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Proton therapy

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Proton therapy is a type of particle therapy which uses a beam of protons to irradiate diseased tissue, most often in the treatment of cancer. The chief advantage of proton therapy is the ability to more precisely localize the radiation dosage when compared with other types of external beam radiotherapy, though it is controversial whether this provides an overall advantage compared to other, less expensive treatments.

Description

In a typical treatment plan for proton therapy, the Spread Out Bragg Peak (SOBP, dashed blue line), is the therapeutic radiation distribution. The SOBP is the sum of several individual Bragg peaks (thin blue lines) at staggered depths. The depth-dose plot of an x-ray beam (red line) is provided for comparison. The pink area represents the additional dose delivered by x-ray radiotherapy which can be the source of damage to normal tissues and of secondary cancers, especially of the skin.[1]
Main article: Radiation therapy § Mechanism of action

Proton therapy is a type of external beam radiotherapy using ionizing radiation. During treatment, a particle accelerator is used to target the tumor with a beam of protons.[2][3] These charged particles damage the DNA of cells, ultimately causing their death or interfering with their ability to proliferate. Cancerous cells are particularly vulnerable to attacks on DNA because of their high rate of division and their reduced abilities to repair DNA damage.

Due to their relatively large mass, protons have little lateral side scatter in the tissue; the beam does not broaden much, stays focused on the tumor shape and delivers only low-dose side-effects to surrounding tissue. All protons of a given energy have a certain range; very few protons penetrate beyond that distance.[4] Furthermore, the dose delivered to tissue is maximum just over the last few millimeters of the particle’s range; this maximum is called the Bragg peak.[5]

To treat tumors at greater depths, the proton accelerator must produce a beam with higher energy, typically given in eV or electron volts. Tumors closer to the surface of the body are treated using protons with lower energy. The accelerators used for proton therapy typically produce protons with energies in the range of 70 to 250 MeV (mega electron Volts: million electron Volts). By adjusting the energy of the protons during application of treatment, the cell damage due to the proton beam is maximized within the tumor itself. Tissues closer to the surface of the body than the tumor receive reduced radiation, and therefore reduced damage. Tissues deeper within the body receive very few protons so that the dosage becomes immeasurably small.[4]

In most treatments, protons of different energies with Bragg peaks at different depths are applied to treat the entire tumor. These Bragg peaks are shown as thin blue lines in the figure to the right. The total radiation dosage of the protons is called the Spread-Out Bragg Peak (SOBP), shown as a heavy dashed blue line in figure to the right. It is important to understand that, while tissues behind or deeper than the tumor receive no radiation from proton therapy, the tissue in front of or shallower than the tumor receive radiation dosage based on the SOBP.

History

The first suggestion that energetic protons could be an effective treatment method was made by Robert R. Wilson[6] in a paper published in 1946 while he was involved in the design of the Harvard Cyclotron Laboratory (HCL).[7] The first treatments were performed with particle accelerators built for physics research, notably Berkeley Radiation Laboratory in 1954 and at Uppsala in Sweden in 1957. In 1961, a collaboration began between HCL and the Massachusetts General Hospital (MGH) to pursue proton therapy. Over the next 41 years, this program refined and expanded these techniques while treating 9,116 patients[8] before the Cyclotron was shut down in 2002. The world's first hospital-based proton therapy center was a low energy cyclotron centre for ocular tumours at the Clatterbridge Centre for Oncology in the UK,[9] followed in 1990 at the Loma Linda University Medical Center (LLUMC) in Loma Linda, California. Later, The Northeast Proton Therapy Center at Massachusetts General Hospital was brought online, and the HCL treatment program was transferred to it during 2001 and 2002. By 2010 these facilities were joined by an additional seven regional hospital-based proton therapy centers in the United States alone, and many more worldwide.[10]

Application

The types of treatments for which protons are used can be separated into two broad categories. The first are those for disease sites that favor the delivery of higher doses of radiation, i.e. dose escalation. In some instances dose escalation has been shown to achieve a higher probability of "cure" (i.e. local control) than conventional radiotherapy.[11] These include (but are not limited to) uveal melanoma (ocular tumors), skull base and paraspinal tumors (chondrosarcoma and chordoma), and unresectable sarcomas. In all these cases proton therapy achieves significant improvements in the probability of local control over conventional radiotherapy.[12][13][14]

