Proton Beam Therapy for Prostate Cancer
Executive Summary
Background
Prostate cancer has the highest incidence of any types of cancer affecting men and accounts for the second highest number of cancer deaths in men. Prostate cancer is typically detected based on digital rectal examination and screening with serum prostate specific antigen (PSA). This Assessment will primarily address patients without distant metastasis, thus focusing on localized prostate cancer, although some proton beam therapy studies have included patients with locally advanced prostate cancer. Treatments for localized prostate cancer include watchful waiting, active surveillance, radical prostatectomy, x-ray (photon) external-beam radiotherapy, and brachytherapy. This TEC Assessment will mainly compare proton beam with or without x-ray external-beam radiotherapy with other radiotherapy modalities. Guidelines currently recommend use of conformal treatment planning techniques. These include 3D conformal radiotherapy, intensity-modulated radiotherapy, and image-guided radiotherapy. Earlier 2D methods are now considered outmoded. Dose recommendations are between 75.6 and 79 Gy. In principle, with proton beam therapy, it should be possible to deliver more favorable dose distributions than with ionizing radiation, thus theoretically allowing a possible improvement of the clinical outcomes.
Objective
This Assessment will compare the effects of proton beam therapy, with or without x-ray external-beam radiotherapy, against alternative radiotherapy modalities and other treatments of prostate cancer. The main outcomes include overall survival, disease-specific survival, biochemical failure, quality of life or symptom status, and genitourinary and gastrointestinal toxicities.
Search Strategy
MEDLINE® was searched (via PubMed) using the disease term “prostatic neoplasms.” This was cross-referenced with the term “proton.” The search was performed for the time period from January 1966 through March 2011 and was limited to English-language articles on human subjects, yielding 234 citations. Electronic searches were supplemented with a review of bibliographies from recent review articles and clinical studies. A technical brief commissioned by the Agency for Healthcare Research and Quality also provided citations.
Selection Criteria
Studies were selected for inclusion in this Assessment that met the following criteria: 1) full-length publications, published in a peer-reviewed journal in the English language; 2) includes patients with documented prostate cancer; 3) comparative trials of any size or single-arm studies of at least 10 patients per with prostate cancer; and 4) reported on one or more relevant outcomes.
Main Results
A total of 9 studies were included in this review; 4 were comparative and 5 were noncomparative. Five studies included patients who received x-ray external-beam radiotherapy plus proton beam boost, one study included a mix of patients with separate results for those given only protons and those given x-rays plus protons, one mixed study lacked separate results and 2 studies only included patients receiving proton beam therapy without x-ray external beam radiotherapy. Among studies using proton beam boost, only one study provides survival outcome data for currently applicable methods of x-ray external-beam radiotherapy. Thus, data on survival outcomes are insufficient to permit conclusions about effects. Three studies on proton beam boost and 2 studies on proton beam alone gave data on biochemical failure, an intermediate outcome based on serial PSA measurement. It is unclear whether biochemical failure consistently predicts survival outcomes. Prostate cancer symptoms were addressed in 2 studies and quality of life in one. Eight of 9 studies report on genitourinary and gastrointestinal toxicity.
Discussion
There is inadequate evidence from comparative studies to permit conclusions for any of the 4 comparisons considered here. Ideally, randomized, controlled trials would report long-term health outcomes or intermediate outcomes that consistently predict health outcomes. Of the 4 comparisons, there was one good quality randomized trial each for 2 of them. One showed significantly improved incidence of biochemical failure, an intermediate outcome of uncertain relation to survival, for patients receiving high-dose proton beam boost compared with conventional dose proton boost. No difference between groups has been observed in overall survival. Grade 2 acute gastrointestinal toxicity was significantly more frequent in the group receiving high-dose proton beam boost but acute genitourinary toxicity and late toxicities did not significantly differ. The other trial found no significant differences were between patients receiving x-ray versus proton beam boost on overall survival or disease-specific survival, but rectal bleeding was significantly more frequent among patients who had a proton beam boost.
Good quality comparative studies are lacking for other comparisons addressed in this Assessment.
Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether proton beam therapy for the treatment of prostate cancer meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria.
1. The technology must have final approval from the appropriate governmental regulatory bodies.
Radiotherapy is a procedure and, therefore, is not subject to U.S. Food and Drug Administration (FDA) regulations. However, the accelerators and other equipment used to generate and deliver charged particle radiation (including proton beam) are devices that require FDA oversight. Senior staff at the FDA’s Center for Devices and Radiological Health indicated that the proton beam facilities constructed in the U.S. prior to enactment of the 1976 Medical Device Amendments were cleared for use in the treatment of human diseases on a “grandfathered” basis, while at least one that was constructed subsequently has received a 510(k) marketing clearance. There are 510(k) clearances for devices used for delivery of proton beam therapy and devices considered to be accessory to treatment delivery systems such as the Proton Therapy Multileaf Collimator. This accessory device can be mounted on a proton beam system and is designed to shape the treatment field perimeter (510[k] marketing approval awarded in December 2009). Between 2001 and 2010, 12 devices classified as medical charged-particle radiation therapy systems received 510(k) marketing approval.
