic acid rescue. Cancer
Chemother Pharmacol. 79:1057-1065. doi: 10.1007/s00280-017-3304-y
12. Larsen EC, Devidas M, Chen S, et al. (2016) Dexamethasone and
High-Dose Methotrexate Improve Outcome for Children and Young Adults
With High-Risk B-Acute Lymphoblastic Leukemia: A Report From Children’s
Oncology Group Study AALL0232. J Clin Oncol. 34:3280-2388. doi:
10.1200/JCO.2015.62.4544
13. Hardy KA, Embry L Kairalla JA, et al. (2017) Neurocognitive
Functioning of Children Treated for High-Risk B-Acute Lymphoblastic
Leukemia Randomly Assigned to Different Methotrexate and Corticosteroid
Treatment Strategies: A Report From the Children’s Oncology Group. J
Clin Oncol. 35:2700-2707. doi: 10.1200/JCO.2016.71.7587
14. Peterson CC, Johnson CE, Ramirez LY, et al. (2008) A meta-analysis
of the neuropsychological sequelae of chemotherapy-only treatment for
pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer. 51:99-104.
doi: 10.1002/pbc.21544
15. Ackland SP, Schilky RL (1987) High-dose methotrexate: a critical
reappraisal. J Clin Oncol. 5:2017-2031. doi: 10.1200/JCO.1987.5.12.2017
16. Cohen IJ, Wolff JE (2014) How long can folinic acid rescue be
delayed after high-dose methotrexate without toxicity? Pediatr Blood
Cancer. 61:7-10. doi: 10.1002/pbc.24770.
17. Spiegler BJ, Kennedy K, Maze R, et al. (2006) Comparison of
long-term neurocognitive outcomes in young children with acute
lymphoblastic leukemia treated with cranial radiation or high-dose or
very high-dose intravenous methotrexate. J Clin Oncol. 24;3858-3864.
doi: 10.1200/JCO.2006.05.9055. Erratum in: J Clin Oncol. 2006 Nov
10;24(32):5181.
18. Kingma A, Van Dommelen RI, Mooyart EL, et al. (2002) No major
cognitive impairment in young children with acute lymphoblastic leukemia
using chemotherapy only: a prospective longitudinal study. J Pediatr
Hematol Oncol. 24;106-114. doi: 10.1097/00043426-200202000-00010
19. Kingma A,Van Dommelen RI,Mooyart EL, et al. (2001) Slight cognitive
impairment and magnetic resonance imaging abnormalities but normal
school levels in children treated with acute lymphoblastic leukemia with
chemotherapy only. J Paediatr. 139:413-420. doi: 10.1067/mpd.2001.117066
20. LoNigro L, DiCatalgo A, Schiliro G (2000) Acute neurotoxicity in
children with B-lineage acute lymphoblastic leukemia (B-ALL) treated
with intermediate risk protocols. Med Pediatr Oncol. 35;449-455. doi:
10.1002/1096-911x(20001101)35:5<449::aid-mpo2>3.0.co;2-x
21. Bonda-Skedi E, Weyl-Ben Harush M, Kaplinsky C, et al (2013) The
correlation between dose of folinic acid neurotoxicity in children and
adolescents treated for osteosarcoma with high dose methotrexate
(HDMTX):a neuropsychological and psychosocial study. J Pediatr Hematol
Oncol. 35;271-275. doi: 10.1097/MPH.0b013e31828c2da1
22. Reaman GH, Sposto R,Sensel MG, Lange B et.al. (1999) Treatment
outcome and prognostic factors for infants with acute lymphoblastic
leukemia treated on two consecutive trials of the Children’s Cancer
Group. J Clin Oncol. 17:445-455. doi: 10.1200/JCO.1999.17.2.445
23. Kaleita T A, Reaman GH, MacLean WE, Sather HN, Whitt JK (1999)
Neurodevelopmental outcome of infants with acute lymphoblastic leukemia,
A Children’s Cancer Group Report. Cancer. 85:1859-6521. doi:
10.1002/(sici)1097-0142(19990415)85:8<1859::aid-cncr28>3.0.co;2-2
24. Duffner PK, Armstrong FD, Chen L, et al. (2014) Neurocognitive and
neuroradiologic central nervous system late effects in children treated
on Pediatric Oncology Group (POG) P9605 (standard risk) and P9201
(lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a
methotrexate consequence? A report from the Children’s Oncology Group. J
