CyberKnife Treatment of Prostate Cancer
CyberKnife
Clinicians Make Responsible Treatment Decisions
Bentzen and
Wasserman argue that “treating early-stage prostate
cancer in ‘one to five outpatient sessions’ with the
CyberKnife is unproven therapy ….” In addition to
accusing CyberKnife clinicians of treating
irresponsibly, this argument ignores the considerable
data in support of a hypofractionated approach to
prostate cancer treatment. First, it should be
acknowledged that radiotherapy in general is a highly
effective modality for treating prostate cancer. It is
also well-established that greater radiation doses yield
a greater rate of long-term freedom from recurrence and
superior survival Hypofractionated CyberKnife treatment
of the prostate is largely based on high-dose-rate (HDR)
brachytherapy (a procedure not mentioned in the
editorial by Bentzen and Wasserman). As with CyberKnife
treatment, HDR brachytherapy has been used as
monotherapy and to deliver a boost dose after
external beam radiotherapy. Fairly long-term efficacy
with minimal toxicity for HDR monotherapy has been
established. Findings such as these, and an early
publication that stated the rationale
for using the CyberKnife to treat prostate cancer and
established that treatment plans rivaling those used in
intensity-modulated radiotherapy could be delivered
using the CyberKnife encouraged its application for
prostate cancer. Thus, CyberKnife clinicians made
the initial decision to treat prostate cancer from a
substantial body of published data—rather than embarking
on an “unproven therapy,” they were simply using a
different device to safely deliver radiation doses and
fractions that had been proven safe and efficacious when
delivered by another method.
The unique
features of the CyberKnife System, and a growing body of
published data that supports its broad application, also
contribute to the confidence of clinicians in their
ability to treat prostate cancer. The vast experience
and clinical results treating intracranial targets with
the CyberKnife gave clinicians confidence to use this
frameless delivery system to treat extracranial targets.
The CyberKnife System was approved by the Food and Drug
Administration in 2001 for treatment of tumors anywhere
in the body that radiotherapy is indicated. The system
can deliver hundreds of uniquely angled radiation beams
with extreme accuracy from a linear accelerator mounted
on a robotic manipulator, making it ideal for treating
extracranial targets in close proximity to critical
structures. Its ability to continually track the target
location with orthogonal X-rays taken frequently during
a treatment fraction, and to automatically correct for
any changes in target position, support its rapid
adoption in applications such as spinal, lung, and
pancreas cancer, despite the close proximity of critical
structures to those targets. Bentzen and Wasserman would
allow marketing based on a device's “superior
operational characteristics,” but technical superiority
and clinical confidence clearly go hand in hand. Thus,
the first clinicians to treat the prostate with the
CyberKnife were confident that they could generate
rational hypofractionated treatment plans and, with
continual, automatic image guidance, deliver them safely
and noninvasively in a much shorter time than using
conventional external beam radiotherapy.
Support for
CyberKnife Treatment of Prostate is Growing
In their
article, Bentzen and Wasserman take Accuray to task
because they could not locate published data that
supported the claims in the press release. It is true
that peer-reviewed data on use of the CyberKnife for
prostate cancer treatment is sparse and the published
follow-up is of short duration. Certainly, claims of
long-term efficacy and safety cannot be made from the
published data, and, indeed, no such claims were made in
the press release. However, Bentzen and Wasserman state,
“If Accuray has more clinical data than we could find,
we would review it.” Therefore, we present data from
studies, some of which include follow-up as long as 3
years, that were presented at meetings, the abstracts of
which were peer reviewed.
Prostate cancer
has been treated with the CyberKnife System under an
institutional review board (IRB)–approved protocol at
Stanford University since December 2003. Hara reported
the early results from 26 low-risk prostate cancer
patients with clinical Stage T1c-T2a, prostate-specific
antigen (PSA) level <10 ng/mL, and Gleason score ≤7 at
the 2006 meeting of the American Society for Therapeutic
Radiology and Oncology. The patients were treated
with 36.25 Gy delivered in five fractions within 5 days.
The dose was delivered to 95% of the planning target
volume, which was defined as the prostate with a 5-mm
margin in all directions, except posteriorly, where it
was reduced to 3 mm. At 18 months after treatment, the
mean normalized PSA level had decreased to 0.22 ng/mL.
