Interactions of Protons With Matter

Proton dose distribution characteristics arise from the way protons interact with the medium they traverse. The primary interactions in order of predominance, are (1) Coulomb interactions with electrons (2) Coulomb interactions with nuclei, and (3) nuclear interactions.

Protons lose most of their energy through interactions with atomic electrons. For 200 MeV protons, for instance, the electronic stopping power in water is 4.49 MeV cm²/gm, whereas the nuclear stopping power is 1.52 × 10⁻³ MeV cm²/gm. The secondary electrons travel very short distances from the path of the proton while ionizing atoms and molecules and depositing energy. The energy deposited by a proton per unit distance traveled (dE/dx, called linear energy transfer or LET) increases inversely as the square of the velocity. Thus, in a uniform medium, monoenergetic protons will travel a well-defined distance, losing energy at an increasing rate before coming to a stop. This leads to the formation of the characteristic Bragg peak. Because the proton is much heavier than the electron, its interactions with electrons do not result in an appreciable change in its direction.

When protons pass in the proximity of nuclei, they are deflected by Coulomb repulsion but without losing a significant amount of energy. Although each deflection is small, multiple such deflections, called multiple Coulomb scattering in totality, result in significant lateral dispersion of protons and are the major contributors to the width of the beam penumbra. Furthermore, when a proton beam passes through a complex heterogeneity, consequent variations in lateral dispersion can lead to substantial dose heterogeneity. It should be mentioned that inadequate management of the lateral dispersion is one of the important weaknesses of the semiempirical methods of dose computation used in current treatment planning systems.

Protons also suffer elastic and nonelastic scattering with nuclei when they traverse media. The cross-section (i.e., the probability) of nuclear interactions is small relative to Coulomb interactions. The primary proton imparts a substantial fraction of its energy to the target nucleus during a nuclear interaction and may scatter through a large angle. In elastic nuclear scattering, the target nucleus only recoils (kinetic energy is conserved); whereas in nonelastic scattering, the target nucleus may be left in an excited state, a nucleon exchange or transfer may occur (e.g., p-n reaction), or the target nucleus may disintegrate into smaller fragments. (A special category of nonelastic scattering is the inelastic scattering in which the excited nucleus emits a γ ray and returns to its ground state.) Recoil nuclei and the heavier fragments are absorbed within very short distances from the point of interaction. However, scattered protons may travel relatively large distances and contribute to a low dose “halo” that must be explicitly taken into account for accurate computation of dose distributions.

Nuclear interactions also result in the production of neutrons, an unwanted byproduct. Neutrons can travel large distances and necessitate the use of a large amount of shielding. They may also induce a significant level of radioactivity in the metallic objects they pass through and are of major concern because of their carcinogenic potential. Experts have cautioned about neutron contaminants when using passively scattered proton beams, especially for pediatric treatments.^1–4 However, the designs of newer treatment delivery systems have substantially reduced neutron contaminants in the incident passively scattered beams. Of course, neutron contamination in the incident scanned beam is essentially zero. Neutrons generated in the patient are unaffected, but their number is relatively small.

The probability of nuclear interactions rises with atomic number and with the energy of protons and, correspondingly, the magnitudes of the halo effect and neutron production. It is estimated that about 20% of protons of energies in the therapeutic range undergo nuclear interactions at some point along their path.

It is worth noting that an important difference between protons and photons is that an attenuator placed in the path of photons changes the intensity (number) of photons with only a small effect on the energy spectrum, whereas for protons, it changes its energy spectrum and has only a small effect on the number of protons.

Proton Accelerators

Protons of energies in the range of 70 to 250 MeV are needed for the treatment of cancers. For passive scattering, an initially monoenergetic beam of desired penetration is modulated to produce protons of a sequence of lower energies to form the required depth dose distribution and scattered mechanically to achieve lateral spreading. For scanning beams, the initial beam is a composite of pencil beams for the range of energies necessary that are spread magnetically to produce the desired dose distribution.

Typically, protons for therapeutic applications are accelerated using a cyclotron or a synchrotron. Both types of accelerators are used in radiation therapy, and each has its advantages and disadvantages. Cyclotrons are more compact and have higher beam intensity. They produce a continuous stream of protons. Protons are accelerated to the maximum of the energy for the specific accelerator. Clinically desired initial energies are then achieved by rapidly inserting mechanical degraders in the proton stream (beam line) before it enters the treatment room.

Synchrotrons, on the other hand, accelerate batches (pulses) of protons to the desired energy levels. Protons gain in energy with each revolution through the accelerator. As soon as a batch has reached the desired energy, it is extracted and transmitted via the beam line to the treatment room for delivery. The extraction may occur over a variable period of time (anywhere from 0.5 to 5 seconds), depending on the application. The accelerator then goes through deceleration and reset steps and starts the next cycle. Each cycle may produce protons of different energy. Generally, synchrotrons have greater energy flexibility, smaller energy spread, and lower power consumption. Because of the pulsed nature of the beam, proton scanning beams with synchrotrons is more complex than for cyclotrons.

The narrow beam of protons produced by the accelerator has a relatively small initial energy and angular spread. After extraction from the accelerator, the beam is directed magnetically through the beam line to the gantry and into the treatment head or “nozzle.” The term nozzle is used in particle therapy to describe the treatment head that the beam passes through after leaving the evacuated beam line. Fig. 69-3 shows the treatment floor configuration at the M.D. Anderson Proton Center (MDACC) and Fig. 69-4 shows the schematics of the passive scattering and scanning beam nozzles of the Hitachi proton synchrotron, the accelerator at MDACC. Its important components are described in the figure caption.

FIGURE 69-3 • The schematic of the treatment floor configuration at M.D. Anderson Cancer Center proton therapy facility. The same proton accelerator serves multiple rooms through the beam line.

FIGURE 69-4 • Schematic drawing of the components of the (A) passive scattering and (B) scanning beam nozzles of the Hitachi proton therapy system in use at M.D. Anderson Cancer Center. The key components of the passive scattering nozzle are the range-modulator wheel, a second scatterer, a range shifter for fine control of the maximum range, a snout to mount the field shaping blocks and compensator, and beam monitoring devices. The most important components of the scanning beam nozzle are the x- and y-scanning magnets and monitor chambers for monitoring the profile, position and dose. Both nozzles also contain x-ray tubes that can be moved in-line for radiographic alignment of the patient.

For PSPT, protons of a small number of discrete initial energies spanning the therapeutic range are directed into the gantry. Only one of these energies is dialed in for a given beam. The beam energy may be further reduced in fine steps using thin slabs of water-equivalent material called range shifters. For scanning beam applications, energies entering the nozzle are much larger in number and at finer steps. For instance, for PSPT, the MDACC system has a set of eight initial energies from 100 MeV to 250 MeV; whereas for the scanning beam, there are 94 energies from 72 MeV to 221 MeV. Protons with these energies have maximum approximate penetration ranging from 4 cm to 30 cm, respectively.

