Proton therapy in Pediatric Malignancies: Update of the Orsay Experience

Reviewer: Christine Hill-Kayser
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 28 de mayo del 2010

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Presenter: Dr. Jean-Louis Habrand
Presenter's Affiliation: Institut Curie Centre De Protontherapie d'Orsay, Division of Medicine and Biophysics, Orsay, France

Background

  • Properties of proton and other particle radiation allow delivery of radiation dose with sparing of normal tissues. The heavy charged nature of protons used therapeutically causes them to deposit maximal energy at their point of stopping. This results in production of a Bragg Peak, or area of high dose distribution, with no exit dose.
  • Precise deposition of dose that is possible through use of proton radiotherapy may allow improvement of the therapeutic/toxicity ratio, allowing delivery of high radiation dose while reducing normal tissue toxicity.
  • Certainly, improvement of this ratio is a goal in treatment of every patient, and proton radiotherapy may plan a role in care of many of them; however, the goal of dose delivery with normal tissue sparing is arguably most important in care of pediatric patients.
  • Radiation has been demonstrated to cause myriad late and long-term toxicities in children, including, but not limited to, neurocognitive deficits, growth delays/deficits, endocrine abnormalities, damage to auditory/visual structures, damage to pulmonary/cardiac structures, skeletal abnormalities, and infertility.
    • The normal tissue-sparing properties of proton and particle radiotherapy may allow prevention or reduction of risk of many of these adverse effects.
  • Several centers worldwide have comprehensive programs for treatment of children with proton therapy. Here, the largest published series of pediatric patient treated with protons, from Orsay, France, is presented.

Methods

  • The authors describe a prospective series of 135 total pediatric patients treated at the Curie Centre De Protontherapy d'Orsay between 1994 and 2009.
    • They note that pediatric patients composed 19% of the patient population with non-ocular tumors treated from 1994 – 2009, and 30% of non-ocular patients treated in 2009.
    • They describe that treatment at their center began in 1991 with treatment of ocular tumors, primarily ocular melanomas, with over 40,000 ocular tumors having been treated at this point.
    • Treatment of deep (or non-ocular) tumors was initiated in 1994, with almost 1000 adult and pediatric patients treated thus far.
  • Of children treated at their center, the vast majority are referred from major academic centers in Paris, France.
  • The pediatric population has been equally male and female.
  • Age has ranged from 18 months to 18 years, with median age of 11 years.
  • Indications for proton treatment in children included a low-grade malignancies located close to critical structures in the brain, orbit, and head and neck.
    • Over half (52%) of children were treated for bone tumors (mainly skull base)
    • 30% were treated for brain tumors (craniopharyngioma, low-grade glioma)
    •  11% were treated for soft tissue sarcomas (mainly rhabdomyosarcoma).
  • Proton radiotherapy was carried out as follows:
    • Stereotactic positioning was utilized for all patients, with neurosurgical placement of fiducials prior to radiation planning.
    • Patients received between 50 and 70 Cobalt-Gray Equivalents (CGE) with conventional fractionation, with total dose depending on diagnosis.
  • Median dose was 57 CGE.
    • Most patients were treated with coplanar beams in a sitting position, although non-coplanar beams have been used more and more frequently for cooperative patients.
    • About 60% of patients received protons for part of their radiation course, and about 40% received proton treatment for the entire course.
  • Since 2007, all pediatric patients have been treated entirely with proton treatment.
    • General anesthesia was used as indicated;
  • The authors note that particular attention needs to be given to the placement of the endotracheal tube if the nasopharyngeal region is within the treatment area, as tube displacement may alter dosimetry.
  • Patients treated under anesthesia were generally treated supine, although occasionally in the sitting position as indicated.

Results

  • Median follow-up was 28 months (range 3 – 164 months).
  • Overall survival (OS) at 5 years was 86% for the entire group [88% for benign processes, and 72% for malignant ones (p < 0.05)].
  • Event free survival (EFS) at 5 years was 74%.
  • 5-year overall survival and event-free survival, respectively, by subgroup were as follows:
    • Craniopharyngioma: 100%/ 69%
  • Authors note that response may be difficult to assess due to prominence of cystic component.
    • Low grade glioma: 100%/ 48%
  • Response to treatment noted to be particularly unpredictable
    • Bone sarcoma: 89%/ 86%
    • Soft tissue sarcoma: 63%/ 68%
  • Incidence of acute toxicities was very low.
  • Late toxicities (median follow-up 28 months, maximum follow-up 11 years) were limited for the most part.
    • 5-7% of patients experienced grade 2 or higher visual toxicity
    • 43% experienced grade 2 or higher pituitary toxicity, with 1% experiencing grade 5 pituitary toxicity.
  • The authors describe their future plans to expand their center; these involve a newly operational isocentric beam which will drastically reduce treatment time per patient.
    • The authors will participate in multiple cooperative group protocols, and also have plans for launch of a craniopharyngioma protocol investigating use of limited surgery with 60 CGE radiation. They expect that the latter protocol will accrue 10-12 patients per year for 3 years, and results will be published within 6 years.

Authors' Conclusions

  • The authors conclude that their results treating pediatric patients with first generation equipment are highly encouraging.
  • They note that their new facility will allow implementation of new clinical investigations in most pediatric malignancies.

Scientific/Clinical Implications

  • The authors present a large, systematic series of pediatric patients treated with proton radiotherapy at their center.
  • Their clinical outcomes appear to be quite good, with limited acute and late toxicity.
  • In the future, more detailed information regarding specific disease-sites would be interesting. For example, how were patients treated surgically? Did they receive chemotherapy? How were these treatments sequenced? Such detail might allow other centers to learn more from the data presented here.
  • The technique utilized demonstrates that excellent treatment may be delivered even in the absence of an isocentric beam; however, the authors note that the new instruments at their facility will allow them to use this limited resource to treat many more patients with a broad range of diagnoses.
  • Further data from the new Orsay center will certainly be of interest in the future, as would more detailed information from the group of patients presented here. Even so, this series represents one of the largest groups of pediatric patients, and is certainly a very important information source in the particle therapy community.


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