Received: 21 March 2000 Abstract Radiation therapy (RT)still plays a major role in the man-agement of intracranial malignan-cies, together with surgical resectionand, more recently, chemotherapy.This is a review of the experiencewith fractionated external beam RT.In medulloblastomas, combined mo-dalities currently achieve a 5-yearsurvival in excess of 70% in low-risksubgroups and 40% in the subgroupsconsidered to be high risk. For thepast decade, the emphasis has beenon the quality of life in cured chil-dren. Recent advances have mainlyaimed at limiting the toxicity of the

“prophylactic” craniospinal irradia-tion by testing dose reductions andaltered fractionations. Technical in-novations have also greatly benefitedgliomas: modern techniques dealingwith 3D CT and MRI-based treat-ment combined with stereotactic po-sitioning of the patients, achieve ahigh degree of conformity that mightimprove both local control and long-term neurocognitive and growth se-quelae.

Keywords Brain tumors · Children ·Radiotherapy

Child’s Nerv Syst (2001) 17:121–133© Springer-Verlag 2001 R E V I E W PA P E R

Jean-Louis HabrandRenaud De Crevoisier

Radiation therapy in the management of childhood brain tumors

Introduction

Brain tumors represent the most common solid tumors inchildren and adolescents, i.e., approximately 20%. Com-pared with those in their adult counterparts, these tumorsare more frequently located in the posterior fossa (55%vs 10%) and those located in the hemispheres are lessfrequently situated in the superficial cortex [14]. More-over, the pathological types present major differences:the astrocytomas and the medulloblastomas are predomi-nant in patients below 15 years of age [45], comparedwith brain metastases and glioblastomas multiforme inadults.[12]. Meningiomas, acoustic neuromas, and pitui-tary adenomas are also extremely rare in this age group.

These differences indicate that despite the commonmajor places of surgical resection and radiation therapyin both groups, clear differences exist in terms of thera-peutic management and outcome. To mention a few.thereis the necessity of irradiating the whole central nervoussystem (CNS) in some major tumor types: medullo-blastomas and, according to stage and treatment policy,

ependymomas, germ cell tumors, and primitive neuro-ectodermal tumors (PNETs) in children. Also, there arepotentially severe, long-term sequelae related to neuro-cognitive and pituitary dysfunctions that predominate inchildren up to 5 years of age. Then, too, chemotherapy isof growing importance, particularly in the treatment ofinfants and children up to 3 years of age [32, 46,96].

The place of radiation therapy in past and current pro-tocols is summarized for the main CNS tumors seen inchildren and adolescents, and its major side effects arereviewed.

Medulloblastoma

Outcome of conventional approaches

The medulloblastoma, a PNET that affects the posteriorfossa, is seen in 20–26% of brain tumors in children. Al-though seen at various ages, it predominates in childrenof around 5 years. One of its salient features is its high

J.-L. Habrand (✉ ) · R. De CrevoisierPediatric Unit, Department of Radiation Oncology, Institut Gustave Roussy, 39 rue C. Desmoulins, 94805 Villejuif Cedex, Francee-mail: habrand@igr.frFax: +33-1-42115253

propensity for metastasizing within the CNS. At the timeof presentation, 5–30% have been reported and 5–10%during the course of the disease [67, 91, 142].

Surgical resection alone, as performed by Cushing inthe 1930s, has no curative intent (1/63 children alive at 3 years) [13]. Medulloblastomas are clearly radiosensi-tive, with 18–44% of cells surviving a dose of 2 Gy inradiobiological experiments [99]. Nonetheless, the ad-junction of local radiation did not substantially improvethe outcome, as reported by the Toronto Group in themid-1950s [76]. Only the introduction of a systematicextended coverage of the CNS dramatically improvedthe survival in an early series to 8 out of 15. Consistentdata of multiple groups indicated a 27–40% 5-year-survival (S) with non-documented benefits beyond thisfollow-up [10, 67]. In the mid 1970s, most authors rec-ommended a standard 35–40 Gy as a “prophylactic”dose to the CNS, plus a boost up to 50–55 Gy in the pos-terior fossa [71, 140]. Together with radiation dose andvolume (22%), the quality of surgical resection (44%)was found to be a prognostic indicator with a 10-yearlife expectancy in Bloom’s series [15]. Some authorshave found a negative impact of a ventriculoperitonealshunt owing to increased systemic failures [80]. Thenegative impact of incomplete resection has been recent-ly confirmed in a Children’s Cancer Study Group study(CCSG) [156].

