Reviewer: Christine Hill, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 26, 2008
Presenter: Torunn Yock, M.D.
Presenter's Affiliation: Harvard University, Massachusetts General Hospital Frances Burr Northeast Proton Center
Type of Session: Reporting
Dr. Torunn Yock is a pediatric radiation oncologist practicing at Massachusetts General Hospital (MGH). At MGH, approximately 60 patients per day are treated with proton radiotherapy on two gantries, and 17% of these are pediatric patients. The MGH experience in treatment of pediatric malignancies with protons is quite extensive, and over 800 children have been treated with protons at MGH thus far. The earliest of these underwent proton irradiation with the fixed-beam Harvard Cyclotron; currently, however, over 400 have been treated at the Frances Burr Northeast Proton Center. At this point in time, experimental protocols for treatment of medulloblastoma, rhabdomyosarcoma (RMS), and other sarcomas are accruing patients at MGH, and have been designed to assess late effects as well as tumor control as endpoints. Protocols for treatment of retinoblastoma and partial brain treatment are on the horizon, and will be open for enrollment in the near future. Dr. Yock shared the MGH experience in treatment of several different pediatric malignancies:
Orbital Rhabdomyosarcoma- Seven pediatric patients have undergone proton irradiation for orbital RMS at MGH, with six years of follow-up. All seven are currently alive without evidence of disease. One patient did experience local failure, but was salvaged with enucleation and stereotactic radiosurgery. Dr. Yock notes that all seven patients have excellent vision, and that a 50% rate of visual impairment has been noted in cohorts treated with photons. Patients treated at MGH have been noted to have mild orbital asymmetry, but have experienced no development of cataracts, keratosis, neuroendocrine issues, or painful dry eye at this point. Dosimetrically, the greatest benefit of proton treatment over photon treatment has been in sparing of the brain and contralateral orbital structures.
Parameningeal Rhabdomyosarcoma- Several investigations regarding proton treatment of parameningeal RMS have been carried out at MGH. A dosimetric study of 10 patients comparing intensity modulated photon radiotherapy versus proton radiotherapy demonstrated, not surprisingly, increased dose conformality with associated sparing of normal tissues such as the whole brain, brainstem, pituitary gland, and hypothalamus. Only the ipsilateral parotid gland and cochlea did not receive decreased dose with proton radiation. A retrospective study of late effects for patients treated for parameningeal RMS at MGH was presented at the Particle Therapy Cooperative Group Meeting two years ago. In this study, 17 patients who had been treated for parameningeal RMS between 1996 and 2005 were evaluated. Median age at time of treatment had been 3.4 years (range 1.5 – 17.6 years), and RMS histology was embryonal in 11 patients, alveolar in four, and undifferentiated in two. Ten patients had intracranial extension. Median treatment dose was 50.4 Cobalt Gray Equivalents (CGE) (range 50.4 – 55.8 CGE), and median follow-up was 4.3 years. Three year overall survival in this group was 61%. Late effects were compared to those published by other groups using photon based irradiation to treat parameningeal RMS, namely the IRS II/ III, which used a combination of three-dimensional conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT) to treat 213 patients (Raney, 1999), results from Memorial Sloan Kettering Cancer Center using IMRT to treat 22 patients (Wolden, 2005), and a series from Iowa University again using a combination of 3DCRT and IMRT to treat 17 patients (Paulino 2000). When late effects were compared, 20% of patients treated with protons developed decreased height as opposed to 48 – 60% of those treated with photons. Facial hypoplasia developed in 60% of patients treated with protons versus 73 – 97% of those treated with photons. Dental issues were present in 30% of patients treated with protons and 100% of those treated with photons. Cognitive deficiencies developed in 10% of those treated with protons versus 20 – 50% of those treated with photons. No visual changes, hearing loss, or second malignant neoplasms were described in patients treated with protons, whereas these effects developed in 9 - 82%, 17 -75%, and 2 – 9%, respectively, of those treated with protons. Although the benefits of proton based treatment for parameningeal RMS seem clear, if not in terms of disease outcome than certainly with respect to late effects, Dr. Yock did make a specific point that adaptive radiotherapy is particularly important in treatment of these tumors with protons. She points out that tumor shrinkage during treatment may considerably alter proton path length, and that the tumor-tissue-air interfaces may change considerably over the treatment course.
