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Title: Stereotactic Body Radiotherapy for Localized Prostate Cancer: PSA Results and Toxicity of a Phase II
Clinical Trial

Article Type: Full Length Article

Section/Category: Clinical Investigation

Keywords: Prostate cancer; Stereotactic Body Radiotherapy; Hypofractionation

Corresponding Author: Dr. Christopher R. King, MD, PhD

Corresponding Author's Institution: Stanford University School of Medicine

First Author: Christopher R. King, MD, PhD

Order of Authors: Christopher R. King, MD, PhD; James D Brooks, MD; Harcharan Gill, MD; Todd Pawlicki,
PhD; Cristian Cotrutz, PhD; Joseph C Presti, MD

Manuscript Region of Origin:

Abstract: Purpose: The radiobiology of prostate cancer favors a hypofractionated dose regimen. We report
results of a prospective Phase II clinical trial of stereotactic body radiotherapy (SBRT) for localized prostate
cancer.
Methods and Materials: 41 low-risk prostate cancer patients with 6 months minimum follow-up received
36.25 Gy in five fractions of 7.25 Gy with image-guided SBRT alone using the Cyberknife. The early (<3
months) and late (>6 months) urinary and rectal toxicities were assessed using validated quality of life
questionnaires (EPIC and IPSS) and the RTOG toxicity criteria. Patterns of PSA response are analyzed.
Results: The median follow-up was 33 months. There were no RTOG grade 4 acute or late rectal/urinary
complications. There were 2 patients with RTOG grade 3 late urinary toxicity and none with RTOG grade 3
rectal complications. A reduced rate of severe rectal toxicities were observed with QOD vs. QD regimen
(0% vs. 38%, p=0.0035). A benign PSA bounce (median 0.4 ng/mL) was observed in 12 patients (29%)
occurring at 18 months (median) after treatment. At last follow-up no patient has had a PSA failure
regardless of biochemical failure definition. Of 32 patients with 12 months minimum follow-up, 25 patients
(78%) achieved a PSA nadir <=0.4 ng/mL. A PSA decline to progressively lower nadirs up to 3 years after
treatment was observed.
Conclusions: The early and late toxicity profile and PSA response for prostate SBRT are highly encouraging.
Continued accrual and follow-up will be necessary to confirm durable biochemical control rates and low
toxicity profiles.
Cover Letter

To: Editor IJROBP

April 4, 2008

Dear Sir,

We wish to submit the following original manuscript for consideration by the IJROBP:

‘Stereotactic Body Radiotherapy for Localized Prostate Cancer: PSA Results and
Toxicity of a Phase II Clinical Trial’

by Christopher R. King, PhD, MD, James D. Brooks, MD, Harcharan Gill, MD,
Todd Pawlicki, PhD, Cristian Cotrutz, PhD, and Joseph C. Presti Jr, MD

Sincerely,

Christopher R. King, PhD, MD

* Manuscript

Stereotactic Body Radiotherapy for Localized Prostate Cancer:

PSA Results and Toxicity of a Phase II Clinical Trial

Christopher R. King, PhD, MD1, James D. Brooks, MD2, Harcharan Gill, MD2,
Todd Pawlicki, PhD1, Cristian Cotrutz, PhD1, and Joseph C. Presti Jr, MD2

1
Department of Radiation Oncology
2
Department of Urology
Division of Urologic Oncology
Stanford University School of Medicine
Stanford, CA

Corresponding author: Christopher R King, PhD, MD

Department of Radiation Oncology
Stanford University School of Medicine
Stanford Cancer Center
875 Blake Wilbur Drive
Stanford, CA 94305

Phone: (650) 736-0698

FAX: (650) 725-8231
E-mail: crking@stanford.edu

Running Title: Stereotactic Body Radiotherapy for Localized Prostate Cancer

Key Words: prostate cancer; stereotactic body radiotherapy; PSA; Hypofractionation

1
CONFLICT OF INTEREST STATEMENT: none of the authors have any conflict of

interest regarding the content, treatment, drugs or technology associated with this report.

ACKNOWLEDGEMENTS: The authors thank Dr. Deep Patel and Dr. Wendy Hara for

their help with data collection while residents in the early phases of this trial, Dr. John

Adler for his exuberant encouragement over the years, and Dr. Jack Fowler and Dr. Dan

Kapp for discussions on radiobiology.