Technical considerations

Several series have emphasized that the posterior fossa isthe most critical site of failure with 75% in the Castro-Vita series [21] and 53% in the Jereb series [78]. Thisauthor also emphasized the importance of adequate cov-erage of the anterior cerebral fossa, especially at the level of the cribriform plate, an area frequently shieldedinadvertently by the ocular blocks. The national panelsof experts that nowadays act as quality-control groupsare paying particular attention to the doses delivered inthese anatomical structures [20, 105]. As the delivery ofa uniform dose to the entire CNS is particularly chal-lenging and implies multiple carefully matched beams(sometimes of different qualities, like photons and elec-trons), detailed dosimetric information needs to be col-lected for every patient. Our group recently analyzed allchildren cases that had had CNS failure following exten-sive radiation as a function of dose uniformity [9]. Noclear dose-affected relationship was found at the site ofmost failures, except at the cribriform plate. These datasuggest that failures due to technical limitations can beminimal in large centers, which can depend on a greaterdegree of collective experience.

Recently, several authors have pointed out the possi-bility of delivering the boost to the posteria fossa using a stereotactic technique. The advantage would be to de-

liver a high dose in a single fraction with elegant sparingof anatomical structures located a few millimeters awayfrom the target volume [155]. Such a technique couldalso be applied to small recurrences located in the post-eria fossa (PF) and treated with a high dose with similaradvantages. The increasing number of early detections ofrecurrences using serial surveillance imaging could in-crease the number of patients able to benefit from suchtechniques and therefore be potentially curable [137].Conformal irradiation delivered with conventional frac-tionation is also gaining wide acceptance. For example,sparing of normal structures like the cochlea could beimproved [54]. Nonetheless, techniques that can sparepart of the PF will need further evaluation since it hasbeen established that failures within the PF arise in ap-proximately half of the cases outside the surgical bed[53].

Modern strategies [111]

Since the mid-1980s, ,the aims of most pilot studies andsubsequent multi-institutional studies have been:

1. To improve the possibility of survival

2. To improve the quality of life of children, especiallythe younger ones and those selected with favorable prog-nostic factors (low-risk groups: i.e., generally with totalor subtotal resection, and no leptomeningeal dissemina-tion) as opposed to unfavorable ones (high-risk groups:i.e., macroscopically incomplete resection and/or lepto-meningeal/systemic dissemination)

It is important to note that radiotherapeutical innova-tions, whether associated with chemotherapeutical pro-grams or not, have represented the cornerstone of thesenew approaches.

Mono-institutional experiences

Interesting studies have attempted to reduce the prophy-lactic dose to the brain and the spine. Brand [17] com-pared two historical series treated successively with“high” (i.e., 30–40 Gy to the spinal axis and 40–50 Gy tothe brain) and then “low” doses of radiation (25 Gy tothe entire CNS). “High-risk” patients experienced anoverall 39% survival versus 80% for “low-risk” patients(see definitions above). No statistical difference was in-troduced by the dose reduction in any of the subgroups.Levin et al. [93] reported an early series of reduced dose,i.e., 35 Gy to the brain and 25 Gy to the spine, combinedwith chemotherapy (procarbazine + hydroxyurea). Anexcellent 65% 5-year-survival was observed for “low-risk” patients, but a disappointing 25% for those consid-ered to be “high risk”.More recently, Packer reported anexcellent 86% 5-year progression-free survival (PFS) by

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a combination of low prophylactic dose (i.e., 23.4 Gy) ofradiation and chemotherapy [115]. A further decrease inthe prophylactic dose has been tested by the PhiladelphiaGroup in conjunction with multiagent chemotherapy[59]. Ten children below 5 years of age received 18 Gyprophylactic doses in the CNS + boost in the PF up to64.8–65.4 Gy. Six-year survival is 70±20%, but thisstudy should be examined with caution owing to thesmall number of accrued patients.

