Phase II Feasibility Study of High-Dose Radiotherapy for Prostate
Cancer Using Proton Boost Therapy: First Clinical Trial of
Proton Beam Therapy for Prostate Cancer in Japan
Keiji Nihei, Takashi Ogino, Satoshi Ishikura, Mitsuhiko Kawashima, Hideki Nishimura, Satoko Arahira and
Radiation Oncology Division, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
Received June 20, 2005; accepted October 10, 2005; published online November 28, 2005
Objective: To assess the feasibility of high-dose radiotherapy for prostate cancer using proton
boost therapy following photon radiotherapy.
inal (GI) toxicities. The study included patients with clinical stage T1-3N0M0 prostate cancer.
Radiotherapy consisted of 50 Gy/25 fx photon irradiation to the prostate and the bilateral seminal
vesicles followed by proton boost of 26 GyE/13 fx to the prostate alone. Hormonal therapy was
allowed before and during the radiation therapy.
Results: Between January 2001 and January 2003, 30 patients were enrolled in this study.
Acute grade 1/2 GU and GI toxicities were observed in 20/4 and 17/0 patients, respectively.
With themedianfollow-up period of30months(range20–45),lategrade1/2GUandGItoxicities
occurred in 2/3 and 8/3 patients, respectively. No grade 3 or greater acute or late toxicities were
observed. All patients were alive, but six patients relapsed biochemically after 7–24 months.
To evaluate the efficacy and safety of proton beam therapy, a multi-institutional phase II trial is in
progress in Japan.
Key words: proton beam therapy – prostate cancer – clinical trial
The age-adjusted prostate cancer incidence rate per 100000
Japanese men has doubled during the last two decades from
9.8 to 19.9, and the incidence increases exponentially as age
rises above 50 years. This is caused by more Westernized
dietary habits, the advancing aging of society and the more
widespread use of screening tests for prostate-specific antigen
(PSA). It is also expected that the situation will continue to
approach that of Western countries in the near future. The issue
of how to manage this disease has thus become an important
topic in Japan as well as in Western countries.
Previous reports have shown that there is a dose–response
relationship in irradiating prostate cancer, and a higher dose
>70 Gy is potentially beneficial for prostate cancer (1,2).
However, other reports have revealed that, with conventional
radiotherapy techniques, rectal complications increase drastic-
ally at >70 Gy (3,4). Several techniques to deliver higher doses
to the prostate have been developed and have become wide-
spread, such as three-dimensional conformal radiotherapy
(3D-CRT), intensity-modulated radiotherapy (IMRT), charged
particle therapy (heavy ion and proton) and brachytherapy.
These techniques can allow good target dose coverage with
a minimal dose to the surrounding normal tissue to improve
tumor control with acceptable toxicity. To evaluate the effi-
cacy and safety of high-dose irradiation for prostate cancer,
dose escalation studies using 3D-CRT or IMRT were conduc-
ted by the Radiation Therapy Oncology Group (RTOG) and
many institutions (5–11). Large series of brachytherapy or
implantation of radioactive sources into the prostate are also
reported, and there are ongoing RTOG trials using brachyther-
apy with or without external beam radiotherapy (12–16).
Charged particles have a physical depth-dose characteristic
called the ‘Bragg peak’. A single proton beam has a low
entrance dose, a maximal dose at a user-defined depth and
no exit dose. The ‘Bragg peak’ can be spread out and shaped
to conform to the depth and volume of an irregular target.
Proton beam therapy (PBT) can thus create an inherently
three-dimensional conformal dose distribution without extra
dose to the surrounding normal tissue compared with con-
formal photon radiotherapy (17).
For reprints and all correspondence: Keiji Nihei, National Cancer Center
Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
Jpn J Clin Oncol 2005;35(12)745–752
#2005 Foundation for Promotion of Cancer Research
by guest on June 8, 2013
In National Cancer Center Hospital East (NCCHE), proton
facilities were introduced and applied to clinical use in 1998,
and we started to conduct a feasibility study of proton boost
therapy following photon therapy for prostate cancer in 2001.
