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.
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. 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).
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.
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).
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.
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.
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).
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. 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.
Physical Comparison of Protons and IMRT
To have a fair assessment of the dosimetric trade-offs between protons and photons, one must compare proton therapy to the most conformal type of photon therapy currently available, which is intensity-modulated radiation therapy (IMRT). With IMRT, more beams are used than in conventional three-dimensional (3D) radiation therapy, and the fluence of each beam is modulated to create a highly target-conformal dose distribution capable of bending around critical normal structures such as the anterior rectal wall. In the United States, IMRT is becoming the dominant method of delivering external-beam radiation to the prostate.
Trofimov et al recently performed a dosimetric comparison of 10 patients whose treatment was planned with both protons (using the currently available 3D conformal proton planning methods) and photon IMRT to a total dose of 79.2 Gy (or GyE). The proton therapy was planned using two lateral parallel opposed beams, while the photon IMRT was planned with seven coplanar beams (Figure 1). This study found that IMRT actually yielded better dose conformality (defined as the ratio of the prescription isodose volume to the volume of the corresponding target), reflecting the fact that a greater volume of nontarget tissue received the prescription dose of 79.2 Gy with proton therapy than with IMRT. Correspondingly, the V70 of the bladder (volume of bladder receiving more than 70 Gy) was 50% higher with proton therapy than with IMRT, although the V70 of the rectum was not significantly different.
In the low-dose range, however, IMRT had worse performance characteristics than proton therapy due to the fact that IMRT spreads out the dose over several beams. The rectal V30 was reduced with protons by between 16% and 53% compared to IMRT. Additionally, the total volume of normal tissue exposed to low and moderate doses of radiation was significantly higher with IMRT than with protons. Figure 2 illustrates the difference between the dose distributions from representative IMRT and proton plans on a single axial slice. For this same patient, the total volume of tissue irradiated to a dose of at least 10 Gy was 1.7 × 103 cm3 with proton therapy compared to 3.5 × 103 cm3 with IMRT.
For the typical patient who receives these treatments, the concern is whether these differences in dosimetric profile between protons and IMRT might translate into differences in acute and late toxicity. Cheung et al from M.D. Anderson recently published the results of normal tissue complication probability modeling to predict bladder toxicity after prostate irradiation. These investigators found that those in whom the hottest 2.9% of the bladder received 78 Gy or more had a significantly higher risk of delayed grade 2 or higher genitourinary (GU) toxicity than those in whom the hottest 2.9% received less than 78 Gy. This raises the possibility that conventionally delivered protons may therefore be no better than (or potentially even worse than) IMRT in terms of GU toxicity.
Similarly, given that rectal doses in the high-dose region appear comparable with IMRT and protons, there is concern that protons, as conventionally delivered, will not allow for dose escalation beyond what will be possible with IMRT. In the future, however, intensity-modulated proton therapy may allow for even more conformal boosting, as described below.
Finally, epidemiologic evidence suggests that hip fractures are associated with both pelvic irradiation and antiandrogen therapy, and given that many patients receive both treatments, and that opposed lateral proton beams deposit a significant amount of dose in the femoral heads, there is concern that proton radiation may result in more hip fractures than IMRT. Unfortunately, these types of questions can only be answered definitively in a randomized trial, for which there is currently an urgent need.