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.
A total of 9 studies were included in this review. Five studies included patients who received x-ray external-beam radiotherapy plus proton beam boost, one study included a mix of patients with separate results for those given only protons and those given x-rays plus protons, one mixed study lacked separate results and 2 studies only included patients receiving proton beam therapy without x-ray external-beam radiotherapy.
Among studies that included patients receiving x-ray external-beam radiotherapy plus proton beam boost, only 3 reported data on overall survival. Of these 3, 2 from the mid-1990s and earlier used outmoded external-beam radiotherapy methods, so results are not applicable to current practice. One early study reported disease-specific survival. Data on survival outcomes are insufficient to permit conclusions about effects. Three studies published since 2004 gave data on biochemical failure, an intermediate outcome based on serial PSA measurement. It is unclear whether biochemical failure consistently predicts survival outcomes. Prostate cancer symptoms were addressed in 2 studies and quality of life in one. Six studies reported on genitourinary toxicity and 6 on gastrointestinal toxicity.
One article described results of 3 noncomparative single-center trials of proton beam therapy without x-ray external-beam radiotherapy in patients with low-, intermediate-, and high-risk prostate cancer. Data separated by risk group were given for PSA progression-free survival and late genitourinary toxicity, while the 3 groups were pooled together for overall survival, symptoms, and gastrointestinal toxicity. The other study that included patients receiving proton beam therapy without x-ray external-beam radiotherapy reported that short-term biochemical failure data were available for 12 patients and late toxicity data for 16 patients.
3. The technology must improve the net health outcome.
The aim of proton beam therapy is to achieve higher doses to small targets, with possibly greater benefit, and create similar or lower risk of adverse events compared with other treatments. Comparative benefits and harms are discussed under Criterion 4.
4. The technology must be as beneficial as any established alternatives.
There is inadequate evidence from comparative studies to permit conclusions to any of the 4 comparisons considered here. Ideally, randomized, controlled trials would report long-term health outcomes or intermediate outcomes that consistently predict health outcomes. Of 2 randomized, controlled trials that have been published, a good quality trial showed significantly improved incidence of biochemical failure, an intermediate outcome, for patients receiving high-dose proton beam boost compared with conventional-dose proton boost. No difference between groups has been observed in overall survival. Grade 2 acute gastrointestinal toxicity was significantly more frequent in the group receiving high-dose proton beam boost but acute genitourinary toxicity and late toxicities did not significantly differ. A single study with intermediate outcome data of uncertain relation to survival is insufficient to permit conclusions about the comparative effects of x-ray external-beam radiotherapy plus either a conventional-dose proton beam boost or a high-dose proton beam boost.
The other randomized trial, also rated good in quality, found no significant differences between patients receiving x-ray versus proton beam boost on overall survival or disease-specific survival, but rectal bleeding was significantly more frequent among patients who had a proton beam boost. This trial used x-ray external-beam radiotherapy methods that are no longer relevant to clinical practice, precluding conclusions about the comparative effects of x-ray external-beam radiotherapy plus either an x-ray boost or a proton beam boost.
The only other comparative study was not randomized, used inadequate statistical methods, and compared quality of life and symptom scale outcomes for x-ray external-beam radiotherapy plus a proton beam boost, watchful waiting, radical prostatectomy, proton beam therapy alone, and x-ray external-beam radiotherapy alone. This study was too small and did not appear to use adequate confounder adjustment procedures, so the observed differences may be distorted by imbalances on important outcome predictors. Regarding use of proton beam therapy without x-ray external-beam radiotherapy, evidence is insufficient. The flawed nonrandomized comparative study noted earlier included a group treated with proton beam therapy alone. Additional noncomparative evidence comes from a case series mixing patients receiving proton beam therapy alone or combined protons and x-rays; reports from 2 other centers provide insufficient evidence.
5. The improvement must be attainable outside the investigational settings.
Whether proton beam therapy improves outcomes in any setting in prostate cancer has not yet been established.
Based on the above, proton beam therapy as a boost to x-ray external-beam radiotherapy and proton beam therapy without x-ray external-beam radiotherapy in the treatment of prostate cancer does not meet the TEC criteria.
Full Study
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adenocarcinoma; ASTRO; boost; carbon ion; CGE; chemistry; chemotherapy; cobalt Gray equivalent; conformal radiotherapy; conventional dose; disease-specific survival; expression; external beam; first-line; gastrointestinal; genitourinary; GI; GU; hypofractionated; hypofractionation; ionizing radiation; irradiation; cancer; limited field; metastatic; MLC; molecular; multileaf collimator; oncology; overall survival; particle beam; particle therapy; pooled analysis; postoperative; prediction; predictive; primary; prognostic; prostate; prostate-specific antigen; prostatic; protons; PSA; radiotherapy; radiotherapy; rectal; RTOG; stereotactic; surgery; toxicity; toxicity; tumour; tumours; wide field; x-ray;