Pediatr Hematol Oncol. 36;8-15. doi: 10.1097/MPH.0000000000000000. PMID:
24345882
25. Cohen I J (2014) Inadequate folinic acid rescue after methotrexate
causing neurocognitive and neuroradiological central nervous system late
effects in children with acute lymphatic leukemia. J Pediatr Hematol
Oncol. 36;501. doi: 10.1097/MPH.0000000000000139
26. Cohen IJ (2017) Neurotoxicity after high-dose methotrexate (MTX) is
adequately explained by insufficient folinic acid rescue. Cancer
Chemother Pharmacol. 79:1057-1065. doi: 10.1007/s00280-017-3304-y
27. Abramowitch M, Ochs J, Pui C-H, et al. (1988) High-dose methotrexate
improves clinical outcome in children with acute lymphoblastic leukemia:
St. Jude Total Therapy Study X. Med Pediatr Oncol.16:297-303. doi:
10.1002/mpo.2950160502
28. Pui C-H, Campanad, Pei D et.al. ( 2009) Treating childhood acute
lymphoblastic leukemia without cranial irradiation. N Eng J Med
360:2370-2741
29. Krull KR, Cheung YT, Liu W, et al. (2016) Chemotherapy
Pharmacodynamics and Neuroimaging and Neurocognitive Outcomes in
Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia. J Clin
Oncol. 34: 2644-2653. doi: 10.1200/JCO.2015.65.4574
30. Conklin HM, Krull KR, Reddick WE, Pei D, Cheng C, Pui CH (2012)
Cognitive outcomes following contemporary treatment without cranial
irradiation for childhood acute lymphoblastic leukemia. J Natl Cancer
Inst. 104:1386-1395. doi: 10.1093/jnci/djs344
31. Sherief LM, Sanad R, El Hadad A, et al. (2018) A Cross-sectional
Study of Two Chemotherapy Protocols on Long Term Neurocognitive
Functions in Egyptian Children Surviving Acute Lymphoblastic Leukemia.
Curr Pediatr Rev. 14:253-260. doi: 10.2174/1573396314666181031134919
32. Fellah S, Cheug YT, Scoggins MA, et al. (2019) Brain Activity
Associated With Attention Deficits Following Chemotherapy for Childhood
Acute Lymphoblastic Leukemia. J Natl Cancer Inst. 111:201-209. doi:
10.1093/jnci/djy089
33. Hann I, Vora A, Harrison G, Harrison C, Eden O, Hill F, Gibson B,
Richards S; UK Medical Research Council’s Working Party on Childhood
Leukaemia (2001) Determinants of outcome after intensified therapy of
childhood lymphoblastic leukaemia: results from Medical Research Council
United Kingdom acute lymphoblastic leukaemia XI protocol. Br J Haematol.
113:103-114. doi: 10.1046/j.1365-2141.2001.02668.x. Erratum in: Br J
Haematol 2001 Jun;113(3):844. Erratum in: Br J Haematol 2001
Sep;114(3):738.
34. Halsey C, Buck G, Richards S, Vargha-Khadem F, Hill F, Gibson B
(2011 The impact of therapy for childhood acute lymphoblastic leukaemia
on intelligence quotients; results of the risk-stratified randomized
central nervous system treatment trial MRC UKALL XI. J Hematol Oncol.
4:42. doi: 10.1186/1756-8722-4-42
35. Rodgers J, Marckus R, Kearns P, Windebank K (2003) Attentional
ability among survivors of leukaemia treated without cranial
irradiation. Arch Dis Child. 88:147-150. doi: 10.1136/adc.88.2.147
36. Iyer NS, Balsamo LM, Bracken MB, Kadan-Lottick NS (2015)
Chemotherapy-only treatment effects on long-term neurocognitive
functioning in childhood ALL survivors: a review and meta-analysis.
Blood. 126:346-353. doi: 10.1182/blood-2015-02-627414
37. Borsi JD, Wesenberg F, Stockland T, Moe PJ (1991) How much is too
much? Folinic acid rescue dose in children with acute lymphoblastic
leukaemia. Eur J Cancer. 27:1006-9. doi: 10.1016/0277-5379(91)90269-j
38. Harila MJ, Winqvist S, Lanning M, Bloigu R, Harila-Saari AH (2009)
Progressive neurocognitive impairment in young adult survivors of
childhood acute lymphoblastic leukemia. Pediatr Blood Cancer.