Late bladder morbidity (Radiation Therapy Oncology Group
scale) was reported as 73% Grade 0, 23% Grade 1, and 4%
Grade 2. Late rectal morbidity was 65% Grade 0, 35%
Grade 1, and 0% Grade 2. No patient developed late Grade
3 or 4 toxicity. Of course, the investigators concluded
that long-term follow-up would be required to confirm
the durability of the PSA reduction and assess for late
toxicity. These data were updated in a presentation in
January 2008 at the CyberKnife Users' Meeting (the
CyberKnife Users' Meeting is held annually by the
CyberKnife Society, an agency that is funded by Accuray
Incorporated and by dues from members; abstracts are
submitted to the Society and are reviewed and accepted
or rejected by a board of CyberKnife User-peers who are
not employed by Accuray Incorporated). King et
al.described 41 low-risk, organ-confined prostate cancer
patients treated with 36.25 Gy in five fractions.
At a median
follow-up of 30 months, they concluded, “within the
limitations of this ongoing prospective trial we have
demonstrated the safety and efficacy of hypofractionated
stereotactic radiotherapy as monotherapy for low-risk
prostate cancer.” Again, the investigators stated the
need for additional long-term follow-up. A paper
reporting this work is in preparation.
At the 2007
CyberKnife Users' Meeting, Freeman reported the results
from the first 40 patients with low-risk,
organ-confined, prostate cancer treated at Naples
Community Hospital (Naples, FL). Patients with clinical
Stage T1c, PSA level <10 ng/mL, and Gleason score ≤7
were treated with 35 Gy in five fractions under an IRB–approved
protocol. The mean PSA level before CyberKnife treatment
was 5.78 ng/mL. At 1 year after treatment, the mean PSA
level was 1.2 ng/mL in the 27 patients who had not
received hormonal therapy and 0.05 ng/mL in the patients
who had. The acute side effects included urinary urgency
and frequency, tenesmus, loose stools, and fatigue in
the first 5–10 days after treatment. No Grade 4
toxicities were reported. At the 2008 CyberKnife Users'
Meeting,
Friedland described their ongoing experience at
Naples Community Hospital with 181 patients with low-
and intermediate-risk prostate cancer treated with
CyberKnife monotherapy under an IRB–approved protocol.
They reported an excellent PSA response at 2 years after
treatment, with most patients regaining baseline
urinary, bowel, and erectile function within 1 month of
treatment. A paper reporting this work is in
preparation.
At the 2007
American Society for Therapeutic Radiology and Oncology
meeting, Choi reported the results from 44
prostate cancer patients treated with the CyberKnife at
the Korea Institute of Radiological and Medical
Sciences. This was a follow-up to a study presented at
the 2006 American Urological Association meeting. Ten
patients with low-risk (PSA level <10 ng/mL, Gleason
score ≤6, Stage T1b-T2a), 25 patients with high-risk
(PSA level >20 ng/mL or Gleason score ≥8), and 9
patients with intermediate-risk (defined as other than
low or high) localized prostate cancer were treated with
the CyberKnife as monotherapy. All but 1 patient was
treated with 32–36 Gy in four fractions. One patient was
treated with 24 Gy in three fractions. At a median
follow-up of 13 months (range, 4–46), the 3-year
biochemical disease-free survival rate was 78.3% and the
3-year overall survival rate was 100%. Four patients
experienced biochemical failure. Of the 44 patients, 14
experienced Radiation Therapy Oncology Group Grade 1 and
2 rectal toxicity and 17 reported Radiation Therapy
Oncology Group Grade 1 and 2 urinary toxicity. No Grade
3 or greater rectal or urinary toxicity was reported.
The investigators concluded that CyberKnife monotherapy
yielded acceptable efficacy and short-term toxicity for
localized prostate cancer.