Altered fractionations have been advocated for thepast 15 years by many authors. Pure hyperfraction inwhich the dose per fraction is decreased (with little or notreatment acceleration) is generally favored. Radiobio-logical models (based on cultured cell lines and the irra-diation of weanling rats), along with preliminary clinicalexperiences, indicate that the long-term side effects ofradiation can be minimized if the dose per fraction islowered, given that the interfraction interval exceeds 6–8 h, to allow for the repair of cellular sublethal injuries[41, 65]. According to these models, tumor controlshould not be compromised by these approaches if theoverall treatment time is kept constant. Pure hyperfrac-tionation can be exploited:

1. To improve long term sequelae if total dose is notmodified compared with conventional fractionation

2. To improve tumor control (but with little or no im-provement in long-term side effects) if the total dose isincreased

The second approach (the increased total dose) has beenadvocated by Allen [4]. Among 23 children with PNETs,15 with a T3b and T4 non metastatic medulloblastomareceived 72 Gy to the posterior fossa and 36 Gy to therest of the CNS, using two daily fractions of 1 Gy each.Based on a popular mathematical representation of cellsurvival curves (i.e., the linear quadratic formalism thatassumes an alpha/beta value of 10 for tumor control andacute reactions, and of 1 for brain and spinal cord long-term tolerance), this altered fractionation might have in-duced a differential biological effectiveness between thetumor and the low-proliferating normal tissues that couldbe estimated respectively to 66 Gy and 24 Gy adminis-tered with a “conventional” fractionation (i.e., 2 Gy oncea day). With a median 78-month follow-up, 14/15 chil-dren are alive and well. As far as the first approach (nomodification in the total dose) is concerned, it has beenadvocated by Prados [121], who administered 24 Gy andlater on 30 Gy as CNS prophylaxis in 2 daily fractions of1 Gy each + boost to the PF. With a median 1.9-year fol-low-up, the rates of spinal failures were of 50% and12.5% according to the dose level, indicating that 24 Gyhyperfractionated is likely to be insufficient, even thoughin the “low risk” group. It should be pointed out that al-tered fractionation does not improve the acute toxicity,which has been reported as more severe, especially when

it is started after chemotherapy. On the other hand, spe-cial attention should be paid to the prolonged treatmentduration induced by the very low doses per fraction test-ed in “maximally” hyperfractionated regimens. Thiscould theoretically allow tumor repopulation beforecompletion of radiation and be related to early failures.One series has recently correlated treatment protractionbeyond 45 days with further failures [31]. Restriction ofirradiation has also been tested in infants and childrenbelow 3 years of age [96]. Promising studies indicatethat in this population a prolonged chemotherapy regi-men can delay the initiation of radiotherapy by 12–18months without compromising the final outcome. Fur-thermore, promising developments, including those ex-perienced by our own group, suggest that in this agegroup, high-dose chemotherapy followed by stem-cellrescue could substitute for the conventional “prophylac-tic” coverage of the whole CNS, and be replaced by fo-cal irradiation only [40].

Multi-institutional studies

Since 1975, the International Society of Pediatric Oncolo-gy (SIOP) has conducted two successive studies: SIOP I(1975–1979) tested in a randomized fashion the value ofchemotherapy associated with a surgical resection and ra-diation therapy [109, 146]: the children were elected toeither receive or not receive 8 cycles of vincristin, CCNU(1, (2-chloroethyl)-3-cyclohexyl-1-nitrosurea (= lomus-tine)) following a CNS irradiation of 30–35 Gy plus a 20 Gy boost to the PF. In 286 patients treated in 44 cen-ters in 15 countries, the 5-year disease-free survival wasstatistically proved to be no different whether chemother-apy was administered or not (56 vs 42%). Nonetheless,subgroups at high risk of local regional failures seemed tobenefit from the addition of chemotherapy (incompleteresection P≤0.007, brain-stem involvement P≤0.001).

Similarly, the Pediatric Oncology Group (POG) andthe CCSG have tested the value of a combination ofCCNU and prednisone in addition to conventional irradi-ation [44]. In 275 patients (179 medulloblastomas), astatistical difference only existed for subgroups with ad-vanced disease in the posterior fossa or the rest of theCNS (46 vs 0% DFS).

