Proton therapy (PT) is a form of highly conformal external-beam radiotherapy used to mitigate acute and late effects following radiotherapy. Indications for treatment include both benign and malignant skull-base and central nervous system pathologies. Studies have demonstrated that PT shows promising results in minimizing neurocognitive decline and reducing second malignancies with low rates of central nervous system necrosis. Future directions and advances in biologic optimization may provide additional benefits beyond the physical properties of particle dosimetry.
Key points
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Stereotactic, imaging-guided proton therapy (PT) is an effective and safe treatment of both benign and malignant skull-base tumors, which allows for improved normal tissue sparing
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Outcomes studies show the promising evidence of side-effect mitigation for skull-base tumors using PT.
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Reducing low and moderate radiation doses allows for the preservation of neurocognition and a reduction in second malignancies.
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High-dose conformity reduces the risk of central nervous system radionecrosis of sensitive neurovascular tissues immediately adjacent to the skull-base.
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Biologic optimization with dynamic arc delivery, relative biological effectiveness , ultrahigh dose rate delivery, and proton boron capture therapy, among others, may further improve the therapeutic ratio (defined as the probability of tumor control and the likelihood of normal tissue damage).
Introduction to proton radiotherapy
With technological developments in mechanical and software engineering and computer processing speeds, the field of radiation oncology has embraced the widespread use of sophisticated and targeted forms of stereotactic, image-guided radiotherapy capable of highly conformal and precise treatment. External-beam radiotherapy (EBRT), the most common form of radiation delivered, is a noninvasive treatment delivery of ionizing radiation in the form of photons or particles. Proton therapy (PT) has the physical advantages of a lower entry dose and limited distal fall-off compared with conventional photon radiotherapy. Clinically, this manifests as delivering equivalent therapeutic doses while reducing unnecessary low- and moderate-dose radiation to surrounding nontargeted normal tissue. , Fig. 1 shows a comparison of proton and photon radiotherapy on CT planning studies for a skull-base meningioma.
In PT, two basic types of treatment delivery exist: double-scattered (DS) and pencil beam scanning (PBS). DS techniques use a brass aperture and Lucite compensator to physically shape the lateral and distal penumbra. In contrast, magnets are used to dose-paint a three-dimensional distribution with PBS. Both treatments rely on the physical property that protons have a reduced entry dose and stop shortly after maximal dose delivery. This is clinically delivered as the spread-out Bragg peak or the summation of multiple individual beams within a clinically therapeutic range. , Fig. 2 shows the individual beamlets and the boost plan geometry for a petroclival chondrosarcoma using a single-field optimization technique. Fig. 3 illustrates how the composite dosimetry compared with volumetric modulated arc therapy leads to reduced radiation within nontargeted normal tissues. Delivering a higher proportion of the treatment dose to the tumor relative to the surrounding normal tissues increases the therapeutic ratio, defined as the probability of tumor control and the likelihood of normal tissue damage.
Proton Therapy for Benign Base of Skull Tumors
The benefits of PT are documented for centrally located benign and low-grade extra-axial brain tumors. Given the excellent local control rates, favorable outcomes, and central location, the proton dosimetry allows a reduction in low- and moderate-dose bath to the frontal lobes, bilateral temporal lobes and hippocampi, circle of Willis, hypothalamic-pituitary axis, and the optic apparatus. These tumors include pituitary adenomas, craniopharyngiomas, and benign meningiomas. Radiosurgical and fractionated proton schema have been documented with high local control rates and fewer toxicities. , , , Proton radiotherapy has demonstrated efficacy in lateralized base of skull (BOS) lesions (eg, vestibular schwannoma) with high control rates and low morbidity. , Other potential roles for PT include benign tumors involving both the brain and spine (eg, hemangioma and hemangioblastoma) when repeat or upfront surgery or other interventional procedures have high morbidity. , Conventional dose regimens range from 45 to 55.8 gray relative biological effectiveness (GyRBE) at 1.8 to 2 GyRBE ( Table 1 ).
| Histology | Conventional Fractionation Dose Regimens |
|---|---|
| Craniopharyngioma | 54 GyRBE at 1.8–2 GyRBE |
| Hemangioma | 45 GyRBE at 1.8 GyRBE |
| Meningioma (WHO grade I) | 45–54 GyRBE at 1.8–2 GyRBE |
| Pituitary adenoma | Secretory 50.4–54 GyRBE at 1.8–2 GyRBE Nonfunctioning 45 GyRBE at 1.8 GyRBE |
| Vestibular schwannoma | 50.4 GyRBE at 1.8 GyRBE |
Pituitary Adenoma
Pituitary adenomas are common benign BOS tumors. Autopsy and radiographic series note that incidental, clinically insignificant findings may be present in as much as 20% of the population; however, they rarely cause issues related to hormone secretion or mass effect from tumor growth. Radiotherapy is indicated for refractory secretory tumors and nonsecretory macroadenomas where medical management would imminently risk causing cranial neuropathy. Radiosurgery is preferred for secretory tumors as the biochemical response rate is more rapid, but it cannot be performed for a large tumor or those abutting the optic apparatus. In those situations, fractionated radiotherapy is indicated. PT is of particular interest as it has been shown to reduce the nontargeted low dose to the temporal lobes and hippocampi in these cases and thus may affect long-term neurocognition. ,
Craniopharyngioma
Craniopharyngiomas are rare sellar tumors most commonly affecting children and adolescents. Radiation is used after subtotal resection, and disease control rates are equivalent to those obtained after macroscopic gross total resection when radiation is given adjuvantly. Given the good prognosis and the typical age at diagnosis and location, several series document the efficacy of proton radiotherapy both in pediatric and adult populations, with local control rates nearing 90% with rare serious toxicity. , ,
Potential cyst expansion is particularly important during radiotherapy; clinical series have shown that up to 25% of patients can develop pseudoprogression in the form of cyst changes or expansion during treatment, necessitating treatment planning changes. It is generally recommended that at least biweekly on-treatment MRI verification is performed to ensure that the prescription dose encompasses the target volume ( Fig. 4 ).