A typical proton accelerator serves multiple rooms. In the newer designs, the beam is switched automatically from one room to the next based on the order of request and priority. At the time of this writing, single-room accelerators are being developed by at least two different commercial vendors.

Therapeutic Proton Beams

A beam of protons entering the nozzle is a focused, circularly symmetric thin pencil. As it traverses the air and monitoring devices, it spreads out slightly by the time it reaches the surface of the medium (patient, phantom, compensator, etc.). Once it enters the medium, the rate of interactions increases substantially. Typical dose distribution in water from such a beam is shown in Fig. 69-1. To be clinically useful, such distributions must be spread out laterally and longitudinally (i.e., in the direction of the beam). This can be achieved by either passively scattering protons with a combination of a rotating range modulation wheel (RMW) and a scattering foil or by varying the energy of the protons before they enter the nozzle and actively scanning with magnets.

Passively Scattered Proton Beans

Conventionally, proton dose distributions of therapeutic interest have been produced by passive scattering. In the technique most commonly employed, an RMW is used to produce protons of a sequence of energies up to a maximum. The RMW is like a propeller that is placed in the path of protons. It has multiple banks of steps of a range of thicknesses each. Fig. 69-5 shows the design of a Hitachi RMW. It has six banks of steps and rotates at 400 revolutions per minute, thus it modulates the initial beam’s energy 40 times per second. As the wheel rotates, the proton beam passes through different thickness of the material and is slowed down to different energies. Angular widths and thicknesses of the steps are designed so that the sum of the resulting individual Bragg peaks results in a flat, homogeneous depth dose distributions of the type shown in Figs. 69-2 and 69-6 and called the SOBP. The thinnest step corresponds to the deepest penetration and the thickest one corresponds to the most proximal Bragg peak desired. SOBPs of in-between widths may be achieved by turning the incident beam off and on repeatedly at predetermined angles during the wheel’s rotation.

FIGURE 69-5 • Two views of a typical range-modulator wheel for the Hitachi proton therapy system. The wheel rotates at 400 rpm and modulates the incident beam six times per rotation, each modulation presents a series of steps to the monoenergetic proton beam producing a series of Bragg peaks. The angular width of each step is proportional to the intensity of the corresponding Bragg peak. These widths are chosen so that the sum of Bragg peaks is a spread-out Bragg peak (SOBP) of the type shown in Fig. 69-6. Turning the incident beam off and then on again on modulator steps less than the maximum thickness is used to produce SOBPs of different modulation widths. In combination with a second scatterer, the range-modulator wheel spreads the beam laterally to a size of predetermined diameter.

Designs and the number of RMWs for a treatment delivery system vary with vendors. The Hitachi system, for instance, has 24 RMWs for each room, or three sets of eight for field sizes of up to 10 cm × 10 cm, 18 cm × 18 cm, and 25 cm × 25 cm, each set of eight corresponding to a range of eight energies. The RMW for a given energy and field size is inserted manually. Field-size specific spreading of protons means fewer neutrons. In the ion beam applications (IBA) design, three RMWs are mounted on a carousel. Each RMW has three separate concentric tracks that can be positioned in the proton beam path to modulate three different initial energies. This design drastically reduces the number of RMWs and allows automated insertion of RMWs.

In the current designs, two scatterers made of high-atomic number materials are used to spread the beam laterally and make it flat within the region of interest. Often, the first scatterer is built into the RMW. The second scatterer plays the same role for protons as the flattening filter for photon beams. Its design is such that the proton energy across the flattened beam is constant, thus assuring beam flatness at depth. The design of the second scatterer depends on the required spreading (field sized) and the initial energy. Thus, multiple second scatterers are required. The Hitachi system, for instance, has nine second scatterers.

The use of scatterers and RMWs reduces the maximum range of protons. The reduction depends on the degree of spreading For instance, whereas the range of the 250 MeV unscattered beam is approximately 36.5 cm in water, it is approximately 32.5 cm when scattered to uniformly cover field sizes up to 10 cm × 10 cm, 28.5 cm to cover fields up to 18 cm × 18 cm, and 25.0 cm to cover fields up to 25 cm × 25 cm.

Field Shaping

When a passively scattered beam is used to irradiate a water phantom, it produces a dose distribution with the depth dose characteristics depicted in Fig. 69-6 and an axially symmetric lateral distribution that tapers off gradually beyond the maximum radius of the intended flat region. To conform the dose distribution laterally to the shape of the target volume (plus appropriate margins), an aperture, typically made of brass of sufficient thickness (2 cm to 8 cm) to absorb incident protons of highest energy, is used (Fig. 69-7). Brass is a compromise material because it produces fewer neutrons than, say, lead or Cerrobend and yet the apertures are sufficiently compact and manageable. As illustrated in the schematic of the Hitachi passive scattering nozzle in Fig. 69-4A, the field aperture fits in a “snout,” a component at the end of the nozzle designed to hold field shaping devices. To achieve sharp beam boundaries, the field aperture is positioned close to the patient. However, the gap between the aperture and the patient reduces the intensity of the hot spots at shallow depths caused by protons scattered from the aperture. As mentioned above, the designers of the new proton therapy systems are considering multileaf collimators to shape the lateral field boundaries.

FIGURE 69-6 • Measured spread-out Bragg peaks for a series of beam widths. The proton beam is “gated on” at the thinnest part of range-modulator wheel and “gated off” when the range-modulator wheel has rotated through a certain angle to achieve the spread-out Bragg peak of desired width.

FIGURE 69-7 • A 2-cm-thick brass aperture used to shape the proton beam. Three identical pieces are required for the 250-MeV proton beam and fewer for lower energies.

To create a dose distribution that conforms to the distal shape of the target, the SOBP of the passively scattered beam is shaped further by using a range compensator. A compensator is usually made of a nearly water-equivalent material such as Lucite (Fig. 69-8). It is designed to degrade the beam energy point-by-point by variable amounts so that the distal edge of the beam conforms to the shape of the target plus a suitable margin. The compensator is the final element in the nozzle. The air gap between the patient and the compensator is minimized to reduce the penumbra by moving the snout close to the patient. The aperture and compensator for each beam are designed by the planning system and the design information is used to fabricate these devices using computer-controlled milling machines.

FIGURE 69-8 • An acrylic compensator, which is patient-specific and designed to conform the distal edge of the beam to the target plus margin.

In computing the compensator thickness at each point, the water-equivalent path length to the distal edge of the target along the ray from the source of protons through the compensator point to the distal edge is determined. The surface irregularities and tissue inhomogeneities are taken into consideration in this computation. The compensator design algorithms used in current treatment planning systems are simplistic and do not adequately account for changes in the lateral scattering of protons caused by heterogeneities and surface and compensator irregularities.

Because the SOBP width for a passively scattered beam is designed to be constant across the entire field, passive scattering provides no control over dose distribution proximal to the target. For a target with highly irregular distal edge, this may lead to a substantial excess volume of high dose proximal to the target.

