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Trikalinos TA, Terasawa T, Ip S, et al. Particle Beam Radiation Therapies for Cancer [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2009 Nov. (Comparative Effectiveness Technical Briefs, No. 1.)

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Particle Beam Radiation Therapies for Cancer [Internet].

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Key Question 1

  • 1.a. What are the different particle beam radiation therapies that have been proposed to be used on cancer?
  • 1.b. What are the theoretical advantages and disadvantages of these therapies compared to other radiation therapies that are currently used for cancer treatment?
  • 1.c. What are the potential safety issues and harms of the use of particle beam radiation therapy?

1.a. What are the different particle beam radiation therapies that have been proposed to be used on cancer?

As of December 2007 at least 61,800 patients have received particle beam radiotherapy around the world for various cancers and other diseases. The vast majority (approximately 54,000 or 87%) have received protons. Fewer patients have received radiotherapy with carbon ions (approximately 4,500 or 7%), helium ions (approximately 2,000 or 3%) or other ions.i

1.b. What are the theoretical advantages and disadvantages of these therapies compared to other radiation therapies that are currently used for cancer treatment?

Particle beams offer the benefit of precise dose localization and have favorable dose-depth distributions, compared with conventional photon beam radiotherapy.6 It is theorized that this translates to favorable clinical outcomes compared to conventional radiotherapy. Particle beams have a steep increase in energy deposition at the Bragg peak, and deposit very little dose in the normal tissues beyond the Bragg peak location (Figure 1). Therefore, the radiation dose in the normal tissues both at the radiation field entry site and around the target area is less compared to photon radiotherapy.

For these reasons, it is expected that when one uses charged particles rather than photons to deliver a specific biologically effective dose to the tumor area, radiation-induced morbidity from normal tissue damage will be smaller. Conversely, one may have the opportunity to deliver higher (even lethal) doses to the tumor area with charged particles rather than photons, while inducing harms comparable to those seen with photon radiotherapy.6

The above is particularly appealing for inoperable tumors located adjacent to critical structures.7 In the case of uveal melanomas for instance, tumors may develop in close proximity to the optic disk, optic nerve and fovea. Proton beam radiotherapy can deliver therapeutic radiation doses with great precision so as to avoid surgical removal of the eye and preserve vision.6 Other examples where precise radiation targeting is critical are tumors of the skull base and spine (e.g., sarcomas, chordomas, and chondrosarcomas), that are adjacent to the brain, brain stem, cervical cord, optic chiasm, and spinal cord.1

It is theorized that the reduced cumulative dose to normal tissues with particle beam rather than photon radiotherapy is particularly beneficial to pediatric patients.6,8 This is because children may be more susceptible to radiation side effects compared to adults.8 In addition, a major concern is the potential for secondary radiation-induced malignancies that can appear long after treatment completion. There is evidence that such secondary malignancies increase with total radiation dose.8

We note that, even with charged particle beams, delivery of radiation therapy can be imprecise. Because of the way charged particles interact with matter, dose deposition with charged particle beams is dependent on tissue inhomogeneities (such as air cavities), posing obstacles to the calculation of the exact location of the distal Bragg peak. 9 Moreover, investigators have described a slight increase in the RBE of charged particles at the distal end of the beam,3 which may affect treatment planning.

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

The following descriptions do not constitute an exhaustive list.

Conventional photon radiotherapy

Conventional radiation therapy utilizes ionizing radiation in the form of X-rays generated by linear accelerators, or gamma rays emitted from isotopes such as Co-60. Photon beams deliver the maximum radiation dose just after entering the surface of human body, and gradually wane in energy deposition with penetration depth (Figure 1). Photon radiotherapy results in larger unnecessary radiation dose to normal structures compared to particle beam therapy. Contrary to particle beam therapy, the targeted tumor volume cannot be covered by a single radiation field in depth and lateral dimensions.

However, conventional radiotherapy is widely available and less costly than charged particle radiotherapy. For many patients in whom a whole region has to be irradiated (e.g., the whole pelvis in some patients with uterine cancer), the high precision of particle beam therapy may not be needed. Finally, substantial clinical experience has already accumulated on the biological effects of photons in various tissues and different doses. This is not true in the case of light ions such as carbon ions, (although it is less of an issue with protons).10


Modern radiotherapy delivery methods capitalize on advances in imaging and radiation treatment planning technologies and allow for much more precise targeting of photon radiotherapy, compared to conventional techniques. The most advanced method for the delivery of high radiation doses with photon beams is IMRT. IMRT delivers conformal radiation to the target tumor, by “crossing” multiple properly shaped radiation fields with various intensities through paths that spare radiosensitive and critical adjacent tissues.2,11 IMRT is already used in many hospitals in the US.

