Systematic Review: Charged-Particle Radiation Therapy for Cancer

Context Charged-particle radiation therapy is an alternative mode of radiation delivery for patients with cancer. This treatment is expensive but is becoming increasingly available. Contribution This review found that published evidence about the benefits and harms of charged-particle radiation therapy was derived mostly from small, single-group, retrospective studies. Of the 17 studies that compared treatments with or without charged particles, none reported statistically significant or important differences in overall or cancer-specific survival or in total serious adverse events. Implication We need better evidence to guide decision making about the indications for and the relative safety of charged-particle radiation therapy for cancer. The Editors In 2008, there were 1.4 million new cases of cancer in the United States (1). Radiation therapy has a pivotal role in the management of many types of cancer, either as the only treatment or as part of a multimodal approach that can include surgery, chemotherapy, or immunotherapy (2). Conventional cancer radiation therapy uses several types of ionizing radiation (x-rays, gamma rays, or electron beams) to treat tumors. Ionizing radiation damages the DNA of tumor and healthy cells alike, triggering complex biochemical reactions and eventually resulting in cell death. Cellular damage increases with absorbed radiation dose (measured in Gy)that is, the amount of energy that ionizing radiation deposits to a volume of tissue. In clinical practice, lethal tumor doses are not always achieved because radiation oncologists aim to balance the desired damage to the tumor and the undesirable radiation-induced injury to adjacent healthy tissues (3). This is generally achieved by targeting the beam to the tumor area through paths that spare nearby critical and radiosensitive anatomical structures; selecting multiple fields that cross in the tumor area through different paths; and splitting the total dose into multiple smaller dose fractions delivered over several days to weeks, which allows damaged normal tissues to recover between treatments. Appropriate targeting and delivery of radiation dose is particularly important for tumors adjacent to critical body structures. One of several technologies that can achieve precise delivery of radiation doses is charged-particlebeam radiation therapy. Charged-particlebeam therapy has been clinically available since 1954 (4), and many investigations of its use have been published. However, its appropriate clinical utilization is controversial, in part because documented clinical superiority over other modern radiation techniques is lacking and it is expensive. We sought to systematically review clinical outcomes and adverse events with charged-particle radiation therapy compared with other treatments in patients with cancer. Methods This article is based on a technical brief produced by the Tufts Medical Center Evidence-based Practice Center for the Agency for Healthcare Research and Quality (5). We applied the following protocol for all steps of our review. We defined charged-particle radiation therapy as irradiation with protons, helium ions, or heavier ions. This explicitly excludes radiation therapy with neutrons or other particles, such as -mesons. We defined conventional radiation therapy as external photon-beam radiation guided by 2- or 3-dimensional imaging with or without the use of treatment planning computers or older technologies and without beam-intensity modulation. The Glossary defines commonly used terms. Overview of Contemporary Conformal Radiation Therapies On the basis of a fact sheet posted on the National Cancer Institute's Web site (6), the following alternative contemporary conformal radiation therapy modalities were considered: photon intensity-modulated radiation therapy, stereotactic radiosurgery, stereotactic body radiation therapy, brachytherapy, and intraoperative radiation therapy. Three of the authors summarized contemporary radiation therapy techniques on the basis of selected review articles and Internet sources. Two of the authors independently screened the first 100 reviews from PubMed and the first 100 results from Google (Google, Menlo Park, California) for relevance to the brief overview by using free text terms (such as particle-beam therapy, proton beam therapy, intensity modulated radiotherapy, stereotactic radiosurgery, stereotactic body radiotherapy, brachytherapy, and intraoperative radiotherapy). Systematic Review of Particle-Beam Radiation Therapy Data Sources and Searches We searched MEDLINE from inception to 2 February 2008 by using such terms as proton, charged particle, and helium ion and text and Medical Subject Heading terms for cancer. The complete search strategy is published elsewhere (5). We limited searches to studies in humans. The search was updated to 11 July 2009 to include only randomized, controlled trials or nonrandomized