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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
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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
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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
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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.
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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
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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
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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.
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