Physical Properties of Proton Radiation

Protons are positively charged particles that are isolated by stripping of the orbital electron from hydrogen. High-energy protons are directed to targets of interest where its energy is subsequently deposited. Proton radiation has a similar biological efficacy as photon radiation which is the most common form of clinically applied radiation therapy. Photons are high-energy X-rays and in contrast to protons, they have no charge or mass. Photons also deposit their energy in the tissue they irradiate. Photon-based therapies have previously been mentioned and include linear accelerator derived treatments and Gamma Knife® therapies.

The primary difference between protons and photons in clinical application is the greater ability of proton beams to conform to the target and thereby decrease unnecessary radiation exposure to surrounding nontarget normal tissues. Protons have finite path lengths. As they decelerate in speed within tissues, they transfer their energy. The greatest deposition of energy is within the last few millimeters of their path length. This final large release of energy is known as the Bragg peak (Fig. 54-1). The path length of a proton beam within a given tissue increases with the beam energy. Multiple proton beam energies can be used to create a spread out Bragg peak (SOBP) to irradiate the entire target to a relatively uniform dose. Because proton beams have a finite travel distance, there is essentially no radiation delivered downstream to where the proton stops. In contrast, photons are partially attenuated by the matter with which they pass through but they do not have a finite path length. To achieve an adequate dose delivery to clinical targets, photon beams deposit both a higher amount of energy upstream to the target and continue to deliver a significant amount of energy downstream to the target. Typically multiple radiation beams from different orientations are used to maintain an adequately low-dose deposition to the normal tissues between the skin surface and target. Overlapping radiation beams within the target achieves the higher and therapeutic dose desired.

FIGURE 54-1 Energy depth–dose profile for proton and photon beams. Proton beams (blue) have a characteristic large energy loss at the end of their beam path length known as the Bragg peak. Proton beams of different energies can be combined to deliver a spread out Bragg peak (SOBP, red) that covers the width of a target at the desired therapeutic dose. Photons (green) continue to lose energy with depth from tissue absorption but do not have the defined path length as compared to protons.

The increased conformality of protons in dose distribution has two primary benefits. It may reduce the risk of adverse effects derived from normal tissue exposure to ionizing radiation. This is the major advantage of protons versus photons for patients with benign meningiomas. Although there is still energy deposited between tissue entry and target, the elimination of all downstream radiation exposure significantly reduces the volume of normal tissues irradiated. This also allows for the selection on many more beam arrangements in proton therapy because downstream irradiation of radiation-sensitive structures is not a concern. When treating irregularly shaped targets such as skull-base meningiomas, proton radiation has both the benefit of diverse beam arrangements and minimization of irradiation of neighboring tissues such as the brain and eyes. Dosimetric studies comparing modern photon-based radiation therapies with proton radiation find that no more than three proton beams are required for meningiomas plans whereas five or six photon beams are required for optimization of each technique.¹ Proton planning is associated with lower volume of normal tissues exposed to low-dose excess radiation. A second study comparing proton and photon planning of intracranial tumors including five cases of meningiomas also found superior conformality with protons.² Although these studies are purely planning studies, it is expected that they will translate into reduction of potential late effects of normal tissue irradiation.

A second important feature of proton therapy is its ability to deliver higher doses than photons while maintaining an equivalent risk of normal tissue injury probability. This is an important concept for managing patients with atypical and malignant meningiomas. It is a direct consequence of decrease in normal tissue volume irradiated and dose delivered to these tissues. With proton radiation, the target dose can be increased while the surrounding normal tissue risk of complication can be maintained equivalent to or less than alternatively achieved with photon radiation. In diseases in which treatment efficacy was limited by insufficient dose, proton radiation may increase the effectiveness of radiotherapy as a treatment modality. As mentioned earlier, in the setting of management of atypical or malignant histologies of meningiomas where doses in excess of 60 Gy may be beneficial to improving local control, the both improved local control and reduction of normal tissue injury can be expected with the use of proton radiation.³

Similar to photon-based radiation therapies, proton radiation can be delivered in multiple treatments as fractionated therapy or in a single fraction as stereotactic radiosurgery. The clinical indication defines the dose and fractionation pattern. Short-course treatments involving high doses per fraction for a few fractions is termed hypofractionated radiation therapy and is an option between traditional fractionated therapy of typically 5 to 6 weeks and single-fraction radiosurgery. Multiple factors including that of tumor location, size and shape, proximity of normal tissues, and patient health are considered to determine treatment dose and fractionation.

Despite the physical properties of protons that would seem to make it a clearly superior form of external beam radiation delivery, the complexity and cost of creating and maintaining such treatment facilities has limited their initial application in the clinics. As of 2008, there are five open clinical proton treatment facilities in the United States. This is an increase from only two centers available prior to 2005. The growing appreciation of proton radiation’s superior dosimetry and clinical implication has fueled the development of several more new proton therapy centers expected to open in the coming years.