SIOP 2, opened between 1984 and 1989, addressedtwo issues in a double randomization [6]:

1. The value of “sandwich” chemotherapy placed be-tween surgery and radiotherapy and made up of an inten-sified chemotherapy regimen (procarbazine, CCNU,methotrexate, vincristine, prednisone) for 1 month

2. The feasibility of decreasing the prophylactic dose ofradiation from 35 to 25 Gy in the subgroup at “low risk.”The preliminary analysis showed that chemotherapy didnot clearly influence the outcome of any subset of pa-

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tients. Low-dose radiotherapy was accompanied by aslightly more unfavorable outcome compared with con-ventional doses of radiation, even when chemotherapywas associated with it.

Later, national and international groups designed differ-ent approaches to the question of whether the childrenwere classified in “low-” or “high”-risk groups.

In “low-risk” groups, POG-CCSG 863 compared a re-duced 23.4 Gy prophylactic dose in the CNS + PF boostwith the standard 36 Gy + PF boost without any addi-tional chemotherapy. An interim analysis showed a dra-matic adverse effect of low-dose radiation (p0.02), andso the study was interrupted [33]. A recent update seemsto indicate that in the long run, there seems to be no dif-ference between the outcomes for the two groups [148].The French Society of Pediatric Oncology (SFOP) hasjust completed a new randomized national study inwhich the “low-risk” group received systematically a 3-month postoperative chemotherapy, alternating the“eight-in-one” drugs with VP 16 and carboplatin, fol-lowed by a reduced prophylactic dose of radiation(CNS=25 Gy, PF=55 Gy). A recent update of the studyshows a promising 70% 3-year survival rate [37]. Theseresults are consistent with those of a close POG studydelaying the administration of chemotherapy at the timeof and after radiotherapy, which has achieved excellent86% and 79%, 3 and 5 year-progression-free survival(PFS) [115].

In “high-risk” groups there is general agreement thatthese patients deserve “conventional” doses of radiation(not less than 30–35 Gy prophylactic and 52–55 Gy inthe PF), combined with a polychemotherapy regimen[16, 156]. The timing still remains controversial, withsome groups advocating postoperative chemotherapy,followed by delayed radiation, and others advocating thereverse [85]. It is possible that protocols with radiothera-py longer than 3 months following surgery might in-crease the risk of early tumor progression. It has beenshown recently that in children below the age of 3 years,a residual primary of more than 1.5 cm2 and gross meta-static foci are strong adverse prognostic factors [156].

Gliomas

Ependymomas

Ependymomas account for approximately 10% of tumorsof the CNS in children [22, 77, 136]. Median age is 5 years, with cases frequently diagnosed between 1 and 2 years. Primary tumors in the spinal cord are also seen,but rarely before 10 years [154]. As far as intracranial-tumors are concerned, 60–75% are located in the PF[66]. According to histological criteria, four grades ofdifferentiation have been described.

Following surgical resection alone, 5-year-survival is in the order of 16% [132]. Adding radiotherapy to the whole CNS has shifted this figure up to 30–61% 5-year-PFS [55, 58, 90, 118, 136] and to 36–67% 5-year-S[13, 55, 58, 102, 118, 136, 150]. Chemotherapy hasshown limited efficacy [26], but has induced prolongedremission in selected recurrent cases [57]. The quality ofresection [127], pathological grade [55, 81], dose of radi-ation to the primary [58, 118], tumor site [98], and theage of the patient at the time of treatment [58] are prog-nostic factors that are not unanimously acknowledged.For example, in the CCG experience [127], in whichchildren received postoperative craniospinal radiationand, in a random fashion, chemotherapy, predictors ofPFS duration included only the completeness of surgicalresection confirmed radiologically (P≤10–4). A prelimi-nary experiment conducted by the POG has suggestedthat hyperfractionation to high dose could be followedby two-fold chances of cure compared with conventionalirradiation in subtotally resected children [84].

One of the most debatable issues for the radiation on-cologist is the place of prophylactic irradiation of thewhole, or part, of the CNS. All series have shown thatspinal metastases are seen in 8–13% of ependymomaslocated in the PF. These findings have motivated thecoverage of the entire CNS, or at least of the spinal axisin these tumor sites. Early detection of spinal seeding,using MRI in the initial work-up, is now routinely per-formed. Focal irradiation in patients with no evidence ofmetastases is again tested by several groups [56, 83, 129,134].

