VOLUME 23 䡠 NUMBER 25 䡠 SEPTEMBER 1 2005

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Randomized Trial Comparing Two Fractionation

From the McMaster University,
Hamilton; University of Toronto,
Toronto; University of British Columbia,
Vancouver; Northeastern Ontario
Regional Cancer Centre, Sudbury; and
Queen’s University, Kingston, Canada.
Submitted June 22, 2004; accepted
April 18, 2005.
Supported by Cancer Care Ontario
and the National Cancer Institute of
Canada–Clinical Trials Group.
Presented at the 45th Annual Meeting
of the American Society for Therapeutic
Radiology and Oncology, Salt Lake City,
UT, October 19-23, 2003.
Authors’ disclosures of potential con-
flicts of interest are found at the end of
this article.
Address reprint requests to Himu
Lukka, MB, ChB, FRCPC, Radiation
Oncology Program, Juravinski Cancer
Centre, McMaster University, 699
Concession St, Hamilton, Ontario,
Canada, L8V 5C2; e-mail: Himu.Lukka@
hrcc.on.ca.
© 2005 by American Society of Clinical
Oncology
0732-183X/05/2325-6132/$20.00
Schedules for Patients With Localized Prostate Cancer
Himu Lukka, Charles Hayter, Jim A. Julian, Padraig Warde, W. James Morris, Mary Gospodarowicz,
Mark Levine, Jinka Sathya, Richard Choo, Hugh Prichard, Michael Brundage, and Winkle Kwan
A B S T R A C T
Purpose
The optimal radiation dose fractionation schedule for localized prostate cancer is unclear.
This study was designed to compare two dose fractionation schemes (a shorter 4-week
radiation schedule v a longer 6.5-week schedule).
Patients and Methods
Patients with early-stage (T1 or T2) prostate cancer were randomly assigned to 66 Gy in 33
fractions over 45 days (long arm) or 52.5 Gy in 20 fractions over 28 days (short arm). The
study was designed as a noninferiority investigation with a predefined tolerance of ⫺7.5%.
The primary outcome was a composite of biochemical or clinical failure (BCF). Secondary
outcomes included presence of tumor on prostate biopsy at 2 years, survival, and toxicity.
Results
From March 1995 to December 1998, 936 men were randomly assigned to treatment; 470
were assigned to the long arm, and 466 were assigned to the short arm. The median
follow-up time was 5.7 years. At 5 years, the BCF probability was 52.95% in the long arm and
59.95% in the short arm (difference ⫽ ⫺7.0%; 90% CI, ⫺12.6% to ⫺1.4%), favoring the
long arm. No difference in 2-year postradiotherapy biopsy or in overall survival was detected
between the arms. Acute toxicity was found to be slightly higher in the short arm (11.4%)
compared with the long arm (7%; difference ⫽ ⫺4.4%; 95% CI, ⫺8.1% to ⫺0.6%);
however, late toxicity was similarly low in both arms (3.2%).
Conclusion
Given the results, we cannot exclude the possibility that the chosen hypofractionated radiation
regimen may be inferior to the standard regimen. Further evaluation involving higher dose
hypofractionated radiation regimens in contemporary radiation settings is necessary.

DOI: 10.1200/JCO.2005.06.153 J Clin Oncol 23:6132-6138. © 2005 by American Society of Clinical Oncology

reported the use of shorter radiation fraction-

INTRODUCTION
Radiotherapy is often recommended to pa-
tients with localized, early-stage prostate
cancer. In the mid-1990s, the most com-
monly used method to deliver radiation was
external beam using a four-field technique.
At that time, there was not consistent agree-
ment on the optimal schedule to be used for
patient treatment.1 Conventional radiation
schedules ranged between 60 and 70 Gy ad-
ministered over 6 to 7 weeks.2-4 Studies from
the United Kingdom, Australia, and Canada
ation schedules,5-8 which seemed to be com-
parable to conventional schedules. However,
these studies were nonrandomized.
There are several advantages for a hypo-
fractionated radiation treatment regimen, in-
cluding convenience for patients, increased
treatment capacity, and decreased cost.9 On
the basis of the ␣/␤ model for prostate cancer
radiation biology, hypofractionation would
theoretically offer increased therapeutic bene-
fit with improved tumor control, without in-
creasing late toxicity.10-12 This is because of

