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Review Future Directions From Past Experience: A Century of Prostate Radiotherapy Matthew C. Ward,1 Rahul D. Tendulkar,1 Jay P. Ciezki,1 Eric A. Klein2 Abstract Prostate cancer is the most commonly diagnosed noncutaneous malignancy in men, yet 100 years ago it was considered a rare disease. Over the past century, radiation therapy has evolved from a radium source placed in the urethra to today’s advanced proton therapy delivered by only a few specialized centers. As techniques in radiation have evolved, the treatment of localized prostate cancer has become one of the most debated topics in oncology. Today, patients with prostate cancer must often make a difficult decision between multiple treatment modalities, each with the risk of permanent sequelae, without robust randomized data to compare every treatment option. Meanwhile, opinions of urologists and radiation oncologists about the risks and benefits involved with each modality vary widely. Further complicating the issue is rapidly advancing technology which often outpaces clinical data. This article represents a complete description of the evolution of prostate cancer radiation therapy with the goal of illuminating the historical basis for current challenges facing oncologists and their patients. Clinical Genitourinary Cancer, Vol. 12, No. 1, 13-20 ª 2014 Elsevier Inc. All rights reserved. Keywords: Brachytherapy, History of medicine, IMRT, Proton therapy, Treatment planning Background Radiation therapy can trace its roots to some peculiar findings first described in 1895 by Wilhelm Röntgen, professor of physics at the University of Würzberg.1 He described these findings along with photographs of the bony structures of the hand and was awarded the Nobel Prize in physics in 1901. The therapeutic effects of radiation were realized equally as early, first in treating severe skin diseases such as lupus. The marketability of radioactive materials was also quickly recognized and in 1905 the young Vice President of Tiffany & Co, George Kunz, was granted the first patent of radium’s broad applications ranging from luminescence to its cytotoxic ability in “destroying germs, microbes, bacteria and the like”2 In 1898 Marie Curie discovered radium and in 1935 her daughter Irène and partner Frédéric Joliot earned the Nobel Prize for describing the artificial creation of radioactive elements.3 In Röntgen’s era, prostate carcinoma was thought to be a rare and insignificant disease. In 1893 the world literature on prostate cancer comprised only of 50 reported cases.4 Today, prostate cancer is 1 Department of Radiation Oncology, Taussig Cancer Institute Department of Urology, Glickman Urological and Kidney Institute Cleveland Clinic Foundation, Cleveland, OH 2 Submitted: Apr 26, 2013; Revised: Aug 16, 2013; Accepted: Aug 27, 2013; Epub: Oct 26, 2013 Address for correspondence: Matthew C. Ward, MD, Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, T28, Cleveland, OH 44195 Fax: 216-445-1068; e-mail contact: [email protected] 1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2013.08.003 known to be the most common noncutaneous cancer in men and accounts for more than 700,000 cases a year.5 In this article, interesting landmark advances in radiation therapy techniques will be highlighted with the goal of illuminating, clarifying, and inspiring future developments in prostate therapy. Brachytherapy (1911-Present) Brachytherapy, or radioactive source implantation, dates back to 1911 when the French physician Octave Pasteau reported the therapeutic effects on prostate cancer with the insertion of radium catheters into the urethra.6 Hugh Hampton Young, already the pioneer of the prostatectomy, experimented with revised methods and new instruments for brachytherapy through 1917.7 During Dr Young’s career, the radium sources were implanted using needles without any type of image guidance, making placement and dose planning unpredictable and bladder-wall implantation common (Fig. 1). Ultimately, the significant side effects attributed to poor planning caused brachytherapy to fall out of favor. In 1952, Dr Rubin Flocks at the University of Iowa described his experience using an aqueous solution of 198Au isotope.8 The patients selected for this procedure were considered inoperable but without evidence of distant metastasis. Gold was selected over radium based on its reduced half-life and its ability to form a suspension. Unfortunately, significant