The second broad class are those treatments where the increased precision of proton therapy is used to reduce unwanted side effects, by limiting the dose to normal tissue. In these cases the tumor dose is the same as that used in conventional therapy, and thus there is no expectation of an increased probability of curing the disease. Instead, the emphasis is on the reduction of the integral dose to normal tissue, and thus a reduction of unwanted effects.[11] Two prominent examples are pediatric neoplasms (such as medulloblastoma) and prostate cancer. In the case of pediatric treatments there is convincing clinical data showing the advantage of sparing developing organs by using protons, and the resulting reduction of long term damage to the surviving child.[15][16] Children with cancer are major beneficiaries, because the proton beams are able to target tumors with great precision, sparing neighboring tissue. That’s especially valuable for children because their bodies are still growing. Traditional radiation often stunts growth in children with cancer.[17]

In the case of prostate cancer the issue is not so clear. Some published studies found a reduction in long term rectal and genitio-urinary damage when treating with protons rather than photons (also known as X-ray or gamma ray therapy). Others showed the difference is small, and limited to cases where the prostate is particularly close to certain anatomical structures.[18][19] The relatively small improvement found may be the result of inconsistent patient set-up and internal organ movement during treatment, which offsets most of the advantage due to increased precision.[19][20][20][21] One source suggests that dose errors around 20% can result from motion errors of just 2.5 mm,[citation needed] and another that prostate motion is between 5–10 mm.[22]

However, the number of cases of prostate cancer diagnosed each year far exceeds those of the other diseases referred to above, and this has led some, but not all, facilities to devote a majority of their treatments slots to prostate treatments. For example two hospital facilities devote roughly 65%[23] and 50%[24] of their proton treatment capacity to prostate cancer, while a third devotes only 7.1%[25]

Overall worldwide numbers are hard to compile, but one example in the literature shows that in 2003 roughly 26% of proton therapy treatments worldwide were for prostate cancer.[26] Proton therapy for ocular (eye) tumors is a special case since this treatment requires only comparatively low energy protons (about 70 MeV). Owing to this low energy requirement, some particle therapy centers only treat ocular tumors.[8] Proton, or more generally, hadron therapy of tissue close to the eye affords sophisticated methods to assess the alignment of the eye that can vary significantly from other patient position verification approaches in image guided particle therapy.[27] Position verification and correction have to ensure that sensitive tissue like the optic nerve is spared from the radiation in order to preserve the patient’s vision.

Comparison with other treatments

The issue of when, whether, and how best to apply this technology is controversial.[28][29][30] As of 2012 there have been no controlled trials to demonstrate that proton therapy yields improved survival, or other clinical outcomes (including impotence in prostate cancer) compared to other types of radiation therapy, although a 5-year study of prostate cancer is underway at Massachusetts General Hospital.[31][32][33][34][34] Proton therapy is far more expensive than conventional therapy.[29][35] As of 2012 proton therapy required a very large capital investment (from US$100M to more than $180M).[28][30][36]

Preliminary results from a 2009 study, including high-dose treatments, showed very few side effects.[37]

X-ray radiotherapy

Irradiation of nasopharyngeal carcinoma by photon (X-ray) therapy (left) and proton therapy (right)

The figure at the right of the page shows how beams of X-rays (IMRT) left frame and beams of protons right frame, of different energies, penetrate human tissue. A tumor with a sizable thickness is covered by the IMPT spread out Bragg peak (SOBP) shown as the red lined distribution in the figure. The SOBP is an overlap of several pristine Bragg peaks (blue lines) at staggered depths.

