gms | German Medical Science

48th Meeting of the Particle Therapy Co-Operative Group

Particle Therapy Co-Operative Group (PTCOG)

28.09. - 03.10.2009, Heidelberg

Protontherapy in pediatric malignancies

Meeting Abstract

  • J.-L. Habrand - Clinical Division, Centre de Protonthérapie de l’Institut Curie à Orsay (ICPO), Orsay, France
  • J. Datchary - Clinical Division, Centre de Protonthérapie de l’Institut Curie à Orsay (ICPO), Orsay, France
  • S. Bolle - Clinical Division, Centre de Protonthérapie de l’Institut Curie à Orsay (ICPO), Orsay, France
  • C. Alapetite - Clinical Division, Centre de Protonthérapie de l’Institut Curie à Orsay (ICPO), Orsay, France
  • S. Helfre - Clinical Division, Centre de Protonthérapie de l’Institut Curie à Orsay (ICPO), Orsay, France

PTCOG 48. Meeting of the Particle Therapy Co-Operative Group. Heidelberg, 28.09.-03.10.2009. Düsseldorf: German Medical Science GMS Publishing House; 2009. Doc09ptcog079

DOI: 10.3205/09ptcog079, URN: urn:nbn:de:0183-09ptcog0798

Published: September 24, 2009

© 2009 Habrand et al.
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Outline

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Pediatric oncology background

Cornerstone of the therapeutical armamentarium until the mid 70’s, paediatric radiotherapy has progressively stepped back at the benefit of chemotherapy which been gratified most of the major advances in this field.A substantial amount of recent or current national and international studies have been advocating the use of exclusive or quasi exclusive chemotherapy in a growing number of indications such as: stage I and II nephroblastomas, favorable histology (SIOP approach), rhabdomyosarcomas (SIOP approach between the early 90’s and the mid 2000’s), benign gliomas in the young (such as the current SIOP-LGG 2004), localized medulloblastomas in the very Young (French SFCE), Ewing’s sarcomas (Euro-Ewing-1999), or Hodgkin’s disease (Euro-Net 2008) with favorable prognostic features. Although it should be acknowledged that most of these studies are not purely chemotherapeutic - since most include a surgical procedure, and even radiotherapy as salvage procedure - pediatric radiotherapy seems on its decline. The reason lies essentially in the risks of severe long term side-effects that wave over these young patients, and later on extend over long-term survivors. Multiple reports have stressed its negative impact on bone and soft tissue growth that impairs final stature and cosmesis, as well as on neuro-cognitive, and endocrinological maturations that affects pubertal development, schooling performances and skills and eventually social and professional integration [Packer, 1987; Donaldson, 1992]; not to mention second cancers (see below). These drawbacks have been certainly minimized in the protocols designed since the late 80’s by clinical investigations that aim to taylor target volume of radiation to residual disease following an initial chemotherapeutic course or following a conservative surgical procedure. Also adapting radiotherapy total dose to prognostic factors, such as “response” to a previous chemotherapy regimen. Among the most striking radiation “de-escalations” that have been permitted by these innovative multidisciplinary approaches we will mention: early stage Hodgkin’s disease (dose-reduction from 40 Gy down to 20 Gy or so, along with substantial volumetric reduction); Ewing’s sarcomas (dose- reduction from 55-60 Gy down to 40 Gy or less); Nephroblastomas (dose-reduction from 35-40 Gy down to 10-15 Gy); neuroblastomas (dose-reduction from 35-40 Gy down to 20-25 Gy); localized medulloblastomas in very youngs (targeting to the posterior fossa only, instead of entire CNS after high dose chemotherapy). There has also been some interest in fractionating the dose by splitting it in two or three smaller fractions, an approach tested in rhabdomyosarcomas and medulloblastomas [Carrie, 2009; Donaldson, 2001].

Potential place of protontherapy

High dose radiotherapy (i.e. = 50 Gy, fractionated). remains mandatory in tumors that don’t “respond” dramatically to an initial chemotherapy regimen- most brain tumors as a paradygme [Habrand, 2001]- or that fail following a protocol free of irradiation -like one can expect in approximately 1/2 unirradiated rhabdomyosarcomas and ¾ non operated non irradiated Ewing’s sarcomas.

The reverse side is an increased risk of complications and sequelae, which is amplified in younger children (i.e. >6 years of age for brain, until puberty for bone growth…), and when high dose is associated with extended target-volume such as in medulloblastomas metastatic to the brain and spinal theca.