For scanning beams, proximal and lateral field shaping is achieved by limiting the positions of the spots to within the target regions only. Presumably, there is no need for an aperture. However, because of the substantial size of pencil beam spots, some consideration is being given to the use of apertures (or multi-leaf collimators [MLCs]). There is also no need for a compensator since the energy of spots can be varied to ensure no protons penetrate beyond the distal edge of the target. It is evident that scanned beams lead to lower dose in the proximal regions. The intensities of the spots are optimized to achieve desired clinical goals.

Proton Treatment Planning

The objective of treatment planning is to determine the configuration and parameters of beams that will lead to an optimum dose distribution. The parameters include the number and directions of proton beams. For the PSPT mode, for each beam these also include distal and proximal margins, lateral margin, beam energy (or the maximum proton range), modulation width, and the characteristics of the aperture, compensator, and range shifter. Energy and modulation width are subsequently used to select the modulator and its parameters and the second scatterer. For scanned beam treatments, the parameters include the intensities and energies of the spots and (possibly) their spacing. Most parameters for the PSPT mode are generally user selected, whereas most parameters for the scanning beam mode are determined by computer-aided optimization. In other words, PSPT mode planning is forward, whereas scanning beam mode planning is inverse.

In current practice for conventional treatment planning, a typical proton planning system uses mode-specific parameters to compute a treatment plan showing dose distributions expected to be received by the patient over the course of radiotherapy. The plans are evaluated using dose distributions and dose-volume histograms. Although many of the steps in the proton and photon treatment planning processes are similar, there are significant differences. Some of these differences arise because of the physical characteristics of protons. Others are the result of the greater vulnerability of protons to uncertainties because of inter- and intrafractional variations in anatomy, the approximate values of the Hounsfield units and proton stopping powers in tissues, and the approximations in models to compute dose distributions, especially in the presence of complex heterogeneities. The range of protons, i.e., the exact point where a beam of protons or its subdivisions stop in the inhomogeneous patient, is uncertain.

Because of these issues, the volumes and margins for targets and normal structures used in treatment planning, as described in International Comission on Radiological Units (ICRU) Reports 50 and 62,^5,6 need to be reconsidered. The concept of planning target volume (PTV) has limitations even for conventional radiotherapy. For instance, assuming that the margins to extend clinical target volume (CTV) to PTV are chosen with appropriate consideration of inter- and intrafractional anatomic variations, the dose volume histogram (DVH) of a PTV represents the worst case scenario: clinical target volume is guaranteed to receive no less than the minimum dose to the PTV. It does not, however, reflect actual dose distribution received by the CTV, which may move around from time to time and from day to day within the PTV.

The situation for protons is still more complex. Anatomic variations, whether along or perpendicular to the beam direction, and other sources of uncertainties mentioned above can affect the depth of penetration. These factors must be considered in designing margins and field-shaping devices, as well as in designing and evaluating treatment plans as a whole.

Biologic Properties

It is assumed that protons, being a low linear energy transfer (LET) radiation, do not differ significantly from photons, from the biologic standpoint. On the basis of numerous in vitro and animal experiments, it has been found that, on average, the relative biologic effectiveness (RBE) of protons is 1.1 relative to cobalt-60 radiation. In clinical practice, physical dose distributions are multiplied by 1.1 to obtain values in units of what is known as cobalt Gray equivalent or CGE. The dose distributions thus obtained are used to compare proton and photon plans or to add proton and photon plans.

However, the biologic interactions of protons may be more complex than what has been assumed so far in clinical practice. Almost all of the experiments to date have been carried out in the middle of the SOBP of a flat homogeneous dose distribution. Furthermore, there is a substantial level of variability in the data. The LET of protons increases as they slow down, and therefore, the RBE increases with increasing depth.^17,18 For example, it has been shown in animal experiments that the RBE at about 1 cm from the distal edge of the beam in an SOBP is about 1.2 compared to 1.1 (from presentation by J. Geuelette at the 45th meeting of PTCOG, Houston, 2006.). The LET distribution, and hence the RBE, in a passively scattered beam that has passed through a compensator and complex heterogeneities may be significantly different from 1.1 because of the spectral changes caused by scattering. Also, in IMPT, dose distributions in which the distal edge of each beam does not conform to the distal edge of the target and, instead, individual pencil beams meet inside the target volume, the LET and the RBE may be quite different from the values for the PSPT for the same physical dose distribution. It is also possible that the biologic interactions of protons with cells and tissues in the presence of chemotherapy or molecular agents are different compared to the corresponding interactions with photons.

Such variations in RBE are ignored in the current practice. For a passively scattered beam, this might mean that the biologically effective dose near the end of the range is uncertain and possibly higher than what is seen on a treatment plan. For this reason, and because of uncertainties in range, aiming the beams toward a normal critical structure is avoided.

Simulation

This attention to details begins with patient simulation.²⁰ Patient simulation is performed on a CT simulator with one or more well-defined imaging protocols. For protons, the CT Hounsfield units (HUs) must be converted to proton stopping power ratios. This conversion is established by the imaging of materials of known elemental composition to establish the relationship between their stopping powers and HUs and then entering the appropriate stopping power conversion factors (stopping power/HU) into the treatment planning system.²¹ These conversion factors may be a compromise to reflect the various imaging conditions, e.g., large CT field of view versus small CT field of view.

Patient positioning for simulation must be an exact duplicate of the patient positioning for the treatment. Generally, the couch used for simulation is not the same as that used for treatments. One approach to address this issue is to digitally remove the imaging couch before treatment planning and replace it with the digitally reconstructed image of the treatment couch (presented by L. Dong at the 46th meeting of PTCOG, Zibo, China, 2007).

Treatment Planning

The proton treatment planning system (TPS) provides the treatment parameters, e.g., proton range, SOBP, gantry angle, couch position, etc.²² For passive scattering, the TPS may or may not provide the monitor units (MUs). For scanning beams, the TPS must provide the MUs per spot as well as the spot location and energy. The proton TPS not only generates the dose distribution but also the information required to construct the apertures and the compensators. Generally, only a limited number of beams are used for proton treatments, as acceptable treatment plans can be generated using two or three beams.

Care must be exercised when choosing a gantry angle in treatment planning. A portion of the proton beam should not intercept the edge of the couch or the edge of a patient positioning device, as this will cause perturbations of the proton beam before the beam reaches the patient. Such perturbations may not be accounted for accurately. The proton beam may also be greatly perturbed in the patient because of the presence of complex heterogeneities. Beam directions that involve complex heterogeneities should be avoided to the extent possible.

Patient-Specific Quality Assurance

There is substantial work to be completed after the radiation oncologist has approved the proton plan. Patient-specific aperture and compensator information must be presented to the shop for production of these devices. Current proton delivery systems do not have multileaf or adjustable collimators and patient-specific beam defining devices must be constructed. Field-defining apertures are fabricated by machining brass or other metals. Compensators, which are designed to address the irregularity and heterogeneity of the body and the target volume along the path of the beam, are generally milled from a low–atomic number material, e.g., acrylic. The designs of both the apertures and the compensators are created in the treatment planning system. Quality assurance is performed on the physical devices themselves after they have been constructed to confirm the appropriate shapes and thicknesses.

