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Executive Summary – Sept. 14, 2009
Particle Beam Radiation Therapies for Cancer
Archive: Report is greater than 3 years old. Findings may be used for research purposes, but should not be considered current.
Table of Contents
Radiotherapy with charged particles can potentially deliver maximal doses while minimizing irradiation of surrounding tissues. It may be more effective or less harmful than other forms of radiotherapy for some cancers. Currently, seven centers in the United States have facilities for particle (proton) irradiation, and at least four are under construction, each costing between $100 and $225 million. The aim of this Technical Brief was to survey the evidence on particle beam radiotherapy.
Effective Health Care Program
The Effective Health Care Program was initiated in 2005 to provide valid evidence about the comparative effectiveness of different medical interventions. The object is to help consumers, health care providers, and others in making informed choices among treatment alternatives. Technical Briefs are designed to provide an overview of key issues related to clinical intervention or health care services, especially those for which there are limited published data or protocol-driven studies. They provide an early objective description of the state of the science, a potential framework for assessing applications and implications, a summary of ongoing research, and information on future research needs.
The full report and this summary are available at www.effectivehealthcare.ahrq.gov/reports/final.cfm
We searched MEDLINE from its inception to July 2009 for publications in English, German, French, Italian, and Japanese. We visited Web sites of manufacturers, treatment centers, and professional organizations for relevant information. Four reviewers identified studies of any design describing clinical outcomes or adverse events with 10 or more cancer patients treated with charged particle radiotherapy. Each of four reviewers extracted study, patient, and treatment characteristics; clinical outcomes; and adverse events for nonoverlapping sets of papers. A different reviewer verified data on comparative studies.
Figure A summarizes study designs, diseases, and outcomes in the 243 eligible papers. Charged particle beam radiotherapy was used alone or in combination with other interventions for both common cancers (e.g., lung, prostate, breast) and uncommon cancers (e.g., skull base tumors, uveal melanomas). Out of 243 papers, 185 were single-arm retrospective studies, and another 35 studies were prospective single-arm trials. The number of included patients ranged from 10 to 2,645 (median 63). Seven studies (3 percent) focused on a pediatric population; most of the remaining studies reported mean or median age above 50 years. The reported followup periods ranged from 5 to 157 months (median, 36 months) for 188 studies that commented on the pertinent data. Thirty-one studies followed patients longer than 5 years. Two studies had mean followup longer than 10 years.
The spectrum of included patients varied depending on the cancer type. For uveal melanoma, for example, particle beam therapy was used for a wide range of melanoma locations (i.e., choroid plexus, ciliary body, or iris) and sizes. For non-small-cell lung cancer and hepatocellular carcinoma, patients who either refused surgery or were ineligible for other types of therapies received charged particle beam radiotherapy. Typically, studies did not provide detailed information on the cancer staging or explicit descriptions of the clinical context—i.e., primary stand-alone or adjuvant therapy to other therapies for newly diagnosed cancer, or salvage therapy after treatment failure to previous therapies.
Figure A. Current clinical evidence on charged particle radiotherapy
Notes: Each circle represents a study, with size proportional to the logarithm of the total number of participants included in a study. The number in each cell indicates the total number of studies. Each row shows studies addressing one specific cancer category, and the columns show study designs with reported clinical outcomes. The “Other” row includes studies reporting multiple different cancers. The “Other” columns include studies reporting any clinical outcomes other than overall survival or cancerspecific survival (e.g., disease-free survival, progression-free survival, tumor response rate, or quality of life).
Abbreviations: CS=cancer-specific survival; GI=gastrointestinal; OvS=overall survival.
Most studies reported patient relevant-clinical outcomes: 151 studies (62 percent) described overall survival; 112 studies (46 percent), cancer specific survival; and 210 studies (86 percent), other surrogate outcomes of overall survival. Some studies reported clinical outcomes that are relevant to the quality of life, such as eye retention rates or visual acuity in uveal melanoma or bladder conservation rates in bladder can cer.
Seventy-five percent of studies (188) reported the adverse events. Not all studies adopted established scales to evaluate adverse events. Generally, the harms or complications observed were sustained in structures (extraneous to the tumors) that were unavoidably exposed to the particle beam in the course of treatment. However, it was not clear whether the reported adverse events were exclusively attributable to charged particle radiotherapy or to other cointerventions in the case of multimodality treatment, or whether they also would have occurred with conventional radiation therapy.
Eight randomized and nine nonrandomized comparative studies compared treatments with or without charged particles. The eight randomized trials were reported in 10 publications and enrolled 1,278 patients in total (Table A). Primary outcomes were explicitly stated in only three trials, which also reported a priori sample size calculations. Three trials pertained to prostate cancer, whereas the remaining dealt with less common cancers (ocular melanoma, skull base and brain tumors, and pancreatic cancer). All trials enrolled a relatively small sample size, ranging from 15 to 393 patients, and studied different comparisons (Table A). Most trials did not compare charged particle radiotherapy with contemporary alternates. No trial reported significant differences in overall or cancer-specific survival or in total serious adverse events.