2
 ABSTRACT

Purpose: The radiobiology of prostate cancer favors a hypofractionated dose regimen.

We report results of a prospective Phase II clinical trial of stereotactic body radiotherapy

(SBRT) for localized prostate cancer.

Methods and Materials: 41 low-risk prostate cancer patients with 6 months minimum

follow-up received 36.25 Gy in five fractions of 7.25 Gy with image-guided SBRT alone

using the Cyberknife. The early (<3 months) and late (>6 months) urinary and rectal

toxicities were assessed using validated quality of life questionnaires (EPIC and IPSS)

and the RTOG toxicity criteria. Patterns of PSA response are analyzed.

Results: The median follow-up was 33 months. There were no RTOG grade 4 acute or

late rectal/urinary complications. There were 2 patients with RTOG grade 3 late urinary

toxicity and none with RTOG grade 3 rectal complications. A reduced rate of severe

rectal toxicities were observed with QOD vs. QD regimen (0% vs. 38%, p=0.0035). A

benign PSA bounce (median 0.4 ng/mL) was observed in 12 patients (29%) occurring at

18 months (median) after treatment. At last follow-up no patient has had a PSA failure

regardless of biochemical failure definition. Of 32 patients with 12 months minimum

follow-up, 25 patients (78%) achieved a PSA nadir 0.4 ng/mL. A PSA decline to

progressively lower nadirs up to 3 years after treatment was observed.

Conclusions: The early and late toxicity profile and PSA response for prostate SBRT are

highly encouraging. Continued accrual and follow-up will be necessary to confirm

durable biochemical control rates and low toxicity profiles.

3
 INTRODUCTION

In the late 1960s through early 1980s, motivated primarily by economy of

resources, a clinical program was open in the UK delivering hypofractionated

radiotherapy for prostate cancer (36 Gy in 6 fractions over three weeks). Although

staging was limited (this was the pre-PSA era), radiotherapy techniques were simple (this

was the pre-CT era) and many of these patients had high-risk features by today’s criteria

(eg. bulky palpable disease or high grade), the update of that clinical experience with 22

years follow-up confirmed the long-term safety and potential effectiveness of this

treatment (1).

Modern understanding of the radiobiology of prostate cancer now offers a

biologic rationale in favor of such a hypofractionated radiotherapy course (ie. large dose

per fraction) over a conventionally fractionated one (ie. 1.8-2 Gy). The first study to

suggest that prostate cancer possesses a radiobiology uniquely different from other

cancers showed that one could quantify the sensitivity of prostate cancer to dose per

fraction by comparing the dose response with permanent low dose-rate brachytherapy to

that from fractionated external beam (2). Using a standard radiobiological model of dose

response (the linear quadratic model) this study showed that prostate cancer possessed an

unusually low  ratio of ~1.5 Gy (ie. a high sensitivity to dose-per-fraction). This 

ratio is low compared with the value of ~10 Gy for other cancers, and is also remarkably

lower than that of late effects for normal tissues, where it is ~3-5 Gy (3). The

implications of such a high sensitivity to dose per fraction were immediately recognized,

4
being that hypofractionation would be a more effective dose regimen for prostate cancer

(4).

Numerous studies have since followed the initial report of a low  ratio for

prostate cancer. A recent review of 17 such studies estimated a mean  ratio of 1.85

Gy (5). There are four contemporary clinical series using external beam hypofractionated

regimens, with dose per fraction ranging from 2.5 to 3.1 Gy (6-9) and one using a linac-

based stereotactic body radiotherapy (SBRT) technique delivering 5 daily fractions of 6.7

Gy (10). There are also several series using HDR brachytherapy combined with

conventionally fractionated external beam with dose-per-fraction ranging from 5.5 Gy to

11.5 Gy (11, 12) and one with HDR brachytherapy monotherapy delivering 8-9 fractions

of 6 Gy each (13). These clinical series have uniformly demonstrated excellent

biochemical control rates and low rectal and bladder toxicities with the use of

hypofractionated radiotherapy.