Proton delivery systems require the determination of the number of MUs to deliver the prescribed dose. The dose prescription may be in units of biologically effective dose and may be converted to physical dose by the physics staff as part of the MU determination process. One approach to the determination of MUs for passively scattered beams is to use the patient dose distribution as input to calculate a “verification plan” in a water phantom. A representative point in the verification plan is chosen that corresponds to a point in the target volume where the dose is relatively uniform. Measurements can then be performed in a water phantom to determine the MUs required to deliver the prescribed dose. One significant parameter, which affects the number of MUs, is the SOBP factor: the smaller the SOBP, the more efficient the dose delivery, i.e., the fewer MUs required to deliver the dose. This factor can change by more than 50% as the SOBP width varies from 2 cm to 16 cm. It is possible to develop a simple manual dosimetry system to independently calculate the MUs required for a specific patient.²³

Treatment Setup and Delivery

Proton therapy is image-guided in that daily images are taken to insure that the isocenter is in the appropriate location relative to the patient. It is customary to have in-room x-ray units, including an x-ray tube in the nozzle that can provide a beam’s eye view as well as an imaging system perpendicular to the nozzle. These images are acquired as digital radiographs. The light field, if there is one, is not used to align the patient. The alignment of the x-ray beam and the proton beam is important and can be difficult to achieve.

Once acquired, the images must be available for review by the radiation oncologist. This can be done by incorporating the images into the electronic medical record (EMR), which would have the images available everywhere in the practice, or by requiring the oncologist to come to the treatment area to view the images. The couch can then be translated to place the isocenter in the correct position within the patient. Depending on institutional practice, a second set of images can then be taken to confirm the couch movement. For a four-isocenter cranial spinal treatment, substantial time will be required for patient alignment.

The actual treatment time—the beam-on time—is relatively short, generally less than one minute per field. Synchrotrons, which have lower dose rates than cyclotrons, have dose rates which range from approximately 50 MU/minute to 150 MU/minute depending on the snout size, SOBP, and (possibly) other beam parameters. Thus, most of the in-room time is spent on patient positioning. Approximately 20 minutes are required to treat two simple proton fields using a synchrotron. This time includes the time to enter the room to change the field-shaping devices. More than 1 hour may be required to treat a five-field, four-isocenter, cranial spinal patient, including the time to anesthetize the patient.

Treatment Safety

Proton treatment delivery systems should, at a minimum, meet the same quality and safety standards as photon systems. Daily pretreatment quality assurance tests should include standard output checks; functional safety features, including the treatment room door interlock; and alignment between the proton beam and the x-ray systems. One interesting difference between proton and photon treatment rooms is that the proton room may consist of three separate spaces, namely the treatment room, the space behind the treatment room (which contains the gantry and electronics), and the space dedicated to x-ray imaging. Thus, proton facilities generally have a room-sweeping alarm, which must be activated before the treatment door is closed, to alert anyone in any space inside the room that radiation will commence soon. This alarm system should be tested every treatment day.

Electronic Medical Record

For modern proton facilities, the proper functioning of information flow must be confirmed daily to ensure that information can be downloaded from the EMR to the proton delivery system and uploaded from the delivery system back to the EMR. This information transfer may be accomplished using the hospital network and, thus, may be dependent on the stability of the network as well as the stability of the specific components in the network. Because of the reliance on the EMR, which is essential, it is difficult to treat with either protons or photons when the radiation oncology network is not functioning.

The DICOM-RT* standard and its extension for particles, DICON-RT-ION, has helped in this information flow from the planning system to the delivery system.²⁴ For protons, information also must flow to the machine shop so that apertures and compensators can be constructed. DICOM-RT-ION is an evolving standard that does not address all situations. An example of a weakness in the standard involves the fixed-beam room, i.e., the treatment room without a gantry. At MDACC, we have developed a software filter between the planning system and the delivery system for the fixed-beam room to account for the different interpretations of or noncompliance with the standard.

Machine Quality Assurance

Periodic (weekly, monthly quarterly, annual) safety and quality-assurance tests should be performed to insure proper operation of the proton delivery system. It is important to define these tests wisely, as there is limited beam time available for such tests and limited recommendations as to which specific tests should be performed. Maugham and Farr have recently provided their recommendations.²⁵ It is possible to have an independent confirmation of the proton scattered and scanned beam calibrations in the same manner as for photon and electron beams, using thermoluminescence dosimetry (TLD) from the Radiological Physics Center (http://rpc.mdanderson.org).

Proton delivery systems generally offer a large number of different options that include beam energies, ranges, snout sizes, and SOBP widths. It is simply not possible to perform tests on each combination of variables. For example, for scattered beams, the MDACC has eight energies, three snout sizes, and the ability to adjust range in water in 1-millimeter increments using range shifters. For the 250-MeV beam alone, this represents approximately 1000 different beam configurations (i.e., unique devices in the beam) for a single beam line.

Protons offer the potential of precise dose deposition with the subsequent sparing of normal tissue.²⁶ High precision is only available if there is a high degree of attention to details. Failure to pay attention to these details may result in a poorer therapeutic outcome compared to photons, given the less forgiving nature of protons.

Meningioma

Approximately 90% to 95% of intracranial meningiomas are benign (WHO grade I), 5% are atypical (WHO grade II), and 3% are malignant (WHO grade III). The primary treatment is surgery. However if the resection is incomplete, recurrence rates of 55% at 10 years and 91% at 15 years have been reported.²⁹ Radiation therapy after incomplete resection has been shown to decrease recurrence in retrospective reviews.^30–33 Aggressive resection is generally not attempted for tumors at certain locations such as the cavernous sinus, petro-clival region, or sphenoid wing because of the associated morbidity. In these situations, primary radiation therapy has also been reported in retrospective reviews to produce good local control.^30,32 Proton therapy to doses of 50 to 74 CGE has been used to treat recurrent or incompletely resected meningiomas. The 3- to 5-year control rates have been reported to be 80% to 100%.^34–37 The result is summarized in Table 69-1. Late complication rates were found to be 10% to 25%. Currently, several institutions are testing hypofractionated proton therapy for benign meningiomas. For atypical and malignant meningiomas, one series reported 5- and 8-year control rates with radiation therapy of, respectively, 38% (atypical)/52% (malignant) and 19% (atypical)/17% (malignant). A nonrandomized comparison between proton therapy and photon therapy demonstrated a superior local control rate for proton therapy (80% versus 17% at 5 years; P = .003).³⁸

