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.
1. Shipley WU, Tepper JE, Prout GR, Jr, et al. Proton radiation as boost therapy for localized prostatic carcinoma. JAMA. 1979;241:1912-5.
2. Vargas C, Fryer A, Mahajan C, et al. Dose-volume comparison of proton therapy and intensity-modulated radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2008;70:744-51.
3. Goitein M. Magical protons? Int J Radiat Oncol Biol Phys. 2008;70:654-6.
4. Vargas C, Wagner M, Mahajan C, et al. Proton therapy coverage for prostate cancer treatment. Int J Radiat Oncol Biol Phys. 2008;70:1492-1501.
5. Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys. 2002;53:1097-1105.
6. Mendenhall NP, Li Z, Hoppe BS, et al. Early outcomes from three prospective trials of image-guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2010 Nov 17. [Epub ahead of print]
7. Travis LB, Hill DA, Dores GM, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA. 2003;290:465-75.
8. Travis LB, Gospodarowicz M, Curtis RE, et al. Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease. J Natl Cancer Inst. 2002;94:182-92.
9. Fontenot JD, Lee AK, Newhauser WD. Risk of secondary malignant neoplasms from proton therapy and intensity-modulated X-ray therapy for early-stage prostate cancer. Int J Radiat Oncol Biol Phys. 2009;74:616-22.
10. Zagars GK, Pollack A. Serum testosterone levels after external beam radiation for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 1997;39:85-9.
11. King CR, Maxim PG, Hsu A. Kapp DS. Incidental testicular irradiation from prostate IMRT: it all adds up. Int J Radiat Oncol Biol Phys. 2010;77:484-9. Epub 2009 Sep 3.
12. Oermann EK, Suy S, Hanscom HN, et al. Low incidence of new biochemical and clinical hypogonadism following hypofractionated stereotactic body radiation therapy (SBRT) monotherapy for low- to intermediate-risk prostate cancer. J Hematol Oncol. 2011;4:12.
13. Nichols RC, Jr, Morris CG, Hoppe BS, et al. Proton radiotherapy for prostate cancer is not associated with posttreatment testosterone suppression. Int J Radiat Oncol Biol Phys. 2011. [In Press].
14. Trofimov A, Nguyen PL, Coen JJ, et al. Radiotherapy treatment of early-stage prostate cancer with IMRT and protons: a treatment planning comparison. Int J Radiat Oncol Biol Phys. 2007;69:444-53.
15. Institute for Clinical and Economic Review (ICER). Management options for low-risk prostate cancer. 2010.
16. Valery JR, Hoppe BS, Henderson R, et al. Risk of hip and femoral neck fractures following proton therapy for prostate cancer. [Abstr.] Int J Radiat Oncol Biol Phys. 2010;78:S192-S193.
17. Telhaug R, Fossa SD, Ous S. Definitive radiotherapy of prostatic cancer: the Norwegian Radium Hospital's experience (1976-1982). Prostate. 1987;11:77-86.
18. Perez CA, Walz BJ, Zivnuska FR, et al. Irradiation of carcinoma of the prostate localized to the pelvis: analysis of tumor response and prognosis. Int J Radiat Oncol Biol Phys. 1980;6:555-63.
19. Lawton CA, Won M, Pilepich MV, et al. Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: analysis of RTOG studies 7506 and 7706. Int J Radiat Oncol Biol Phys. 1991;21:935-9.
20. Paulson DF, Lin GH, Hinshaw W, et al. Radical surgery versus radiotherapy for adenocarcinoma of the prostate. J Urol. 1982;128:502-4.
21. Duttenhaver JR, Shipley WU, Perrone T, et al. Protons or megavoltage X-rays as boost therapy for patients irradiated for localized prostatic carcinoma. An early phase I/II comparison. Cancer. 1983;51:1599-1604.
22. Shipley WU, Verhey LJ, Munzenrider JE, et al. Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. Int J Radiat Oncol Biol Phys. 1995;32:3-12.
23. Yonemoto LT, Slater JD, Rossi CJ, Jr, et al. Combined proton and photon conformal radiation therapy for locally advanced carcinoma of the prostate: preliminary results of a phase I/II study. Int J Radiat Oncol Biol Phys. 1997;37:21-9.
24. Slater JD, Rossi CJ, Jr, Yonemoto LT, et al. Conformal proton therapy for early-stage prostate cancer. Urology. 1999;53:978-84.
25. Slater JD, Rossi CJ, Jr., Yonemoto LT, et al. Proton therapy for prostate cancer: the initial Loma Linda University experience. Int J Radiat Oncol Biol Phys. 2004;59:348-52.
26. Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA. 2005;294:1233-9.
27. Zietman AL. Correction: Inaccurate analysis and results in a study of radiation therapy in adenocarcinoma of the prostate. JAMA. 2008;299:898-9.
28. Zietman AL, Bae K, Slater JD, et al. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09. J Clin Oncol. 2010;28:1106-11.
29. Mayahara H, Murakami M, Kagawa K, et al. Acute morbidity of proton therapy for prostate cancer: the Hyogo Ion Beam Medical Center experience. Int J Radiat Oncol Biol Phys. 2007;69:434-43.
30. Nihei K, Ogino T, Onozawa M, et al. Multi-institutional phase II study of proton beam therapy for organ-confined prostate cancer focusing on the incidence of late rectal toxicities. Int J Radiat Oncol Biol Phys. 2010 Sep 8. [Epub ahead of print]
31. Coen JJ, Bae K, Zietman AL, et al. Acute and late toxicity after dose escalation to 82 GyE using conformal proton radiation for localized prostate cancer: initial report of American College of Radiology phase II study 03-12. Int J Radiat Oncol Biol Phys. 2010 Oct 5. [Epub ahead of print]
32. Konski A, Speier W, Hanlon A, et al. Is proton beam therapy cost effective in the treatment of adenocarcinoma of the prostate? J Clin Oncol. 2007;25:3603-8.
33. Peeters A, Grutters JP, Pijls-Johannesma M, et al. How costly is particle therapy? Cost analysis of external beam radiotherapy with carbon-ions, protons and photons. Radiother Oncol. 2010;95:45-53.
34. Arcangeli G, Saracino B, Gomellini S, et al. A prospective phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2010;78:11-18.
35. Brada M, Pijls-Johannesma M, De Ruysscher D. Proton therapy in clinical practice: current clinical evidence. J Clin Oncol. 2007;25:965-970.
36. Tepper JE. Protons and parachutes. J Clin Oncol. 2008;6:2436-7.
37. Goitein M, Cox JD. Should randomized clinical trials be required for proton radiotherapy? J Clin Oncol. 2008;26:175-6.
38. Glatstein E, Glick J, Kaiser L, et al. Should randomized clinical trials be required for proton radiotherapy? An alternative view. J Clin Oncol. 2008;26:2438-9.