Description and Pros and Cons of Radiotherapeutic Alternatives to Particle Beam Therapy

The following descriptions do not constitute an exhaustive list.

Cautionary Note

Charged particle radiotherapy is less tolerant than photons of inadequacies in the planning, optimization and execution of radiation therapy. As the delivery of radiotherapy becomes more precise, several issues become more important. First, despite advances in medical imaging, the ability to distinguish tumor tissue from normal tissue is often limited, and this should be accounted for during treatment planning. Second, even when patient immobilization is excellent, one has to compensate for target tissue movements due to respiration, pulse, or peristalsis (e.g., using respiratory gating, widening the treatment volume margins or using other techniques). Third, with repeated treatments, it is important to accurately reproduce the alignment of the beam with the target area, and to account for the shrinkage of the irradiated target tissues as treatment sequence progresses.

Various charged particles (i.e., protons, helium or carbon ions) have different depth-dose distributions. Especially for light ions (such as carbon ions) and less so for protons, RBE values can vary with energy and/or depth. This means that isodoses (in Gy) in a given tissue (tissue volumes that receive the same radiation dose) do not necessarily correspond to biologically iso-effective doses (in GyE) (tissue volumes that have received the same biologically effective dose).¹⁰ In addition, the early and late radiosensitivity of various tissues could be different compared to what is known from photon radiotherapy.¹⁰ Therefore treatment plans generated by different methods for light ions may not result in identical actual doses in a given patient. In contrast to other ions, to date experience with protons suggests that for the same biological dose, the sensitivity of different tissues to protons is the same as with photons.

Instrumentation

Figure 2 outlines a proton beam radiotherapy facility that has 5 treatment rooms, 1 with a fixed beam and 4 with rotational gantries. This is one of several possible layouts of a particle beam treatment facility.

Figure 2

Schematic of a proton beam radiotherapy facility. Redrawn schematic of a proton therapy center. Adapted from a schematic of the Rinecker Proton Therapy Center, RPTC, Munich, Germany, under construction by ACCEL Instruments (http://www.proton-therapy.com; (more...)

The following describes the course of a particle beam used for radiotherapy of cancer, from its generation, to the patient room.

1. The charged particles are generated by an ion source. The ion source is specific to the type of the charged particle (i.e., is different for protons, helium ions or carbon ions).
2. The main accelerator is typically a cyclotron, a large device that can accelerate the charged particles to higher energies (typically above 50 MeV). For clinical uses, the maximum energies that charged particle accelerators achieve are between 230 and 250 MeV (some centers have a maximum clinical energy of 430 MeV see Appendix F, Table F1 for details).
3. The accelerated particle beam is then transported by a series of tubes that are under vacuum and shaping and focusing magnets towards the patient treatment rooms. Special devices (wedges) can decrease particle energy (speed) to desirable levels.
4. The largest facilities in the world have 5 rooms (Appendix F) for treatment administration. In the treatment rooms, the particle beam has either fixed direction (“fixed beam” – horizontal, vertical, or at a specific angle), or can be delivered to any desirable direction by use of rotational gantries. Gantries are large devices that can rotate 360 degrees (full circle) to deliver the particle beam at the angle specified by the radiotherapy team.
5. Finally, the beam delivery nozzle has the ability to shape the beam so that it conforms to the stereometry of the tumor (both the cross-section shape of the tumors and the shape of the distal surface, by using collimators and compensators, respectively).
6. Patients are properly positioned to receive therapy. At least some centers use robotic instrumentation that is able to position patients accurately with 6 degrees of freedom (6 directions of movement or rotation).
7. There is also a therapy control system that provide the interface to control and monitor equipment to deliver treatment to the patient.

The stages outlined above can differ for facilities that use other types of accelerators such as synchrotrons or synchrocyclotrons rather than cyclotrons. For example, synchrotrons offer the ability to control the energy, intensity and even the shape of the beam with electronic means, rather than physical means (wedges), but they deliver the beam in pulses rather than continuously. More detailed discussion of technical information is outside the scope of this Technical Brief.

Treatment Planning Software/Systems

Several pieces of software were developed for treatment planning since the early 80’s. Table 1 provides a list of treatment planning software/treatment planning systems released up to 2002.¹⁵

Table 1

List of treatment planning software/systems for particle beam therapy up to 2002.