injury to the rectal mucosa was reported in up to a third of cases. Gold ultimately lost popularity likely because of expense and a high complication rate, but the interest in brachytherapy remained. Clinical Genitourinary Cancer February 2014 - 13 A Century of Prostate Radiotherapy Figure 1 Radium Needles Inserted by Hugh Hampton Young in 1917. Significant Toxicity Resulted From Seed Placement in the Bladder Wall During Early Brachytherapy Attempts 14 - Between 1956 and 1971, Dr Willet Whitmore experimented with various isotopes, including 222Radon, 192Iridium, and 125 Iodine. Ultimately he reported a novel 125I technique in which the source was sealed in titanium cylinders and implanted into the prostate using an open retropubic approach.9 The procedure was considered “well tolerated” despite patients remaining hospitalized for up to 9 days after the open procedure. Dr Whitmore’s work, however, was considered groundbreaking because of a low complication rate, with 19 of 26 patients reporting no complications. This represented a significant leap forward from earlier brachytherapy experiences and revitalized interest in brachytherapy as a feasible method of prostate cancer therapy. Although the retropubic approach to seed implantation provided proof that when placed properly, radioactive seeds are well-tolerated, the open procedure had few advantages over a retropubic radical prostatectomy. It was not until percutaneous source placement could be guided that the true advantages of brachytherapy were realized. In 1983, Dr Holm from Denmark applied transrectal ultrasound to the guidance of 125I seed placement.10 This new technique allowed for accurate dose distribution, minimized the risk of injury to the nearby bladder or rectum, and spared the patient an open procedure, thus capitalizing on the advantages of low-dose rate (LDR) brachytherapy. In the modern era, the Radiation Therapy Oncology Group (RTOG) 00-19 phase-II trial combined LDR brachytherapy with dose-reduced external beam in an attempt to achieve dose escalation by exploiting the dosimetric advantages of each technique.11 In this study, the authors concluded that the grade 3 toxicity was elevated when compared with other RTOG studies using external beam radiation therapy (EBRT) or brachytherapy alone. However, in the absence of long-term randomized data, the exact benefit of this approach remains Clinical Genitourinary Cancer February 2014 unclear. RTOG 0232 will provide the first phase III data investigating the combination of EBRT with LDR brachytherapy, therefore highlighting the importance of randomized trials in the evolution of radiation therapy techniques. High-dose rate (HDR) brachytherapy was designed to further address planning challenges and was first described in a textbook report by Bertermann and Brix published in the Netherlands in 1990.12 This technique employs a temporary 192Iridium source rather than permanent 125I seeds. The advantage to HDR brachytherapy is that the placement of the source is verified using computed tomography (CT) imaging before irradiation. Martinez et al at William Beaumont published the first phase I/II data documenting the procedure’s feasibility in 1995, a study which was followed by multiple investigations into the potential use of HDR brachytherapy as a boost to external beam in intermediate- to highrisk patients.13-16 In 1999, investigators began to consider the use of HDR treatments alone in low-risk prostate cancer patients.17,18 There have been 2 single-institution phase III trials investigating the benefits of HDR boost to EBRT with each author concluding that there was a benefit to dose escalation.19,20 Recently, the American Brachytherapy Society published a consensus statement regarding the use of HDR brachytherapy.21 Although there is evidence for the role of HDR brachytherapy, in the absence of highquality, multiinstitutional randomized data with patient-reported toxicity outcomes, the choice of technique remains the personal preference of the physician. Early External Beam Radiation Therapy (1904-1960) The evolution from kilovoltage radiation therapy through the development of modern megavoltage therapy defines the most significant development in the first 50 years of prostate therapy. External beam radiation was first used to treat prostate cancer by the French physicians Imbert and Imbert in 1904, seven years prior to the introduction of radium catheters.22,23 Waters and Pierson