External-beam radiation is a highly effective curative treatment option for men with localized prostate cancer.[1,2] Over the past several decades, efforts have been made to improve the “therapeutic ratio” of radiation by increasing dose to improve cure rates without causing a substantial increase in side effects. Due to its potential to create superior dose distributions, proton therapy is considered by many to be the best available form of external radiation therapy. Here we will critically examine the evidence supporting the use of protons in the treatment of prostate cancer.

Theoretical Advantages and Disadvantages of Protons

Photon beams deposit their dose continuously as they traverse tissue so that the volume in the beam’s path beyond the primary target also receives a measurable amount of falloff dose. Proton beams, on the other hand, deposit a large share of their dose in the “Bragg peak” over a relatively short distance close to the end of the particle’s track in tissue. Beyond the Bragg peak, the position of which is determined by the beam energy, protons deliver almost no additional exit dose. This property has allowed proton beams to effectively spare critical structures that are located very close to the target, and thus, this modality has been used successfully in the treatment of certain optic tumors, central nervous system tumors, base-of-skull diseases, and pediatric malignancies.[3]

In theory, the superior depth-dose characteristics should always give protons a clear advantage over photons if the photon beams are replaced one-by-one with proton beams. However, localization of the dose in the Bragg peak also makes the proton dose distributions highly sensitive to uncertainties in the particle range in tissue, which affects different treatment sites and beam directions to a varying degree. Additionally, using the same beam configuration for the proton and photon treatments is usually not practical. Thus, the extent to which the theoretical advantage of the proton dose can be engaged and realized differs among disease sites.

In the treatment of prostate cancer, the day-to-day variation in the patient setup, as well as rectal and bladder filling, may significantly affect the range of protons in tissue.[4] This makes some of the beam directions commonly used in photon therapy (eg, posterior-anterior) less suitable for proton irradiation. To minimize the effects of the range uncertainties, prostate patients are typically irradiated using opposed lateral proton beams, which generally forces at least a portion of the dose-limiting anterior rectal wall into the high-dose region. Therefore, demonstrating the potential advantage of protons is not as clear-cut in prostate cancer as in some other sites, and requires careful clinical and dosimetric studies, several of which are described below.

Dose Escalation Improves Cancer Control

There is currently ample evidence from five randomized controlled trials demonstrating that dose escalation can improve prostate cancer–specific outcomes, particularly for those with intermediate-risk disease based on prostate-specific antigen (PSA) level, clinical T category, and biopsy Gleason score. The earliest evidence comes from the M.D. Anderson Cancer Center, where 301 patients with T1-T3 disease were randomized to 78 vs 70 Gy (prescribed to isocenter). After a median follow-up of 8.7 years, the investigators found that the higher dose improved freedom from biochemical or clinical failure (78% vs 59% at 8 years, respectively; P = .004), with the greatest benefit seen in those with an initial PSA greater than 10 ng/mL (78% vs 39% at 5-years, respectively; P = .001).[5]

Similarly, a Dutch trial by Peeters et al randomized 669 patients with T1b to T4 prostate cancer to 78 vs 68 Gy (to isocenter) and detected an improvement in freedom from failure at 5 years (64% vs 54%, respectively; P = .02). On subgroup analysis, however, the investigators found that the benefit was limited to patients with intermediate-risk disease.[6]

A study from Ontario randomized 104 patients with intermediate- and high-risk disease to 75 Gy in 6.5 weeks delivered by external-beam radiation therapy (EBRT) plus implant vs 66 Gy in 6.5 weeks by EBRT alone and found that dose escalation reduced biochemical failure (29% vs 61%, respectively; P = .0024).[7]

More recently, a Loma Linda University/Massachusetts General Hospital (MGH) study of 393 mainly low- and intermediate-risk patients randomized to 79.2 vs 70.2 Gy-equivalents (GyE) used a mix of photons and protons and prescribed to the target volume. These investigators found that all risk strata of patients experienced a significant improvement in freedom from biochemical failure with the higher dose.[8]

Finally, Dearnaley et al have published their randomized trial from the British Medical Research Council showing that among men who all received short-course hormonal therapy, treatment with 74 vs 64 Gy resulted in improvements in 5-year outcomes for all patients.[9]

While none of the trials published to date has been powered to detect a difference in overall survival, the Radiation Therapy Oncology Group (RTOG) 0126 study is currently attempting to do just this by accruing over 1,500 patients to a large randomized trial of 79.2 vs 70.2 Gy.

Protons for Dose Escalation: Evidence From Clinical Trials

No randomized trials have directly compared the efficacy of protons and photons in the treatment of clinically localized prostate cancer. Clinical experience with the use of protons in dose escalation comes from the combined Loma Linda/MGH trial mentioned above. In this study, all patients received 50.4 Gy in 1.8-Gy fractions to the prostate and seminal vesicles using conformal photon therapy in a four-field configuration. The randomization was to either a 19.8-GyE or 28.8-GyE prostate boost via protons in 1.8-GyE fractions, to a total dose of 70.2 or 79.2 GyE. Overall, treatment to the higher dose with protons was tolerable, but came at the cost of an increase in late grade 2 rectal morbidity (8% vs 17%; P = .005).[8]

However, new preliminary data from an analysis of patients in this trial who received a detailed validated quality-of-life questionnaire suggest that there is no significant difference in long-term patient-reported quality of life between the high-dose and conventional-dose arms.[10] This evidence is a clear proof of principle that protons can be used to escalate dose without causing a significant difference in patient-reported quality of life, which is more relevant than physician-reported measures of toxicity.

The randomized trials using photons from the UK and the M.D. Anderson Cancer Center also had quality-of-life components, and it will be interesting to see whether they find additional patient-reported morbidity. It is currently unknown whether the use of protons for the entire course of treatment, rather than just the boost, could improve toxicity profiles further and allow for an even greater increase in dose. This is the subject of an ongoing Loma Linda University/MGH prospective study treating patients to 82 GyE with protons only.