Medical and Pediatric Oncology 32:216–218 (1999)
POSITION PAPER
‘‘CNS-Friendly’’ Chemoradiotherapy in Pediatric Neuro-oncology
P.N. Plowman, MA, MD, FRCP, FRCR*
Key words: brain tumors; childhood cancer; radioprotection; brain damage
I read with interest the supplement devoted to the
issues raised in the Fourth International Conference on
long-term complications of treatment of cancer in chil-
dren [1]. The first two review articles were aimed at the
long-term sequelae of radiotherapy and chemotherapy in
the treatment of CNS tumors, and I would like to com-
ment and provoke thought on these matters.
Hopewell stresses the high dependence of CNS toler-
ance on daily dose fraction size [1]. Although the data he
cites specifically applies to the endpoint of necrosis,
there are data to support this high dependence for lesser
endpoints, such as neuropsychological sequelae. Thus,
children receiving cranial radiation prophylaxis in the
1970s to 2,400 cGy in 8 × 300 cGy fractions suffered
more neuropsychological sequelae than those receiving
this total dose in 12–15 fractions of 200 cGy daily frac-
tions or less (L. Janoun, personal communication).
Bleyer stresses the synergistic morbidity to the normal
nervous system of chemotherapy and radiotherapy and
uses cisplatin as an example [1]. Other data confirm this
potentially dangerous association with regard to normal
tissue morbidity [2]. Platinum-based chemotherapy is
critical to the modern successful chemotherapy results in
several CNS tumors that also require radiotherapy
(sometimes whole neuraxis radiotherapy): germ cells tu-
mors, medulloblastoma/PNET, and pineoblastoma spring
immediately to mind.
Previous authors have reported the increased likeli-
hood of sensorineuronal hearing loss when both cisplat-
in-based chemotherapy and radiotherapy encompassing
the middle ear are used in conjunction [3–5]. Some au-
thors concluded that radiotherapy given first increased
the likelihood (as Bleyer illustrates for methotrexate/
radiation interactions), but our own data did not suggest
that the order of administration mattered greatly [6]. We
further suggested that the substitution of carboplatin for
cisplatin in these circumstances would be the ‘‘CNS-
friendly’’ action to take. We also drew radiotherapists’
attention to the greater possibilities of screening the inner
ear from radiation portals. From this center, Vija-
yaraghaven et al. [7] reported the same comorbidity, with
regard to an enhanced chance of myelitis and dementia,
© 1999 Wiley-Liss, Inc.
when cisplatin-based chemotherapy is used in conjunc-
tion with CNS radiotherapy. We have recently extended
these observations in high-risk patients treated on a syn-
chronous protocol: 12 patients received combination cis-
platin/CNS radiation and 4 developed unexpected neuro-
toxicity, 3 with early onset of dementia (of varying se-
verity), and 1 with a Brown-Sequard syndrome. None of
the 13 patients receiving carboplatin/CNS radiation (al-
beit on shorter follow-up) have developed CNS toxicity
[8].
We have subsequently taken the research data that
both Hopewell and Bleyer reviewed and incorporated it
into clinical practice; I believe these treatment protocols
are of interest to clinicians concerned about the long-
term sequelae to which Dennis et al. and Mulhern et al.
address in their contributions to the supplement [1]. First,
we demonstrated that carboplatin is an active agent in
CNS germ cell tumors and medulloblastoma/PNET [9]
and then devised a ‘‘CNS-friendly’’ chemotherapy regi-
men omitting potent sensitisers to radiation [10]. Sec-
ondly, we took the CNS radiobiological studies such as
those reviewed by Hopewell in the supplement and dis-
missed the classic shrinking field radiotherapy technique
in favor of a differential daily dose (DDD) neuraxis/
primary tumor site technique—a CNS-friendly radio-
therapy method to complement the CNS-friendly chemo-
therapy regimen [11,12]. We have recently reported good
results of these methods in treating CNS germ cell tu-
mors [13].
We were criticized for dropping the daily dose for
medulloblastoma neuraxis radiotherapy and our critics
expected a higher rate of relapse within the neuraxis
[14–16]. Bates and Williams [15] used linear quadratic
modeling to compare the predicted isoeffective doses as
a function of the a/b ratio for normal tissue and tumor.
Department of Haemotology and Oncology, The Hospital for Sick
Children, London, England, and Department of Clinical Oncology, St.