The purpose of this study was to assess the feasibility of high-
dose radiotherapy for prostate cancer employing proton boost
therapy following photon radiotherapy. The institutional
review board reviewed and approved the trial protocol.
There were three reasons why we adopted the photon/proton
combined treatment. First, we followed the experiences of
Loma Linda University Medical Center (LLUMC) and
Massachusetts General Hospital (MGH) who also used com-
bination therapy at the beginning (18,19). Second, it was our
first experience of using the proton beam for prostate cancer
and the safety was not confirmed. Third, the proton
machine was unfortunately unstable at the beginning and a
longer schedule of proton treatment was considered to be
PATIENTS AND METHODS
The primary endpoint was acute grade 3 or greater genitour-
inary (GU) and gastrointestinal (GI) toxicities. The secondary
endpoints were to evaluate the other toxicities, the PSA-failure
free survival and the overall survival.
Late toxicities are often regarded as an important issue after
high-dose radiotherapy. Although the relationship between
acute and late toxicities is not clear, we decided to use
acute toxicities as the primary endpoint of the current study,
so that safety of the treatment could be ensured as soon as
possible. Late toxicity was also monitored afterwards and if
severe late toxicity was observed, the study would be suspen-
ded for evaluation of the safety by the study committee.
Acute toxicities were evaluated by National Cancer Insti-
tute-Common Toxicity Criteria (NCI-CTC) ver2.0 within
90 days from the beginning of radiotherapy. Thereafter, late
toxicities were evaluated by the RTOG/EORTC (European
Organisation for Research and Treatment of Cancer) late radi-
ation morbidity scoring schema. PSA failure was defined using
the American Society for Therapeutic Radiology and Onco-
logy (ASTRO) consensus definition based on three consecut-
ive PSA rises, and the date of the failure was backdated to
the midpoint between the nadir and the first rise (20). The
Kaplan–Meier method was used to evaluate the PSA-failure
free survival and the overall survival. The base date for
reckoning a period of time was the day on which the radio-
PATIENT ELIGIBILITY CRITERIA
The eligibility criteria of this study were (i) pathologically
(1997UICC); (iii) performance status 0–2; (iv) no serious com-
plications; (v) appropriate organ functions; (vi) no previous
history of pelvic radiotherapy; (vii) no previous surgery; and
(viii)writteninformedconsent. Hormonaltherapy wasallowed
before and during the radiation therapy, but was stopped after
the radiation therapy.
To estimate the local disease extension and distant metastasis,
all patients received physical examinations, bone scans, and
pelvic CT and/or MRI. All biopsy slides were reviewed by
institutional pathologists to confirm Gleason scores (GS) as
a pathological grade. Pretreatment serum PSA values were
obtained before both radiotherapy and hormonal therapy.
Initial PSA value and GS were not included in the eligibility
criteria, because the primary endpoint was to assess the
prostate and the bilateral seminal vesicles followed by proton
boost therapy of 26 GyE/13 fx to the prostate alone. The unit of
‘GyE’ means the photon equivalent dose calculated from the
physical dose and the relative biological effectiveness (RBE).
The RBE in our institution was defined as 1.1 from previous
biological experiments (21).
In the photon treatment, the clinical target volume (CTV)
was defined as the prostate and the bilateral seminal vesicles,
and the planning target volume (PTV) was defined as the CTV
plus 10 mm margins for interfraction prostate motion and set-
up error in all directions and 5 mm was added to the PTV for
penumbra margin. The photon beam was delivered by 240?arc
dynamic conformal technique (Fig. 1a). The patient position
was aligned with laser markers in the usual manner, and veri-
fication of patient positioning was performed at the beginning
of the treatment and whenever necessary thereafter.