A possible concern is that IMRT has a higher integral radiation dose1 and increases in the total volume of tissues exposed to radiation compared to conventional radiation therapy. It is theorized that this may translate to higher risk for secondary radiation-induced malignancies, especially in pediatric populations.11

Stereotactic radiosurgery with photons

Photon stereotactic radiosurgery uses multiple photon beams of relatively low intensity that converge to the same area, effectively delivering a single, high-dose fraction of external radiation to a target lesion in the central nervous system. With advances in imaging technologies and immobilization techniques that take better account of tumor motions caused e.g. by respiration, this technique is now possible for cancers located outside the central nervous system. It is now considered one of several approaches to deliver ablative radiation doses directly to the target lesion with acceptable toxicity in adjacent normal tissues.12,13

However, stereotactic radiosurgery with photons is typically not used to irradiate large tumor areas.


Brachytherapy is another type of radiation therapy where one inserts small encapsulated radioactive sources in or adjacent to the treatment volume. Depending on the type of the source (and the intensity of the radiation) these may be inserted permanently or transiently. The sources emit beta radiation or alpha particles, which deposit all their energy in the immediately neighboring tissue, delivering very little dose to distal tissues. Depending on the type of cancer, the radiation source may be placed adjacent to the tumor (e.g., outside the sclera for some ocular cancers or in the uterus for some gynecologic malignancies), or may be directly implanted in the tumor (e.g., for prostate cancer).14

Brachytherapy has very specific indications. The insertion of the radioactive sources requires minor invasive procedures.

1.c. What are the potential safety issues and harms of the use of particle beam radiation therapy?

Generally speaking, the expected harms from a dose of radiation to a given tissue are considered to be determined by the biologically effective dose, rather than the type of the radiation (photon vs. charged particles).

We found no claims that any harm was specific to the nature of the radiation (i.e., charged particles vs. other types) in the literature we examined. Moreover, we found no mention of non-radiation related harms incurred by the instrumentation used to deliver radiotherapy with charged particles (e.g., injuring a patient during positioning in the treatment room).

In the previous sections we discussed expected benefits and harms stemming from the differential depth-dose distributions of different radiation delivery methods.

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.

Key Question 2

  • 2.a. What instrumentation is needed for particle beam radiation and what is the FDA status of this instrumentation?
  • 2.b. What is an estimate of the number of hospitals that currently have the instrumentation or are planning to build instrumentation for these therapies?
  • 2.c. What instrumentation technologies are in development?

2.a What instrumentation is needed for particle beam radiation and what is the FDA status of this 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.

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 (; (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.

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

2.b. What is an estimate of the number of hospitals that currently have the instrumentation or are planning to build instrumentation for these therapies?

As of this writing, at least 29 institutes around the world are currently operating facilities for particle beam radiation therapy (Appendix F, Table F1): 7 in Japan, 6 in the US, 3 in Russia, 2 in each of Switzerland, France, and Germany, and 1 in each of England, Canada, Italy, China, Sweden, South Africa and Korea. Table 2 lists the ones that are currently operating in the US.

Table 2. Currently operating particle beam facilities in the US.

Table 2

Currently operating particle beam facilities in the US.

There are at least 3 large facilities that are in construction phase in the US (Table 3). Around the world at least 9 additional particle beam centers have been planned, and 7 of them are in construction phase (4 in Germany, 1 in Switzerland, 1 in Italy and 1 in France; Appendix F, Table F2). As mentioned in the next section, several US hospitals have expressed interest in building smaller scale proton beam facilities.

Table 3. Large particle beam facilities that are being built in the US.

Table 3

Large particle beam facilities that are being built in the US.

2.c. What instrumentation technologies are in development?

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).

Key Question 3

Section C describes the results of a systematic scan of the eligible published literature.

Literature Selection

Our electronic searches yielded 4747 studies, 470 of which were retrieved in full text (Figure 3). Finally, 243 papers were included in the literature scan. The update search for comparative trials did not identify any additional eligible studies published after the initial search. Appendices C and D list the citations of the retrieved eligible papers and of the excluded papers (along with reasons for exclusion). Appendix E lists the citations of the case reports and case series papers that were examined for harms.

Figure 3. Flow of the literature.

Figure 3

Flow of the literature. The original search is shown on the left. The update search for comparative studies is shown on the right. * Russian and Dutch

3.a. Types of cancer and patient eligibility criteria

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.