provided the first report of palliative radiation for bone metastases from prostate cancer in 192324 but it was not until 1930 that Smith and Peirson reported on definitive local therapy. Despite the prostate residing deep within the pelvis, 200-kV Röntgen rays were used, given to an “erythema” dose from 1 anterior and 1 posterior field (Anteroposterior (AP)/Posteroanterior (PA) technique) with an occasional perineal field.25 Although results showed an excellent relief of pain, external radiotherapy showed insufficient efficacy because of the superficial dose deposition of kilovoltage therapy and an inability to localize the prostate.25,26 Indeed, as late as 1946 there were no reported cases of cure using radiation alone.27 In 1941, when Huggins, Stevens, and Hodges reported the discovery of androgen deprivation, external radiation as a definitive cure lost popularity.28 In the mid-1950s, just as the limitations of androgen deprivation were realized, Flocks et al described the new 198Au interstitial therapy, results which ignited a renewed interest in radiation as an adjunct therapy.8 In the same year, Henry Kaplan and Edward Ginzton began attempts to build a new high-energy medical linear accelerator after hearing about a new “atom smasher” at a cocktail party. Determined to apply this technology to medicine, the first patient was treated in 1956. A child with retinoblastoma, having Matthew C. Ward et al Figure 2 Upright Treatment Technique in the Pre-Image Guidance Era With Early Immobilization Techniques From the Original Report Using the Stanford Linear Accelerator Figure 3 Anteroposterior (AP)/Posteroanterior (PA) Field Design in Early Cobalt Therapy Showing Complete Coverage of the Rectum and Bladder in the High-Dose Treatment Field. Although Cobalt Units Were Superior to kilovoltage Units by Providing Higher Photon Energies (Therefore Increased Depth of Dose Deposition), the AP/ PA Technique has Been Replaced in the Modern Era by Conformal Therapies. Without Advanced Treatment Calculations and 3-Dimensional Planning, This was a Superior Treatment Technique Because it Avoided “Hot Spots” Inherent to Multifield Techniques such as Intensity-Modulated Radiation Therapy Reproduced with permission from George et al. Cobalt-60 telecurietherapy in the definitive treatment of carcinoma of the prostate: a preliminary report. J Urol 1965; 93:102-9. Reproduced with permission from Bagshaw et al. Linear accelerator supervoltage radiotherapy. VII. Carcinoma of the prostate. Radiology 1965; 85:121-9. had his first eye removed, was in danger of going blind from a contralateral recurrence. After using this new “atom smasher” combined with an automobile jack and a large block of lead, the child was treated effectively and the megavoltage “Stanford” linear accelerator was born.29 Megavoltage therapy was the first step forward to effective prostate therapy because only megavoltage photons have the depth of penetration necessary to deposit significant doses to the deep pelvis. Megavoltage data for prostate cancer treatment did not appear until 1962 when the Stanford researchers, Bagshaw and Kaplan, presented at the Tenth International Congress of Radiology,30 and their clinical data were not published until 1965.31-33 This initial study was the first to show that survival rates with EBRT were comparable with prostatectomy and achieved a tolerable side effect profile. The prescription was for 4.7 MeV x-rays to deliver 7000 rads in 6 weeks, a regimen surprisingly similar to standard fractionation regimens used today (Fig. 2). In 1973, the “Stanford Series” was published, marking the first large (310 patients) study to show that definitive treatment was well tolerated, effective, and could preserve sexual function in approximately 60% of patients.34 As the megavoltage linear accelerator began to gain popularity, so did the applications of 60Cobalt. The isotope 60Cobalt was discovered in 1938 at the University of California, Berkley.35 In August of 1951, the first therapeutic cobalt unit was installed at the University of Saskatchewan after being designed by Dr Harold Johns and then graduate student, Lloyd Bates.36 Cobalt was described as the “poor man’s radium” and by the end of the 1950s, the 60Co units were marketed as the new cutting-edge technology.37 Marketing of megavoltage 60Co units provided strict competition to the 250-400 keV orthovoltage (kilovoltage) units and the new “supervoltage” (500-1000 keV) units. Many physicians