In the proton boost therapy, the CTV was defined as the
prostate alone and the treated volume was defined as the CTV
plus 5 mm margin for PTV margin in all directions, and 5 mm
was added to the PTV for penumbra margin. Daily verification
of patient positioning was performed by the image subtraction
method using digital radiography (22). The daily actual images
were compared orthogonally with the reference images and the
subtracted images were adjusted so that the pelvic bone struc-
ture disappeared (Fig. 2). Since daily verification of patient
positioning was performed, the PTV margin in the proton
boost therapy took only the interfraction prostate motion
into account. The proton beam was delivered by lateral
opposed portals (Fig. 1b).
Although the eligibility criteria included patients from low-
risk to high-risk, the same target volume definition was applied
to all cases to assess the feasibility of the treatment. The
dose–volume histograms (DVHs) of the rectum and the urinary
bladder were all checked while planning each of the photon
and the proton treatments, but no DVH constraints were used
in the current study.
746Proton beam therapy for prostate cancer
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To control rectum and bladder filling, all patients were
instructed to urinate and drink half a liter of water 30 min
before each treatment and were encouraged to have a regular
bowel movement to empty their rectums. Both legs were fixed
by a vacuum cushion in the supine position for patient immob-
ilization. Using our way of patient positioning and rectal/
bladder filling, we previously analysed the interfraction pro-
state motion and set-up error quantitatively (23) and confirmed
that the PTV margin in the current study described above was
necessary and sufficient.
All patients were seen by radiation oncologists once or twice
a week during the radiation therapy to assess subjective
symptoms including urinary frequency, urgency, retention,
painful urination, rectal discomfort, diarrhea, anal pain, rectal
bleeding and so on. After the completion of radiation therapy,
subjective symptoms and biochemical data were followed up
every 3 months during the first 2 years and every 6 months
thereafter. Radiographic examinations and biopsy were not
performed unless clinical disease progression was suspected.
We determined <15% grade 3 GU/GI toxicities as acceptance
of feasibility. Initially, 15 evaluable patients were to be
accrued to assess the feasibility of this study. If no acute
grade 3 or greater GU/GI toxicities were observed, the feas-
patients would be accrued to assess the efficacy. This would
provide at least 90% confidence (0/15) that the true toxicity
rate was <15%. However, if one grade 3 or greater GU/GI
toxicity was observed, then an additional evaluable 10 patients
would be accrued. If no further grade 3 or greater GU/GI
toxicities were observed, the feasibility of this study would
be approved and five evaluable patients would be accrued to
assess the efficacy. This would provide at least 90% confid-
ence (1/25) that the true toxicity rate was <15%. If two or
more grade 3 or greater toxicities were observed in the first
15 patients, then accrual would be suspended and the events
will be reviewed by the Assessment Committee of the study.
This study design has a detection power of 73% when the true
acute grade 3 or greater GU/GI toxicities are <10%. In total,
30 patients were to be accrued.
When the first 15 patients were followed up for 90 days from
the beginning of the radiotherapy, no acute grade 3 or greater
GU/GI toxicities occurred. Therefore, the feasibility of this
study was approved and further 15 patients were accrued.
In total, 30 patients were enrolled in this study between
January 2001 and January 2003. The patient and tumor char-
acteristics (Table 1) were as follows: median age, 73 (range
54–87); T1c/T2a/T2b/T3a, 4/8/11/7; median initial PSA value,
19.2 (range 4.7–66.9); Gleason score 4–5/6/7/8–10, 4/15/8/3;
and previous hormonal therapy Yes/No, 21/9. The median
duration of hormonal therapy was 7 months, ranging from
1 to 23 months. Three prognostic risk groups were defined
as follows: low-risk group, iPSA <10, GS <6 and T1-2; high-
risk group, iPSA >20, GS >8 or T3; and intermediate-risk
group, all others except for the above. There were 5/11/14
patients in the low/intermediate/high-risk groups, respectively.
Acute grades 1 and 2 GU toxicities were observed in 20 and
4 patients, respectively. The four grade 2 cases were all urinary
frequency and urgency. There were 17 grade 1 GI toxicities.
