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 theissues raised in the Fourth International Conference onlong-term complications of treatment of cancer in chil-dren [1]. The first two review articles were aimed at thelong-term sequelae of radiotherapy and chemotherapy inthe 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 hecites specifically applies to the endpoint of necrosis,there are data to support this high dependence for lesserendpoints, such as neuropsychological sequelae. Thus,children receiving cranial radiation prophylaxis in the1970s to 2,400 cGy in 8 × 300 cGy fractions sufferedmore neuropsychological sequelae than those receivingthis 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 normalnervous system of chemotherapy and radiotherapy anduses cisplatin as an example [1]. Other data confirm thispotentially dangerous association with regard to normaltissue morbidity [2]. Platinum-based chemotherapy iscritical to the modern successful chemotherapy results inseveral CNS tumors that also require radiotherapy(sometimes whole neuraxis radiotherapy): germ cells tu-mors, medulloblastoma/PNET, and pineoblastoma springimmediately to mind.

Previous authors have reported the increased likeli-hood of sensorineuronal hearing loss when both cisplat-in-based chemotherapy and radiotherapy encompassingthe middle ear are used in conjunction [3–5]. Some au-thors concluded that radiotherapy given first increasedthe likelihood (as Bleyer illustrates for methotrexate/radiation interactions), but our own data did not suggestthat the order of administration mattered greatly [6]. Wefurther suggested that the substitution of carboplatin forcisplatin in these circumstances would be the ‘‘CNS-friendly’’ action to take. We also drew radiotherapists’attention to the greater possibilities of screening the innerear from radiation portals. From this center, Vija-yaraghaven et al. [7] reported the same comorbidity, withregard to an enhanced chance of myelitis and dementia,

when cisplatin-based chemotherapy is used in conjunc-tion with CNS radiotherapy. We have recently extendedthese 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 ofthe 13 patients receiving carboplatin/CNS radiation (al-beit on shorter follow-up) have developed CNS toxicity[8].

We have subsequently taken the research data thatboth Hopewell and Bleyer reviewed and incorporated itinto clinical practice; I believe these treatment protocolsare 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 inCNS 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 asthose reviewed by Hopewell in the supplement and dis-missed the classic shrinking field radiotherapy techniquein 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 goodresults of these methods in treating CNS germ cell tu-mors [13].

We were criticized for dropping the daily dose formedulloblastoma neuraxis radiotherapy and our criticsexpected a higher rate of relapse within the neuraxis[14–16]. Bates and Williams [15] used linear quadraticmodeling to compare the predicted isoeffective doses asa function of the a/b ratio for normal tissue and tumor.

Department of Haemotology and Oncology, The Hospital for SickChildren, 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

Medical and Pediatric Oncology 32:216–218 (1999)

© 1999 Wiley-Liss, Inc.

Their modeling led them to believe that there would be areduction in the neural toxicity but a worsening in tumorcontrol rates, when our DDD method substituted the clas-sic shrinking field technique. Wheldon et al. [16] usedmore lengthy mathematical modeling to lead to their con-clusion that DDD methodology might be adequate forslowly growing tumors, but that for others the therapeuticefficacy would be compromised. In fact, we have evi-dence of good response of medulloblastoma to less thanconventional dose fractions (Fig. 1) and the in vitro ra-diobiological studies of Deacon et al. [17] in the homolo-gous tumor: neuroblastoma (demonstrating that therewas no shoulder on the single-cell survival curves forradiation damage) may well be relevant here. Clearly,there is a need for a larger trial but this has not caught theenthusiasm of practitioners in the U.K.

The lack of publications on stereotactic radiosurgeryin the pediatric neuro-oncology literature and the lack ofpublications on neuroprotectors are two other aspectsthat need to be addressed in the next decade. Stereotacticradiotherapy practiced as single fraction obliterativetherapy or, using the relocatable frame and fractionation[18], allow a very much more ‘‘concentrated’’ dose de-livery of radiation. This must have important uses inpediatric neuro-oncology and we are using it more andmore for boost therapy for low-grade tumors, sometimesfor a persisting active (PET-positive) tumor nidus aftertherapy with surgery and conventional radiation andsometimes in primary therapy [19]. If we could establishthat CNS-friendly chemotherapy was effective for neur-axis prophylaxis, then we might be able to deliver pro-phylactic therapy to the whole neuraxis by chemotherapyand focused radiotherapy to the higher-risk primary tu-mor. One problem with this approach is that the neuraxisblood-brain barrier may be more intact than in the regionof the primary tumor, whatever its type. This issue has

recently been reviewed by us [13].We also recently re-ported some integrity of the blood-brain barrier in CNSgerm cell tumor patients, certainly in so far as HCG isconcerned (although, interestingly, less than predictedfrom the systemic germ cell data) [20].Unfortunately, weran into trouble with too great a reliance on primarychemotherapy in infant medulloblastoma [21], althoughthe 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 ofeffect of indomethacin and Bleyer [1] reviews the long-known radioprotective potential of WR2721 (amifos-tine), although I personally cannot see this agent beingroutinely used intrathecally and/or intraventricularly inclinical practice. I did not wholly agree with the reason-ing that it might be a chemoprotector in conjunction withalkylating agents. Some sulphydryl-containing agents, ifdelivered with radiation (as for example mesna cover forhigh-dose cyclophosphamide at the time of total bodyirradiation) could be counterproductive [23].

In cooperation with Hopewell, we have recently hadmore 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 clinicaltrials. We have started such a study in the treatment ofarteriovenous malformations with single fraction radio-surgery. This is an ideal situation for testing a protectorof CNS radiation sequelae—we argue, as the brain isbeing subjected to high-single-dose fraction therapy andthe risks of complications are known.

In summary, there is much that can be done to explorethe reduction in late morbidity from CNS chemoradio-therapy and it is now time to build on the known data innew CNS-friendly clinical directions.

Fig. 1. Sagittal T1 MRI of spine in achild with spinal metastasis of medullo-blastoma.Left: Before neuraxis radio-therapy. Right: After neuraxis radio-therapy to 3,000 cGy, during which thedaily fraction size to the spine was 125cGy/day. The ‘‘drop-metastasis’’ hasdisappeared during the radiotherapy. (Asubsequent radiation boost was deliv-ered to this site, after the right panelscan).

Chemoradiotherapy for CNS Tumors 217

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