were cautious about their adoption because of unknown effects on deeper tissues and the inability to judge clinical effect according to skin reaction alone (historically, dose was monitored according to skin reaction although this became obsolete with modern megavoltage, “skin sparing” therapy).38 The first case of using 60Co as an external treatment in prostate cancer was published in 1964 by Dr George and colleagues at the US Naval Hospital in San Diego.39 This 3-field technique was given 6 days per week, 200 rads per day to a total dose of 8000 rads. Many patients required a 2-week treatment break and most patients experienced a “mild proctitis.” The 3-field technique common in this era included standard AP-PA fields with an additional perineal field (Fig. 3). A 4-field “box” modification to this approach was common, which added opposed lateral fields to the AP-PA fields. Anatomic bony landmarks on plain radiographs were used to define field shape and estimate the location of the Clinical Genitourinary Cancer February 2014 - 15 A Century of Prostate Radiotherapy Figure 4 Timeline of Prostate Cancer Radiation Therapy 1875 1875-Therapeutic castration first described by the Russian surgeon Pelikan. 1895-Röntgen describes the "Röntgen" ray, later named the x-ray. 1898-Radium discovered by the Curies. 1904-Imbert and Imbert describe first external beam case. Young describes perineal prostatectomy. 1905-George Kunz granted first US Patent for the medical uses of radium. 1890 1911-Pasteau uses radium catheters as the first brachytherapy. 1923-Palliative external beam for prostate metastases. 1929-First cyclotron opens in Berkeley, CA. 1930-kV External Beam Radiotherapy as definitive treatment for prostate cancer. 1905 1934-Coutard fractionation theory widely accepted. 1935-Joliot & Joliot-Curie awarded the Nobel Prize for artificially synthesizing radioactive elements. 1938-60Cobalt discovered at UC-Berkley. 1941-Huggins describes androgen ablation effect on prostate carcinoma. 1920 1946-Theory of using protons for therapeutic purposes published. 1950-Limitations of androgen deprivation realized. 1951-First Cobalt unit designed, University of Saskatchewan, Canada. 1952-198Au interstitial therapy described. Kaplan & Ginzton begin building Stanford Accelerator. 1954-Computerized algorithm for external beam dose calculations. 1935 1956- Dr. Whitmore begins experimenting with 222Rn, 192Ir and 125I in permanent brachytherapy. 1960-PSA Identified by Dr. Flocks at the University of Iowa. 1962-First megavoltage linear accelerator data for prostate cancer. 1964-First data to support the use of 60Cobalt in prostate cancer. Dr. Hara identifies PSA in semen. 1950 1965-Takahashi credited with the first multi-leaf collimator. 1971-First patient imaged with computed tomography (CT). 1973-"Stanford Series" becomes the first large trial to show efficacy & tolerance to MeV EBRT. 1976-First delivery of protons to treat prostate cancer--Harvard Cyclotron in association with MGH. 1977-CT considered for use in prostate radiotherapy planning 1965 1979-PSA purified from prostatic tissue 1980-PSA identified in blood. 1983-Dr. Holm from Denmark uses TRUS guidance to deliver 125I brachytherapy. 1986-FDA approves PSA in monitoring for cancer relapse. 1980 1987-Swedish SRMS becomes the first IMRT system. 1988-Gold fiducials for tracking prostate motion during conformal therapy described in Alberta, Canada. 1990-First report of HDR brachytherapy for prostate cancer. Loma Linda opens first hospital-based proton accelerator. 1994-IMRT applied to prostate. FDA approves PSA as a screening test for prostate cancer. 1995 1997-First ASTRO consensus definition for biochemical failure after radiation. 1998-DaVinci robot used in prostatectomy. 1999-HDR explored as curative treatment at William Beaumont hospital. BATTM system developed. 2003-Calypso® transponders described at the 45th Annual ASTRO Meeting. 2006-Revised ASTRO consensus definition for biochemical failure. 2010 2012-USPSTF recommends against routine PSA screening in the general population. Abbreviations: ASTRO ¼ American Society for Radiation Oncology; EBRT ¼ external beam radiation therapy; FDA ¼ Food and Drug Administration; HDR ¼ high-dose rate; IMRT ¼ intensitymodulated radiation therapy; MGH ¼ Massachusetts General Hospital; PSA ¼ prostate-specific antigen; SRMS ¼ Scanditronix Racetrack Microtron System; TRUS ¼ transrectal ultrasound; UC ¼ University of California; USPSTF ¼ United States Preventive Services Task Force. Figure courtesy of the Cleveland Clinic Center for Medical Art and Photography. 