Module 5: Clinical Outcomes by Disease Site - The Use of Proton Therapy in the Treatment of Cancers and Benign Diseases of the Central Nervous System
Benign Disease: Arteriovenous Malformations (AVM), Acoustic Neuromas (AN), and Meningiomas
There are a number of benign diseases which can be treated with radiation. However, because these are benign diseases, the amount of toxicity which is acceptable is less than when treating a malignant disease. Protons could potentially decrease toxicity to normal tissues, limiting toxicity and allow escalation of the dose of radiation, improving local control. There have now been a number of centers who have reported their experience using protons to treat AVM, meningiomas and acoustic neuromas.
Acoustic Neuromas (AN) arise from Schwann cells which surround the vestibular portion of the vestibulocochlear nerve. AN's comprise approximately 8% of adult brain tumors and occur at a median age of 50 years. Approximately 10% of patients who develop AN have a condition called neurofibromatosis type 2. The majority of patients will present with tinnitus or hearing loss, and slightly more than half will have unsteadiness or vertigo. Prior studies have shown that stereotactic radiation is effective (97% recurrence free survival at 10 years) and has good preservation of function (70% of patients with unchanged hearing, 79% with facial nerve preservation, 73% with trigeminal nerve preservation).
AVM's occur in about 0.1% of the population. 90% of AVM's are supratentorial and most of the remaining AVM's are located in the posterior fossa. They account for approximately 1-2% of all strokes. Stereotactic radiation can be used to treat AVM's with success, depending on the size of the AVM. An 80% ablation rate is seen in AVM's of less than 3 cm, with AVM's larger than 3 cm responding anywhere from 30-70% of the time. Higher doses appear to be more effective.
Meningiomas arise from the arachnoid cap cells of the meninges, and 90% of them are benign. They account for approximately 13-30% of all primary intracranial tumors. Radiation therapy is commonly used for incompletely resected tumors, recurrent tumors, and as a primary treatment. Prior studies have shown that radiation decreases recurrence rates in patients who are incompletely resected (~50%) and prolongs the time to recurrence. The best candidates for stereotactic radiation have meningiomas measuring approximately 3 cm in size. Patients seem to have comparable rates of control with surgery versus stereotactic radiation; however 5-10% of patients will develop complications related to radiation.
A recent retrospective, single institution study from Stellenbosch University, South Africa, has examined the local control rates in81 patients treated for AVM, 41 for meningioma, and 64 for acoustic neuroma. The majority of the patients were treated with proton radiosurgery as the proton beam was available only two days a week and only small fields were available due to limitation related to the passive scatter beam that was used. Patients were treated with 2-3 fractions total with fractions given twice per week.
Results of the study were as follows:
- Median Age: 34 years
- Male/Female Ratio: 1.8
- Median ICRU reference dose: 20.1 CGE
- Median volume: 15.6 cc (range: 1.7 to 110.6 cc)
- Median Follow Up: 4.8 years
- Overall Obliteration: 52% and this was volume dependent (<14 cc 75% and for patients with AVM >14 cc 46%)
- Clinical Outcome: 53% of patients had a good response and 34% of patients had stable disease. The AVM's in this study tended to be larger than in prior studies. When examining results comparing AVM measuring 20-30 cc treated in the present study with prior studies of similar sized AVM treated with stereotactic radiosurgery results were comparable per the authors.
- Median Age: 53 years
- Male/Female Ratio: 3
- Median ICRU reference dose: 21.5 CGE
- Median volume: 8.4 cc (range: 2.6 to 63 cc)
- Median Follow Up: 6.8 years
- Radiologic Control: (defined as the absence of growth) 89%
- Clinical Improvement: 60% It was noted by the authors that there were a significant number of patients who did not have a radiological response but who did have a clinical response. As with AVM, these meningiomas tended to be larger compared with prior radiosurgery studies but the results were comparable to prior radiosurgery studies per the authors.
- Median Age: 42 years
- Median ICRU reference dose: 16.3 CGE
- Median volume: 7 cc (range: 1 to 45.7 cc)
- Median Follow Up: 5.3 years
- Radiologic Control: (defined as the absence of growth) 95%
- Hearing/Facial Nerve Preservation: 61%/87% It was noted by the authors that half of patients had hearing loss prior to treatment. They noted that the median dose in the present study was higher than prior radiosurgery studies (generally 12-13 Gy). The authors note that results from this study were consistent with prior radiosurgery studies examining treatment of acoustic neuromas. They did note that protons were particularly useful in the treatment of bilateral acoustic neuromas.