Astrocytomas

Astrocytomas represent 35% of all brain tumors [141].Most malignant varieties arise in the supratentorial area,unlike the benign ones, which are commonly seen in thecerebellar area. The outcome of malignant forms has abetter reputation than their adult counterparts, especiallyin children below 10–12 year of age [117]. This is proba-bly due to the larger number of anaplastic astrocytomasand smaller proportions of glioblastomas multiforme(GB). Overall, the rate of 5-year survival is around40–50% [38]. The outcome of GB remains as poor as inthe adult series and less than 20% [35]. Most authorsagree that low-grade astrocytomas that are completelyresected microscopically do not require further therapy.Postoperative irradiation of other cases remains standardpractice, especially in the inoperable deep-seated lesionsthat are more common in children than in adults. Fromthe adult experience, it is interesting to note that doses ofradiation in excess of 45 Gy do not seem to improve lo-cal control in incompletely resected forms [79].All these tumors are irradiated focally, i.e., the tumor bed+ a safety margin of 2–3 cm around it, although some

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authors have advocated the coverage of the entire CNSin oligodendroglioma of the PF, an entity extremely rarein children [112]. Modern techniques based on 3D CTand MRI (Fig. 1) virtual simulation allow multiple ar-rangements of coplanar and non-coplanar tailor-madebeams (Fig. 2) that can dramatically limit the dose re-ceived by the normal brain. The evaluation of rival treat-ment plans can nowadays be optimized using integraldose-volume histogram (DVHs) intercomparisons bothfor the target (Fig. 3) and for the surrounding anatomi-cal structures. In the future, more refined biological indi-ces evaluating normal tissue complication probabilities(NTCP) and tumor control probability (TCP) might behelpful.

Gliomas of the optic pathway

These represent 5% of all brain tumors and are essential-ly benign histologically (pilocytic astrocytomas). Theoverall very slow pace of the disease allows an initial

watch-and-see policy in the majority of cases. In the caseof tumor progression, various therapeutical approachescan be discussed: surgical resection of a tumor limited toone optic nerve with deteriorated vision [36], low-dosecontinuous chemotherapy, especially in younger chil-dren, [75] and radiotherapy, especially in cases of rapidvisual deterioration. Doses in the range of 40–50 Gy arerecommended [47, 152]. Extensive coverage of both op-tic nerves and chiasm was used before the introductionof modern imaging. Unfortunately, owing to the frequentassociation with type 1 neurofibromatosis, these patientswere also at higher risk of late radiation injuries [60].

Nowadays, several authors point out that target volume can be more economically focused on radiologi-cal abnormalities [30,97]. Following radiotherapy, a65–90% local control has been reported [5, 28, 30, 36,47, 106, 152]. Visual improvement can be expected inmore than half the cases [27, 70]. Re-irradiation of recur-rent disease with moderate doses has been reported to in-duce prolonged remission in rare cases [152].

Brain-stem gliomas

These comprise 15% of brain tumors. Benign forms,generally assessed on their radiological aspect, site, andclinical behavior represent a minority of them. A surgi-cal resection of the purely exophytic forms can be at-tempted and is facilitated by the use of the ultrasonicscalpel and neuronavigation [43]. In this group, Stroinkhas reported 10/11 children alive [143]. Unfortunately,the vast majority of brain-stem tumors present with atypical malignant evolution with rapidly progressivemultiple cranial-nerve palsies and, on imaging, a diffusehypodense aspect [1, 2, 101]. These forms are generallylethal within a year [42, 49, 64]: this has motivated manyinnovative pilot and multi-institutional studies that havetested chemotherapy, high-dose megatherapy, combinedchemoradiation, and radiotherapy alone with unconven-tional fractionations. As field failures represent 88% of

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Fig. 1 Digitally reconstructedradiograph produced in 3D vir-tual simulation of a base of theskull malignancy

Fig. 2 Beam’s eye view of anon-coplanar beam. The grosstumor volume is represented ingray and surrounded by the as-sumed microscopic extensions.The dotted line corresponds tothe beam’s aperture (the samepatient as in Fig. 1)