Immobilization Techniques for Proton Radiation Therapy

Patients must be comfortably, safely, and securely positioned in a reproducible position for daily radiation treatments. Commercial products exist to facilitate efficient and patient friendly immobilization techniques but the limited number of proton treatment facilities has led to the development of various custom immobilizations tailored to specific treatment facilities. Proton beams are more sensitive than photons to the shape and density variations of immobilization materials and must be accounted for during both design of immobilization and treatment planning.

Two immobilization devices have been developed at the Massachusetts General Hospital (MGH) specifically for the use of intracranial proton radiation therapy. Patients are in a comfortable supine position. One immobilization incorporates a rounded carbon fiber occipital support and low-density cushion with a light weight aluminum halo frame that encircles the head. Custom dental molds position the patient’s head relative to the frame. This frame is used to treat intracranial targets that do not extend to the base of skull. An alternate device is an intracranial mask, that utilizes a standard head-cup and a custom designed polyfoam mask of perforated thermoplastic reinforced with a similar but solid sheet of polyfoam. This device allows treatment fields to extend lower than the aluminum halo frame and can be used with patients with poor or no dentition.

For intracranial proton stereotactic radiosurgery, an additional step can be incorporated to improve accuracy of patient immobilization and alignment. At MGH, patients undergo a minimally invasive procedure to place three 1-mm diameter stainless steel spheres within the outer table of the skull. These ball bearings serve as fiducial markers that define the reference coordinates for alignment which is obtained from subsequent CT imaging. Local anesthetic to three areas of the scalp (typically bilateral frontal and a single posterior parietal sites) is applied followed by creating 3-mm pits into the outer table of the skull and the stainless steel fiducial inserted. The procedure requires approximately 15 minutes with virtually no blood loss and excellent patient satisfaction.

Treatment Planning and Delivery for Proton Radiation Therapy

Proton radiation treatment planning is similar to that of other radiation therapy planning in that it is CT-based. Targets and critical structures are outlined. Between one and six optimized beams are used, depending on the geometry of target and normal tissues. Careful port design should maximize sharp lateral and distal dose fall-off by avoiding beams directed tangential to bony ridges or through heterogeneous areas such as the mastoids, sinuses, and auditory canals. Field specific collimation and distal range compensation are used to provide conformal beam shaping. Various ranges of beam energies are superimposed to create the SOBP. Dose distribution is typically far more uniform regardless of target dimensions as compared to photon-based treatments for either fractionated or stereotactic therapies. Frequently excellent sparing of irradiation of surrounding normal structures can be achieved (Fig. 54-2). Daily high precision treatment alignment is achieved with on-board diagnostic imaging. Anatomic bony landmarks are used for alignment. Skull fiducial markers provide added assurance of this accuracy. Verification imaging is performed prior to each treated field.

FIGURE 54-2 Clinical example of a skull-base meningioma planned by (A) proton and (B) photon radiation. A three-field technique was used in both plans, consisting of opposed lateral and superior oblique beams. Color lines designate isodoses. Proton radiation achieves greater conformality to the target and exposes a smaller volume of normal tissue to radiation. Note that the 35 Gy line in magenta excludes majority of temporal lobes in the proton plan but not photon plan.

Fractionated Proton Radiation Therapy

Limited experience with fractionated proton radiation in the treatment of meningiomas suggests equivalence in tumor control as compared to other forms of radiotherapy. A report from the National Accelerator Center on the efficacy and toxicities of proton radiation therapy included five cases of fractionated stereotactic radiotherapy (54.1–61.6 GyE in 16–28 fractions) in the management of skull-base meningiomas.⁴ The mean follow-up period was 40 months. Local control was maintained in all patients and provides some preliminary data in support of its use. In regards to morbidity, no patient experienced an acute toxicity but one patient developed a decrement in short-term memory.

At the Paul Scherrer Institute (PSI) in Switzerland, a novel form of proton radiation delivery using a scanning beam has been developed with the goal of achieving greater conformal radiation delivery. This spot-scanning beam technology has bean applied to the treatment of 16 patients with intracranial meningiomas.⁵ These patients were otherwise treated in typical fractionated radiotherapy fashion with a median dose of 56 GyE. Local control at 3 years was 92%. Treatment-related adverse effects were found in 3 of 16 patients and included cases of retinopathy, optic neuropathy, and brain necrosis. The authors note that all sequelae occurred when the respective normal tissues were irradiated to higher doses than currently employed normal tissue dose constraints. Thus, this data served to support both the equivalent efficacy of proton radiation to photon therapies and to reaffirm currently accepted dose constraints of normal neurologic tissues.