Vestibular Schwannomas
Vestibular schwannomas are nerve sheath tumors affecting the vestibulocochlear nerve. Most are unilateral and sporadic, whereas a few are hereditary and bilateral (<5%). Observation is the primary management for newly diagnosed tumors, as approximately one-third will show growth within a time that precipitates therapeutic intervention. If treatment is indicated, surgery and radiation provide excellent control rates. Radiation has a lower rate of facial nerve injury and better hearing preservation than upfront surgery. , , Pseudoprogression after treatment is a common feature of vestibular schwannoma. Thus, a transient, self-limited increase in the tumor size is a known phenomenon and should not be considered treatment progression ( Fig. 5 ). Accordingly, it should be clinically observed, particularly in the absence of new or worsening neurologic symptoms. ,
Meningioma
The diagnosis of an extra-axial tumor as meningioma can often be made radiographically and therefore is one of the few diseases that can be treated with radiation without tissue confirmation (85% are benign). Like other benign BOS tumors, 5-year local control rates are over 95% with PT. , , , Recent studies have shown that the utilization of gallium Ga 68-DOTATATE positron emission tomography improves target delineation for radiation treatment planning, particularly useful for difficult-to-interpret postsurgical skull-base cases ( Fig. 6 ).
Malignant Skull-Base Tumors
In addition to low- and moderate-dose reduction, PT provides a high-dose conformal radiotherapy for BOS malignancies. These tumors include bone sarcomas (eg, chordoma and chondrosarcoma), sinonasal tumors, soft tissue sarcomas (eg, rhabdomyosarcoma, hemangioblastoma, and extracranial hemangiopericytoma), and carcinomas with perineural invasion (PNI). PTs role is to limit moderate- and high-dose radiotherapy to adjacent sensitive neurovascular structures such as the brainstem, brain parenchyma, and optic apparatus. Conventional dose regimens range from 50 to 78 GyRBE at 1.8 to 2 GyRBE and are summarized in Table 2 .
| Histology | Conventional Fractionation Dose Regimens a |
|---|---|
| Chordoma | 70 –78 GyRBE at 1.8–2 GyRBE |
| Chondrosarcoma | 70–74 GyRBE at 1.8–2 GyRBE |
| Carcinomas | 60–70 GyRBE at 1.8–2 GyRBE |
| Meningioma (WHO grade II/III) | 54–60 GyRBE at 1.8–2 GyRBE |
| Hemangioblastoma | 50–55.8 GyRBE at 1.8–2 GyRBE |
| Soft tissue sarcoma | 50–66 GyRBE at 1.8–2 GyRBE |
| Sinonasal tumors | 50–70 GyRBE at 1.8–2 GyRBE |
a Dose ranges dependent on extent of residual disease and histology
Chordoma and Chondrosarcoma
Chordoma and chondrosarcoma are extradural osseous sarcomas with a long history of being treated with proton radiotherapy. Chordomas are remnant embryonic notochord tissues that form the nucleus pulposus. Histologically, they are most associated with Brachyury expression, and subtypes include conventional, dedifferentiated, and poorly differentiated. Maximal safe resection followed by radiotherapy is the initial treatment strategy except for poorly differentiated chordomas, for which induction chemotherapy is considered. Anatomically, the clivus is divided into three segments (sellar, sphenoidal, and nasopharyngeal), which are used to determine surgical planning and approaches. Lesions of the middle third of the clivus are associated with the highest rates of gross total resection, followed by the upper and lower thirds. Lower third or craniocervical junction chordomas often present in a tent-like fashion both anteriorly and posteriorly to the dens ( Fig. 7 ). , , , , As chordomas are relatively radioresistant, studies have shown that dose escalation above 70 GyRBE and PT are associated with increased survival. Studies with high-dose conformal photon therapy have also been performed, including radiosurgery. , , ,
Chondrosarcomas are cartilaginous BOS tumors. Compared with chordomas, which are typically midline, chondrosarcomas are usually paramedian and often arise from petroclival synchondrosis. A comparison of the radiographic features of chordoma is depicted in Table 3 . Although the 10-year progression-free survival after radiotherapy for chordoma ranges from 50% to 65%, chondrosarcoma is generally over 85%. Studies have shown that radiotherapy may improve survival and decrease recurrence. In addition, although both pathologies are considered radioresistant with improvement in outcomes with doses greater than 70 Gy, the mechanism for the different disease responses is unknown. , Given the complexity of managing chordoma and chondrosarcoma, database studies from high-volume centers have also shown associations with improved survival. ,
| Feature | Chondrosarcoma | Chordoma |
|---|---|---|
| Location | Paramedian | Midline |
| Calcifications | Intralesional calcifications common | No internal calcification |
| CT | Lytic lesions with a moth-eaten appearance and endosteal scalloping | Bony destruction |
| T1 signal intensity | low to intermediate | low to intermediate |
| T2 signal intensity | High | High |
| T1 + gadolinium | Heterogenous enhancement | Heterogenous enhancement |
| Diffusion-weighted Imaging | High ADC value Low to intermediate restriction |
Low to intermediate ADC value Mild to moderate restriction |
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