Results from a Prospective Trial of Proton Radiotherapy for Medulloblastoma: Clinical Outcomes including Hearing and Neurocognitive
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado:: 4 de octubre de 2011
Presenter: Torunn Yock, MD
Presenter's Affiliation: Massachusetts General Hospital, Boston, MA
- Medulloblastoma is a type of brain tumor that occurs in infants and young children, and this type of brain tumor represents approximately 20% of all pediatric brain cancers.
- Medulloblastoma almost always occurs in children less than 15 years old, and most commonly between the ages of 5-6 years.
- At the time of diagnosis, patients are divided into standard and high-risk medulloblastoma, based on involvement of the CNS outside of the tumor bed, of which 1/3 are high-risk.
- After surgery to attempt complete resection of the tumor, external beam radiation to the entire CNS (craniospinal irradiation, or CSI) is recommended to prevent the tumor from coming back in this area. Even if complete surgery is performed, low-dose radiation to the brain and spine is very important for local control. This is the region that is most at-risk for the tumor returning.
- Much attention has understandably been paid to the possible long-term complications of radiation therapy to the brain and spine of a growing child. These complications can include deficits in memory, learning, social/emotional adjustment, hormone levels, hearing, and growth problems. The development of such side effects depend on many factors, including extent of pre-radiation surgery, amount and location of brain that is treated with radiation, age of the child at diagnosis, type and dose of chemotherapy given, and how much radiation dose is given.
- Ototoxicity and neurocognitive functioning are easily quantified and common side effects following cranial irradiation.
- Proton radiotherapy has superior dosimetic characteristics, and radiation plans generated with protons have superior DVH parameters than intensity modulated radiotherapy (IMRT) plans with avoidance of organs at risk, which may help reduce the development of ototoxicity and neurocognitive decline in pediatric patients undergoing radiation therapy for medulloblastoma.
- The authors of this study sought to evaluate the benefit of proton radiotherapy in pediatric medulloblastoma. They hypothesized that because proton therapy irradiates less normal tissue, it is therefore likely to mitigate the late effects associated with radiotherapy for pediatric medulloblastoma.
Materials and Methods
- This is a Phase II trial, funded by the NIH, examining the effects of proton irradiation in pediatric medulloblastoma patients.
- The primary objective was to report DFS and OS in this cohort. The secondary objective was to report the severity of radiation toxicities encountered.
- The 3 specific outcomes which were measured included: 1) hearing deficiency, 2) endocrine abnormalities, and 3) neurocognitive decline.
- 60 pediatric patients were prospectively enrolled from May 2003 to December 2009 and 59 were evaluable for analysis.
- Eligibility criteria:
- Histologic diagnosis of medulloblastoma: standard-risk or high-risk, with imaging and pathology reviewed at MGH.
- All patients underwent surgical resection of the primary tumor and adjuvant platinum-based chemotherapy.
- Patients were allowed to enroll in other Children's Oncology Group (COG) protocols, and 10 patients were co-enrolled.
- Radiation Therapy
- CSI doses ranged from 18-36 Gray-Equivalents (GyE), with median dose 23.4 GyE. Patients received tumor bed boost to a total of 54 or 55.8 GyE.
- Assessments: Several standard measurement tools were used to measured audiologic, endocrine and neurocognitive outcomes.
- Audiology exams were performed at baseline (BL) and yearly thereafter.
- Neurocognitive and IQ testing was done at BL and at years 1, 3, and 5 following XRT.
- Median age 6.6 yrs, range 3.5 - 22 years; Male/Female ratio was 1.3
- 44 patients were standard risk while 15 patients were high risk.
- Median follow-up is 3.7 years (range 0.5-7.0 yrs).
- 20% of patients were noted to have posterior fossa syndrome after surgery and prior to adjuvant radiation.
- Three-year overall survival (OS) and progression-free survival (PFS) for the entire group is 87% and 81%.
- 3-year overall survival (OS) for standard risk was 90% and 3-year OS for high risk was 82%.
- 3-year progression free suvival (PFS) for standard risk and high risk is 83% and 76%.
