ABSTRACT: Proton therapy has been used in the treatment of cancer for over 50 years. Due to its unique dose distribution with its spread-out Bragg peak, proton therapy can deliver highly conformal radiation to cancers located adjacent to critical normal structures. One of the important applications of its use is in prostate cancer, since the prostate is located adjacent to the rectum and bladder. Over 30 years of data have been published on the use of proton therapy in prostate cancer; these data have demonstrated high rates of local and biochemical control as well as low rates of urinary and rectal toxicity. Although before 2000 proton therapy was available at only a couple of centers in the United States, several new proton centers have been built in the last decade. With the increased availability of proton therapy, research on its use for prostate cancer has accelerated rapidly. Current research includes explorations of dose escalation, hypofractionation, and patient-reported quality-of-life outcomes. Early results from these studies are promising and will likely help make proton therapy for the treatment of prostate cancer more cost-effective.
Proton therapy (PT) has been used in the management of cancer for over 50 years. The unique pattern of radiation dose deposition associated with protons—the characteristic spread-out Bragg peak (SOBP)—was recognized as early as the 1950s as a tool that radiation oncologists could use to deliver highly conformal radiotherapy to cancers located adjacent to critical organs. Until 1991, PT was only available at physics research centers; these facilities typically offered relatively low-energy protons delivered through a fixed beam, so clinical applications were limited. The prostate, with its close proximity to the rectum, bowel, and bladder, was recognized early on as an ideal site for the application of PT. At the Massachusetts General Hospital in Boston, PT was used as a “boost” to conventional radiation therapy in prostate cancer as early as the late 1970s. The first clinically dedicated facility opened at Loma Linda University in Loma Linda, California in 1991, complete with sufficiently high-energy protons to penetrate to central tumors, with a gantry system to deliver PT from any angle, and offering treatment of prostate cancer solely with PT. Early results of PT from these two institutions have been promising, leading to a burgeoning interest in PT for prostate cancer at other institutions that have acquired PT. While there is much theoretical and early clinical promise, many questions remain regarding the degree of potential benefit and the cost-effectiveness of PT in prostate cancer. This review discusses the rationale, history, and current status of PT for prostate cancer—and controversies regarding it.
Rationale: The Physics of Proton Therapy and X-Ray Therapy
The patterns of radiation dose deposition in tissue associated with PT and X-ray therapy (XRT) differ significantly. With XRT, most X-rays pass through the patient, depositing radiation energy along the beam path and leaving a track of radiation damage, much like that left by a bullet, from the skin surface through which the beam enters to the skin surface through which it exits. Because the X-rays in these interactions are absorbed, the dose deposited along the beam path is reduced gradually as the X-ray beam passes through the patient. Since radiation damage is proportional to dose and not specific to cancer cells, this pattern of dose deposition with X-rays delivers more dose to nontargeted normal tissue. This unnecessary dose to the nontargeted normal tissue contributes considerably to the “integral dose” (dose deposited in the entire patient body).
Historically, there have been two basic strategies for dealing with the problem of integral dose with X-rays: 1) the use of higher-energy X-rays, which reduces the dose to normal tissues within the first few centimeters of the entrance path, and 2) the use of additional X-ray beams whose paths overlap only over the targeted tumor, which increases the dose to the cancer relative to the dose to any particular section of normal nontargeted tissue, at the expense of exposing more normal tissue to low doses of radiation. This second strategy is the basis for three-dimensional conformal radiation therapy (3DCRT), stereotactic radiosurgery and stereotactic body radiation therapy (SBRT), Cyberknife, intensity-modulated radiation therapy (IMRT), image-guided IMRT, and volumetric modulated arc therapy.
Most XRT for prostate cancer is delivered with an IMRT technique. IMRT is a sophisticated XRT technique that employs multiple radiation beams aimed at the target from different directions, with the beams varying in size and shape during treatment delivery to create a highly conformal radiation dose distribution in which the volume of tissue receiving a “high” dose of radiation conforms precisely to the three-dimensional (3D) volume of the target. This technique is a significant improvement over simpler, conventional radiation therapy techniques used historically, which deliver a high radiation dose to a volume of tissue that is much larger and less conformal—and that thus includes substantially more normal tissue. However, because of the increased number of X-ray beams used with IMRT, a much larger volume of non-targeted tissue receives low radiation doses than is the case with the simpler conventional radiation therapy techniques. With IMRT, as in other XRT techniques based on overlapping beams, integral dose is redistributed over a larger volume of nontargeted tissue compared with simpler historical techniques, but it is not reduced.