Low-Grade Glioma

The first treatment for low-grade glioma is surgical resection whenever feasible. After a gross total resection, the patient can usually be observed without adjuvant therapy. For incomplete resection, a randomized trial has demonstrated that adjuvant radiation therapy could reduce the incidence of tumor recurrence but did not influence survival.³⁹ However, if the tumor is not situated in an eloquent area where a recurrence could potentially cause significant neurologic deficit, postoperative radiation therapy could be postponed until there is evidence of recurrence. This approach is particularly relevant in children, because the delay in radiation therapy could postpone the potential effect of radiation on the development of the young brain. The use of conformal proton therapy has been reported in 27 children with progressive or recurrent low-grade astrocytomas.⁴⁰ The radiation doses were from 50.4 to 63 CGE. After a mean follow-up period of 3.3 years, local control and survival rates were, respectively, 87% and 93% for central tumors, 71% and 86% for hemispheric tumors and 60% and 60% for brainstem tumors. All children whose tumors were controlled maintained their performance status. All children with optic pathway tumors experienced stable or improved vision. Moyamoya syndrome was diagnosed in one child with Type 1 neurofibromatosis. In adults, a small prospective phase I/II trial for patients with low-grade (Dausmas–Duport grade 2) and intermediate grade (Daumas–Guport grade 3) gliomas has been reported.⁴¹ This was a dose escalation trial in which grade 2 tumors received 68.2 CGE and grade 3 tumors received 79.7 CGE. The majority of patients did not have total resection. The 5-year survival for patients with grade 2 tumors was 71% and for those with grade 3 tumors was 23%. The major cause of death was tumor recurrence. Three of seven survivors had evidence of radiation necrosis. The authors did not find improvement in outcome for patients with grade 2 and 3 gliomas with these radiation doses and scheme. The result is not surprising in view of the results of two randomized trials using photon therapy on WHO grade II astrocytomas showing no statistical difference between 50.4 Gy and 64.8 Gy and between 45 Gy and 59.4 Gy.^42,43

Glioblastoma

Currently, there is little justification to use proton therapy on patients with glioblastoma except in the context of a clinical trial with a well-defined rationale. A phase II trial to assess whether dose escalation to 90 CGE with conformal protons and photons in accelerated fractionation would improve the local control of glioblastoma and patient survival has been reported.⁴⁴ In this study, the eligibility criteria included age between 18 and 70 years, Karnofsky performance status greater than or equal to 70, residual tumor volume of less than 60 ml and a unilateral, supratentorial location. The median survival was 20 months and 2- and 3-year survival rates were, respectively, 34% and 18%. The median survival appeared superior to that in comparable conventionally treated patients, but this is not a prospective randomized trial. Interestingly, most tumor recurrence occurred in areas that received doses of 60 to 70 CGE and only one patient developed recurrence in the 90-CGE volume. Several patients developed radiation necrosis without tumor recurrence, and their survival time was found to be longer than for those patients who developed tumor recurrence. Quality of life was not reported in this study.

Craniopharyngioma

Craniopharyngioma is curable with complete surgical excision. However, in many cases, the tumor can adhere densely to adjacent critical structures such as the optic nerve/chiasm and hypothalamus. This is particularly true for the adamantinomatous type of craniopharyngioma that more commonly occurs in children. In such situations, aggressive attempts at resection could cause significant morbidity. Several retrospective reviews have demonstrated equivalent cure rates after gross total resection and after radiation therapy following tumor cyst decompression and/or biopsy.^45–47 In one series, the neurocognitive outcome was found to be better after radiation therapy than after surgery.⁴⁸ Proton therapy has been used in a small number of patients and the 5- and 10-year local control rates have been reported to be 93% and 85%, respectively.^49,50 About 20% of children were found to have learning difficulties but the functional status in adult patients was reported to be unaltered from the preradiotherapy status. Some patients developed new-onset panhypopituitarism. With strategic selection of proton beam directions, proton therapy has a distinct dosimetric advantage over photon therapy.⁵¹ Whether the advantage would result in improved functional outcome is a question for prospective clinical studies.

Pituitary Adenoma

Surgery, whether transphenoidal or via craniotomy, is the primary treatment for pituitary adenoma. If the tumor invades the cavernous sinus, has a large suprasellar extension adherent to the optic chiasm or the floor of the third ventricle, or significantly erodes the bony floor of the sella, there is a relatively high risk of residual microscopic or macroscopic disease after surgery and a resultant risk of tumor recurrence. Postoperative radiation therapy in doses of 45 to 50.4 Gy has produced a 10-year relapse-free survival rate of over 90%.⁵² This benign tumor is appropriately irradiated with a conformal technique (protons or photons). A small series using proton therapy has been reported.⁵³ The follow-up period was relatively short. Forty-four out of forty-seven patients showed no tumor progression. The only morbidity was hypopituitarism, which may or may not be related to the proton therapy.

Medulloblastoma

Craniospinal irradiation is the cornerstone of potentially curative therapy for most patients with medulloblastoma. Several dosimetric studies comparing protons and photons showed a clear advantage of proton therapy in its ability to reduce the radiation dose to the eyes, optic chiasm, hypothalamus-pituitary axis, cochleae, thyroid, lungs, heart, liver, and kidneys.^54–56 The lack of exit dose with proton therapy is most evident in the treatment of the spine as part of craniospinal irradiation. Fig. 69-9 demonstrates the proton dose distribution within the vertebral bodies and the subsequent fatty change in the marrow corresponding to the proton dosimetry (a form of in vivo dosimetric verification). Another study estimated that proton therapy for medulloblastoma could reduce the risk of second malignancy by approximately ten-fold when compared to photon therapy.⁵⁷ A cost-effectiveness evaluation also concluded that proton therapy could be cost effective and cost-saving when compared with conventional photon therapy in the treatment of children with medulloblastoma.⁵⁸ The potential to significantly reduce late effects of craniospinal irradiation by protons has led to an increasing number of patients with medulloblastoma being treated with proton therapy. Prospective studies to evaluate and compare the late morbidity and quality of life in patients treated with proton therapy or photon therapy are underway.

FIGURE 69-9 • Correspondence between proton dose distribution within the vertebral bodies and the subsequent fatty change in the marrow.

(Courtesy A. Mahajan, M.D., Anderson Cancer Center.)

Chordoma/Chondrosarcoma

Chordoma and chondrosarcoma can occur at the base of skull or spine and usually present significant therapeutic challenges. Although surgery is an important modality of treatment, complete surgical resection of the tumor is not always possible. Radiation therapy has been used postoperatively for subtotally resected tumors as well as for recurrence after surgery. Conventional photon radiation techniques have not allowed high doses of radiation to be delivered safely and doses such as 50 to 55 Gy have produced local recurrence rates of 80% to 100%.^59,60 In the past, higher doses (66 to 80 CGE) could be delivered only with conformal proton therapy and the reported results were better than those with photon therapy.^61–64 For chondrosarcoma at the base of skull, the 3- and 5-year local control rates after proton therapy were, respectively, 91.6% to 94% and 75%. For chordoma at the base of skull, the 3- to 4-year local control rates after proton therapy were 53.8% to 87.3%, and the 3- to 5-year survival rates were 80.5% to 93.8% (Table 69-2). Proton therapy has also been used to treat chordoma and chondrosarcoma in pediatric patients with reported local control rates of 60% and 100%, respectively.⁶⁵ Proposed prognostic factors include gender and residual tumor volume.^60–62 These high doses of radiation deliverable with protons have been associated with significant complications such as cranial nerve injury and brain necrosis in 7% to 18% of patients.^66,67 Currently, two prospective randomized studies compare 70 CGE with 78 CGE and 72 CGE with 80 CGE to test whether the higher doses could improve the rate of tumor control. In the spine, especially the sacrum, high doses of proton/photon-beam radiation therapy have also been used to treat chordoma either alone or combined with surgery.⁶⁸ An interesting observation was that proton therapy was more effective when used postoperatively for the primary tumor than when used for recurrent chordomas. Local control by surgery and radiation was 12 out of 14 for primary tumors and one out of seven for recurrent tumors. Proton therapy alone with doses of 73 CGE or higher produced local control in three out of four patients. The tolerance of cauda equine has been shown to be different between men and women in this population of patients. The TD 5/5 and TD 50/5 were estimated to be, respectively, 55 CGE and 72 CGE for men and 67 CGE and 84 CGE for women.⁶⁹