No patient experienced grade 3 or greater acute toxicity
With a median follow-up period of30 months (range 20–45),
late grades 1 and 2 GU and GI toxicities occurred in 2 and 3,
and 8 and 3 patients, respectively. The three grade 2 GU tox-
icities were two urinary frequency and one gross hematuria,
and the three grade 2 GI toxicities were all rectal bleeding
(Table 3). No patient experienced grade 3 or greater late
toxicity. In 10 patients who experienced grade 1 or 2 rectal
bleeding, the events occurred at 8–17 months with a median of
14 months after the radiation therapy.
can provide good dose coverage to the prostate and reduce the unnecessary
irradiated volume of both the ventral and dorsal portion of the body. Isodose
80%; light purple, 50%; purple, 20%. Red line shows the planning target
Jpn J Clin Oncol 2005;35(12)747
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Between those who received hormonal therapy and those
who did not, there was no difference in the acute toxi-
cities, but the latter group experienced more late toxicities
(5/9, 55%) than the former (9/21, 43%). One patient who
had previously received transurethral resection of the prostate
did not suffer any late toxicity at 20 months after the
All patients were alive, but six patients relapsed biochem-
ically after 7–24 months. The PSA-failure free survivals for
all patients are shown in Fig. 3. The PSA-failure free survivals
at 1 year and 2 years were 93% (95% confidence interval
(CI) = 84–100%) and 77% (95% CI = 63–94%), respectively,
by ASTRO definition.
HIGH-DOSE RADIOTHERAPY FOR PROSTATE CANCER
cancer was demonstrated by Patterns of Care Study and
other institutional studies in the 1980s (1,2). A higher local
Figure 2. Image subtraction method for verification of patient positioning.
Table 2. Acute genitourinary and gastrointestinal toxicities
Table 1. Patient and tumor characteristics (n = 30)
Median age (range) (years)73 (54–87)
Clinical T category (UICC 1997)
Median (range) (ng/ml)19.2 (4.7–66.9)
Previous hormonal therapy
Duration (range) (months)7 (1–23)
Prognostic risk group
748Proton beam therapy for prostate cancer
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control rate was obtained as the radiation dose to the prostate
increased to >70 Gy. Regarding toxicity it was also reported
that serious complications drastically increased when using
doses >70 Gy, if the conventional radiation technique was
used (3,4). As computed radiography and radiotherapy devices
developed, more precise radiotherapy techniques were put into
clinical use, such as 3D-CRT, IMRT, particle therapy and
brachytherapy. These techniques can allow good target dose
coverage with a minimal dose to the surrounding normal tissue
when performing high-dose radiotherapy for prostate cancer.
Many institutions have tried to conduct high-dose external
beam radiotherapy with >70 Gy for prostate cancer using
3D-CRT or IMRT (5–8). They reported satisfactory clinical
outcomes of high-dose radiotherapy for prostate cancer,
including both efficacies and morbidities, but these single
institutional data cannot confirm the usefulness of high-dose
radiotherapy as a standard treatment for prostate cancer. To
evaluate the safety and to determine the recommendable dose
of high-dose radiotherapy, RTOG started to conduct a dose
escalation study (RTOG 9406) using 3D-CRT (9–11). The
patient accrual has finished and the safety of high-dose 3D-
CRT will be confirmed. There are several large series treating
patients with localized prostate cancer by using permanent
implant brachytherapy with or without external beam
radiotherapy for >10 years (14–16). To confirm these retro-
spective data, RTOG also started to conduct prospective stud-
ies of permanent implant brachytherapy with or without
external beam radiotherapy.
Until now, there have been two phase III studies with final
results, comparing high-dose with standard-dose radiotherapy
for prostate cancer. One was conducted by MGH using
proton boost therapy (24), and the other was conducted by
MD Anderson Cancer Center using 3D-CRT (25). In the
MGH trial, patients with T3-T4NX/N0-2 prostate cancer
received 67.2 Gy by photon radiotherapy or 75.6 Gy by
photon/proton combined therapy. There was no significant
difference between the two groups in any survival outcome.