Megavoltage X-ray therapy may be described as having more "skin sparing potential" than proton therapy: x-ray radiation at the skin and at very small depths is lower than for proton therapy. One study estimates that passively scattered proton fields have a slightly higher entrance dose at the skin (~75%) compared to therapeutic megavoltage (MeV) photon beams (~60%).[1] X-ray radiation dose falls off gradually, causing unnecessary damage to tissue deeper in the body and damaging the skin and surface tissue opposite the beam entrance. The differences between the two modalities depends on (a) the width of the SOBP, (b) the depth of the tumor, and (c) the number of beams being used to treat the tumor. The X-ray advantage of reduced damage to skin at the entrance is partially counteracted by damage to skin at the exit point. Since X-ray treatments are usually done with multiple exposures from opposite sides, each section of skin will be exposed to both entering and exiting X-rays. In proton therapy, skin exposure at the entrance point is higher, but tissues on the opposite side of the body than the tumor receive no radiation. Thus, x-ray therapy causes slightly less damage to the skin and surface tissues, and proton therapy causes less damage to deeper tissues in front of and beyond the target.[3]

A very important consideration in comparing these modalities is whether protons are delivered using the scattering method (historically, the most common method) or a spot scanning method. Spot scanning can adjust the width of the SOBP on a spot by spot basis, thereby reducing the volume of normal tissue located within the high dose region. In addition, spot scanning allows for intensity modulated proton therapy (IMPT) which actually means that individual spot intensities are determined by means of an optimization algorithm which allows the user to balance the competing goals of tumor irradiation and normal tissue sparing. The ability of using spot scanning is machine and institution-dependent.

Surgery

The decision to use surgery or proton therapy (or in fact any radiation therapy) is based on the tumor type, stage, and location. In some instances surgery is superior (e.g. cutaneous melanoma), in some instances radiation is superior (e.g. skull base chondrosarcoma), and in some instances they are comparable (e.g. prostate cancer). In some instances, they are used together (e.g. rectal cancer or early stage breast cancer). The benefit of external beam proton radiation lies in the dosimetric difference from external beam x-ray radiation and brachytherapy in cases where the use of radiation therapy is already indicated, rather than as a direct competition with surgery.[11] However, in the case of prostate cancer, the most common indication for proton beam therapy, no clinical study directly comparing proton therapy to surgery, brachytherapy, or other treatments has shown any clinical benefit for proton beam therapy. Indeed, the largest study to date showed that IMRT compared with proton therapy was associated with less gastrointestinal morbidity.[38]

Side effects and risks

Main articles: Radiation therapy § Side effects, and Adverse effect

Proton therapy is a type of external beam radiotherapy, and shares risks and side effects of other forms of radiation therapy. Proton therapy has been in use for over 40 years, and is a mature treatment technology. However, as with all medical knowledge, understanding of the interaction of radiation (proton, X-ray, etc.) with tumor and normal tissue is still imperfect.[39][40]

Costs

Proton therapy is expensive. The sophisticated technology required for proton therapy suggests that proton therapy will continue to be more expensive than conventional radiotherapy treatments. The question is whether the proposed improvements from proton therapy justify the increased cost of these treatments. Goitein & Jermann [41] performed an analysis and determined that the relative cost of proton therapy is approximately 2.4 times that of x-ray therapies. This relative cost is expected to reduce as proton technology becomes more widely available. A similar analysis by Lievens & Van den Bogaert[42] determined that the cost of proton therapy is not unrealistic and should not be the reason for denying patients access to this technology. In some clinical situations, proton beam therapy is clearly superior to the alternatives [43][44] Another study in 2007, expressed concerns about the effectiveness of proton therapy for treating prostate cancer[45] Although, with the advent of new developments in proton beam technology, such as improved scanning techniques and more precise dose delivery ('pencil beam scanning'), this situation may change considerably.[46] Amitabh Chandra, a health economist at Harvard University, has been quoted as saying that "Proton-beam therapy is like the death star of American medical technology... It's a metaphor for all the problems we have in American medicine.”[47] However, another study has shown that proton therapy in fact brings cost savings.[48] The advent of second generation, and much less expensive, proton therapy equipment now being installed at various sites may change this picture significantly.[49]