comparative studies. Study Selection Four of the authors screened abstracts and further examined the full-text articles of all potentially eligible abstracts. We included studies of any design describing charged-particle radiation therapy in at least 10 patients with cancer and reporting any clinical outcome (survival, local tumor control, and change in symptoms) or any adverse event. We included studies regardless of whether charged-particle radiation therapy was used as standalone treatment or as part of multimodal therapy. We accepted studies published in English, German, French, Italian, and Japanese. We excluded studies that evaluated only treatment planning or dosimetry without providing any data on clinical outcomes or adverse event. We also excluded studies in which more than 20% of the patients did not have malignant conditions. Studies with fewer than 10 patients were screened for adverse events. Data Extraction and Assessment of Evidence Four authors independently recorded study characteristics (design, eligibility criteria, and follow-up period), patient characteristics (type of cancer, age, sex, and comorbidity), treatment characteristics (type of particle, total biologically effective dose, number of fractions, duration of radiation therapy, and prior and concurrent treatments), clinical outcomes (overall or cause-specific survival, outcomes related to local or distant tumor control, and others), and adverse events. One of the authors abstracted quantitative data on the rates of clinical outcomes only from comparative studies, which another author verified. Disagreements were resolved by consensus. We considered clinically significant adverse events to be those that were grade 3 (severe and undesirable adverse events, which included any adverse event resulting in inpatient hospitalization or prolongation of hospitalization, any persistent or substantial disability or incapacity, or a congenital anomaly or birth defect), grade 4 (life-threatening adverse events), or grade 5 (adverse eventrelated death). We also defined late adverse events as those that were reported 3 or more months after irradiation (unless the primary study used a different definition) (7). We also recorded authors' opinions on whether the reported toxicities and adverse events were specifically attributable to radiation therapy. We assessed the hierarchy of evidence of cancer-related health outcomes by adapting an established classification system (8, 9). We considered randomized, controlled trials to provide the strongest evidence, nonrandomized comparative studies the next strongest, and single-group studies the weakest. We categorized efficacy outcomes as overall survival, cancer-specific survival, and all other efficacy outcomes (for example, quality of life; a surrogate outcome of overall survival, such as disease-free survival or progression-free survival; or local control rates). Data Synthesis and Analysis For all included studies, we provided descriptive statistics for study designs, clinical and treatment characteristics, and clinical outcomes and adverse events reported, using the publication as the unit of analysis. For comparative studies, we identified those with overlapping populations by comparing author lists, years, and centers of treatment. Role of the Funding Source The study was funded by the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, which helped formulate the initial study questions but did not participate in the interpretation of the findings, or preparation, review, or approval of the manuscript for publication. Results Charged-Particle Radiation Therapy and Alternative Contemporary Conformal Radiation Therapy Techniques Contemporary conformal radiation therapy techniques have better dose distribution than conventional external photon radiation therapy; investigators claim that the former offer better tumor control because of safe dose escalation and fewer radiation-induced complications because of superior sparing of normal tissue. This makes conformal radiation therapy particularly appealing for surgically unapproachable tumors located adjacent to critical structures, such as the brainstem, cranial nerves, or the spinal cord. Charged-Particle Radiation Therapy Charged-particle radiation therapy uses beams of protons or other charged particles, such as helium, carbon, neon, or silicon, but only protons and carbon ions are currently in clinical use (10). Charged particles represent advancement over photons because the former have superior depthdose distribution. Photons or electron beams deposit most of their energy near the surface (skin and normal tissues), with progressively smaller dose at larger depths, where the tumor may be located. In addition, photons continue to deposit the dose of radiation in normal tissues beyond the tumor. In contrast, charged particles deposit a low dose near the surface and almost all their energy in the final millimeters of their trajectory in the tumor; tissues beyond the