An experience using spot-scanning proton beam irradiation for spinal chordoma has been reported.⁷⁰ The median dose used was 72 CGE and dose to the center of spinal cord was limited to 54 CGE. The 3-year overall survival and progression-free survival were 84% and 77%, respectively. The presence of metallic surgical implants was found to be associated with an increase in the rate of local failure. One reason could be that the implants caused “cold spots” in proton dose distributions in the tumor. Postoperative gross residual tumor above 30 ml was also negatively associated with overall survival and progression free survival. In this series, 4 out of 26 patients developed late adverse events.

Paranasal Sinus Tumors

Tumors in this region have a variety of histologies, including squamous cell carcinoma, carcinoma with neuroendocrine features, adenoid cystic carcinoma, adenocarcinoma, and sarcoma. They tend to present in a locally advanced stage and often involve the orbit and the base of skull, and therefore treatment can be challenging. Surgery is usually the first treatment, but adequate negative margins are difficult to achieve without significant morbidity. High doses of postoperative radiation therapy are frequently needed. Before the introduction of IMRT, high radiation doses could be satisfactorily delivered only with proton therapy. A dosimetric comparison between intensity modulated photon therapy and intensity modulated proton therapy showed comparable target dose conformation, but only protons could spare critical structures at all dose levels while simultaneously providing acceptable dose homogeneity within the target volume.⁷¹

The outcomes for 102 patients with locally advanced sinonasal cancers treated with a combination of protons and photons with or without surgery was recently reported.⁷² Patients who had complete surgical resection received a median dose of 67.6 Gy (range: 59.4 to 77.6 Gy); those who had partial resection or biopsy received median doses of 75.4 to 75.6 Gy (range: 55.4 to 79.4 Gy). Five-year local control rates were 82% to 95% irrespective of the extent of surgery. Complete resection was, however, associated with better disease-free survival and lower rate of distant metastasis than incomplete resection. The overall 5-year survival was worse for patients with squamous cell carcinoma (about 40%) than for patients with neuroendocrine tumors or adenoid cystic carcinoma (almost 70%). A separate analysis of visual outcome of a group of patients treated on an accelerated fractionation schedule demonstrated that 70 CGE could be delivered to the tumor with acceptable ophthalmologic complications (5-year probability of late effects of normal tissues [LENT]/common toxicity criteria [CTC] grade 2 or higher being 20.7% [±7.8]).⁷³

Uveal Melanoma

To date, the largest number of patients treated with proton therapy has been those diagnosed with uveal melanoma. Dosimetric comparison with stereotactic photon therapy showed similar dose conformation, but lower doses to the ipsilateral lachrymal gland and total sparing of the contralateral eye as well as lower doses to the thyroid.^74,75 The proton radiation doses used have been between 50 and 70 CGE, usually delivered in four fractions. A randomized trial testing 70 CGE versus 50 CGE did not show a significant difference in tumor control rates, rates of metastasis, or the overall complication rates,⁷⁶ but the lower dose may be prudent for parapapillary and paramacular tumors to reduce complications. The 3- to 15-year local control rates and eye retention rates have been reported to be, respectively, 95% or higher and 84% to 92%.^77–79 Even for large uveal melanomas (i.e., at least 10 mm maximum thickness or at least 20 mm maximum basal diameter), the 2-year local control rate was 67% and the 2-year metastasis-free survival was 90% and visual acuity 20/200 or better was achieved in 25% of the treated patients.⁸⁰ Despite the high local control rate, death from metastasis could occur in over 50% patients with poor prognostic features. Liver is the most common site of metastasis. Reported prognostic factors include age, gender, tumor size, ciliary body involvement, retinal detachment, and local tumor recurrence.^77–7981 Complications include rubeosis iridis, neovascular glaucoma, cataracts, and radiation vasculopathy (maculopathy and papillopathy). Cumulative 5-year rates of 64%, 35%, and 68%, respectively, for radiation maculopathy, radiation papillopathy, and vision loss have been reported.⁸² The complication rates appeared to be correlated with radiation dose to the macula and optic disc and enhanced by a history of diabetes. A second course of proton beam radiation therapy has been used in a small series of patients who developed recurrent uveal melanoma after an initial course of proton therapy.⁸³ The doses of the second course ranged between 48 to 70 CGE. The 5-year local control rate and eye-retention rates were, respectively, 69% and 55%, and the 5-year metastasis-free survival was 73%. About a quarter of the reirradiated patients maintained useful vision.

Pediatric Sarcomas

A small series of pediatric patients with orbital rhabdomyosarcoma treated with PSPT has been reported.⁸⁴ At a median follow-up of 6.3 years, six out of seven patients achieved local control. A dosimetric comparison against 3D conformal photon plans showed that protons were associated with lower doses to the brain, pituitary, hypothalamus, temporal lobes, and contralateral orbital structures. Another small series of children with rhabdomyosarcoma or other soft-tissue sarcomas treated with spot-scanning proton therapy has been reported.⁸⁵ After a median follow-up of 18.6 months, 83.3% of children with rhabdomyosarcoma achieved local control, whereas 50% of those with nonrhabdomyosarcoma did so. As the number of proton therapy centers increases, more children with rhabdomyosarcoma or other sarcomas are being and will be treated with proton therapy, usually in combination with chemotherapy. More results will, hopefully, be available in a few years.

Thoracic Tumors (Non–Small Cell Lung Cancer)

The clinical experience with proton therapy for thoracic tumors primarily has involved the treatment of non–small cell lung cancer (NSCLC). NSCLC may be the area that realizes the most incremental benefit over traditional photon therapy owing to the high doses of radiation required to obtain adequate local control, the sensitivity of normal lung tissue to low radiation doses (e.g., 20 Gy), and the potential use of concurrent chemotherapy with the subsequent intensification of radiation toxicity. Proton therapy’s ability to deliver high radiation doses with relatively few entrance beams has led to its use for both early localized and locally advanced lung cancers.