Treatment centers

As of August 2013, there were 43 particle therapy facilities in the world, representing a total of 121 treatment rooms available to patients on a regular basis. They are located in Canada, China, Proton Therapy Center Czech (Proton Therapy Center Czech, http://en.ptc.cz/), France, Germany, Italy, Japan, South Korea, Poland, Russia, South Africa, Sweden, Switzerland, the UK and the US.[50] 28% of the proton therapy facilities are located in the US and 23% are located in Japan and more than 96,537 patients had been treated.[51]

One hindrance to universal use of the proton in cancer treatment is the size and cost of the cyclotron or synchrotron equipment necessary. Several industrial teams are working on development of comparatively small accelerator systems to deliver the proton therapy to patients.[52] Among the technologies being investigated are Superconducting synchrocyclotrons (also known as FM Cyclotrons), ultra-compact synchrotrons, Dielectric wall accelerators,[52] and linear particle accelerators.[53]

United States

Proton treatment centers operating in the United States as of 2013 (in chronological order of first treatment date) include:[54][55]

Institution Location Year of first treatment Comments
University of California, Davis, Crocker Nuclear Laboratory[56] Davis, CA 1994 Ocular treatments only (low energy accelerator)
Loma Linda University Medical Center[57] Loma Linda, CA 1990 First hospital based facility in USA
Francis H. Burr Proton Center (formerly NPTC) at Massachusetts General Hospital (MGH) Boston, MA 2001 Continuation of Harvard Cyclotron Laboratory/MGH treatment program that began in 1961
Indiana University Health Proton Therapy Center Bloomington, IN 2004 Formerly MPRI
University of Florida College of Medicine-Jacksonville[58] Jacksonville, FL 2006
University of Texas MD Anderson Cancer Center[59] Houston, TX 2006
INTEGRIS Cancer Institute of Oklahoma[60] Oklahoma City, OK 2009 First of a number of planned ProCure facilities
CDH Proton Center[61] Warrenville, IL 2010 Second of a number of planned ProCure facilities
Roberts Proton Therapy Center - University of Pennsylvania Health System[62] Philadelphia, PA 2010 The largest proton therapy center in the world,[citation needed] it is part of a medical complex that includes the Hospital of the University of Pennsylvania, the Perelman Center for Advanced Medicine, and the Children's Hospital of Philadelphia.
Hampton University Proton Therapy Institute Hampton, VA 2010
ProCure Proton Therapy Center[63] Somerset, NJ 2012 Third of a number of planned ProCure facilities
ProCure Proton Therapy Center[64] Seattle, WA 2013 Fourth of a number of planned ProCure facilities
Siteman Cancer Center[65] St. Louis, MO 2013 First of the new ultra-compact, lower cost facilities to treat a patient.
Provsion Proton Therapy Center[66] Knoxville, TN 2014

See also

References

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Further reading

  • Greco C, Wolden S. Current status of radiotherapy with proton and light ion beams. Cancer. 2007 Apr 1;109(7):1227-38 PMID 17326046
  • "Use of Protons for Radiotherapy", A.M. Koehler, Proc. of the Symposium on Pion and Proton Radiotherapy, Nat. Accelerator Lab., (1971)
  • "Protons in Radiation Therapy: comparative Dose Distributions for Protons, Photons and Electrons, A.M. Koehler, W.M. Preston, Radiology, 104(1):191-195 (1972)
  • "Bragg Peak Proton Radiosurgery for Arteriovenous Malformation of the Brain" R.N. Kjelberg, presented at First Int. Seminar on the Use of Proton Beams in Radiation Therapy, Moskow (1977)
  • "Fractionated Proton Radiation Therapy of Cranial and Intracrainial Tumors" Austin-Seymor, M.J. Munzenrider, et al. Am.J.of Clinical Oncology 13(4):327-330 (1990)
  • "Proton Radiotherapy", Hartford, Zietman, et al. in Radiotheraputic Management of Carcinoma of the Prostate, A. D'Amico and G.E. Hanks. London,UK, Arnold Publishers: 61-72 (1999)
  • "Case studies reports, Proton Therapy Center Czech, http://en.ptc.cz/medical/case-studies/
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