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 Hypofractionation in Prostate Cancer
the presumed low ␣/␤ ratio of prostate tumors compared with
the surrounding normal tissue. This randomized trial was de-
signed to determine whether a hypofractionated treatment
regimen of 52.5 Gy in 20 fractions administered over 28 days
was as effective as the conventional treatment regimen of 66 Gy
in 33 fractions administered over 45 days for men with early-
stage prostate cancer.
PATIENTS AND METHODS
Study Population
Men with early-stage adenocarcinoma of the prostate (T1-2
according to International Union Against Cancer TNM classifica-
tion) were eligible for the trial. Patient exclusion criteria were as
follows: a prostate-specific antigen (PSA) level of more than 40
␮g/L; previous therapy for prostate carcinoma (other than biopsy
or transurethral resection of the prostate); previous hormone
therapy; prior or active malignancy other than nonmelanoma skin
cancer, colon cancer, or thyroid cancer treated a minimum of 5
years before the trial and presumed cured; a simulated volume
exceeding 1,000 mL; previous pelvic radiotherapy; presence of
inflammatory bowel disease; diagnosis of serious nonmalignant
disease that would preclude radiotherapy or surgical biopsy; geo-
graphically inaccessible for follow-up; a psychiatric or addictive
disorder that would preclude obtaining informed consent or ad-
herence to protocol; inability to commence radiotherapy within
26 weeks of the date of last prostatic biopsy; and failure to provide
informed consent to participate in the clinical trial.
Participating centers included eight Ontario regional cancer
centers (Hamilton, Princess Margaret Hospital, Toronto Sunny-
brook, Sudbury, Kingston, Windsor, London, and Thunder Bay)
and eight additional Canadian centers (the Vancouver and Fraser
Valley Cancer Centres in British Columbia, CancerCare Manitoba
in Winnipeg, the Nova Scotia Cancer Centre in Halifax, the Saint
John Regional Hospital in New Brunswick, the Dr Leon Richard
Oncology Centre in Moncton, the Newfoundland Cancer Treat-
ment and Research Foundation in St John’s, and the Saskatoon
Cancer Centre in Saskatchewan). Recruitment for the centers
outside Ontario was coordinated through the Clinical Trials
Group of the National Cancer Institute of Canada. Written in-
formed consent was obtained from eligible patients before assign-
ment to treatment. The institutional review board at each
participating center approved the study protocol.
Treatment Regimens
Patients were assigned to one of two treatment regimens
according to a central computer-generated randomization sched-
ule within strata defined by PSA (ⱕ 15 ␮g/L v ⬎ 15 ␮g/L), Gleason
score (2 to 6 v 7 to 10), method of lymph node assessment (surgical
v radiologic), and treatment center. Before random assignment,
patients completed radiotherapy simulation and treatment plan-
ning. Serum urea, creatinine, hemoglobin, WBC, and platelet
count were also required within 4 weeks before random assign-
ment. All patients were required to have had a pelvic computed
tomography (CT) scan or pelvic lymph node sampling within 12
weeks of random assignment. Patients with enlarged nodes on CT
scan (ⱖ 1.5 cm) were required to proceed through histologic
confirmation. Samples were obtained using fine-needle aspiration
cytology or lymph node dissection. If aspiration of an enlarged
node was negative, further lymph node sampling was necessary. A
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Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
chest x-ray and bone scan were performed within 12 weeks of
random assignment. Patients were required to have a PSA mea-
surement within 6 weeks of commencing radiotherapy.
Patients were randomly assigned to receive prostate irradia-
tion consisting of either 66 Gy in 33 fractions over 45 days (long
arm) or 52.5 Gy in 20 fractions over 28 days (short arm). Radiation
was delivered daily, from Monday through Friday. The intention
was to treat the prostate gland alone with a 1.5-cm margin. CT
planning was mandatory for all patients. Shielding, where appro-
priate, was used to keep the planning target volume under 1,000
mL. Patients were treated in the supine position with a full bladder
before each treatment. The target volume was treated using a
four-field box technique or using three fields in patients with
prosthetic hips. The borders defining the treatment volume in-
cluded a 1.5-cm margin on all sides except posteriorly, where, at
the discretion of the radiation oncologist, the margin could be
reduced to 1 cm. Shielding was done using either multileaf colli-