We repeat the note made in the answer to key question 2.c that–especially for light ions such as carbon ions and less so for protons–RBE values depend on energy and/or depth, complicating treatment planning.¹⁰ Because this is an active area of research, treatment plans generated by different methods for light ions may not result in identical actual doses in a given patient.¹⁰

FDA Status of Proton Therapy Equipment

There are several companies that are undertaking construction of large scale particle treatment instrumentation and facilities. Currently, the FDA has cleared specific devices as substantially equivalent to a medical cyclotron using protons that was in commercial use during the 1960s and 70s. All US facilities that are currently active have FDA cleared instrumentation.ⁱⁱ

Accreditation and Training

There is no specific mandatory accreditation for the operation of particle beam facilities. The specialized personnel would have to become proficient with the treatment planning software and in the operation of the patient positioning platforms and the rotational gantries.

Training programs have been ongoing at the Massachusetts General Hospital and at the Loma Linda University for the past few decades. The training covers various aspects of proton therapy.

It is also advertised that, in the US, training programs are slated to be provided at the ProCure Training and Development Center (Bloomington, Indiana), a private center that will simulate a working proton therapy facility. The center is advertised to provide clinical, technical, interpersonal and administrative training for radiation oncologists, medical physicists, dosimetrists, radiation therapists and other staff.ⁱⁱⁱ

Proton Beam Therapy Using Conventional Accelerators (Cyclotron)

The current particle beam treatment facilities are large and costly (Table 3). Private companies design smaller instrumentation that can fit in a single room and will be able to treat one patient at a time (with protons only – not with other charged particles). According to company websites, the same room will accommodate the cyclotron, the proton beam delivery system, a treatment couch with pendant control, a radiographic patient positioning system, proton beam treatment planning, and a link to a treatment record and verification system.^iv The cost of this newer instrumentation is reported to be 20 million US dollars.

Details on the proprietary technologies that allow the shrinkage of the whole facility to a single room have not been disclosed. However, it is reported that the key technological advancement is the construction of a cyclotron that operates at a very large magnetic field (10 Tesla, using superconducting technology). The cyclotron weighs less than 20 tons, a 90% decrease in weight compared to other proton therapy cyclotrons.

As is the case for larger facilities, the new technology is advertised to include robotic patient positioning system, enabling clinicians to automatically reposition a patient from the control room.

The first such unit will be operated in the Barnes-Jewish Hospital, St Louis, Missouri, in late 2009.^v This center expects to treat approximately 250 patients each year. According to news items and press releases, several other hospitals have expressed interest in this new instrumentation, including Broward General at Ft. Lauderdale,^vi Orlando Regional at Orlando, Florida,^vii and Tufts Medical Center, Boston, Massachusetts. At least 17 hospitals have indicated interest in these smaller systems.

The FDA has not yet cleared this new instrumentation.

Proton Beam Therapy Using Non-Conventional Accelerators (Dielectric Wall Accelerator)

Other companies have recently announced plans to built small (room size) proton beam therapy facilities using a dielectric wall accelerator instead of a cyclotron.^viii

The FDA has not yet cleared this new instrumentation (which is still in early development stage).

Types of Cancer Studied

Particle beam therapy has been used in a variety of cancers in the published literature. More than half of the identified papers described treatment of ocular cancers (uveal melanoma in particular), and cancers of the head and neck (brain tumors, and tumors arising from skull base, cervical spine and nearby structures).

In order of decreasing number of studies, the following types of malignancies were also described: gastrointestinal (esophageal cancer, hepatocellular carcinomas of the liver, pancreatic cancer), prostate, lung, spine and sacrum, bone and soft tissue, uterine (cervix and corpus), bladder, and miscellaneous (skin cancer or a compilation of a center’s experience with a variety of cancers treated there) (Appendix G, Summary Table).

Figure 4 summarizes all identified papers per cancer type and center where the study was conducted. Studies shown in the same cell (i.e., studies from the same center describing a specific cancer) may include overlapping populations. Specific centers appear to have special interest on certain cancer types (Figure 4).