|Cancer Type||Center||Comparison||N||Survival (overall/ specific)|
|Abbreviations: CPO=Centre de protonthérapie d’Orsay; GI=gastrointestinal; LLU=Loma Linda University; MGH=Massachusetts General Hospital; N=number of enrolled patients; RT=radiotherapy; TTT=transpupillary thermotherapy; UCSF=University of California San Francisco.|
|Ocula (uveal melanoma)||MGH (US)||Higher vs. lower dose proton RT||188||No/No|
|UCSF (US)||Helium RT vs. I125 brachytherapy||136; 184||Yes/Yes|
|CPO (France)||Proton RT vs. proton RT + laser TTT||151||Yes/Yes|
|Head/neck (skull base chordoma/chondrosarcoma)||MGH (US)||Higher vs. lower dose proton RT||96||Yes/No|
|Head/neck (brain glioblastoma)||UCSF (US)||Higher vs. lower dose proton RT||15||Yes/Yes|
|GI (pancreatic cancer)||UCSF (US)||Helium RT vs. photon RT||49||Yes/Yes|
|Prostate||MGH and LLU (US)||Photon RT + standarddose proton vs. photon RT + highdose proton||393||Yes/Yes|
|MGH (US)||Photon RT + local photon boost vs. photon RT + local proton boost||202; 191||Yes/Yes|
Nine nonrandomized comparative studies were reported in 13 papers (estimated 4,086 unique patients). Comparators assessed in the nonrandomized comparative studies are shown in Table B. Charged particle radiotherapy was compared with: brachytherapy for uveal melanoma (four studies); conventional photon radiation for other cancers (six studies); surgery (three studies). None of the studies used advanced statistical analyses, such as propensity score matching or instrumental variable regressions, to better adjust for confounding. Overall, no study found that charged particle radiotherapy is significantly better than alternative treatments with respect to patient-relevant clinical outcomes.
|Cancer Type||Center||Comparison||N||Survival (overall/ specific)|
|Ocular (uveal melanoma)||CPO (France)||Proton RT vs. I125 brachytherapy||1,272||Yes/No|
|UCSF (US)||Helium RT vs. I125 brachytherapy||766||No/No|
|MGH (US)||Proton RT vs. enucleation||556||Yes/Yes|
|UCSF (US)||Helium RT vs. I125 brachytherapy||426||No/No|
|CCO (UK)||Proton RT vs. I125 brachytherapy vs. Ru106 brachytherapy||267||Yes/No|
|MGH (US)||Proton RT vs. enucleation||120||Yes/Yes|
|UCSF (US)||Proton RT vs. proton RT + laser TTT||56||No/No|
|Head/neck (skull base adenocystic carcinoma)||GSI (Germany)||SFRT/IMRT vs. SFRT/IMRT + carbon (ion) boost||63||Yes/Yes|
|Uterus||NIRS (Japan)||Carbon RT vs. photon RT + brachytherapy||49||No/No|
|GI (bile duct)||UCSF (US)||Proton RT vs. photon RT||62||Yes/Yes|
|UCSF (US)||Surgery + photon RT vs. surgery + proton RT||22||No/No|
|Prostate||LLU (US)||Watchful waiting vs. surgery vs. Standalone photon RT vs. photon RT + proton boost RT vs. Standalone proton RT||185||No/No|
|MGH (US)||photon RT + photon boost vs. photon RT + proton boost||180||Yes/Yes|
Remaining Issues and Future Research
In summary, a large number of scientific papers on charged particle radiotherapy for the treatment of cancer currently exist. However, these studies do not document the circumstances in contemporary treatment strategies in which radiotherapy with charged particles is superior to other modalities. Comparative studies in general, and randomized trials in particular (when feasible), are needed to document the theoretical advantages of charged particle radiotherapy to specific clinical situations.
This Technical Brief did not intend to assess outcomes or evaluate the validity of claims on the safety and effectiveness of particle beam radiotherapy. Such questions need to be addressed in comparative studies.
The available slots for particle beam radiotherapy are very limited, and this may have impacted the design of studies conducted to date. Most eligible studies were noncomparative in nature and had small sample sizes.
It is likely that focused systematic reviews will not be able to provide a definitive answer on the effectiveness and safety of charged particle beam radiotherapies compared with alternative interventions. This is simply because of the relative lack of comparative studies in general, and randomized trials in particular.
Comparative studies (preferably randomized) are likely necessary to provide meaningful answers on the relative safety and effectiveness of particle beam therapy vs. other treatment options in the context of current clinical practice. This is especially true for the treatment of common cancers.
Charged particle radiotherapy can deliver radiation doses with high precision anywhere in the patient’s body, while sparing healthy tissues that are not in its entry path. This can be a very important advantage for specific tumors that are anatomically adjacent to critical structures. However, it is very likely that, as this technology becomes increasingly available (and as the associated costs decrease), it will also be increasingly used with much broader indications. This anticipated diffusion of the technology can have important implications (economic, regarding prioritization of resources, and potentially on health outcomes). Especially for many common cancers, such as breast, prostate, lung, and pancreatic cancers, it is essential that the theorized advantages of particle beam therapy vs. contemporary alternative interventions are proven in controlled clinical trials, along with concomitant economic evaluations.
This executive summary is part of the following document: Trikalinos TA, Terasawa T, Ip S, Raman G, Lau J. Particle Beam Radiation Therapies for Cancer. Technical Brief No. 1. (Prepared by Tufts Medical Center Evidence-based Practice Center under Contract No. HHSA-290-07-10055.) Rockville, MD: Agency for Healthcare Research and Quality. September 2009.
For More Copies
For more copies of Particle Beam Radiation Therapies for Cancer: Technical Brief Executive Summary No. 1 (AHRQ Pub. No. 09-EHC019-1), please call the AHRQ Clearinghouse at 1-800-358-9295.