16 - Clinical Genitourinary Cancer February 2014 Matthew C. Ward et al prostate. Examples of typical margins include the ischial tuberosities (correlated with the inferior aspect of the prostatic urethra) inferiorly or 1 cm posterior to the anterior border of the pubic symphysis anteriorly. To aid in localization, Foley catheter balloons filled with contrast material were used to delineate the bladder neck. Rectal enemas were helpful to delineate the rectum. Iliac nodal coverage was accomplished by expanding the field size from approximately 6 cm 6 cm for local disease to perhaps 15 18 cm for nodal disease.40 Although there were improvements in technique, the technological developments allowing the delivery of megavoltage therapy to the prostate defined the most significant advances in the first half of the 20th century. Improvements in Modern Radiation Therapy (1960-Present) Since the introduction of the megavoltage linear accelerator and the 60Cobalt unit in the 1950s, advancements in external radiation therapy have been a series of continuous and rapid improvements in computation power, imaging techniques, disease detection, target localization, and understanding of the governing sciences. The idea of applying computers to radiation planning was first conceived in 1955 in an effort to decrease the amount of effort required in calculating dose distribution, described as a “tedious and timeconsuming operation.”41 Since this time, computers have advanced from punch cards to multicore processors, and along with it, have advanced the abilities of the machinery. The CT scan, a key development in pelvic treatment planning, was first conceived by the electrical engineer Godfrey Hounsfield. Mr Hounsfield’s idea was funded by the company Electric and Musical Industries, a company that had profited greatly from the sales of a groundbreaking English band named the Beatles. Hounsfield, using a lathe to rotate the gamma-ray source, built a scanner which took 9 days to image a bottle. When Hounsfield’s idea was combined with the South African physicist Allan Cormack’s theory and Dr Jamie Ambrose’s clinical expertise, the first patient was imaged in 1971.42 The CT scan made an immediate impact on radiotherapy and the first description of 3-dimensional “conformal” prostate radiation treatment planning was published in 1977.43 Interestingly, 1977 was the same year the first magnetic resonance (MR) images of a human were produced.44 In the modern era, MR images of the prostate can be fused with CT images to provide additional soft tissue resolution during treatment planning for conformal EBRT. Software packages now exist, which incorporate automated deformable image registration algorithms, the value of which are being investigated. Intensity-modulated radiation therapy (IMRT), the next advance evolving from 3-D conformal therapy, has had a medical and economic effect on modern prostate therapy. 3-D conformal therapy was the natural next step after the CT scan was used for treatment planning and includes using blocks and collimators to conform the field shape to the target, thus reducing bladder and bowel dose. IMRT took the concept of 3-D conformal therapy further by allowing the user to define a target and avoidance structures, then allow the computer to inversely optimize a plan using beams which were of variable, or modulated, intensity. The development of the first IMRT system was not possible without the refinement of the 3-D conformal radiation therapy treatment planning systems and software tools developed in the 1980s and early 1990s through several National Cancer Institute collaborative research contracts.45 The foundations of 3-D planning technology were solidified through these groups, including developments in dose-volume histograms, biologic effect models, and tumor control data. Another key component, the multi-leaf collimator, is credited to Dr Shinji Takahashi’s Japanese group in 1965.46 Although many groups set the stage for true IMRT, the first complete modern delivery system was the Scanditronix Racetrack Microtron System developed at the Karolinska Institute in Stockholm, Sweden in 1987.47 Shortly after the development of this system, the concepts of IMRT were first applied to prostate carcinoma in 1994 at the Memorial Sloan-Kettering Cancer Center in New York.48,49 Since its development, IMRT