mator or poured blocks. Differential weighting was used to achieve
optimal dose distribution. The dose was prescribed at the iso-
center, and the dose within the target volume was required to be
within 5% of the isocenter dose. All patients were treated with a
ⱖ 10-MV linear accelerator. To confirm adequate coverage, port
films were taken of the anterior and lateral pelvic fields of each
patient in the treatment position on the first day of treatment. For
further quality assurance, the first 30 patients from each center
underwent real-time review. If this was satisfactory, random spot
checks were performed on 20% of the remaining plans.
Follow-Up
After completion of radiation therapy, patients were ob-
served after 4 weeks, at 6 months after random assignment, and
then every 6 months thereafter. At each visit, patients underwent a
medical history and physical examination with a digital rectal
examination, except for the first 4-week postradiotherapy visit.
Urinary and rectal symptoms were assessed at baseline and then
weekly during radiotherapy (four times for the 52.5-Gy group and
six times for the 66-Gy group) to document acute toxicity. Subse-
quently, toxicity was assessed at 2 weeks (by telephone) and at 4
weeks after radiotherapy, at 6 weeks after radiotherapy for the
52.5-Gy group, and at visits every 6 months thereafter. PSA was
measured at each follow-up visit starting with the 6-month post-
randomization visit. Transrectal ultrasound-guided biopsy of the
prostate was scheduled 2 years after completion of radiotherapy.
Patient follow-up continued until clinical evidence of metastases
was found.
Outcomes
The primary outcome was biochemical or clinical failure
(BCF). For this trial, BCF was defined as a cluster of any one of the
following events (whichever occurred first): three consecutive in-
creases in PSA,13 clinical evidence of failure (local or distant),
commencement of hormonal therapy, or death as a result of
prostate cancer. Blinded assessment was used to verify the occur-
rence of BCF and to determine the earliest date of failure. Al-
though the trial was originally designed with biopsy positivity at 2
years after randomization as the primary outcome, the emerging
literature suggested that the combination of BCF was the optimal
measure of efficacy.13 Therefore, before the study completion and
data unblinding, an amendment was issued and approved by
the study Steering Committee (September 14, 2001) to change
the primary outcome to BCF. The protocol modification was
then distributed to all participating clinical centers. Secondary
6133
 Lukka et al
outcomes included local persistence of tumor on biopsy of the
prostate at 2 years (biopsy positivity), overall survival, and acute
and late radiation-induced toxicity.
The criterion for local disease recurrence was based on the
clinical evaluation of the prostate at the time of digital rectal
examination. Signs or symptoms of local recurrence were con-
firmed through prostate biopsy. Biopsies reported as suspicious
were classified as positive, and biopsies reported as equivocal were
classified as negative. Criteria for distant disease recurrence of
metastases outside of the prostate included recurrent tumor found
in regional pelvic lymph nodes, bone (abnormal bone x-rays or
bone scan), liver (abnormal liver scan, ultrasound, or CT scan),
and lung (abnormal chest x-ray consistent with metastases).
Asymptomatic patients who presented during follow-up with an
increasing PSA were investigated at the physician’s discretion with
a further bone scan and an abdominal and pelvic CT scan (if the
bone scan was negative). If both scans were negative, a prostate
biopsy was undertaken to determine clinically the cause of the
increase. In patients with only PSA failure, effort was made to
prolong the interval between treatment and biopsy to avoid false-
positive biopsy. Treatment at the time of relapse for metastatic
symptoms, clinical evidence of recurrence or residual disease, or
PSA failure was at the discretion of the treating physician. Physi-
cians were asked to refrain from intervening based solely on the
results of the 2-year postradiotherapy biopsy.
The investigating physician or clinical trials nurse assessed
radiation toxicity using the standardized National Cancer Insti-
tute of Canada toxicity scale and graded toxicity according to
specific criteria for each symptom on a 5-point scale ranging from
0 (nontoxic) to 4 (severe toxicity). The effects of radiation therapy
on the GI system (anorexia, diarrhea, GI bleeding, nausea, pain/
cramping, proctitis, and vomiting), the genitourinary system