Early
clinical observations of 10 localized prostate cancer
patients treated with the CyberKnife using a HDR-like
dose distribution were presented at the 2007 American
Society for Therapeutic Radiology and Oncology annual
meeting. The data were recently published by Fuller The
IRB-approved study sought to determine whether the
CyberKnife could create and deliver treatment plans with
a dose distribution that approximated those delivered by
HDR brachytherapy. Patients were treated with 38 Gy in
four fractions. For each patient, a simulated HDR plan
was designed using 15–20 simulated HDR catheters to
match the CyberKnife dosimetry. The CyberKnife plans
did, indeed, approximate the HDR dosimetry within the
planning target volume and consistently resulted in
lower radiation exposure to the urethra, suggesting that
patients treated with the CyberKnife stereotactic
radiosurgery system would have decreased urethral
toxicity compared with patients treated with HDR
brachytherapy. The preliminary clinical results
demonstrated an 86% reduction in the PSA value at 6
months after treatment, with minimal toxicity. Again,
longer follow-up is needed to assess the long-term
efficacy and safety of HDR-like dosimetry using the
CyberKnife System for localized prostate cancer.
CyberKnife
Clinicians Participate in Clinical Development of
Prostate Cancer Treatment
With the
resources of the CyberKnife Society, interested
CyberKnife users have met frequently during the past
several years to develop protocols for a number of
emerging CyberKnife applications. The CyberKnife
community has always displayed caution when planning new
treatments. The caution is reflected in the painstaking
work of the CyberKnife Society Protocol Development
Committee, under the direction of Dr. Robert Meier of
the Swedish Cancer Center in Seattle and Dr. Irving
Kaplan from Beth Israel in Boston. In addition to
describing specific patient selection criteria and
treatment parameters, the final prostate cancer
protocols require patients to be counseled regarding the
pros and cons of CyberKnife treatment, the clinical
findings to date are discussed, and the lack of
long-term efficacy and toxicity data is stressed.
Accuray is
sponsoring two
multi-institutional Phase II studies to collect
long-term data on tumor control, biochemical
disease-free survival, overall survival, and
cancer-specific survival in low- and intermediate-risk
prostate cancer patients treated with the CyberKnife
System. One, led by Dr. Robert Meier, involves 18
centers nationwide, including academic institutions,
community hospitals, and free-standing CyberKnife
centers. Each center has received IRB approval for
participation in the study. The study will also assess
acute and late gastrointestinal, genitourinary, and
sexual function toxicities and quality-of-life indexes
for 5 years after CyberKnife treatment. Low-risk
patients include those with clinical Stage T1b-T2a, PSA
level <10 ng/mL, and Gleason score ≤6; intermediate-risk
patients include those with clinical Stage T1b-T2b, PSA
level of 10–20 ng/mL, or Gleason score 7.
Patients will be
treated with 40 Gy delivered to the prostate and 36.25
Gy delivered to the planning target volume in five
fractions. The study will enroll 298 patients and is
expected to reach accrual within 18–24 months.
The
second clinical
study is being led by Dr. Donald Fuller of the
San Diego CyberKnife Centers. In that study,
early-stage, low- and intermediate-risk prostate cancer
patients will be treated with
38 Gy in four
fractions delivered in an HDR-like treatment plan.
This differs from the previous protocol, in which a more
homogeneous dose distribution will be delivered. In the
second study, the dose will be prescribed to the <66%
isodose line, with the goal of delivering approximately
150% of the prescription dose to the periphery of the
prostate. It is in the peripheral zone that most
prostate cancer cells have been reported to reside.
Again, acute and late toxicity, biochemical disease-free
survival, overall survival, and cancer-specific survival
will be assessed during the 5 years after treatment.
This study will enroll 253 patients and currently
involves seven CyberKnife centers nationwide.
Clinical Development
and Marketing Messages
The goals of
this rebuttal were to outline some of the evidence that
guided the initial decisions to use the CyberKnife
System to treat prostate cancer, describe ongoing
research, publicized in meetings and in print, on
CyberKnife treatment of prostate cancer, and to indicate
the commitment of Accuray and the CyberKnife community
to the responsible development of prostate cancer
protocols and clinical studies. We hope that this brief
review has provided the context for Accuray's decision
to release to the press the September 2007 piece marking
the 1,000th prostate cancer patient treated with the
CyberKnife System. The intent of the press release was
only to give potential customers and investors a sense
of the growing confidence of the CyberKnife community
that they are able to deliver high-dose,
hypofractionated radiotherapy to the prostate using a
method that has led to excellent, albeit short-term,
clinical outcomes, and does so, most importantly,
without causing the patient serious injury.
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