has become immensely popular, increasing from use in only 0.15% of prostate cases in 2000 to 95% of cases in 2008, although it has also attracted some controversy related to reimbursements and physician self-referral.50,51 With the increased accuracy afforded by conformal therapy comes an increased risk of a geographical miss because of organ motion. Image-guided radiation therapy (IGRT) is a technique used to avoid a geographical miss and to allow for decreased margins necessary to account for inter- and intrafraction motion.52 IGRT can be accomplished via portal films or more recently via the conebeam CT scan. Portal films include plain-film images taken using the therapeutic portal, producing a “beams-eye” view of the patient. It is difficult to precisely identify the first to apply the concept of the portal film for localization although the first report in the literature came from Dr Haus and colleagues at the University of Chicago in 1970.53 Images obtained from the megavoltage source, although still in use today, are poor because of increased prevalence of Compton scattering over the photoelectric effect at higher energies. Today modern linear accelerators are equipped with basic kilovoltage CT scanners, termed “cone-beam,” to delineate from the helical scanners used in diagnostic imaging. These techniques allow for alignment of bony anatomy and interfraction motion corrections although defining the location of the prostate and tracking intrafraction motion remains a challenge. In an attempt to directly identify the prostate and track its motion, 3 primary strategies have been developed including the implantation of fiducial markers, the use of transabdominal ultrasound (B-mode Acquisition and Targeting [BAT]; Best Nomos, Pittsburgh, PA) and the implantation of electromagnetic seeds for real-time tracking (Calypso; Calypso Medical, Seattle, WA). Gold fiducials were first used in 1988 in Alberta, Canada by Murphy and Porter.54 These techniques were further developed at the University of Michigan in the early 1990s.55,56 The BAT system was developed in the late 1990s by the Nomos Corporation in Sewickley, Pennsylvania, and first compared with CT in 1999 by researchers at the Fox Chase Cancer Center in Philadelphia.57 Although both approaches provided a method to track intrafraction motion, neither provided the ability to track organ motion in real-time. The Calypso system was developed to tackle the challenge, and the first report of its use took place in 2003 at the 45th Annual American Society for Radiation Oncology Meeting by a collaborative group from the University of Michigan, William Beaumont, and the newly formed Calypso Medical Technologies.58 Using these technologies, the margin surrounding the prostate given Clinical Genitourinary Cancer February 2014 - 17 A Century of Prostate Radiotherapy Table 1 Toxicity Outcomes from Major Historical Trials Comparing Modalities Technique Study Kilovoltage Hultberg, 194627 30 Gy 180 kV photons 198 Ray, 195472 Injection 411 keV g-rays Conventional vs. 3-D Conformal Koper, 199973 (n ¼ 266) 66 Gy, 4-field 25 MV photon 3-D Conformal vs. IMRT Zelefsky, 200174 (n ¼ 1100) Proton Boost Proton Radiation Oncology Group 95-0975 (n ¼ 196) Beaumont/CEC76 (n ¼ 454) Au LDR (103Pd) vs. HDR (192Ir) Dose Energy 66 Gy, 3-D CRT 75.6 Gy 3-D CRT 64.8-70.2 Gy, IMRT 50.4 Gy, 3-D conformal proton boost to 70.2 Gy 120 Gy, LDR 38-42 Gy, HDR LDR (125I) vs. IMRT with BAT Guidance Cleveland Clinic77 (n ¼ 311) 144 Gy, LDR 70 Gy in 28 fractions, 80 Gy BED, IMRT 15 MV photon 10-23 MV photons; 160-250 MV protons 21 keV g-rays Urinary Toxicity (Grade 2) Rectal Toxicity (Grade 2) “.after radiation discomfort always increased with more frequent urinations and smarting or pain in connection therewith.” Up to one-third have “some injury to the rectal mucosa” 16% 32% 16% 10% 10% 22% 19% 12% 2% 13% 26% 3% 397 keV (average) x and g-rays 28 keV x and g-rays 15% 1.5% 4.3% 1.7% 6-10 MV photons 11% 7.8% Abbreviations: BAT ¼ B-mode Acquisition and Targeting; CEC ¼ California Endocurietherapy Center; CRT ¼ conformal radiation therapy; HDR ¼ high-dose rate; IMRT ¼ intensity-modulated radiation therapy; LDR ¼ low-dose rate. 18 - to account for motion and set-up error (termed the planning target volume, or PTV) has decreased from the original 6 cm 6 cm fields prescribed during original 3- or 4-field “box” techniques to 3 millimeters given with highly conformal therapies today. As expected, toxicity has generally