Fowler et al. (14) proposed several hypofractionated dose regimens for prostate

cancer based on the assumption of a low  ratio. They showed that a significantly

higher therapeutic ratio (ie. simultaneous higher rates of tumor control rates and lower

incidence of toxicities) could be achieved with these dose regimens. Although none are

proposed as optimal, the gain in therapeutic ratio is proportional to the dose-per-fraction

size. In this report we present our experience with an ongoing prospective phase II

clinical trial using SBRT for localized low-risk prostate cancer that delivers 36.25 Gy in

5 fractions of 7.25 Gy, focusing on the early and late rectal/bladder toxicities as well as

the patterns of PSA response.

5
 METHODS AND MATERIALS

Patient eligibility

In December 2003 we began an IRB-approved phase II clinical trial of

hypofractionated SBRT for low-risk prostate cancer. Eligible patients were newly

diagnosed with biopsy proven prostate cancer presenting with low-risk features. The

criteria for low-risk were pre-biopsy PSA of 10 ng/mL or less, biopsy Gleason grade of

3+3 or lower, and clinical T-stage T1c or T2a/b based on the AJCC 6th ed. (15). We

allowed a Gleason grade of 3+4 if present in fewer than 2 out of a 10-12 core biopsy and

involving less than 5 mm in aggregate tumor length. All biopsy grading was obtained at

our institution. Patients with prior treatment (hormone therapy or TURP) were excluded.

As of 3/08 there were 53 patients enrolled in this trial, with 41 having a minimum of 6

months of follow-up who form the study population of this report. The median age was

66 years (range 48-83 years). The median initial PSA was 5.6 ng/mL (range 0.7-10, and

a single patient enrolled with a PSA of 15.6 with stage T1c, Gleason grade 3+3 involving

2 mm in 1/12 cores). There were 30 patients with clinical stage T1c, 10 were T2a and

one T2b. Biopsy Gleason grade was 3+3 in 29 patients and 3+4 in 12 patients.

Treatment specifics

The Cyberknife (Accuray, Inc., Sunnyvale CA) was used to deliver image-guided

SBRT. Three gold fiducials were placed in the prostate via trans-rectal ultrasound

guidance. A same-day CT scan was obtained with patients in the supine position and in

6
an alpha cradle, at 1.25 mm slice thickness and indexing. Anatomical contouring of the

prostate, seminal vesicles, rectum, bladder, penile bulb and femoral heads were done.

Dose was prescribed to the planning target volume (PTV) that consisted of a volumetric

expansion the prostate by 5 mm, reduced to 3 mm in the posterior direction. In order for

the prescription dose to cover 95% of the PTV, normalization was required to the 89-90

% isodose line (ie. the resulting dose heterogeneity was 10-11 %). In Figure 1 we show a

typical dose-volume histogram (DVH). In arriving at an optimal treatment plan great

care was made to respect the rectal tolerance, which is particularly important when

delivering hypofractionated radiotherapy. Our rectal DVH goals were <50% rectal

volume receiving 50% of the prescribed dose, <20% receiving 80% of the dose, <10%

receiving 90% of the dose and <5% receiving 100% of the dose. The course of

radiotherapy consisted of 5 fractions of 7.25 Gy for a total dose of 36.25 Gy. Treatments

were given over 5 consecutive days for the first 21 patients and 3 times a week

subsequently. From the linear quadratic equation one can derive the equivalent biologic

dose when given at 2 Gy per fraction (EQD2) from that of a hypofractionated course for

any tissue or tumor type by the simple relationship: EQD2 = D[ +d]/[+2], where D

is the total dose given at dose d, the dose-per-fraction. Our hypofractionated dose

regimen corresponds to a tumor EQD2 of 90.6 Gy (assuming an  of 1.5 Gy), a normal

tissue late effect EQD2 of 74.3 Gy (assuming an  of 3 Gy) and an acute toxicity

EQD2 of 52.2 Gy (assuming an  of 10 Gy).

7
Follow-up and Toxicity scoring

Patients were followed every 3 months with PSA and quality of life (QOL)

questionnaires. All patients have baseline QOL data. The International Prostate

Symptom Score (IPSS) (16) and Expanded Prostate Cancer Index Composite (EPIC) (17)

validated questionnaires were used. Toxicity was also scored on the Radiation Therapy

Oncology Group (RTOG) urinary and rectal toxicity scale (18). Available data are at

baseline and are categorized as early (at 3 months) and as late (6 months and later).