Although surgical resection may be the treatment of choice for early stage (i.e., stage I) NSCLC, many patients are deemed medically inoperable or refuse to undergo thoracotomy. Proton therapy affords an opportunity to treat these patients effectively with higher radiation doses in a hypofractionated manner. The physical properties of proton beams allow good dosimetric coverage, and the utilization of fewer entrance beams minimizes dose to normal lung tissue. This may be even more critical in patients who have poor baseline pulmonary reserve. Shioyama and colleagues published their clinical experience in treating 51 NSCLC patients with proton therapy (protons alone: 33; photons and protons: 19) at the University of Tsukuba.⁸⁶ Twenty-eight of these patients had stage I disease and were treated to median doses of 70 Gray (Gy) (range: 60 to 81 Gy) for stage IA (n = 9) and 78 Gy (range: 60 to 93 Gy) for stage IB (n = 19). The median fraction size was 3 Gy (range: 2 to 6 Gy). Five-year local control rates were 89% and 39%, respectively, with 5-year overall survival rates of 70% and 16%, respectively. Only one patient experienced grade 3 toxicity, and no patients had grade 4 or higher toxicities.

This initial data led to a phase I/II trial of hypofractionated proton therapy in 21 stage I NSCLC patients (11 stage IA, 10 stage IB) by the same group.⁸⁷ The first three patients received 50 Gy in 10 fractions and subsequent patients received 60 Gy in 10 fractions. The RBE was considered 1.0 for protons in this study (versus the more commonly used RBE of 1.1). With a median follow-up of 25 months, local progression-free rates for stage IA and IB patients were 100% and 90%, respectively. The 2-year overall and cause-specific survival rates were 74% and 86%, respectively. Two patients experienced late grade 2 toxicity, but no patient had grade 3 or higher toxicity.

In a similar phase II trial, investigators from Loma Linda University Medical Center treated 68 patients with stage I NSLC (29 T1, 39 T2) with hypofractionated proton therapy.⁸⁸ The initial 22 patients received 51 CGE in 10 equal fractions and the subsequent 46 patients received 60 CGE in 10 fractions. In contrast to the Tsukuba study, the proton RBE in this study was considered to be 1.1. All patients had a minimum follow-up interval of 12 months with a median follow-up of 30 months. The 3-year local control rates were 87% for T1 tumors and 49% for T2 tumors, and the corresponding median survival durations were 39 and 19 months, respectively. Patients who received 60 CGE had significantly better 3-year overall survival rates than patients receiving 51 CGE (55% versus 27%, P = .03). No cases of pneumonitis or esophageal or cardiac toxicity were noted.

The clinical data on proton therapy for locally advanced lung cancer (stage III) is limited and often combines protons with photons. Comparative dosimetric studies suggest that proton therapy may have a benefit over photon therapy even if IMXT is used. Shioyama and colleagues published their small experience of treating eight stage III and 1 stage IV patients with proton therapy to gross tumor volume and photon therapy to the primary and elective regional lymph nodes without concurrent chemotherapy.⁸⁶ The 2-year and 5-year overall survival rates were 62% and 0% and the corresponding cause-specific survivals were 70% and 0%, respectively.

In a prospective study, Bush and colleagues from Loma Linda reported their experience with eight stage IIIA NSCLC patients treated with combination photons (45 Gy in 1.8-Gy fractions) and protons (28.8 CGE in 1.8-CGE fractions delivered as concomitant boost with the last 16 photon treatments) to a total dose of 73.8 CGE.⁸⁹ Concurrent chemotherapy was not routinely used. The 2-year overall survival and disease-free survival rates were 13% and 19%, respectively. The majority of the failures were distant (four of six) with only one in-field recurrence.

Although the early clinical experiences with proton therapy for locally advanced NSCLC were not impressive, one must consider that a significant portion of the radiation dose was given via photons, concurrent chemotherapy was not used, and 4D CT was not used for treatment planning. In a dosimetric comparative study, Chang and colleagues from MDACC showed significant reduction in dose to the normal lung, spinal cord, heart, and esophagus with the use of proton therapy compared to 3D photon therapy or IMXT (Fig. 69-10).^90,91 These investigators purport that these dosimetric “savings” with proton therapy will allow further dose-escalation and concomitant use of chemotherapy in stage III NSCLC with fewer side effects. This has led them to initiate a prospective study of proton therapy with concurrent chemotherapy for stage III patients.

FIGURE 69-10 • Dosimetric comparison between 3D-conformal photon therapy versus conformal proton therapy for stage III (T2N2) non–small cell lung cancer.

(From Chang JY, Zhang X, Wang X, et al. Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or intensity-modulated radiation therapy in Stage I or Stage III non–small cell lung cancer, Int J Radiat Oncol Biol Phys 2006;65:1087–1096.)

Abdominal Tumors (Liver Tumors)

Proton therapy has the capacity to be used in various tumors of the abdomen, but the main historical clinical experience has been with hepatocellular carcinoma (HCC). Although surgical resection may be the preferred therapy, the extent and location of the lesion and/or the poor medical condition of the patient (e.g., secondary to cirrhosis) may be a contraindication for the use of surgery. Radiation therapy has been shown to be effective, but the high doses needed for local control and the radiosensitivity of liver tissue complicate the use of conventional photon therapy, especially for large lesions in medically compromised patients. Similar to the situation with NSCLC, proton therapy allows dose-escalation radiotherapy with relatively few entrance beams, thereby minimizing the exposure to the nonaffected liver.

The proton group at the University of Tsukuba reported their retrospective experience with proton therapy in 162 patients treated from 1985 to 1998.⁹² Several patients had multiple tumors treated (usually simultaneously) resulting in 192 total tumors irradiated. All the treatments were delivered using hypofractionated regimens (3.5 to 5 Gy) and total doses ranged between 50 Gy (10 fractions) to 84 Gy (24 fractions) with an RBE of 1.0. Two ports (lateral and anterior/posterior) were typically used, but other angles were used when necessary to avoid overdosing the gastrointestinal tract (Fig. 69-11). At a median follow-up interval of 31.7 months (range: 3.1 to 133.2 months), the 5-year local control rate was 86.9% and the corresponding overall survival rate was 23.5%. Survival appeared to be impacted by the level of liver dysfunction, with over 50% dying without tumor progression (e.g., liver cirrhosis). The acute side effects were limited primarily to elevation in liver enzymes (9.7%) and only five patients had grade 2 or higher late toxicity. Subsequent publications by this group have shown that proton therapy may be an effective modality for repeat treatments as well as for patients older than 80 years.^93–95

FIGURE 69-11 • Proton treatment plan for hepatocellular carcinoma (60 Gy in 10 fractions).

(From Hata M, Tokuuye K, Sugahara S, et al: Proton beam therapy for aged patients with hepatocellular carcinoma, Int J Radiat Oncol Biol Phys 2007.)