In the MD Anderson trial, 305 patients with T1–T3 prostate
cancer were randomized to receive a standard-dose of 70 Gy
or a high-dose of 78 Gy. The freedom from failure rate at
6 years in the high-dose group (74%) was significantly better
than that in the standard-dose group (64%). To assess the
efficacy of high-dose radiotherapy in a multi-institutional set-
ting, RTOG is now conducting a phase III study comparing a
high-dose of 82.28 Gy with a standard-dose of 72.93 Gy for
Thus although there are many promising outcomes and wide
experiences of high-dose radiotherapy for prostate cancer, the
topic remains under investigation and the optimal dose for
each risk group has not been established.
PBT FOR PROSTATE CANCER
PBT for prostate cancer started at MGH in the 1970s (18). In
the phase III trial previously described, there was no signifi-
cant difference in survival outcomes between high-dose and
standard-dose groups (24). At LLUMC, >1200 patients with
prostate cancer were treated by PBT. They used photon radio-
therapy to the pelvis at 45 Gy followed by proton boost to the
prostate at 30 Gy for high-risk patients, and PBT alone with a
total dose of 74 Gy for low-riskpatients. The overall 5year and
8 year actuarial biochemical disease-free survival rates were
75 and 73%, respectively (26,27). MGH and LLUMC cooper-
atively completed the phase III trial using proton boost
therapy following photon radiotherapy, which randomized
patients with early prostate cancer to receive a dose
of 70.2 or 79.2 Gy. They are now conducting another dose
escalation phase I/II study using >80 Gy of PBT alone.
In Japan, PBT was first used at Tsukuba University in 1985.
They experienced PBT with 14 prostate cancer patients, but
the evaluation was performed retrospectively and this cannot
be considered as an establishment of policy for PBT for
prostate cancer in Japan. In NCCHE, PBT was applied to
clinical use in 1998, and the present study for prostate cancer
started in 2001. Owing to the small number of patients and
short duration of follow-up, the effectiveness of PBT for pro-
state cancer should not be assessed from the current study.
However, because no patient experienced any grade 3 or
greater toxicities, the feasibility of the proton boost therapy
following photon radiotherapy was confirmed.
Table 3. Late genitourinary and gastrointestinal toxicities
Urinary retention 3000
Proportion of PSA failure-free
Figure 3. PSA-failure free survival for all patients.
Jpn J Clin Oncol 2005;35(12) 749
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DOSE DISTRIBUTION AND TOXICITIES
We analysed the rectal DVHs using the current study cohort.
The rectal DVHs in the photon/proton combined therapy (the
current study) were comparedwith those produced by planning
in PBT alone. Figure 4 shows the apparent advantage of the
rectal DVHs using PBT alone compared with those using
photon/proton combined treatment (28). In that study, the rec-
tal DVH using PBT alone was much superior to the DVH
constraints of 3D-CRT and just comparable to those of
IMRT introduced by other institutions and clinical trials.
Comparison of late GI toxicities between other series of
external radiation therapy is shown in Table 4. The frequency
of late grades 2 and 3 GI toxicities in RTOG 9406 (11) was less
than that of other reports, but this was probably owing to the
lower total doses with a smaller fraction size of 1.8 Gy rather
than 2.0 Gy.LLUMCreported 21%lategrade 2GI toxicities in
patients who received photon/proton combined therapy or PBT
alone (27). Because they considered isolated rectal bleeding
(grade 1) and transfusion (grade 3) as grade 2, the true fre-
quency of late grade 2 GI toxicities was supposed to be <21%.
Table 4 shows that the frequency of grades 1 and 2 late rectal
toxicities in the current study was comparable to that of other
reports using high-dose external beam radiotherapy.