Central Nervous System Tumors- Neurocognitive delays are certainly at the forefront of consideration of radiotherapy technique in treatment of CNS tumors in children. Dr. Thomas Merchant and colleagues at St. Jude’s Children’s Research Hospital have performed IQ modeling studies demonstrating that age and brain radiation dose are significant factors in determining IQ deficits secondary to radiotherapy. They were quoted by Dr. Yock as stating that “each Gray of exposure had similar effects on IQ,” certainly promoting an argument for improved brain sparing using proton radiotherapy.
Craniopharyngioma: Dr. Yock described data with respect to a cohort of 24 pediatric patients treated with proton radiotherapy at MGH from 2001 – 2007. Median dose was 52.2 CGE (range 52.2 – 54 CGE), and treatment was delivered using a four-field approach. Although 24% of patients required replanning during the course of radiotherapy for cystic tumor enlargement, outcomes have been excellent: Median follow-up is 50 months, and local control rates are 100%.
Low-grade Glioma: Dr. Yock reviewed MGH data on 30 pediatric patients treated with proton radiotherapy at MGH from 1995 – 2006. Median age was 10 years (range 2 – 21 years); 60% of tumors were WHO grade 1, 20% WHO grade 2, and 20% unbiopsied. Median tumor dose was 52.2 CGE, and median follow-up 44 months. At this point, two patients have developed local recurrences (one anaplastic astrocytoma and one pleomorphic xanthoastrocytoma) -- disease free survival is 93%, and overall survival 100%. With respect to late effects, two patients, both with initial disease presentation at less than two years of age and with tumor compression of the circle of Willis, have developed Moya Moya syndrome. Both are alive and well, but have required surgical intervention. Six patients have undergone baseline and follow-up neuropsychiatric evaluation spanning approximately two years. Over that time period, no significant IQ loss has been noted. Of all 30 patients, 23% were noted to have neuroendrocrine deficits at the time of presentation; an additional 23% have developed new neuroendocrine deficits since completing treatment.
Medulloblastoma: Dr. Yock discussed the benefit of proton irradiation in delivering both phases of medulloblastoma radiotherapy – the craniospinal portion and the posterior fossa boost. She pointed out the complete lack of exit dose associated with craniospinal proton irradiation, and the resultant avoidance of dose to the heart, lung, bowel, and ovaries. She also discussed the potential to deliver dose only to the thecal sac, rather than the entire vertebral body, in children whose growth is complete. She explained that several patients treated early on at MGH developed severe esophagitis, and that MGH physicians have found that shifting the penumbra slightly in the posterior direction to avoid delivering dose to the esophagus has largely remedied this issue. With regard to the second phase of medulloblastoma treatment, the posterior fossa boost, Dr. Yock described the ability of proton irradiation to spare normal brain tissue, including the temporal lobes and cochlea, protection of which is particularly important since patients usually receive platinum-based chemotherapy. Additionally, use of protons may allow significant reduction in exit dose, sparing large portions of the supratentorial brain. This is true both when children receive boost dose to the entire posterior fossa, and when the boost is delivered only to the tumor bed. Although techniques vary somewhat between institutions currently, the issue of medulloblastoma boost is currently under investigation in a phase III Children’s Oncology Group study. With regards to partial brain treatment, Dr. Yock explained that MGH employs a method of delivery using posterior oblique fields rather than the traditional opposed lateral beams. This adjustment has been made to allow more complete sparing of the lenses while still allowing coverage of the cribiform plate.
Conclusions Dr. Yock concluded by explaining the potential future implications of scanning beam proton therapy and intensity modulated proton therapy in pediatric radiation oncology. Both of these techniques are expected to further increase conformality. At this point in time, when about 70% of children with cancer are ultimately cured, use of techniques to reduce risk of growth and development abnormalities, as well as second malignancies, are of great importance. Dr. Yock expressed her opinion that proton beam irradiation should and could be the standard of care in pediatric radiation oncology with in the next five to ten years, and that new technologies will increase the importance of this change even further.