Bartholomew’s Hospital, London, England
*Correspondence to: Dr. P.N. Plowman, St. Bartholomew’s Hospital,
London E.C.1, United Kingdom.
Received 6 August 1998; Accepted 8 September 1998

Fig. 1. Sagittal T1 MRI of spine in a
child with spinal metastasis of medullo-
blastoma. Left: Before neuraxis radio-
therapy. Right: After neuraxis radio-
therapy to 3,000 cGy, during which the
daily fraction size to the spine was 125
cGy/day. The ‘‘drop-metastasis’’ has
disappeared during the radiotherapy. (A
subsequent radiation boost was deliv-
ered to this site, after the right panel
scan).
Their modeling led them to believe that there would be a
reduction in the neural toxicity but a worsening in tumor
control rates, when our DDD method substituted the clas-
sic shrinking field technique. Wheldon et al. [16] used
more lengthy mathematical modeling to lead to their con-
clusion that DDD methodology might be adequate for
slowly growing tumors, but that for others the therapeutic
efficacy would be compromised. In fact, we have evi-
dence of good response of medulloblastoma to less than
conventional dose fractions (Fig. 1) and the in vitro ra-
diobiological studies of Deacon et al. [17] in the homolo-
gous tumor: neuroblastoma (demonstrating that there
was no shoulder on the single-cell survival curves for
radiation damage) may well be relevant here. Clearly,
there is a need for a larger trial but this has not caught the
enthusiasm of practitioners in the U.K.
The lack of publications on stereotactic radiosurgery
in the pediatric neuro-oncology literature and the lack of
publications on neuroprotectors are two other aspects
that need to be addressed in the next decade. Stereotactic
radiotherapy practiced as single fraction obliterative
therapy or, using the relocatable frame and fractionation
[18], allow a very much more ‘‘concentrated’’ dose de-
livery of radiation. This must have important uses in
pediatric neuro-oncology and we are using it more and
more for boost therapy for low-grade tumors, sometimes
for a persisting active (PET-positive) tumor nidus after
therapy with surgery and conventional radiation and
sometimes in primary therapy [19]. If we could establish
that CNS-friendly chemotherapy was effective for neur-
axis prophylaxis, then we might be able to deliver pro-
phylactic therapy to the whole neuraxis by chemotherapy
and focused radiotherapy to the higher-risk primary tu-
mor. One problem with this approach is that the neuraxis
blood-brain barrier may be more intact than in the region
of the primary tumor, whatever its type. This issue has
Chemoradiotherapy for CNS Tumors 217
recently been reviewed by us [13].We also recently re-
ported some integrity of the blood-brain barrier in CNS
germ cell tumor patients, certainly in so far as HCG is
concerned (although, interestingly, less than predicted
from the systemic germ cell data) [20].Unfortunately, we
ran into trouble with too great a reliance on primary
chemotherapy in infant medulloblastoma [21], although
the experience of others is more positive.
Hopewell mentions the data on neuroprotectors.
While our colleagues in neurology are actively research-
ing neuroprotectors [22], neuro-oncologists may be lag-
ging behind. Hopewell [1] refers to a trial with lack of
effect of indomethacin and Bleyer [1] reviews the long-
known radioprotective potential of WR2721 (amifos-
tine), although I personally cannot see this agent being
routinely used intrathecally and/or intraventricularly in
clinical practice. I did not wholly agree with the reason-
ing that it might be a chemoprotector in conjunction with
alkylating agents. Some sulphydryl-containing agents, if
delivered with radiation (as for example mesna cover for
high-dose cyclophosphamide at the time of total body
irradiation) could be counterproductive [23].
In cooperation with Hopewell, we have recently had
more promising results using the orally active gamma-
linoleic acid [24]. This interesting new approach to nor-
mal tissue dose modulation needs to be put into clinical
trials. We have started such a study in the treatment of
arteriovenous malformations with single fraction radio-
surgery. This is an ideal situation for testing a protector
of CNS radiation sequelae—we argue, as the brain is
being subjected to high-single-dose fraction therapy and
the risks of complications are known.
In summary, there is much that can be done to explore
the reduction in late morbidity from CNS chemoradio-
therapy and it is now time to build on the known data in
new CNS-friendly clinical directions.
218 Plowman
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