Figure 4

All identified studies per center and cancer type. Each publication is represented by a circle, with size proportional to the logarithm of the total sample size. The red numbers in the right hand corner of each cell denote the total number of studies (more...)

Specific Patient Inclusion and Exclusion Criteria

The vast majority of studies were retrospective cohorts describing the experience of a center in treating several types of cancer. The spectrum of included patients varied depending on the cancer type (Appendix G, Summary Table). For example, particle beam therapy was used in patients with non-small cell lung cancer (most stage I disease) who either refused surgery or had inoperable cancer. For uveal melanoma, particle beam therapy was used for a wide range of melanoma locations and sizes. For bone and soft tissue tumor, patients with either inoperable or metastatic disease were studied. Many studies did not provide information on the cancer staging of the included patients.

Mean or Median Ages

Only 7 papers focused on pediatric or adolescent populations, and they described the treatment of head and neck cancers or of soft tissue sarcomas.^16–22

In the remaining papers, mean (or median) ages ranged from 29 to 81 years of age, and many of them described populations with mean age above 50 years (Table 4).

Table 4

Distribution of mean or median ages per cancer category excluding 7 studies on pediatric or adolescent populations.

Periods of Patient Enrollment

Identified studies reported on patients who were treated from the early 1970’s onwards. Fifty-five percent of the papers reported the centers’ experiences with particle beam therapy over a time span of 10 years or longer.

Type of Charged Particle Radiation Used

Details on Instrumentation and Treatment Planning Algorithms

The identified studies did not provide details on the source of the particles, the accelerator, or the transportation of the beam to the patients (refer to Sections A and B for relevant information).

The description of the treatment planning algorithms (software/method) used by different centers is heterogeneous. Studies mentioned various specific pieces of software (e.g. EYEPLAN for ocular cancer), or alluded to the use of unspecified “treatment planning software” or “treatment planning system.”

RCTs

The identified RCTs compared lower vs. higher doses of particle beam therapy; particle beam therapy vs. other radiotherapy (e.g., brachytherapy or external photon therapy) or vs. a combination with additional therapy (e.g. laser thermotherapy for uveal melanoma). Table 6 lists the exact comparisons.

Nonrandomized Comparative Studies

Table 7 shows the identified 13 nonrandomized comparative studies. Comparators varied according to cancer type. For example, particle beam radiotherapy (as the only treatment) was compared to eye enucleation or brachytherapy in several studies on uveal melanoma. For treatment of other cancers particle beam radiotherapy was typically one of two or more components of the compared patient management strategies.

Table 7

Comparators assessed in the nonrandomized comparative studies.

Prior Interventions

Particle beam therapy has been explored as to both primary therapy for de novo cases and salvage therapy for relapsed and/or refractory cases. Studies on ocular melanoma, prostate cancer, non-small lung cancer, bladder cancer, breast cancer, and skin cancers mainly included untreated de novo cases without prior therapy. On the other hand, most hepatocellular cancer cases enrolled in the literature had already received prior therapeutic interventions such as transcatheter arterial chemoembolization (TACE), percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), surgery, or photon irradiation. Studies on malignant tumors in the head, neck, and spine, some gastrointestinal cancers, bone and soft tissue sarcoma treated at least some recurrent/refractory cases (who had already failed surgery) in addition to de novo cases, chemotherapy, or conventional photon radiotherapy.

Concurrent Interventions

Particle beam radiotherapy has been used alone, as a localized booster therapy on top of conventional radiotherapy, or in combination with other interventions. In most studies on ocular melanoma, hepatocellular carcinoma, non-small lung cancer, and uterine cancer, treatment consisted of irradiation (particle beam or photon plus particle beam) alone. Studies on other cancers described a combination of interventions including surgery or chemotherapy. For example, most treatment strategies employed for malignant tumors in the head, neck, and spine (mainly chordoma or chondrosarcoma) and breast cancer included surgery followed by adjuvant local irradiation. Radiotherapy for prostate cancer usually accompanied neoadjuvant, concurrent, or adjuvant hormonal therapy. Bladder cancer studies adopted multi-modality therapy comprising transurethral resection of the tumor lesion followed by chemoradiotherapy. Some head and neck cancer studies and bone and soft tissue sarcoma studies also employed chemoradiotherapy depending on tumor histology.