Fig. 3 Intercomparison between four different treatment plans fora brain stem tumor. The optimal one corresponds to 55 Gy distrib-uted uniformly in ≥95% of the target volume

the failures, inclusion of the whole brain is no longerrecommended. Pure hyperfractionation that allows theadministration of a higher tumor dose without excessivetoxicity has been largely tested with escalated doses bythe groups in North America. The dose per fractionranged generally between 1 and 1.26 Gy, administeredtwice a day. Tumor control has remained desperatelylow: a median of 9 months’ survival following 66 Gy[86]; 23% 2-year-survival after 70.2 Gy [50]; 14% 3-year survival after 72 Gy [113], 7% 2-year survivalfollowing 75.6 Gy [51]; and an 11% 3-year-survival after78 Gy [114]. It is interesting to note that radiation necro-sis has been documented at 75 Gy and above, includinglethal cases [52,113]; it is not surprising that an attemptto test the “intermediate” 70.2 Gy. dose level combinedwith cis platinum in a randomized fashion versus a con-ventional 54 Gy arm also failed to influence the outcomeof the disease [100]. There is definitely a need for differ-ent therapeutical approaches to be tested: for example,the new radiosensitizing agents such as topo isomerase Iinhibitors [88] or radiotherapeutic innovations like the Boron Neutron Capture Therapy [108].

Pineal tumors

Pineal tumors represent only 0.3–3% of pediatric braintumors. In addition to their rarity, their management iscomplicated by the diversity of the histological subtypesthat can be observed. Three major types can be individ-ualized: the germ-cell tumors (dysgerminomas, terato-mas, yolk sac tumors, choriocarcinomas, and mixedforms); the very rare parenchymal tumors (pineoblasto-mas and pineocytomas); and the gliomas. Radiosensitiv-ity is correlated to some extent with the pathology. Puredysgerminomas have a reputation of high sensitivity(but probably somewhat less that their gynecologicalcounterpart) unlike the other germ-cell subtypes that donot seem to differ dramatically from classical gliomas.Another salient feature of several of these tumors istheir propensity for giving multiple foci locoregionally(third ventricle, supra- and intrasellar areas) and some-times a leptomeningeal seeding. This risk has been esti-mated at between 8 and 23%, with dysgerminoma (sem-inoma) and pineoblastoma being in the upper range[95]. This has conditioned a complex therapeutic ap-proach based on “prophylactic” irradiation of the entireCNS [72] and/or chemotherapy [3, 7, 8, 29, 133]. Aswith medulloblastomas, surgical resection alone cannotbe considered as a curative measure of malignant le-sions. Furthermore, despite major technical advances, acomplete resection is rarely made possible. Until recent-ly, radiation therapy has remained the cornerstone ofmanagement. Until the 1980s, it was common practiceto test the radiosensitivity of an unbiopsied lesion by afirst course of radiation. Pure dysgerminoma was as-

sumed in the case of a good tumor response and the ra-diation program completed with whole CNS coverage ata low dose. If the response was poor, non-seminomatoussubtypes were assumed and high-dose focal radiationwas recommended [125]. Most children are currentlymanaged with an unequivocal diagnosis based on tumormarkers or histological specimens. Using radiation ther-apy alone, the outcome of pure dysgerminomas at 5years ranges between 70 and 100%. Several authors stilladvocate the use of whole CNS prophylaxis that reducesleptomeningeal metastases to less than 10% [72]. An-other approach is to irradiate, as a prophylactic measure,only those children with positive CSF or leptomeningealdissemination on the initial MRI [138]. Other groupsrecommend irradiation of the whole brain alone or theventricular system [139]. Combined chemoradiation isalso gaining wide acceptance and, in the majority ofchildren that are good responders to an initial poly-chemotherapy regimen, focal irradiation alone. Doses tothe primary extend from 30 to 40 Gy in pure dysge-minomas and up to 50–55 Gy in other germ-cell tumorsthat are more radioresistant. Where indicated, prophy-lactic CNS irradiation of dysgerminoma ranges between20 and 30 Gy.

Craniopharyngiomas

Craniopharyngiomas represent less than 10% of intracra-nial tumors in this age group, but half of the sellar tu-mors. Although they are histologically benign„locallytheir behavior is very aggressive. Exceptionally malig-nant variants have also been described. Their manage-ment is still controversial. Radical resection has beenrecommended for several decades as the mainstay oftreatment, but is followed by a 20–30% relapse rate anda high morbidity affecting mainly the visual and the en-docrinological status [69, 145]. On the other hand, par-tial resection is less toxic but at the cost of a 70% risk oflocal failure. These findings have stimulated the interestin a combination of less aggressive surgery and postop-erative irradiation, particularly in children who fail a pre-vious surgical resection. With this approach, local con-trol looks similar to that of radical resection with lesstoxicity [48, 62, 150, 153]. Nonetheless, recent radio-therapeutic series indicate that the optimal dose might beabove 55 Gy, fractionated [62, 123, 144]. At such doselevels, high-precision techniques (like fractionated ste-reotactic photons or protons) are preferable in order tospare close anatomical structures like the optic pathwayand the third ventricle [147]. Owing to the close proxim-ity of the optic pathway to the tumor volume, we wouldnot advocate the use of single fractions but of conven-tionally fractionated regimens.