improved along with the more advanced techniques and decreased margins, as summarized in Table 1. Although conformal therapy and target delineation is helpful, there are limits to the clinical benefit obtained using conformal therapy alone. Developments in the basic science of radiobiology have helped define the alpha-beta ratio (a fundamental property of tissue-defining radiosensitivity) for prostate carcinoma. These developments suggest that the therapeutic ratio of radiation therapy might be improved not only by conformal therapy but also by hypofractionation.59,60 There are varying degrees of hypofractionation. Standard fractionation is typically given at 1.8 to 2 Gy per fraction to a total dose of 74 to 80 Gy. “Moderate” hypofractionation can be given using conformal therapies such as IMRT with schemes such as 3 Gy per fraction to a total dose of 60 Gy. “Extreme” hypofractionation would include schemes such as 7 Gy per fraction to a total of 35 Gy.60 These extreme schemes require even greater precision than IMRT alone can allow, and therefore are termed stereotactic body radiation therapy (SBRT), although HDR brachytherapy is also a method of extreme hypofractionation. SBRT can be applied via a number of technologies including the well-known robotic linear accelerator known as the CyberKnife (Accuray, Sunnyvale, CA) and the standard linear accelerator-based systems such as with Novalis Radiosurgery (BrainLab, Munich, Germany) or the Varian TrueBeam STx (Varian Medical Systems, PaloAlto, CA). The precise technique of SBRT delivery varies by institution but typically Clinical Genitourinary Cancer February 2014 includes image guidance and motion tracking in real-time using multiple beams or perhaps a volume-modulated arc (VMAT) technique such as RapidArc (Varian Medical Systems). VMAT techniques decrease the time needed to treat by continuously delivering therapy as the gantry rotates rather than using the typical step-and-shoot technique. SBRT is typically the most conformal therapy available with prescription margins that approximate 3 to 5 mm. One of the first series published that reported the results of SBRT for prostate cancer appeared in 2007, and included patients treated as early as 2000.61 SBRT remains the most recent development in radiotherapy for prostate cancer and therefore the data supporting its use, although positive, are relatively immature compared with alternative techniques. History of Proton Therapy In addition to brachytherapy and conventional external beam, heavy-particle therapy typically using protons has gained popularity over the past decades. The clinical significance of the famed “Bragg Peak” has been highly debated over the recent years, particularly in light of the expense of the cyclotron. The credit of building the first cyclotron is given to Dr Ernest Lawrence of the University of California, Berkeley. His cyclotron began operating in 1929, for which he later received the Nobel Prize in Physics in 1939. The first consideration that protons generated with a cyclotron could be used therapeutically was explained by Dr Robert Wilson at Harvard University in 1946.62 This was during the era of Harvard’s second cyclotron, the first of which was built in 1937 and used primarily to generate radioactive isotopes. The first cyclotron was dismantled in 1943 and sent to Los Alamos, New Mexico, for use in the Manhattan Project.63 Matthew C. Ward et al Immediately after the war, Harvard secured funding to build the second cyclotron, which opened officially in 1949. It was not until 1976 that protons would be used to treat prostate cancer, using the Harvard cyclotron in association with Massachusetts General Hospital.64 The first feasibility study consisting of Harvard’s experience with a proton boost in 17 patients was published in 1979.65 As more patients were treated using protons, the door was opened for the multiple phase III reports which have subsequently been published, all showing the efficacy and noninferiority of various treatment techniques.66,67 However, to date there have been no large prospective randomized controlled trials directly comparing highdose proton therapy with modern IMRT.64 The recent history of proton therapy includes many questions about the economic feasibility of protons. The modern-day cost a hospital would sustain to build a proton therapy unit lies between $100 and $150 million, representing a significant long-term investment.64 One 2007 cost analysis, making