Hypofractionated Proton Radiation Therapy

Experience with hypofractionated proton radiation is limited. The largest reported experience from the Svedberg Laboratory in Uppsala, Sweden describes the treatment results of 19 patients with meningiomas.⁶ With the exception of one patient, all cases were skull-base tumors. Patients were treated with 24 GyE divided in four daily fractions. No failures and no neurologic injury have occurred yet with a minimum follow-up of at least 36 months. Although this follow-up time is relatively short, this study suggests that hypofractionated treatments might be an excellent treatment option offering greater patient convenience as compared to standard fractionated therapy. The experience at the National Accelerator Center also included the treatment of 18 patients treated with hypofractionated stereotactic radiotherapy (3 fractions, mean dose 20.3 GyE).⁴ Sixteen (89%) patients remained at least clinically stable whereas two patients showed tumor progression. Thus, control rates by hypofractionated proton radiation were comparable to photon-based methods. Two patients experienced temporary cranial nerve dysfunction. Two other patients developed late neurologic toxicities of partial hearing loss and temporal lobe epilepsy.

Combined Photon-Proton Therapy

Combined modality radiotherapy with both photons and protons has been used successfully and may maximize the number of patients able to benefit from the limited resources of proton therapy. In these regimens, only a portion of the radiation fractions is delivered with protons and the remainder is given by photons. Among a French report of 51 patients with presumed benign meningiomas of the skull base treated with a combined proton-photon approach to a median dose of 60.6 GyE, the 4-year local control rate was 98%.⁷ No significant adverse effect was reported at a median follow-up of 21 months. Longer follow-up will be needed to truly assess the potential late effects of therapy. A second mixed photon-proton series of 46 patients with subtotally resected or recurrent meningiomas reported a recurrence free survival rate at 5 and 10 years of 100% and 88%, respectively.⁸ Median dose was 59.0 GyE with a range of 53.1 to 74.1 GyE. Among survivors, the treatment toxicity rate was 20% at both 5 and 10 years and was described as a result of accepted high dose constraints to the normal tissues. All treatment-related morbidity occurred as a result of normal tissue irradiation to doses exceeding commonly recognized neural tissue dose tolerances.

Proton Stereotactic Radiosurgery

Proton radiosurgery is a relatively new application of proton radiation. Similar to that of photon-based methods such as linear accelerator or Gamma Knife® radiosurgery, treatment is delivered in a single setting. Dosimetrically, proton radiosurgery differs from both linear accelerator and Gamma Knife radiosurgery in that the dose is highly uniform within the treatment target. The uniform dose has less areas of both underdosing and overdosing. This may lead to improve local control and decrease normal tissue injury, respectively. The experience of treatment of 44 benign meningiomas at MGH with proton radiosurgery has thus far shown a three year local control rate of 91%.⁹ Median dose delivered was 13 GyE (range 10–15 GyE). Transient neurologic symptoms that may have been attributable to treatment included seizures in two patients, hydrocephalus requiring shunting in one patient, and facial pain in one patient. An additional patient developed hypopituitarism from direct pituitary irradiation. Although this is the only available proton radiosurgery data currently available, the preliminary results are promising for an effective, safe, and patient friendly modality of managing small meningiomas.

Proton Therapy in Atypical and Malignant Meningiomas

Atypical and malignant meningiomas represent a subset of meningiomas that may benefit from multiple properties of proton radiation. As with benign meningiomas, a reduction of radiation toxicity may be achieved as a result of increased dose conformality that minimizes unnecessary normal tissue radiation exposure. In addition, an improved tumor control rate may be feasible with the delivery of higher radiation doses without increase of the morbidity rate. In a series from Massachusetts General Hospital, 31 patients with atypical or malignant skull-base meningiomas were treated with either photons alone (15 patients) or mixed photon–proton radiation therapy (16 patients).³ With mean doses of 62 GyE for atypical meningiomas and 58 GyE for malignant meningiomas, the local control rates at 5 years were 38% and 52%, respectively. Improved local control correlated with doses greater than or equal to 60 GyE and with the use of proton radiation. This may reflect the benefit of greater dose homogeneity with proton radiation which decreases the probability of spots of underdosing which is more common with photon therapy alone. Among the atypical meningiomas cases, those treated to greater than or equal to 60 GyE achieved a 5-year local control of 90% as compared to 0% for those receiving less than 60 GyE. Similarly among the malignant meningioma patients, 5-year local control following greater than or equal to 60 GyE was 83% as compared to 14% for lower doses. Thus, local control of atypical and malignant meningiomas was improved with higher doses. The cost of using higher doses was a 9% late complication rate (with ≥59 Gy). Proton radiation may be a mechanism of achieving necessary higher doses while minimizing acceptable rates of normal tissue injury.

In summary, equivalent control rates of unresected or partially resected benign meningiomas can be achieved with proton radiation as compared to other radiation therapeutic modalities. Doses of 54 to 60 Gy achieve local control rates of 85% to 100% at 5 years. At these doses, lower control rates are achieved with atypical and malignant meningiomas and existing data suggest a benefit of dose escalation, which is feasible with proton radiation. The role of proton radiosurgery as compared to fractionated protons is best defined for small to intermediate sized tumors, particularly those of irregular contours. Hypofractionated proton radiation in few fractions with variable doses depending on the size, location, clinical history, and patient performance status may be a balance in some situations to avoid the inconvenience of several weeks of radiotherapy and unacceptable risk of normal tissue injury with single-fraction radiosurgery.