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PNETs

With the exception of medulloblastomas, these are raretumors that can occur anywhere in the CNS. Followingthe initial description of a small round-cell neoplasm,various histological classifications have been proposed,generally based on the presence or absence of cellu-lar differentiation (pineoblastoma, medulloepithelioma,ependymoblastoma) [128]. These tumors seem to have incommon a particular aggressiveness that requires a com-bined approach based on surgery, radiation therapy, andchemotherapy. As most of them arise in the supratentori-um in very young children, some groups, including ourown, emphasize a prolonged chemotherapy regimen,completed by high-dose megatherapy. Nonetheless, radi-ation therapy remains mandatory in older children and incases of progressive disease. Focal irradiation in supra-tentorial sites and whole CNS coverage in infratentorialsites is generally recommended. Long-term results re-main poor, with ≤45% 3-year-event-free survival (EFS)[104]. PNETs of the pineal area (pineoblastomas) seemto fare better (61% 3-year-PFS) by combined chemother-apy and craniospinal radiation [74].

Radiation-induced toxicity and sequelae

It is estimated that the number of neurons cannot be ex-pended after the 6th month of fetal life. During the first 3 years of life and to some extent up to 6 years, cerebraldevelopment includes cellular and axonal hypertrophycombined with a multiplication of dendrits and interneu-ronal connections [34]. The myelinization process ismaximal until 2 years of age, but remains detectable upto puberty, and possibly even later. Demyelinizationrepresents the most striking microscopic alteration fol-lowing radiation and is responsible for white-matter ne-crosis. Pathogenesis is still unclear. It could be relatedto alterations of the microvasculature (affecting the en-dothelial cells), or of the oligodendrocytes that producemyelin. Two major clinical syndromes have been de-scribed following radiation, both in children and inadults:

1. Cerebral radionecrosis whose risk has been estimatedto 5% at 55 Gy fractionated, 15% at 60 Gy, and 20% at65 Gy [103].

2. Necrotizing leukoencephalopathy and mineralizingmicro-angiopathy [82, 119]; this should be suspected ifseizures, somnolence, motor deficits, and ataxia are pres-ent. Pathologically, multifocal white-matter necrosis canbe detected with loss of myelin sheath and oligodendro-cytes. In mineralizing microangiopathy, neocalcificationsare also detectable, especially in the basal ganglia. Ra-diologically, typical white-matter alterations are com-

monly reported in the irradiated volume, together withcerebral atrophy, ventricular dilatation, and sometimes,calcifications [24]. Clinical manifestations are not corre-lated with the intensity of radiological changes.

Neurological complications have been extensively docu-mented following CNS prophylaxis therapy in acutelymphoblastic leukemia (ALL). In this situation, the al-terations actually reflect the toxicity of a combination oflow-dose radiation (i.e., ≤24 Gy) delivered to the wholebrain with concomitant intrathecal and/or systemic che-motherapy (mainly methotrexate). Up to 45% of childrenwill develop complications within 1 year [25]. Solidbrain tumors treated at 45 Gy and more also developsimilar complications, including the so-called “somno-lence” phenomena and confusing neurological deficits[11]. The number of children affected by clinicallyasymptomatic complications has increased with the wideuse of MRI in the follow-up, as mentioned by Laitt et al.in ALL [87]: 9/35 irradiated children versus only 1/24 ina control group not irradiated. This included the earlydetection of radiation-associated second malignancies.Russo found late radiographic changes in over half thecases of medulloblastomas treated with hyperfraction-ation, but none with overt clinical symptoms [130].