(bladder changes, cystitis, fistula formation, frequency, hematu-
ria, ureteral obstruction, and genitourinary pain), the skin, and
fatigue/general malaise were evaluated using the 5-point scale.
Statistical Analysis
The study was designed as a noninferiority investigation re-
quiring 450 patients per treatment arm. The sample size calcula-
tion was based originally on the ability to demonstrate that the
percentage of patients with biopsy positivity at 2 years in the short
arm was no worse than the long arm (suggested in the literature to
be 25%) by more than an absolute difference of 7.5%, with a
one-sided ␣ ⫽ .05 and a power of 80%. With time from random
assignment to BCF as the primary outcome measure and a BCF
probability over 5 years estimated at approximately 40% in either
group, we estimated that a sample size of 940 men provided
approximately 80% power to demonstrate noninferiority with the
same 7.5% tolerance.
Overall survival was defined as the time from random assign-
ment to death from any cause or to the date of the last visit for
patients still alive. For the time to BCF outcome, patients without
events were censored on the date of their last visit or prostate-
unrelated death. Treatment groups were compared using a two-
sided 90% CI for the difference (long arm minus short arm) of the
cumulative BCF probability at 5 years. A lower confidence limit
greater than ⫺7.5% indicated noninferiority. All time to event
outcomes were summarized using the Kaplan-Meier method. In
addition, hazard ratios (short arm relative to long arm) and their
respective 95% CIs were calculated for BCF and overall survival
using the Cox proportional hazards model.
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Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
For the toxicity assessment, acute toxicity was defined as
events occurring up to 5 months after randomization, and late
toxicity included events occurring after 5 months. Risk differences
(long arm minus short arm) and 95% CIs were calculated using
the modified Wilson score method.14 All statistical analyses, which
were based on the intent-to-treat principle, were undertaken by
the study statistician using data provided by the Coordinating and
Methods Centre of the Ontario Clinical Oncology Group located
in Hamilton, Ontario, Canada.
RESULTS
Study Population
Nine hundred thirty-six patients were recruited for the
trial between March 1995 and December 1998; 470 patients
were randomly assigned to receive 66 Gy in 33 fractions
over 45 days, and 466 patients were randomly assigned to
receive 52.5 Gy in 20 fractions over 33 days. The median
follow-up time for all patients was 5.7 years (minimum, 4.5
years; maximum, 8.3 years). The treatment groups were
well balanced in terms of baseline characteristics and risk
group stratification (Table 1).
During the study, seven patients did not receive radia-
tion (five patients in the long arm and two patients in the
short arm), one patient in the short arm crossed over to the
long arm, and three patients in the long arm received alter-
nate radiation dose and fraction combinations (22 Gy in 11
fractions, 52 Gy in 26 fractions, and 52.8 Gy in 20 fractions).
All other patients completed the prescribed treatment.
BCF
At the time of analysis, 236 patients in the long arm and
263 patients in the short arm experienced BCF (Fig 1). Table
2 lists the events according to the outcome type and radia-
tion therapy schedule. The 100 patients who died during the
study of non–prostate cancer causes without experiencing
BCF (54 patients in the long arm and 46 patients in the short
arm) were censored on the date of death. At 5 years, the
Kaplan-Meier estimates of BCF in the long arm and short
arm were 52.95% and 59.95%, respectively. The difference
was ⫺7.0% (90% CI, ⫺12.58% to ⫺1.42%). Because the
lower bound is less than the predefined tolerance of ⫺7.5%,
we could not exclude the possibility of the short arm being
inferior. Overall, a hazard ratio of 1.18 (95% CI, 0.99 to
1.41) in favor of the long arm was estimated.
Biochemical failure was also assessed using the
Vancouver15 and Houston16 definitions of post-treatment
failure. Using the Vancouver criteria, 50.0% of patients in the
long arm and 55.8% of patients in the short arm experienced
PSA failure. Using the Houston definition, 37.7% of patients in
the long arm and 42.3% of patients in the short arm experi-
enced PSA failure.
Overall Survival
Overall, there were 166 deaths during the study period
(89 deaths in the long arm and 77 deaths in the short arm).
JOURNAL OF CLINICAL ONCOLOGY
 Hypofractionation in Prostate Cancer