RESULTS

PSA response

The median follow-up was 33 months (range 6 to 45 months). The patterns of

PSA response after completion of SBRT show a gradual decline. Figure 2 shows the

median PSA as a function of time after RT. To date no patient has experienced a PSA

failure regardless of the biochemical failure definition used. The median PSA nadir was

0.32 ng/mL (range 0.03 to 2.65). We present in Table 1 the proportion of patients

achieving a given PSA nadir threshold at 1, 2 and 3 years after RT. We note that 25 out

of 32 patients (78%) with 12 months minimum follow-up achieved a PSA nadir 0.4

ng/mL. It is also worth noting that a greater proportion of patients continue to achieve a

given nadir threshold as a function of time up to 3 years. A benign PSA bounce (defined

here as a PSA rise of 0.2 ng/mL or more above its previous nadir with a subsequent

decline to that nadir or lower) was observed in 12 patients (29%). The median time to

8
PSA bounce was 18 months (range 12 to 33 months) after RT and the median bounce

height was 0.39 ng/mL (range 0.2 to 2.47). We present in Figure 3 the typical pattern of

PSA for three patients experiencing a benign bounce. Note that 2 to 3 bounces occur

during the follow-up time.

Urinary/Rectal Toxicity and QOL

In Table 2 we summarize the patient self-reported urinary and rectal QOL score at

baseline, and 3 months, 1 year and 2 years after completion of SBRT. Two patients

reported ‘terrible’ (QOL score 6) urinary symptoms at 3 months and were those patients

who reported ‘mostly dissatisfied/unhappy’ (QOL score 4-5) at baseline. We note that

although the urinary QOL scores deteriorated somewhat at 3 months, they recovered and

in fact improved over baseline at 1 and 2 years, with over 90% of patients reporting QOL

scores below 3. The rectal QOL became worse at 3 months but never reached the ‘big

problem’ QOL score. With 89% of patients reporting ‘no problem’ (QOL score 1) at

baseline, about half were still reporting ‘very small/small problem’ (QOL score 2-3) at 1

and 2 years, suggesting a residual of long-term low-level rectal symptoms.

In Table 3 we report the late urinary and rectal toxicities on the RTOG scale, and

compared them with the crude incidence of late toxicities from the high-dose arm of

Univ. of Texas MD Anderson (MDA) dose-escalation trial (78 Gy prescribed at the

isocenter in 2 Gy fractions using 3D conformal techniques) (19). We note that no patient

suffered any grade 4 urinary toxicity and that the incidence of grade 2/3 urinary toxicities

is higher compared with the MDA trial. There were no grade 3 or 4 rectal toxicities and

the incidence of grade 2/3 rectal toxicity is lower than seen with the MDA trial.

9
 Finally, we compare the late urinary and rectal QOL among patients treated QD

with those treated QOD in Table 4. While there were no significant differences in low-

level urinary or rectal QOL at baseline, we note that the QD group had more patients who

scored small problems compared with the QOD group. A significant improvement in

high-grade rectal toxicities was noted in the QOD group. No patient in the QOD group

reported a QOL score 4-5, for either any individual rectal symptom or for the overall

QOL, whereas in the QD group 8 patients (38%) reported a score of 4-5 for any

individual rectal symptom (p=0.0035) and 5 patients (24%) reported a score of 4-5 for the

overall QOL (p=0.048). For the urinary QOL there was no significant difference

between the QD and QOD groups (p=0.34) although 4 patients reported a score of 4-6 for

the QD group compared with 1 for the QOD group.

DISCUSSION

Urinary/Rectal Toxicity and QOL

The outcomes from this clinical trial demonstrate that a hypofractionated course

of stereotactic radiotherapy for localized prostate cancer is associated with urinary and

rectal toxicities that are of the expected nature and severity as those experienced with

conventionally fractionated courses of external beam radiotherapy. There was no severe

urinary toxicity (RTOG grade 4), and the two patients who experienced the worst

problems were those who at baseline had described their urinary QOL as ‘mostly

dissatisfied/unhappy’. Interestingly, after peaking at around 3 months, most patients

10
returned to near baseline levels of urinary satisfaction, and many have in fact improved

above baseline levels at two years. An increase in the use of medications (eg. alpha

blockers) is likely to be the explanation for this observation. Although the incidence of

low-grade (RTOG grade 1 and 2) late urinary toxicity is about double that observed from

the MDA dose-escalation trial, it has not resulted in a significant degradation of patients’

urinary QOL. An evolving refinement of our technique to improve the dosimetry with

the Cyberknife by using a urethral ‘tuning’ structure to limit the dose heterogeneity from

encroaching on the urethra will likely lessen this toxicity in the future.