Cognitive dysfunctions are also well documented fol-lowing radiation in youngsters. Most documented caseshave been reported following prophylactic brain irradia-tion of ALL and medulloblastomas [25, 27, 122, 126].The intensity of symptoms seems mainly correlated withthe age of the child at the time of irradiation [23], withthe total dose administered, with the volume of brain en-compassed, and possibly with the fractionation of thedose. Devastating deterioration has been reported in chil-dren up to 3 years of age following 35–40 Gy in thewhole brain, and severe deterioration can still occur upto 6 years of age [74, 89]. They rarely become manifestbefore the 3rd year follow-up and then regularly deterio-rate until adulthood. The classical report by Hirsch et al.in the early1980s compared a series of children irradiat-ed for a medulloblastoma in the whole CNS with a seriesof children only operated on for a cerebellar astrocytoma[68]. Global IQ exceeded 90 in 2 and 62%, respectively,writing and reading were altered in 82 and 37%, and be-havior was affected in 93 and 59%. School performancewas severely compromised in 75 and 27%, respectively.For Bloom, the cut-off age is around 5 years, with 38.7%children under this age severely deteriorated (i.e. toIQ<69) and only 4.9% above this age. It is likely that thedose de-escalation that has been attempted by severaloncological groups in low-risk medulloblastomas (from35 down to 25 Gy and even 18 Gy “prophylactic”) andin standard risk ALL (from 24 to 15–18 Gy) will reducesubstantially the risk of severe cognitive dysfunction[59, 61, 107] and also of growth impairment [110].Nonetheless, a recent update on children below 5 years

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of age still showed growth redardation following ex-tended 18 Gy “prophylactic” + cis platin [59].

In localized supratentorial tumors that require partialbrain irradiation (but generally in doses in excess of 45 Gy), the relationship with further disturbances is stillpoorly documented. Sparing the prefrontal cortex isprobably of major importance for IQ preservation [124].Deep sites (near the third ventricle and the basal ganglia)and localizations in the right hemisphere have been cor-related with poor outcome [27, 73, 120, 126]. Irradiationof the posterior fossa alone carries its own risks [94] ofintellectual impairment, mainly memory disorders, al-though they are less severe [61]. Interestingly, it hasbeen postulated recently that the cerebellum could con-tribute to mental skills through thalamic and frontal pro-jections [92].

We will also mention the pituitary failures followingirradiation of tumors located in or close to the sellar area.GH and TSH-RH hormones are the most sensitive [18,39, 116]. The risk of pituitary disorders has been set at75% following conventional doses in medulloblastomas.Both GH deficiency following moderate doses or radia-tion (≥24 Gy) and direct impact of ionizing radiation tothe vertebral plates (in case of spinal irradiation) havebeen incriminated in the genesis of growth impairment.The administration of GH can only improve the former..High doses to the cochlea has been made responsible forhypoacusis and stimulated interest in the irradiation ofposterior fossa tumors for elegant beam arrangements(based on conformal posterior oblique fields) that sparethe internal ear [54]. Ovarian transposition should not beomitted when radiation is targeted at the lower sacral fo-ramina in girls.

Recently our group has showed the risk of cerebralvasculopathy in children irradiated for tumors situated

close to the Willis arteries [60]. In association with type-1 neurofibromatosis, 13/69 (19%) children irradiated foran optic glioma presented with clinical and radiologicalsymptoms of vasculopathy.

Future directions

We must emphasize that most of the reported long-termside effects of RT come from old series dealing with“conventional” approaches: high doses administered tothe whole brain or large cerebral volumes. Considerableimpact can be expected in the future from modern strate-gies that deal with:

• More restricted irradiated volumes as permitted byconformal techniques. In such aspects, brachytherapy,intensity modulated photon beam [19], and heavycharged particle programs [63] deserve intensive investi-gations. Combined chemo-radiotherapeutic approachescan also help decrease the need for “prophylactic”medulloblastoma like craniospinal irradiation.

• Optimized delivery of the dose, including biologicalaspects that exploit a differential effect between tumorand normal cell population. Altered fractionation studiesand laboratory experiments on radiosensitivity genesmanipulations are in progress but still largely prelimi-nary.

• Scrutinized neuropsychological evaluations regularlyperformed in the follow-up of patients until adulthood inorder to evaluate the impact of new strategies, and possi-bly to rehabilitate some intellectual deficiencies [131].

Acknowledgement We are grateful to Mrs Anne-Marie Dumainfor her help in the preparation of the manuscript.

128

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