As the RTOG 9406 study reported, severe late toxicities
(grade 3) significantly decreased using 3D-CRT compared
with those observed in historical studies using conventional
radiotherapy. However, moderate late toxicities (grade 1/2)
were unexpectedly increased by high-dose radiotherapy
using 3D-CRT (11). Grades 1 and 2 toxicities are not severe
but have a significant impact on a patients’ quality of life, so it
becomes a matter of great importance how we can reduce
both severe and moderate late toxicities. As shown in Table 4,
Memorial Sloan Kettering Cancer Center reported reduced
actuarial incidences of moderate toxicities (grade 2) by
using IMRT, even with a higher dose level (6). As described
above, because PBT alone can produce rectal DVH just as well
as IMRT, it is expected that not only grade 3 but grade 1/2
toxicities can be reduced by using PBT alone, at least to the
same extent as when using IMRT. And the discussion thus far
about rectal toxicities can also be applied to GU and other
Figure 4. Comparison of average rectal DVHs between photon/proton
combined therapy and proton therapy alone.
Table 4. Comparison of late gastrointestinal toxicities between other reports
Institution/study (reference no.) Dose (Gy) Radiation
MSKCC phase I/II (5,6) 64.8–813D-CRT16%10%1%5
81 3D-CRT– 12%2%3
81IMRT– 2% 0.5%3
MDACC phase III (8) 78 3D-CRT28%19% 7%6
23% (grade 2/3)2
12% (grade 2/3)2
RTOG 94-06 (9,10)68.4 3D-CRT– 9% (grade 2/3)3.1
73.8 3D-CRT– 9% (grade 2/3)2.2
79.2 3D-CRT24% 8% (grade 2/3)3.1–3.6
LLUMC (27)74–75Photon/proton and
The current study7627% 10%0% 2.5
MSKCC, Memorial Sloan Kettering Cancer Center; MDACC, MD Anderson Cancer Center; RTOG, Radiation Therapy Oncology Group; LLUMC, Loma Linda
University Medical Center.
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COMPARISON WITH IMRT
By using IMRT, multiple portals of photon beams three-
dimensionally expose a large volume of the surrounding nor-
mal tissues to low radiation doses. In contrast, PBT alone
can generate sufficient dose coverage to the prostate by lateral
opposed portals with no radiation exposure to the ventral and
dorsal portion of the body (Fig. 1b). Discussed from such a
viewpoint as difference in physical characteristics between
photon and proton beams, it is suggested that PBT alone
can further reduce the toxicity compared with IMRT. Because
of using just lateral opposed portals, the conformity of the
prescribed dose to the target volume by PBT is poorer than
that by IMRT, but intensity-modulated proton therapy which
is now developing for clinical application will improve the
conformity of the current PBT and realize more ideal dose
painting in the target volume in the future (29).
Regarding the risk of second malignancy as long-term
sequelae, Brenner et al. (30) reported interesting data from
the Surveillance, Epidemiology and End Results (SEER)
Program cancer registry (1973–93). Radiotherapy for prostate
cancer was associated with a small but statistically significant
increase in the risk of second solid tumors, particularly for
long-term survivors, relative to treatment with surgery. By
sparing the large volume of the surrounding normal
tissues from exposure of low radiation doses, it is expected
that using PBT to treat prostate cancer can decrease the
risk of radiation-related second malignancy. Diagnosis at
younger ages and earlier stages is resulting in longer survival
times for patients with prostate cancer, and radiation-related
Although MGH and LLUMC have large experiences using
PBT, the data of retrospective analysis and combination with
photon therapy were included. A multi-institutional prospect-
ive clinical trial can further confirm the efficacy and safety of
proton therapy. As discussed above, because the dose distri-
bution generated by PBT alone is superior to that by photon/
proton combined treatment (the current study), the feasibility
of the current study should warrant the safety of PBT alone for
prostate cancer with the same total dose. There are now five
institutions with proton facilities in Japan, and we are conduct-
ing a multi-institutional phase II trial in which we treat low-
and intermediate-risk prostate cancer by PBT alone with a total
dose of 74 GyE. The primary endpoint is the incidence of grade
2 rectal bleeding at 2 years. This study will certainly confirm
the clinical advantage of PBT for prostate cancer.
This paper was presented at the 40th semi-annual meeting of
Particle Therapy Cooperative Group (PTCOG) in Paris, 2004.
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