Table 1. Baseline Characteristics of Patients According to

Randomized Allocation
Long Arm: 66 Gy Short Arm: 52.5
in 33 Fractions Gy in 20 Fractions
(n ⫽ 470) (n ⫽ 466)
No. of No. of
Characteristic Patients % Patients %
Age, years
Mean 70.3 70.0
Range 53-84 53-84
PSA, ␮g/L
Mean 10.4 10.6
Range 0.4-40 0.3-39
Gleason score
2-4 41 9 35 8
5 65 14 67 14
6 171 36 181 39
7 155 33 134 29
8-9 38 8 49 11
Tumor stage
T1A 3 1 0 0
T1B 13 3 9 2 Fig 1. Biochemical or clinical failure (BCF) by randomized treatment arm.
T1C 116 25 114 25
T2A 122 26 135 29
T2B 123 26 130 28 biopsied patients in the long arm and in 50.9% of biop-
T2C 93 20 78 17 sied patients in the short arm (risk difference ⫽ 2.3%;
ECOG performance status 95% CI, ⫺5.1% to 9.8%).
0 385 82 387 83
1 72 15 67 14 Radiation Toxicity
2 4 1 4 1 During the acute period, 7.0% of patients in the long
Missing 9 2 8 2 arm and 11.4% of patients in the short arm experienced
With hypertension 157 33 177 38
grade 3 or 4 GI or genitourinary toxicities (risk difference ⫽
With diabetes 45 10 54 12
Strata
⫺4.4%; 95% CI, ⫺8.1% to ⫺0.6%; Table 3). During the
PSA ⱕ 15, GL 2-6, Rad 225 48 217 47 monitoring of late toxicity, 3.2% of patients in both treat-
PSA ⱕ 15, GL 2-6, Surg 6 1 10 2 ment arms experienced severe toxicities (risk difference ⫽
PSA ⱕ 15, GL 7⫹, Rad 132 28 131 28 0.0%; 95% CI, ⫺2.4% to 2.3%; Table 3). Overall, genitouri-
PSA ⱕ 15, GL 7⫹, Surg 14 3 10 2
nary toxicity represented two thirds of these events.
PSA ⬎ 15, GL 2-6, Rad 49 10 48 10
PSA ⬎ 15, GL 2-6, Surg 2 1 6 1
PSA ⬎ 15, GL 7⫹, Rad 37 8 36 8 DISCUSSION
PSA ⬎ 15, GL 7⫹, Surg 5 1 8 2

Abbreviations: PSA, prostate-specific antigen; GL, Gleason score; Rad,

radiologic evaluation of lymph nodes; Surg, surgical evaluation of lymph This is the first randomized trial to evaluate a high dose per
nodes; ECOG, Eastern Cooperative Oncology Group. fraction in the context of a hypofractionated radiation

Table 2. Biochemical or Clinical Failure by Event Type and Treatment

Of the total number of deaths in the long arm, 18 were Short Arm: 52.5
caused by prostate cancer compared with 13 prostate can- Long Arm: 66 Gy Gy in 20
in 33 Fractions Fractions
cer–related deaths in the short arm. At 5 years after random (n ⫽ 470) (n ⫽ 466)
assignment, overall survival was estimated as 85.2% and Event Type No. of No. of
87.6% in the long and short arms, respectively (hazard ratio ⫽ (as first event) Patients % Patients %
0.85; 95% CI, 0.63 to 1.15; Fig 2). PSA failure 199 42 217 47
Treatment intervention 29 6 34 7
Prostate Biopsy at 2 Years Distant failure 4 1 10 2
Prostate biopsies were performed on 73% of the Local failure 1 ⬍1 2 ⬍1
patients (342 of 470 patients in the long arm and 340 of Prostate cancer death 3 ⬍1 0 0
466 patients in the short arm). The median time to Total 236 50 263 56
postradiotherapy biopsy was 26 months (range, 19 to 37 Abbreviation: PSA, prostate-specific antigen.
months). Positive biopsies were detected in 53.2% of