53;156-161. doi: 10.1002/pbc.21992
39. Lofstad GE, Reinfjell T, Hestad K, Desth TH (2009) Cognitive outcome
in children and adolescents treated for acute lymphoblastic leukaemia
with chemotherapy only. Acta Paediatr. 98:180-186. doi:
10.1111/j.1651-2227.2008.01055.x
40. Lofstad GE, Reinfjell T, Weider S, Diseth TH, Hestad K (2019)
Neurocognitive Outcome and Compensating Possibilities in Children and
Adolescents Treated for Acute Lymphoblastic Leukemia With Chemotherapy
Only. Front Psychol. 10:1027. doi:10.3389/fpsyg 2019.01027
41. Reinfjell T, Lofstad GE, Veenstra M, Vikan A, Diseth TH (2007)
Health-related quality of life and intellectual functioning in children
in remission from acute lymphoblastic leukaemia. Acta Paediatr.
96:1280-5. doi: 10.1111/j.1651-2227.2007.00383.x
42. Moricke A, Zimmermann M, Reiter A, et al. (2010) Long-term results
of five consecutive trials in childhood acute lymphoblastic leukemia
performed by the ALL-BFM study group from 1981 to 2000. Leukemia.
24:265-284. doi: 10.1038/leu.2009.257
43. Reiter A,Schrae S, Ludwig W-D, et al. (1994) Chemotherapy in 998
unselected childhood acute lymphoblastic leukemia patients. Results and
conclusions of the multicenter trial ALL-BFM 86. Blood. 84:3122-33
44. Reiter A, Schrappe M, Tiemann M, et al. (1999) Improved treatment
results in childhood B-cell neoplasms with tailored intensification of
therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM
90. Blood. 94:3294-306.
45. Krappmann P, Paulides M, Stöhr W, et al. (2007) Almost normal
cognitive function in patients during therapy for childhood acute
lymphoblastic leukemia without cranial irradiation according to ALL-BFM
95 and COALL 06-97 protocols: results of an Austrian-German multicenter
longitudinal study and implications for follow-up. Pediatr Hematol
Oncol. 24:101-109. doi: 10.1080/08880010601123281
46. Hardy KK, Embry LM, Kairalla JA, et.al. (2017) Reply to I.J. Cohen.
J Clin Oncol. 35:3989-3990. doi: 10.1200/JCO.2017.75.7252
47. Borsi JD, Moe PJ. (1987) A comparative study of the pharmacokinetics
of methotrexate in the dose range of 0-5g/m2 to 33.6g/m2 in children
with acute lymphoblastic leukemia. Cancer 6 0:5-13.
48. Milano G, Thyss A, Serre Debeauvais F,et.al.(1990) CSF levels for
children with acute lymphoblastic leukemia treated with 5g/m2
methotrexate .A study from the EORTC Childrens Leukemia Cooperative
group Eur J Cancer 4:492-495.
49.Millot F, Rubie H, Mazingue F, Mechinaud F, and Thyss
A.(1994)Cerebrospinal fluid drug levels of leukemic children receiving
intravenous 5g/m2 methotrexate. Leukemia and Lymphoma 14:141-144.
50 Shkalim-Zemer V,Toladano H,Ash S et al.(2005) Highly effective
reduced toxicity dose-intensive pilot protocol for non- metastatic limb
osteosarcoma (SCOS 89)Cancer Chemotherapy Pharmocology 76:909-916.
51. Buendia MTA, Lozano JM, Saurez VGE , Saavedra G,Guevera G.(2008) The
impact of acute lymphatic leuhkemia treatment on the central nervous
system results in Bogata Colombia. J Peadiatr Hematol Oncol 30:643-50.
Table headings
Table 1 Studies with adequate folinic acid rescue without cognitive
deterioration.
Table 2. Studies with inadequate folinic acid rescue and cognitive
deterioration.
Table 3 Studies with several protocols with differences in folinic acid
adequacy analyzed
together preventing analysis of results.
Table 4 Studies with significant serious methodical problems.