a number of assumptions, found that protons were not cost-effective over IMRT for most patients with prostate cancer.68 Despite this consideration, there are more than a dozen proton facilities either in planning or under construction in the United States alone. Certainly the debate over therapy for prostate cancer will continue for many years as randomized data evaluating the many recent technological advances are reported. To summarize (Fig. 4) chronicles the improvements in proton therapy in parallel with brachytherapy and photon radiotherapy, each of which have advanced at an astonishing pace. Adjuvant and Salvage Radiation Therapy Discussion regarding the value of external radiation as an adjunct to surgery appeared as early as the 1920s.69 In 1930 Smith and Peirson discussed radiotherapy’s role in general, believing that x-ray therapy should be applied only to unresectable or recurrent cases rather than immediately after a “successful” prostatectomy.25 Case reports of megavoltage therapy applied using Cobalt machines and the Stanford accelerator were reported in the 1960s soon after the technology became available.39 In the 1970s, retrospective data emerged, and in the mid-1980s, numerous authors published on the topic. The paradigm changed in the early 1990s when the prostatespecific antigen defined the concept of biochemical recurrence, setting the precedent for modern salvage therapy.70,71 However, only since the 2005 report of European Organisation for Research and Treatment of Cancer 22911 have prospective data guided therapy. Future Directions The future of prostate radiotherapy is controversial. Patient selection will certainly play a significant role as the option of active surveillance becomes a more realistic possibility for low-risk patients, although the myriad of modern treatments available remains tempting for both patients and physicians. Changes in health care economics will challenge expensive technologies in the absence of data to prove superior outcomes. Furthermore, multi-institutional randomized controlled clinical trials with patient-reported outcomes will continue to provide solutions to today's clinical challenges such as hypofractionation and dose-escalation. Only time, however, will reveal which technologies will prove superior in the management of this complex disease. Conclusion It has been more than 100 years since Röntgen first discovered radiation. In the early days, prostate cancer was considered a rare disease. Since Röntgen’s era, advances in screening, detection, and longevity have caused prostatic carcinoma to become the most frequently diagnosed noncutaneous cancer in men. The most common presentation of prostate cancer has changed from diffuse bone metastases with urinary obstruction to an asymptomatic microscopic focus of disease. Meanwhile, radiation therapy has advanced from a radium catheter in the urethra to the complex 3-dimensional techniques which are standard today. Nearly every year has seen some significant advancement in the therapy of the disease, and the speed of research shows no indication of slowing. Although these advancements have shown benefits, the rate of discovery has outpaced randomized controlled data, presenting clinicians and patients with significant challenges in selecting optimal treatment strategies. Throughout history, skeptics have frequently questioned new technologies, a necessary trend which continues today. It is encouraging, however, that from the very beginning, physicians and scientists have depended on research to move forward, as Röntgen said after making his peculiar observation, “I did not think, I investigated.” Today’s physicians are challenged with the same charge, because evidence-based advances are needed as much today as they were in 1885. Today and forevermore, let the physicians of the future learn from the wise, data-driven decisions made by the physicians of the past. Acknowledgments Dr. Ward would like to acknowledge Dr. Robert Nesbit, Professor Emeritus of the Medical College of Georgia at Georgia Regents University, for his inspiration and opportunity to investigate the history of medicine and for his service to trainees throughout his distinguished career. Disclosure The authors have stated that they have no conflicts of interest. References 1. Dam H. The new marvel in photography. McClure’s Magazine 1896; 6:403. 2. Kunz GF, Inventor. Luminous Composition. 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