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 Lukka et al

for treatment evaluation. The 2-year postradiotherapy bi-

Fig 2. Overall survival by randomized treatment arm.
schedule for early-stage prostate cancer. Results from this
trial showed that there was a difference of 7% in biochem-
ical failure at 5 years between the shorter fractionation arm
(2.625 Gy per fraction) and the long fractionation arm (2
Gy per fraction). This difference fell within the predefined
tolerance of 7.5% (noninferiority range) established for the
trial. However, the lower limit of the 95% CI did fall outside
of the predefined tolerance. Given this finding, we cannot
exclude the possibility that the short arm may be worse
than the long arm in terms of 5-year biochemical failure.
In comparison, the percentage of 2-year positive biopsies
and overall survival at 5 years were similar in both treat-
ment arms of the trial.
We recognize that overall survival was the most impor-
tant outcome for this study, but given the long natural
history of prostate cancer, a surrogate outcome was chosen
opsy was originally chosen as the surrogate outcome be-
cause evidence supported its reliability and accuracy.17-19
Before study completion and data analysis, the primary
outcome was changed to BCF based on emerging evidence
supporting the value of PSA for measurement of treatment
effect.13 The American Society for Therapeutics Radiology
and Oncology (ASTRO) definition of PSA failure was used
as one of four composite outcomes in this study to define
biochemical failure. We anticipated that most BCF events
would be a result of biochemical failure based on the
ASTRO definition of the failure. However, we recognized
that adherence to the strict definition of PSA failure (three
consecutive PSA increases) would not capture all events;
hence, the other events (clinical or distant failure, cancer
death, or commencement of hormonal treatment) were
included in the definition of BCF. Although the ASTRO
definition is the most widely accepted definition of PSA
failure, it is associated with limitations.20,21 In our study,
similar results were demonstrated by substituting the
Vancouver15 and Houston16 definitions of PSA failure for
the ASTRO definition. PSA doubling time of less than 3
months is a new outcome that has been proposed as a
surrogate outcome for cancer-specific mortality in prostate
cancer.22 However, it is not yet universally accepted as a
surrogate outcome.23 For the purposes of this analysis, we
have limited the analysis to primary and secondary out-
comes identified in the protocol.
Events of radiation toxicity were detected throughout
the study period. Grade 3 or 4 genitourinary and GI toxic-
ities were reported by a relatively small percentage of pa-
tients in both arms of this study. The difference in incidence
of acute radiation toxicities was interesting; patients in the
long arm fared approximately 5% better than patients in
the short arm. However, the number of reported late toxic-
ities was similarly low in both treatment arms (3.2%). The
␣/␤ model for prostate cancer would be predictive of this

Table 3. NCIC Grade 3 or 4 Toxicity by Period, Site, and Treatment

Long Arm: 66 Gy in Short Arm: 52.5 Gy in
33 Fractions 20 Fractions
(n ⫽ 470) (n ⫽ 466) Long Arm ⫺ Short Arm
No. of No. of
Period and Site Patients % Patients % % Difference 95% CI (%)
Acute, ⱕ 5 months
GI 12 2.6 19 4.1 ⫺1.5 ⫺4.0 to 0.8
GU 23 4.9 40 8.6 ⫺3.7 ⫺7.0 to ⫺0.5
GI or GU 33 7.0 53 11.4 ⫺4.4 ⫺8.1 to ⫺0.6
Late, ⬎ 5 months
GI 6 1.3 6 1.3 0.0 ⫺1.7 to 1.6
GU 9 1.9 9 1.9 0.0 ⫺1.9 to 1.9
GI or GU 15 3.2 15 3.2 0.0 ⫺2.4 to ⫺2.3

Abbreviations: NCIC, National Cancer Institute of Canada; GU, genitourinary system.