- 51 patients were assessed with a neurocognitive evaluation at baseline and 31 have follow up evaluations. Mean Full Scale Intelligence Quotient (FSIQ) at baseline and followup are 107 and 101 (paired t-test: 0.065).
- No significant drop in FSIQ, Verbal IQ (VIQ), or Performance IQ (PIQ) (all standard measurements) was seen for this cohort. Mean baseline and follow up VIQ 110 and 109 (p=0.27), PIQ, 106 and 102 (p=0.09).
- Younger children (< 7 years old) did have a statistically significant larger decline in FSIQ than older children.
- However, a statistically significant decline in processing speed from baseline to follow up was seen Processing speed dropped from 99.5 at baseline to 85.2 at FU (p=0.002).
- 11 other tests of neuropsychiatric functioning did not reveal any statistically significant change.
- 8% of patients had POG grade 3-4 ototoxicity at baseline.
- 160 audiograms were collected and 139 were of sufficient quality for analysis. Median dose to the cochlea was 29.5 GyE (standard risk) and 41.6 GyE (high risk). 53 patients have baseline audiograms and 37 patients have at least 1 follow up audiogram.
- Pediatric Oncology Group (POG) grade 3 or 4 hearing deficit at follow up (mean 3.5 years) was 21.6% ears. (Paulino, et. al. 2010 showed 25% rate with IMRT)
- Dosimetric analysis showed that median doses to the cochleas were found to be significantly lower compared to IMRT plans for SR risk patients (25.3 GyE for protons vs. 29.5 Gy for IMRT). The differences were not statistically different for HR patients due to the higher CSI doses required in this setting.
- All pts received cisplatin or carboplatin. The cumulative dose of cisplatin (n=24) was 338 mg (range 108- 583 mg/m2).
- This is a relatively small number of patients undergoing neurocognitive and IQ evaluation after treatment.
- No valid control group was presented.
- There could be a selection bias with a selected subset of patients with higher IQs given that they are seeking out treatment at an academic center. They also have more access to resources to help compensate for neurocognitive, hearing, and endocrine deficiencies.
- Though follow up is the longest we have with pediatric medulloblastoma following proton therapy, it is only 3 years. The differential in outcomes may be greater with additional follow-up. Neurocognitive decline in particular has been demonstrated to persist for many years after completion of radiotherapy in patients treated with IMRT (Merchant TE, 2007).
- Results of this prospective trial of protons for medulloblastoma confirm acceptable tumor control comparable to that seen with photons while demonstrating some mitigation of neurocognitive deficits.
- Although the cochlea dose was lower with protons than with traditional radiation using IMRT, hearing deficits were not vastly different from historical IMRT controls.
- With additional time, increased hearing and neurocognitive deficits will likely emerge.
- Over the past several decades, the survival of patients with medulloblastoma has risen dramatically. However, much attention has now turned to the toxicity associated with surgery, radiation, and chemotherapy, and the development of novel ways to decrease these toxicities are emerging. The potential cure comes at a substantial cost with debilitating long-term side effects in children.
- Proton therapy offers a significant decrease in the amount of normal tissue irradiation both with CSI (exit radiation to the heart, lungs, breasts) as well as the additional radiation to the tumor bed (cochlea, hippocampus, and temporal lobes). As proton beam therapy is being implemented in a growing number of radiation therapy centers in the world, evidence of enhanced efficacy should be present before this expensive treatment is widely employed.
- Dosimetric comparisons seen in the literature theoretically give an advantage to protons as they would offer more normal tissue sparing and benefit to some patients, especially children. However, the magnitude of clinical benefit remains uncertain.
- The authors of this trial have executed a well-designed trial. This study reports on important early data from a prospective cohort of patients treated with proton radiotherapy examining neurocognitive functioning and ototoxicity at 3 years.
- They performed a very thorough clinical evaluation of toxicity with standardized measurement tools, and while their short term data appears to be favorable, more long term data from this investigation will be important in ascertaining whether the differences between the two groups persist with longer follow-up.
- The next COG trial hopes to attempt to lower the cisplatin chemotherapy dose to potentially mitigate additional hearing damage.