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.

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.

3.b. Type of radiation, instrumentation, and algorithms used

Type of Charged Particle Radiation Used

Proton beam therapy

One hundred twenty-seven papers reported proton beam radiation therapy for various types of cancer. Proton therapy was administered mainly as a single radiation modality, either stand-alone therapy or a part of combined modality therapy (e.g., surgery followed by adjuvant radiotherapy), for ocular melanoma, bone and soft tissue sarcomas, non-small cell lung cancer, hepatocellular carcinoma, and breast cancer. For other cancers, such as malignant tumors in the head, neck, or spine (mainly consisting of chordoma or chondrosarcoma), prostate cancer, bladder cancer, uterine cancer, particle therapy was used either as booster irradiation of the main target lesion on top of conventional photon irradiation, or as the sole treatment.

Administered doses and fractionations thereof were heterogeneous and varied by the type of cancer. Studies administered protons or photon plus protons with mean total dose ranging from 32 to 94 GyE depending on cancer category. When used as booster therapy, proton irradiation was added on top of conventional photon radiotherapy of 40 to 50 Gy. The reported fraction size varied across and within cancer categories, ranging from 2.0 to 5.0 GyE in most instances. Most commonly, the scheduled total activity was fractionated into approximately 20 to 40 doses (one per day) necessitating a one- to two-month treatment period. In some studies where protons where the only radiotherapy (e.g., in non small cell lung cancer and breast cancer) a “hypofractionated” approach was used, with fraction doses in excess of 5.0 GyE, and approximately 2 weeks’ duration.23–28 Most ocular melanoma studies adopted a four or five fraction strategy, which was completed within a week.

Carbon ion beam therapy

Thirty-nine publications mainly from two institutions (NIRS, Japan and GIS, Germany) reported use of carbon ion beam therapy. In most cases, carbon ion therapy was used as the only radiation treatment. Treated cancers included malignant tumors in the head, neck and spine, non-small cell lung cancer, prostate cancer, uterine cancer, bone and soft tissue sarcomas, ocular melanoma, and hepatocellular carcinoma.

Most studies administered carbon-ions with mean total dose between 50 and 70 GyE with 15 to 25 treatment fractions during the overall treatment period of one to two months. Lung cancer and ocular melanoma studies used “hypofractionated” approaches with the mean total dose of 70 to 76 GyE administered within a week.29–32

Helium/Neon/Silicon ion beam therapy

A single currently inactive facility (University of California, Lawrence Berkeley Laboratory) reported 35 studies on the use of helium, neon or silicon ions from 1982 to 1998. Treated cancer categories were mainly limited to malignant tumors in the head, neck and spine, ocular melanoma (helium ions only), and some gastrointestinal cancers. These ions were used either as a local booster irradiation following conventional photon irradiation or as the only radiation therapy. Most studies administered total doses between 60 to 76 GyE in 30 to 37 fractions during two to three months, except for ocular melanoma studies in which four to five high-dose fractions were administered within 1–2 weeks.

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.”

3.c. Study design and size

We identified 10 RCTs and 13 nonrandomized comparative studies (see Comparators in this section). The remaining 220 studies were single-arm studies (case series or cohort studies); 185/220 were retrospective in design.

Table 5Number of papers per cancer type and study design

Cancer typeSingle armRCTsNonrandomized comparativeTotal
Bone/soft tissue6006

GI: gastrointestinal [cancers]; RCT: randomized controlled trial

Figure 6 shows histograms of study sample sizes per cancer category. Overall, 46 studies described more than 300 people. Among them were 1 RCT33 and 4 comparative nonrandomized trials.34–37

Figure 6. Sample sizes of studies per cancer type.

Figure 6

Sample sizes of studies per cancer type. GI: Gastrointestinal The horizontal axis has been transformed to a logarithmic scale to accommodate the large range of total number of included patients per study. The reference lines at 30 and 300 are arbitrarily (more...)

Figure 7 and Figure 8 show how the identified studies break down into single arm studies, and comparative ones, respectively, per cancer type and center.

Figure 7. Noncomparative studies per center and cancer type.

Figure 7

Noncomparative 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 noncomparative (more...)

Figure 8. Randomized and nonrandomized comparative studies per center and cancer type.

Figure 8

Randomized and nonrandomized comparative studies per center and cancer type. Each publication is represented by a red circle (randomized trials, RCTs) or a blue square (nonrandomized comparative studies, nonRCT) with size proportional to the logarithm (more...)