6136 JOURNAL OF CLINICAL ONCOLOGY

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Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
 Hypofractionation in Prostate Cancer
comparable late toxicity.24,25 The small but significant
increase in acute toxicity could be related to a higher net rate
of stem-cell depletion in the rectal and bladder mucosa.
This depletion results from an increased rate of dose accumu-
lation in the hypofractionated arm compared with the con-
ventional arm (13.1 v 10 Gy/wk, respectively). This same
mechanism has been purported to cause the increase in acute
toxicity observed in hyperfractionation protocols.26
Compared with other tumors, several studies have con-
cluded that the ␣/␤ ratio for prostate cancer is low, in the
range of 1.0 to 3.0.11,27 However, the debate on this issue
continues. Some recent publications have concluded that
the low ␣/␤ ratio reported in previous studies may actually
be an artifact resulting from tumor hypoxia.28-30 If the ␣/␤
value for prostate cancer is less than for normal tissue
(nominally 3 Gy), it could be argued that a high dose per
fraction regimen would result in a therapeutic gain by im-
proving tumor control with acceptable late toxicity.25,27
Models based on a low ␣/␤ ratio predict that a therapeutic gain
would require a larger fraction size and a higher biologic effec-
tive dose than what was used in this study. In fact, for all ␣/␤
ratios between 0.85 and infinity, the ␣/␤ model predicts that
our chosen hypofractionated regimen would result in a lower
tumor control rate relative to the conventional fractionation
schedule. Therefore, given our current understanding of the
␣/␤ ratio, the results of this study do not contribute meaning-
fully to the debate on the ␣/␤ ratio for prostate cancer. Another
interpretation of this data arrived at by comparison of the
study results with the dose-response curve from published
retrospective studies has suggested that the results are consis-
tent with a low ␣/␤ ratio for prostate cancer.25,31
The dose chosen in the hypofractionated regimen was
based on clinical experience from two Canadian centers and
published studies at the time of study design.5-8 Given the
acute toxicity results in this study, it would have been im-
possible to further escalate the dose using our treatment
technique. Thus, evaluation of high dose per fraction regi-
mens using techniques that reduce toxicity, such as
conformal-beam radiation or intensity-modulated therapy,
is recommended.9
The percentage of positive biopsies reported in this trial
was similar in the long and short treatment arms, which is a
finding that somewhat contradicts the results of biochemi-
cal failure. Postradiotherapy biopsies are no longer a gold
standard for measurement of treatment effect because they
are associated with inherent problems that limit interpreta-
tion. First, there is evidence suggesting that 2 years is too
early and that biopsies should not be taken before 30 to 36
months after radiation to minimize false-positive rates.32
Second, sampling error of biopsies as a result of number and
length of obtained cores can affect biopsy evaluation.33
Several studies have documented that increased biopsy
sampling (standard of six biopsies v 10 or 12) has a better
probability of detecting prostate cancer and may lower
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Copyright © 2005 American Society of Clinical Oncology. All rights reserved.
false-negative rates.34,35 Last, differentiating residual tumor
from postradiotherapy effects can be difficult to judge even
when assessed by an experienced tumor pathologist.32 The
postradiotherapy biopsy results presented here are based on
the report from the original pathologist. Overall, caution
should be exercised when interpreting the 2-year biopsy
results, particularly when drawing comparisons to the re-
sults of biochemical failure.
In the early 1990s when this trial was designed, a four-
field technique was the standard method of radiation deliv-
ery. In recent years, conformal radiation has evolved as the
technique more often used, and in some centers, intensity-
modulated radiation therapy is used. These radiotherapy
tools allow for higher doses of radiation to be delivered to
the prostate and for the margin around the prostate to be
decreased.36-38 Standard total doses of external-beam radi-
ation used to treat early-stage prostate cancer patients now
range from 70 to 78 Gy.39,40 It could be argued that the total
dose of 66 Gy delivered in 2-Gy fractions used in the long
arm would be biologically comparable to 70.2 Gy delivered
in 1.8-Gy fractions.10,11 However, this dose is still low com-
pared with current clinical doses. Both the technique and
dose of radiation used in this study limit the generalizability of
the results to current practice. Recent information supports
the use of adjuvant hormones and potentially pelvic radiother-
apy in the treatment of high-risk patients. However, when the
study was designed, this was not universally accepted as stan-
dard practice and, hence, was not part of the study design.
This is the first reported randomized trial comparing a
high-dose hypofractionated radiation schedule to a longer
conventional dose per fraction schedule. Given the results
of this study, we cannot exclude the possibility that the
chosen hypofractionated radiation treatment regimen is infe-
rior to the standard regimen for early-stage prostate cancer
patients. However, this is only a preliminary analysis and dis-
cussion of the results; 5 years is not considered a long period of
follow-up for prostate cancer. Further evaluation at 10 years of
the outcomes between the two arms of the study is awaited.
The results discussed here do have important implications for
our understanding of the radiobiology of prostate cancer. Fu-
ture studies evaluating high dose per fraction regimens are
encouraged using modern methods of radiation delivery.
■ ■ ■
Acknowledgment
We thank S. Bouma for manuscript preparation; T.
Finch, S. Chambers, and Q. Guo for data management;
and Drs Daya, Jones, Scrigley, Wright, Dayes, Wu, Poon,
Hodson, Fyles, Dixon, Milosevic, Rheaume, Sagar, Youssef,
and Whelan for their assistance with this study
Authors’ Disclosures of Potential
Conflicts of Interest
The authors indicated no potential conflicts of interest.
6137

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