The results of this study suggested that outcomes from proton based radiosurgery were comparable to photon based radiosurgery. However, the lesions in the present study tended to be larger than in prior photon based radiosurgery protocols and it appeared that proton based radiosurgery provided better outcomes in patients with bilateral AN. Spot scanning beam proton therapy may allow even greater control of the dose distribution and spare even more normal tissue, which due to the location of these masses is critical.
In addition to the data from South Africa, the Uppsala facility in Sweden has published its experience treating AVM's (Vernimmen FJ et al., Int J Radiat Oncol Biol Phys. 2005 May 1;62(1):44-52.). Of 85 patients treated, 64 had long term follow up. The majority of patients were treated with 2 or 3 fractions with a minimum target dose of 17.35 single fraction equivalent cobalt Gray equivalent doses. In AVM's less than 14 cc there was a 67% obliteration rate as compared to AVM's 14 cc or greater, which had an obliteration rate of 43%. Grade IV acute complications were seen in 3% of patients and delayed effects in 23% of patients. Other studies have suggested that proton therapy may be more effective than photon based therapy in larger AVM's (Levy RP et al., Acta Oncol 1999;38:165-9.).
The Uppsala facility in Sweden has also published results on approximately 140 patients with residual grade I skull base meningiomas treated with proton therapy (Gudjonsson O et al., Acta Neurochir (Wien) 1999;141:933-40., Gudjonsson O et al., Eur J Nucl Med 2000;27:1793-9., and Blomquist E. et al., Acta Oncologica,44:8,862 — 870). Patients were treated with fractions of 5 or 6 CGE in four fractions. Eight year progression free survival was 85-90%.
Data from the Paul Scherrer Institute, Switzerland examined 16 patients treated with spot-scanning proton radiation (Weber DC et al., Radiother Oncol 2004;71:251-8.). All patients had untreated, recurrent or residual meningiomas. The median dose was 56 CGE in 1.8 or 2 CGE fractions. The three year progression free survival was 92.7% with a local control rate of 91.7%. Cumulative 3 year toxicity free survival was 76.2%. While their results were similar to those obtained with photon therapy, treatment times were shorter with comparable toxicity. Theoretically, less normal brain was radiated, which could potentially lead to a decrease in long term neurocognitive deficits.
There is very limited, older data on the use of proton therapy in pituitary adenomas (Kjellberg RN et al., N Engl J Med 1968;278:689-95. and Minakova Y et al., Med Radial (Moscow) 1983;28:7-13.). Given the age of these studies, newer data is needed to determine the role of proton therapy in pituitary tumors.
Studies of the use of protons in adult CNS tumors is limited. A phase II study from Massachusetts General Hospital examined the use of accelerated fractionated radiation therapy using a combination of photons and protons in patients with glioblastomas (Fitzek M. et al., J Neurosurg. 1999 Aug;91(2):251-60.). Patients were treated with 180 cGy bid to a total dose of 90 CGE. All patients had unilateral supratentorial tumors with 60 ml or less of residual tumor. Actuarial survival at 2 and 3 years was 34% and 18% respectively. Median survival was 20 months. All 23 patients developed enhancement on follow up scans and 15 had tissue evaluation. 7 of 15 patients had radiation necrosis and had a significantly longer survival. Only 1 of 15 patients failed in the 90 CGE volume. The authors suggest that these findings demonstrated that accelerated fractionation to 90 CGE provided local control in almost all patients and that the 20 month median survival was likely due to this improved local control. Unpublished data from Uppsala, Sweden demonstrated a 3-5 month improvement in overall survival compared with "conventional radiation" (Blomquist E. et al., Acta Oncol. 2005;44(8):862-70.). In the 80 patients studied, all received proton therapy as a boost after external beam photon therapy.
Uveal (ocular) melanoma is rare, but it is the most common primary ocular neoplasm. Uveal melanoma is normally treated with plaque therapy for small lesions, but large lesions often require enucleation (removal of the eye). The role of proton radiotherapy in adult uveal melanoma has been well established, and has the advantage potentially preserving vision in eyes with large tumors. Between 1975-1986, 1006 adult patients were treated with protons at the Harvard Cyclotron, and excellent local control and probability of eye retention were achieved. Ten children with ocular melanoma were treated with protons in Boston (70 CGE in 5 fractions). All the children were alive and locally controlled at over 10 years of follow-up. Similar results have been seen at the Paul Scherrer Institute, Switzerland where four fractions to 60 CGE was used.
Links to reviews of recent abstracts and presentations regarding proton therapy for uveal melanomas:
- Ocular Melanoma and Proton Therapy
- Proton Therapy of Uveal Melanomas: Thirty years Experience
- Proton radiation therapy of ocular melanoma at PSI - long-term clinical exam
- Proton therapy of ocular tumors for very young children under general anesthesia