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Introduction and background

Pediatric tumors represent approximately 2% of ma-lignancies, and have the propensity for rapid localevolution, and early disseminatian. Nonetheless theyhave enjoyed considerable improvement in their outco-me for the past three decades, with a long term survi-val close to 70% vs 40% in the early seventies. This hasbeen mainly attibuted to the unique sensitivity of thesetumor-types to the chemotherapeutic agents. Nonethe-less radiotherapy still plays a crucial role in the localcontrol of the majority of solid neoplasms, especiallybrain tumors, soft part sarcomas, and high risk Ewing’ssarcomas, nephroblastomas, and neuroblastomas. Un-fortunately its use has been associated with multiplelong-term side-effects, especially in young children,that make their management a formidable challenge.In this context, radiotherapeutical innovations (particu-larly those that improve ballistical selectivity), are ofparamount importance, since they can minimize unne-cessary irradiation of normal organs close to (or abut-ting) the tumor. They include conformal, intensity mo-dulation of the beum, stereotactic mono or multifractio-nated, and proton beam therapy to mention a few. In-tra op electron therapy has long proven valuable inadult conditions, esp in intra abdominal sites. In chil-dren there has been a considerable interest for intra op

brachytherapy (generally low dose-rate), in institutionswith special expertise, and promising results on localcontrol and long term toxicity have been reported espin soft part sarcomas of the genital-urinary tract, incombination with chemotherapy. Preliminary investiga-tions have also been conducted using intra op elec-trons in soft tissue and bone sarcomas, neuroblasto-mas, nephroblastomas, and hepatoblastomas2, 4, 5.

Rationale for radiotherapyin neuroblastoma3

Neuroblastoma represent approximately 5-10% ofpediatric malignancies. Its sallent features are domina-ted by the frequency of metastases at the time of pre-sentation (approx 50%), and by the young age at pre-sentation (med age 2 years) that makes the manane-ment highly challenging in terms of further growth dis-turbances. Therapy of early disease (stages I and II)consists in immediate surgery followed by chemothe-rapy in most instances. Outcome is excellent in the ran-ge of 70-80%. Problems occur in advanced diseases(stages lIl and IV), that also include the subgroup withbiological markers of aggressiveness (mainly myc-Namplification). Long term outcome is by the order of30%. Reasons for failures are mainly metastases butfrequently associated with local failures as well. As foras local control, radiotherapy can play a role generallycombined with surgery, but also sometimes used alone.

Radiosensitivity of neuroblastoma looks spectacularin palliative situations such as the Hutchinson syndro-me, and other bony metastases. It has also been de-monstrated on biological grounds and clinical curativesituations. Doses as low as 4-5 Gy fractionated, caninduce long term control in IVs stages, seen in infantsthat present with liver (and sometimes cutaneous) invol-vement. Doses adapted to children age, ie in the range

** Department Radiation Oncology, Institut Gustave-Roussy,Villejuif, Francia

** Department Pediatric Surgery, Bicêtre University Hospital,Kremlin-Bicêtre, Francia

# Trabajo presentado en las 3as Jornadas Oncológicas Inter-nacionales, Madrid 17-19 junio 2004.

Artículo Especial

Intra operative electron beam therapy in pediatric neuroblastomas. A French Project#

J. L. Habrand*, F. N’Guyen*, H. Martelli**

of 25-40 Gy, are routinely used in most institutions inthe curative management of children with post op resi-dues, with N+, or with biological markers of aggressi-veness. In the most recent US and European studies lo-wer doses are being explored, ie 20 Gy or so, fractio-nated.

As recent series emphasise the risk of local failureeven though in advanced, metastatic presentations, in-dications for radiotherapy are expending. For exam-ple, in the current European multicentric study, mana-gement of advanced presentations combines an inten-sive multi drug therapy followed by surgery and syste-matic irradiation. Recommendations regarding targetvolume have also evolved towards the inclusion of lar-ger volumes encompassing the pre op extension, dueto the risk of marginal misses, following a geographi-cally highly restricted policy.

On an other hand, multiple long-term side-effects asmentioned above, can be expected in younger chil-dren, that can affect the development of the muskulos-keletal, endocrine, central nervous, vascular systems,much more considerably than in adults, along with anincreased sensitivity to the carcinogenic effect of thera-peutic agents used in cancer. Doses as low as 20 Gycan still impact significantly on most of these, esp if lar-ge volumes of normal organs are encompassed. Forexample, side effects related with the management ofaLdominal neuroLlastomas can affect liver, kidney, in-testinal functions, as well as spinal grawth. A typicalexample of a dose-distribution in a neuroblastoma pa-tient is seen on Figure 1.

Rationale for intra operative electronsand practical considerations6, 7

This technique consists in the administration of a sin-gle dose of electrons, given during a surgical procedu-re that generally also aims to take out gross disease.Doses in the range of 10 to 35 Gy are recommendedin Western countries, and frequently combined withexternal beam therapy.