In contrast to X-rays, protons have mass and thus do not travel an infinite distance; rather, they stop in tissue at a distance proportional to their acceleration. In addition, protons are 1,800 times as heavy as electrons, the primary subatomic particles with which they collide. Unlike X-rays, which are absorbed in these interactions, protons lose relatively little energy along the beam path until the end of their range, at which point they lose the majority of their energy, producing a characteristic sharp peak in radiation energy deposition known as the Bragg peak. Thus, a typical proton beam disperses a low constant dose of radiation along the entrance path of the beam, a high uniform dose throughout the range of the SOBP, and no exit dose, eliminating much of the integral dose inherent in X-ray therapy. In contrast to XRT, the majority of radiation energy from a proton beam is actually deposited in the targeted cancer. Because the width of the Bragg peak is only 4 to 7 mm, in actual clinical practice, an SOBP is produced by adding a series of proton beams with appropriate energies to cover the full thickness of a particular target with a uniform dose.
Figure 1 is a comparison of typical radiation dose distributions achieved with PT and IMRT for a patient with low-risk prostate cancer. The relative radiation dose levels are indicated by the color wash, with red representing the highest radiation doses and blue indicating the lowest doses. As is apparent, there is a higher integral dose with IMRT compared with PT; with PT, a much larger proportion of the rectum receives either no radiation dose or only a very small dose. Figure 2 shows a comparison of dose-volume histograms for the rectum and bladder with the PT and IMRT treatment plans. The x-axis charts radiation dose and the y-axis charts the percentage of organ receiving the corresponding dose. Due to the proximity of the anterior wall of the rectum and the base of the bladder to the prostate, the volumes of these organs receiving high radiation doses are similar for the IMRT and PT plans. However, there are significant differences in the volumes of bladder and rectum receiving medium- and low-dose radiation in the PT plan compared with the IMRT plan. It should be noted that proton therapy for prostate treatments is typically delivered using two lateral or slightly lateral oblique beams, taking full advantage of the ability of protons to stop before the contralateral femoral heads. Proton beams at such large depths do not necessasrily possess an advantage of reduced beam penumbra compared with IMRT treatments, as pointed out by Goitein. However, the ability of proton prostate therapy to avoid beam entrance and exit through bladder and rectum allows maximum sparing of these critical organs, such that large percentages of these volumes receive essentially no dose. At the same time, the robustness of such beam arrangements has been shown to be adequate for intra-fraction prostate movements up to 5 mm. Given the growing body of literature demonstrating an association between gastrointestinal (GI) and genitourinary (GU) complications with dose-volume histograms of the rectum and bladder, including the volumes receiving low and moderates doses, the reduction in integral dose to these structures with PT will likely translate into fewer GU and GI toxicities.[5,6]
Along with the lower dose to the rectum and bladder, the lower integral radiation dose with PT compared with XRT may result in other benefits to patients with prostate cancer. The relationship between the volume of tissue exposed to low radiation doses and secondary malignancies has been established in pediatric cancers.[7,8] Fontenot et al of the MD Anderson Cancer Center in Houston have evaluated the risk of secondary malignancies with IMRT compared with PT in patients with early-stage prostate cancer and have shown that PT should reduce the risk of secondary malignancies by 26% to 39% compared with IMRT. Due to concerns regarding urinary incontinence and erectile dysfunction with surgery, the use of radiotherapy in younger men with prostate cancer has increased. Particularly in these younger patients with prostate cancer, PT may result in a measurably lower rate of secondary malignancy than is seen with IMRT.
Integral dose may affect other organs located close to the treatment field. Some investigators have suggested that the low-dose scatter radiation to the testes from 3DCRT, IMRT, and SBRT may reduce testosterone levels.[10-12] However, in a study from the University of Florida Proton Therapy Institute in Jacksonville, PT had no significant effect on testosterone levels in patients during the first 2 years of follow-up. It is possible that preserving testosterone levels may result in preservation of libido and prevention of fatigue following treatment. Doses to the penile bulb may be less with PT than with IMRT, which may also help preserve erectile function after radiation therapy. Not all structures, however, receive less integral dose with PT than with XRT. In a study from Massachusetts General Hospital, Trofimov demonstrated higher doses to the femoral neck with PT. This has led to some concern regarding the possibility of an increased risk of femoral neck fractures in patients treated with PT. In an analysis from the University of Florida Proton Therapy Institute with a median follow-up of 2 years, no increased risk in hip fracture was observed among 400 consecutive men treated with PT compared with the number of fractures expected in this population, based on patient comorbidities and as determined by the World Health Organization FRAX tool for assessing hip fracture risk.