In this setting, technological advances that aim to optimize dose-gradient between tumor and normal tissues should be looked for in order to give adequate dose to the tumor, and to minimize toxicity. A substantial number of ballistical innovations dealing with photons are under evaluation at the moment. We will mention the intensity-modulation of the beam, which is now widely available in developed countries, and tomotherapy, cyberknife, stereotactic radiotherapy (either uni or multifractionated) less accessible. We will remind that protons offer unique ballistical advantages due to sharp distal and – to most of their path – lateral fall-off of the dose. It should also be mentioned that proton technology is relatively new and might benefit soon in routine from considerable developments, such as the spot-scanning and the intensity modulation of the beam [Goitein, 2002; Lomax, 1999 and 2004;]. Unlike sophisticated photon-techniques, protons achieve a high conformation at the price of a much limited number of beams, which in turn considerably limits the integral dose delivered to the organs located close or distant to it. Sparing from “mid” (approx. 15–40 Gy) and “low” (<15 Gy or so) doses, a salient feature of protons, is of paramount importance in children since these dose-ranges are implicated in injuries to several organs in youngs (brain, cartilage, kidney, bowel, ovaries…). This also includes secondary malignancies as far as lowest doses. Miralbell [2002] using theoretical models based on radioprotection, showed that this risk might be 2 to 15 fold less in medulloblastomas and rhabdomyosarcomas compared with photons. This was recently supported by a clinical report from Boston that matched 500 proton patients (mainly adults) treated over 2 decades, with 1400 photon ones that showed a 50% reduction of secondary malignancies [Chung, ASTRO abstr, 2008]. On another hand, Hall [2006] has pointed out the potential risk of carcinogenicity linked with “first generation” proton equipments in terms of increased secondary low-energy neutrons emission generated by the distal part of the beam’s line itself. Fortunately most (if not all) current beam lines have been improved that minimize neutron emission. Moreover the forthcoming spot-scanning technology should be virtually free of risk.

Pre clinical and clinical experiences

Main dosimetrical investigations concern the brain and head and neck regions and show almost invariably a better sparing of surrounding normal organs – esp. in the mid and low dose ranges – whereas little (or no) advantage on target volume - esp. when IMRT photons is included-. Posterior fossa irradiation is a paradigm of improved sparing of normal structures using protons. In one study [Lee, 2005], 65% cochlea could be spared doses = 20 Gy vs 15% for photons. In another study mean dose was decreased from 75% to 25% by replacing photons by protons [Lin, 2000]. In a third study [St Clair, 2004] dose to 90% pituitary decreased from 60% with 3D conformal photons, to 20% with IMRT, and <1% with protons. This would be even more convincing if brain (or temporal lobes only) were included in the OARs, an advantage that also concerns optic pathway gliomas [Fuss, 1999] and craniopharyngiomas [Merchant, 2008]. For the same authors, temporal lobes D50 seems to be reduced by 40%, and half volume receives between 20 and 40 Gy. These advantages can impact on further cognitive function and Miralbell [1997] estimates the risk for a severe IQ loss (ie 10 points) be 2% or less at 8 years against 30% with photons. Merchant [2008] has also predicted an improved IQ following protons in craniopharyngioma and in medulloblastoma. In the latter, spinal irradiation is generally requested at the same time as cranial irradiation. Protons can provide an elegant sparing of intra thoracic and intra abdominal organs compared with photons. Saint Clair [2004] estimates that cardiac D50 (dose deposited mainly to the posterior cardiac wall) is close to 0 using protons vs. 70 and 30% using 3D conformal and IMRT photons, respectively. Protons can also limit the dose to the vertebral bodies using a posterior beam abutted to the anterior canal [Krejcarek, 2007]: in older children this might improve bone marrow exposure and so haematological toxicity (clinical experiments conducted in adults with lung malignancies do evidence an improved tolerance to combined chemo-radiations: [Komaki, PTCOG abstr, 2008]) and in a long run, preserve spinal growth as well. Miralbell [19] estimates this gain close to 5cm on final height in a 10 year-old child. In younger children this policy likely doesn’t apply given the risk of spinal deformities that follows an inhomogeneous vertebral irradiation. Unfortunately electrons for the spine were not tested by this author, but distal and lateral fall-off of the dose is supposed to be poor at high energy. Intra orbital malignancies – such as retinoblastomas [Krengli, 2005] and rhabdomyosarcomas [Hug, 2000] – are equally challenging in terms of the multiplicity of structures to be spared and of patient’s set-up (frequently under GA). Furthermore positioning of the eyeball remains uncertain throughout the whole simulation and treatment process. Dealing with a fixed horizontal beam also limits the number of available beams’ angulations (e.g. an anterior beam requests a child in a seated position which has just been made available under GA at our institution). It is remarkable that in the Boston experience most intra orbital structures (retina, optic nerve, bones, lens, and lachrymal gland) could be spared an additional 20 to 40% dose compared with photons [Yock, 2005]. This might translate into clinically relevant functional and cosmetic advantages. The difference was even more striking as far as the contra lateral orbit although it concerned much lower dose levels.