In a prospective phase II study, Bush and colleagues from Loma Linda treated 34 HCC patients with proton therapy to a total dose of 63 CGE in 4.2-CGE fractions (RBE = 1.1).⁹⁶ This translates to a total dose of approximately 75 CGE in 2-CGE fractions. Beam angles were customized to the patient’s anatomy and tumor location but a two-beam arrangement (paired right posterior oblique ports) was most commonly used. All patients had a minimum follow-up period of 6 months and, at a median follow-up interval of 20 months, the 2-year local control rate was 75% and the overall survival rate was 55%. The treatments were well tolerated with few patients having signs of significant radiation-induced liver disease; however, six patients developed ascites after treatment.

Pelvis (Prostate)

The most common pelvic tumor treated to date with proton therapy has been prostate cancer. Proton therapy has offered a relatively straightforward treatment planning option for dose-escalation radiotherapy in this disease. One of the first randomized dose-escalation trials was performed using a proton boost. Shipley and colleagues conducted a randomized trial in 202 men with locally advanced prostate cancer (T3-4, N0-2), comparing 75.6 versus 67.2 CGE using 50.4 Gy delivered with four-field photons followed by either 25.5 CGE with protons (single perineal field) or 16.8 Gy via photons.⁹⁷ Patients were treated from 1982 to 1992 (many in the pre–prostate-specific antigen [PSA] era) and no hormone therapy was given. With a median follow-up of 61 months (range: 3 to 139 months), there were no significant differences in overall, disease-specific, or recurrence-free survival. There was a trend toward improved local control in the higher dose arm with 5- and 8-year local control rates of 86% and 73%, respectively, versus 81% and 59%, respectively, in the conventional dose arm. Only patients with poorly differentiated tumors showed a statistically significant local control benefit on subset analysis (5-year rates of 94% versus 64%, respectively; P = .0014). The 8-year actuarial rectal toxicity rates were higher in the high dose arm (32% versus 12%; P = .002). However, the majority of men (31 of 34) with rectal bleeding were scored as RTOG grade 2 or less. Urinary toxicity rates were initially not significantly different, but a subsequent chart review of some of these patients suggested more persistent urinary issues in the high dose arm.⁹⁸ The results of this study may not have applicability for modern proton therapy since these patients would likely receive combined hormonal and radiation therapy today, the majority of the dose was delivered via photons, and the perineal boost technique may not be optimal and has been largely abandoned. The last point may be especially true if one considers that the proton therapy was delivered with a split-course (1-week break) and a gold fiducial marker was placed in the apex. Depending upon the size of the marker, it may have resulted in dose shadowing at the target or inaccuracy in the CT numbers on the treatment planning scan because of metallic artifacts.⁹⁹

The largest single institution experience in treating prostate cancer with proton therapy was published by Slater and colleagues from Loma Linda. They reported their retrospective experience using proton therapy (with and without combination photon therapy) in 1255 men with T1-3 prostate cancer treated from 1991 to 1997.¹⁰⁰ Patients initially were treated with 30 CGE using opposed lateral proton beams to the prostate and seminal vesicles followed by 45 Gy to the first- and second-echelon pelvic lymph nodes using four-field photons. In later years, pelvic nodes were electively irradiated with photons on the basis of a >15% risk of lymph node involvement according to the Partin nomogram. Men with a <15% risk received proton therapy alone to the prostate and seminal vesicles to a dose of 74 CGE prescribed to isocenter. Proton treatments were performed with the assistance of a water-filled endorectal balloon, which helped minimize prostate motion and displaced the posterior and superior rectum away from the treatment fields. With a median follow-up interval of 62 months (range: 1 to 132 months), the 5-year and 8-year actuarial biochemical disease-free survival rates were 75% and 73%, respectively (using 1996 ASTRO consensus definition of three consecutive rises backdated). Significant independent predictors of biochemical outcome included pretreatment PSA, Gleason score, and posttreatment PSA nadir. Severe toxicity rates were low, with only 1.2% of patients experiencing late toxicities of RTOG grade 3 to 4. In a previous report with fewer patients and shorter follow-up, this group reported the 3-year late gastrointestinal and genitourinary RTOG grade 2 toxicity rates as 6% and 5%, respectively.¹⁰¹

These promising results led to a subsequent randomized dose-escalation trial comparing 70.2 versus 79.2 CGE (delivered at 1.8 CGE per fraction) in 393 men with T1b-2b prostate cancers with PSA <15 ng/mL between 1996 and 1999.¹⁰² All men received a combination of protons first (19.8 CGE versus 28.8 CGE) to the prostate with a 5-mm margin followed by 50.4 Gy with four-field photons to the prostate and seminal vesicles. With a median follow-up interval of 5.5 years (range: 1.2 to 8.2 years), there was a significant difference in 5-year biochemical control rates in favor of the high-dose arm (61.4% versus 80.4%; P < .001). This also was the first published dose-escalation study that showed a benefit to dose-escalation radiation for low-risk patients. The reader should be aware that the initial publication of this study in 2005 was flawed by an error in the statistical analysis of biochemical failure. Specifically, the original publication erroneously defined any three PSA rises as a failure rather than three consecutive rises.

A subsequent reanalysis revealed that when the correct method for calculating the ASTRO-defined failure was used, the differences in PSA outcomes between the treatment arms remained significant (5-year biochemical control rates of 78.8% versus 91.3%; P < .001).¹⁰³ Subset analysis showed a significant benefit to higher radiation doses for low risk patients with 5-year biochemical control rates of 82.6% versus 97.3% (P < .001) and intermediate risk patients (74.5% versus 87.4%; P = .02) (Fig. 69-12). Severe toxicity rates were low in either arm with grade 3 toxicity rates of only 3% and 2% in the conventional- and high-dose arms, respectively. Significantly more late grade 2 rectal toxicity was reported in the higher dose arm (17% versus 8% for the conventional dose arm; P = .005). However, these rates appear to be lower than seen in previously published dose-escalation trials with photons alone.^104–106 Late grade 2 urinary toxicities were not significantly different between the two arms (18% to 20%). Preliminary data suggests that health-related quality of life between these two arms were also not significantly different.¹⁰⁷ The favorable outcomes and tolerability with high-dose radiation using protons for a portion of the treatment has led to a phase I/II study investigating the tolerability and efficacy of 82 CGE (in 2-CGE fractions) for men with T1c-2b prostate cancers and PSA ≤15 ng/mL (American College of Radiology 0312).

FIGURE 69-12 • Freedom from biochemical failure comparing conventional-dose (70.2 CGE) versus high-dose (79.2 CGE) radiation therapy with combination protons and photons. CGE, Cobalt Gray equivalent.

(From Zietman AL: Correction: inaccurate analysis and results in a study of radiation therapy in adenocarcinoma of the prostate, Jama 299:898-899, 2008.)

Future improvements in proton therapy for these tumors will likely be founded on similar improvements for photon delivery. For example, the advent of 4D CT for treatment planning will improve target definition in tumors of the lung and liver. This is especially important for lung tumors since the relative tissue densities in the thorax vary greatly with a corresponding difference in radiologic path length. Improved knowledge and consistency of the radiologic path length in the proton beam path will result in better treatment plans.^8,108 4D treatment planning may also be helpful in subsequent gating of proton therapy and has been used in the lung and liver by the group at Tsukuba.^86,87,92,93