• The advantages are multiple: 1/ better target defi-nition with the surgeon; 2/ more limited fields compa-red with external beam due to more restricted “safety”margins (lack of PTV); possibility of removing normalstructures (such as small bowel, ureters, bile duct) fromthe beam; and so 3/ possibility of delivering sofe hig-her doses. 4/ lack of hospitalisation, and reduced ra-diations hazarUs of staff and family, compared withLDR brachytherapy.

• The disadvantages include 1/(theoretically) a les-ser efficiency on hypoxic tumor cells (something thatcan be overcome to some extent, by a previous debul-king of the gross hypoxic tumor component, or by theadministration of sensitizing agenis); 2/ difficulty ofdisplacing specific organs such as kidney or majornerves/ nerve-roois; 3/ technical constrainis that canmake the session uneasy or impossible (size of suspi-cious area that requires beams’ maiching, thick resi-dual requiring higher energy electrons, “sloping” loca-tion such as lateral/anterior wall, making electron-co-ne docking challenging); 4/ necessity of a perfect coo-peration between surgeons, radiation oncologists, andin children, pediatric oncologisis; 5/ cumbersomeequipment.

More specifically to children, it should be emphasi-zed that radiation therapy, surgery, and chematherapy

J. L. Habrand y cols.

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Fig. 1. External beam irradiation of a high risk neuroblasto-ma in a 2 year-old girl. Prescribed dose: 20 Gy. 3 field-technique. Dose-distribution in a transverse plan. Entire ip-si lateral kidney and most hepatic gland are unduly inclu-ded in high isodoses.

Fig. 2. Same patient as Fig. 1. Coronal view.

are rarely done in a single institution, and that casesare relatively uncommon even in referral centers. Lastbut not least, anatomical structures are dismul compa-red with adults ones (esp in young children), that re-quires adapted cones and highly expert hands.

Towards a National Project

With the limitations in pediatric oncology mentionedabove, only a project collecting cases on a large (na-tional) basis could end up with a satisfactory accrualwithin a reasonable time-scale. For example, giventhat there are approx 80 new neuroblastoma cases peryear in our country, and that “advanced” cases (ie me-tastatic at presentation + myc-N amplified) represent ±half, 40 children could be good candidates. Our im-pression is that half this figure only, would be readilyaccessible for IORT at our institution, during the firstyear, making 20 “realistic” indications, at least in thebeginning. The rest would still benefit from “conventio-nal” fractionated external beam, and possibly repre-sent a “control” group, with detailed informations avai-lable since most are part of the current internationalSIOP study.

A recent German experience8 shows that 8-10 Gyare sofe and effective, and would be more or less equi-valent to the current fractionated dosage (20 Gy). Doseconstraints to the normul structures (spinal cord, kidney,nerves) would certainly deserve special attention com-pared with adults, due to the lack of detailed informa-tions in this age-group, and potentially to the enhancingeffect of prior chemotherapeutic administration.

A key- issue that has emerged recently, and thatmakes the technique much more attractive in our speci-fic environment, is the possibility to test miniaturizedcompact and mobile accelerators (Mobetron comp,Calif, USA)1. Although simple in design, and able toproduce electrons of limited energy-range only (max12 MeV), they look perfecily suited to most pediatricconditions.

Conclussions

The preliminary experience accumulated in pediatricmalignancies, esp neuroblastoma, in US and abroad,make experiments in this field, highly attractive both interms of local control, and toxicity. Due to the limitednumber of pediatric cases, such a program should beconducted in conjunction with active adult ones. Thisbrings further organisational problems, since both sur-gical environments (operating rooms, anesthesiologists,medical and technical staff) are rarely located in thesame place/ institution. New technologies, based oncompact-mobile accelerators, can certuinly help “revi-sit” the old concept of intra op therapy.

References

1. Goer DA, et al. Potential of mobile introoperative radio-therapy technology. Surg Oncol Clin N Am 2003; 12:943-54.

2. Haos-Kogan DA, et al. Intra operative radiation therapyfor high-risk pediatric neuroblastoma.

3. Habrand JL, et al. Radiotherapy in neuroblastoma. InNeuroblastoma. Brodeur GM et al. Ed. Elsevier Pub Ams-terdam 2000; 37:479-96.

4. Nag S, et al. Intra operative electron beam treatment forpediatric mulignancies: the Ohio State University expe-rience. Med Pediatr Oncol 2003; 40:360-6.

5. Schomberg PJ, et al. Intra operative electron irradiation inthe management of pediatric malignancies. Cancer1997; 79:2251-6.

6. Schomberg PJ, et al. Pediatric malignancies: IORT aloneor with EBRT. In Intra operative irradiation. Techniquesand results. Gunderson LL et al Ed. Humana Press Pub,Totowa 1999; 25:455-70.

7. Valentini V, et al. Intra operative radiotherapy: Currentthinking. EJSO 2001; 28:180-5.

8. Zachariou Z, et al. IORT (Intrcoperative radiotherapy) inneuroblastoma: experience and first results. Eur J PediatrSurg 2002; 12:251-4.

Oncología, 2004; 27 (10):605-607

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