Acute Leukemias - Republican Scientific Medical Library

a 21.8 · Conclusions 271
lapsed despite receiving IT methotrexate for 9 months
post transplant.
21.7 Toxicity of CNS Prophylaxis and Treatment
CNS-directed therapy involving single- or multipleagent
IT approaches, whether alone or particularly
when combined with cranial irradiation, can induce significant
toxicities [1]. The earliest understanding of the
effects of ALL and its treatments on the CNS was based
on autopsy studies. Price et al. [80, 81] described major
neuropathologic findings including subacute leukoencephalopathy,
mineralizing microangiopathy, and subacute
necrotizing leukomyelopathy. Multiple retrospective
outcome studies have been published concerning
cognitive, motor, and behavioral functioning of surviving
ALL patients. These include mostly patients that
were initially diagnosed and treated during their childhood.
Some of these effects may be attenuated with lower
doses of irradiation (e.g., 1800 rads) more frequently
used in recent trials [82, 83].
A recent study including 1612 consecutive pediatric
patients with newly diagnosed ALL treated on sequential
protocols at St. Jude Children’s Research Hospital
[84] between 1967 and 1988 analyzed the long-term effects
of cranial irradiation. With a median follow-up
duration of 15.9 years, the cumulative incidence of brain
tumors at 20 years was 1.39%. Twenty- two brain tumors
(10 high-grade gliomas, one low-grade glioma, and 11
meningiomas) were diagnosed in 21 patients after a
median latency of 12.6 years (high-grade gliomas,
9.1 years; meningiomas, 19 years). The use of dose-intensive
antimetabolite therapy together with cranial irradiation
also increased the risk of brain tumors [77].
The psychosocial outcomes of surviving cancer as a
child or adolescent are complex. Among 9535 young
adults who survived ALL [85], 17% had depressive, somatic,
or anxious symptoms. About 10% reported moderate
to extreme pain as a result of their cancer therapy,
and 13% expressed frequent fears related to their cancer
experience. The role CNS therapy had in the genesis of
these symptoms is difficult to estimate.
The Children’s Cancer Group also investigated the
impact of CNS treatment on scholastic performance of
593 adult survivors of ALL and compared them with
409 sibling controls [86]. Survivors treated with
2400 rads cranial irradiation were much more likely
to enter special education or learning disabled pro-
grams. In general, survivors were as likely to finish high
school and enter college as the controls, but those
treated with 2400 rads or treated before the age of
6 years were less likely to enter college than those
who received less amounts of radiation. There were
no gender differences in educational achievements. In
addition, moderate doses of radiation (2400 rads) are
associated with obesity, particularly in female patients
treated at a young age. In an analysis of 1765 adult survivors
of childhood ALL, female survivors who had received
cranial irradiation with > 2000 rads were two to
three times more likely to be obese in comparison with
siblings of childhood cancer survivors [87].
Although less well studied, significant toxicity has
also been reported with CNS prophylaxis in adults, including
neurologic changes, acute and chronic neurotoxicity,
decreased tolerance to systemic chemotherapy,
and infections associated with therapy-related immunosuppression.
The use of prophylactic cranial irradiation
in patients with small lung cancer has resulted in borderline
dementia in 25% of patients, moderate to
marked neuropsychologic deficits in 50%, and significant
emotional distress in 16% [88]. In adults with leukemia
and lymphoma, minor but significant neuropsychological
symptoms are also frequently detected.
Because spinal irradiation can result in growth retardation
[89], long-term neurologic changes and cardiac
dysfunction [90], it is now used less frequently. In
addition, as mentioned earlier, strategies using IT and
high-dose systemic chemotherapy have significantly reduced
the incidence of CNS leukemia.
21.8 Conclusions
Without CNS prophylaxis, CNS leukemia will occur in
approximately 30–50% of patients with ALL in CR. With
effective CNS prophylaxis, most adults with ALL will remain
free of CNS leukemia. During the last decades,
multiple approaches for CNS prophylaxis have been developed
with combination of IT, HDST, and cranial irradiation.
Excellent results can be achieved with regimens
that do not include radiation therapy. The exclusion of
radiotherapy decreases acute and long-term toxicities.
A prophylactic approach tailored to the risk of CNS
leukemia has proven valuable in childhood ALL, and in
at least one adult study. Further studies should focus on
defining risk groups for CNS leukemia, and designing
effective prophylaxis for each group. In view of the poor