3.d. Comparators

In total we identified 10 papers describing 8 RCTs (Table 6) and 13 papers describing nonrandomized comparative studies.34–46

Table 6. Comparators assessed in the randomized controlled trials.

Table 6

Comparators assessed in the randomized controlled trials.


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.

Table 7

Comparators assessed in the nonrandomized comparative studies.

3.e. Length of followup

Followup duration varied per type of cancer. For example, in patients with glial tumors it ranged from 5 to 39 months, whereas in patients with uveal melanoma it ranged from 6 to 120 months. This partly reflects expected survival in each cancer type, as well as the different time periods over which patients with different cancers were enrolled and studied (Figure 5).

Figure 5. Enrollment periods for studies per cancer.

Figure 5

Enrollment periods for studies per cancer. GI: Gastrointestinal [cancer] Shown are enrollment periods of identified studies per cancer classification. Each paper reporting information on coverage periods is represented by a thin horizontal line. Papers (more...)

Figure 9 summarizes the mean or median followup duration for the 188 studies that reported this information. Almost all (171/188) reported a mean followup longer than 12 months and 31 reported mean followup longer than 5 years. Many studies did not report how many people were lost to followup (or were excluded due to incomplete followup).

Figure 9. Followup duration per cancer type.

Figure 9

Followup duration per cancer type. GI: Gastrointestinal The red reference lines correspond to mean followup duration of 12, 60 and 120 months.

3.f. Concurrent or prior treatments

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.

3.g. Outcomes measured

Almost all studies reported overall survival, either as crude rates at specific followup durations (e.g., at 5 years or at the end of followup) or as time-to-event analyses (e.g., Kaplan Meier curves). A sizable fraction of these studies also reported cause specific survival.

Many studies also reported rates of local control. However, the definitions of local control were heterogeneous within and across cancer types. Some defined local control anatomically (e.g., “no radiographic evidence of increase in size”18); some defined it by anatomic and clinical criteria (e.g., “absence of tumor growth on followup scans and absence of clinical signs of progression”); some used broad and non-specific criteria (e.g., “absence of evidence of tumor”30); and some used more detailed classification: e.g., one study defined local (“any recurrence at or adjacent to the initial primary site”) vs. regional (“any recurrence in the regional lymph nodes”) vs. metastatic (“any hematogenous recurrence”) recurrence.57

Most studies also reported crude rates of metastasis or distal disease. Cancer specific outcomes were also described. For example, studies on uveal melanoma reported rates of eye retention, vision retention, visual acuity and changes in tumor size, and studies on bladder cancer reported rates of bladder conservation.

3.h. Adverse events, harms, and safety issues reported

Approximately 20 percent of the studies used either the RTOG/EORTC (e.g., Hata 200758) or the LENT-SOMA scales (e.g., Hug 200218) to grade severity when reporting the harms or complications. A number of the studies made the distinction of acute vs. late complications, but “acute” and “late” were not uniformly defined across studies. A typical definition for late events was at least 3 months after the radiation treatment. Studies often reported the number of specific harms and adverse events; however, these counts overlap, because the same patient may have experienced multiple harms. The number of patients who experienced at least one severe or serious adverse event was not routinely reported.

Most studies provided a textual description of the harms or complications. Generally, the harms/complications observed were sustained in structures (extraneous to the tumors) that were unavoidably exposed to the particle beam in the course of treatment (see Summary Table of Appendix G, where serious adverse events are summarized –less serious harms like alopecia, eye lash loss, mild dermatitis were reported in the various studies but not summarized in this table). As seen in the Summary Table (Appendix G), serious harms that can appear in the treatment of cancer with particle beam therapy (alone or with other treatments) can be debilitating, irreversible, and life threatening. However, as mentioned in the Methods it is often impossible to ascribe specific harms to (particle beam) radiotherapy rather than chemotherapy or other cointerventions.

In screening through case reports and case series of less than 10 people, we did not identify mention of an adverse event or harm that was not already listed in the studies included in the literature scan.



Source http://ptcog​ – last accessed 10/29/2008, and Levin 2005.1


Source: http://www​.accessdata​​.cfm, Product Code “LHN” (last accessed 10/29/2008)


The information pertains to the Clinatron250™ or Monarch250™ proton beam radiotherapy system, by Still River Systems; the information is accessible at http://www​.stillriversystems​.com/products.aspx?id=50 (last accessed 10/29/2008).


Source: http://www​.browardhealth​.org/body.cfm?ID=2066 (last accessed 10/29/2008)

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