Fewer intercomparisons have also been brought out in extra cranial sites, such as the abdomen and the pelvis. Intra abdominal neuroblastomas are particularly challenging since they concern frequently very young children (i.e. <2 years of age), heavily treated with intensive chemotherapy and surgery. The tumors are spreading along the vertebral column, which imposes homogeneous irradiation of multiple vertebrae and appropriate sparing of one or both kidneys, liver, bowel etc…Hug [2001] optimized dose-distribution for different anatomical configurations of a tumour treated to 34 Gy. D50 was kept below 16 Gy to the homolateral and 10 Gy to the contra lateral kidneys, along with 27 Gy, D80 to the liver. In intra pelvic bony sarcomas, one intercomparison [Lee, 2005] stresses the advantages using protons in distant areas receiving low dose levels (including improved sparing of ovaries for example), unlike closer organs – such as bowel and bladder – in which the benefit remained unclear.

Clinical results [Habrand, 2008; Hug, 2002; Luu, 2006; Noel, 2003; Timmermann, 2007] still concern less than 200 published cases. These data confirm the excellent local control – = 70% – in selected indications (most were slow growing benign processes) and excellent tolerance to treatment. Follow-up is generally too short to make any firm conclusion on the long-term outcome.

Economical impact

Pediatric tumors have become a priority in many of the ongoing or of the forthcoming facilities worldwide. Several ones are still in development in collaboration with or with logistical support from major pediatric oncological institutions. We will mention, in Europe: Paris-Orsay, Essen, and Heidelberg; in US: Philadelphia, Boston, and Houston. Pediatric oncology groups have expressed similar interests for future plans in UK, Italy, Spain, and as far as France, for a second project coupled with heavy ions, in Lyon. It is remarkable that pediatric tumors still represent in Orsay and in Boston 30% and 20% of the non-ophthalmological patients respectively. About thirty centers of proton therapy are expected to be operational within the next decade, with perhaps half of them able to initiate sound pediatric programs. This should favor enrolment of more young patients, speed-up initiation of radiotherapy -a prerequisite of competitivity- and development of collaborative protocols, including referals of patients abroad. A rough estimate of the potentially curable pediatric solid tumors in France is by the order of 700 (out of 2000 pediatric malignancies). This would correspond to 4,000 cases or so in the EU (about the same in US), equivalent to #500 cases/center of expertise (if 8 European centers of expertise). This offer looks reasonably realistic and well manageable in such centers, with the implementation of one isocentric gantry suite, full time devoted to pediatric patients.It is indeed unlikely that protons will remain confined to selected indications in children - i.e. the most challenging cases in terms of dose and constraints to critical organs - given their superior dose-distribution at all dose-levels in most cases, including better compliance with the international regulations (ALARA principles). It is more likely that they will eventually represent the reference radiotherapeutical approach at least in developed countries with few contra-indications (for example, interposition of heavy surgical metallic implants, or presence in the PTV of large air gaps abutting critical structures). What is debatable is whether they should go through prior randomized clinical studies with photons in order to corroborate “physical” evidences. This issue has raised considerable debates in adults [Brada, 2007; Goitein, 2008; Suit, 2008] where the “jury is still out”. Another stimulating issue will be the place of heavy ion therapy (carbon ions mainly) which is supposed to add biological advantages to the Bragg peak ballistics. Last but not least are the financial constraints. If the investment cost of a proton therapy centre equipped with at least two isocentric gantries is approaching 100 M€, cost per patient will certainly be cut down when more patients are included in proton programs. The cost per session should also set the exact cost of sophisticated photons for equipoise. In France, the cost of a medulloblastoma treated with photons ± electrons is now approaching 50% that of protons (approx. 500 vs 1100 €/ fraction). A similar estimate has been made by Goitein [2003] for other indications if throughput of patients was sufficient (by the order of 1,000/year). Lundkvist [2005] came up with the conclusion that if the entire burden of therapy was taken into account (including cost of sequelae and loss of productivity), the overall cost following protons could be even less than photons.

Conclusion

Pediatric tumors still represent a major therapeutical challenge mainly in terms of long term side-effects of therapy. For example, heavy chemotherapy has transformed the prognosis of brain tumors in very young children [Ridola, 2007] or of “high risk” Ewing’s bone sarcomas [Claude, in press] but at the price of an unexpected severe or lethal toxicity when combined with radiotherapy. Protontherapy which has still proven remarkably safe and efficient in a variety of slow growing tumor processes in the adults (located in the eye, skull base, and spine) might play in a near future in this age-range, a major role in the therapeutical armamentarium.