In comparing our results we note that the MDA data are of a much longer median

follow-up time of 8.7 years. In addition, their study showed an actuarial increase in

toxicity with time achieving a plateau at around 5 years (19). Since our follow-up is

much shorter we must remain cautious about the interpretation of our late urinary and

rectal toxicities since it is fully expected that these will continue to appear at least up to 5

years after treatment. We also note that comparison with the MDA results assumes that

our patients had a similar baseline QOL profile as theirs.

There were no severe rectal toxicities (RTOG grade 3 or 4) observed. A decline

in patients’ rectal QOL score appears to plateau around 3 months after RT, persisting at

the ‘very small/small problem’ up to 2 years after RT. No significant difference in the

incidence of low-grade rectal toxicity (RTOG grade 1 and 2) was observed when

compared with the MDA dose-escalation trial.

11
QD vs. QOD

Our data allowed us to study differences in late toxicities between patients treated

over 5 consecutive days (QD) and those treated every other day (QOD). A significant

improvement was observed for late rectal problems when treatment was given QOD,

where 0/20 patients reported a score of 4 or 5 compared with 8/21 patients when treated

QD (p=0.0035) for any rectal symptom, and 0/20 vs. 5/21, respectively, for overall rectal

QOL (p=0.048). Although fewer patients experienced a QOL score 4-6 for late urinary

problems with QOD vs. QD treatment, 1/20 vs. 4/21, it was not significant (p=0.34). The

apparent improvement in rectal toxicity with QOD vs. QD regimen, if real, is interesting

for what it suggests about the repair kinetics of hypofractionated radiation damage to the

rectum. The data for late bladder and rectal toxicity suggests a repair half-life of ~1 hour

(eg. 20). Thus after 24 hours the repair of sublethal damage is complete (it should be

nearly complete after 5 half-lives) and no further gain (or reduced toxicity) would be

observed with a longer interval between dose fractions. One possible explanation of our

observations is for a much longer repair half-life, on the order of at least ~8 hours, since

repair is incomplete by 24 hours but approximately complete by 48 hours. This seems

unlikely since it is inconsistent with previous data on repair kinetics. Other possible

explanations are that either we are seeing the effects of normal tissue repopulation of

rectal mucosa, or that late damage actually results from vascular injury. Although these

are only hypotheses, it is possible that either a separate mechanism of repair for late rectal

effects or a different nature of radiation damage is present with hypofractionation. We

are cautious about over-interpreting this data, but given our observations we favor

treating with a longer interval between fractions for hypofractionated dose regimens.

12
PSA response

The patterns of PSA response from our trial are highly encouraging. It is

interesting to note the high proportion of patients (78%) with 12 or more months of

follow-up achieving a low PSA nadir of 0.4 ng/mL. It is also worth noting that the PSA

nadir achieved is progressively lower as time goes by, up to 3 years. This continued late

PSA response after RT for prostate cancer is well-known and is consistent with the

radiation biology of prostate cancer behaving similarly to that of late effects in normal

tissues. What if our radiobiological hypothesis for prostate cancer is wrong and that it in

fact possesses an  ratio that is similar to other tumors (ie. ~10 Gy)? In that case the

tumor dose from our hypofractionated regimen, EQD2 = 52 Gy, would be seriously

inadequate. An estimate of the 5-year biochemical control rate based on the dose-

response for low-risk prostate cancer is predicted to be only ~40% for 52 Gy, as opposed

to ~90% for 78 Gy. Although our follow-up time is relatively brief, we have not

observed a biochemical failure so far.

We have also shown that a benign PSA bounce was present after hypofractionated

RT at roughly the same frequency, timing and magnitude as has been described after

permanent brachytherapy (21) or after external beam radiotherapy (22).

13
 CONCLUSION

This study suggests that hypofractionated radiotherapy for localized prostate

cancer has an early and late toxicity profile no worse than with dose-escalated

radiotherapy delivered at conventional fractionation. The favorable biochemical response

observed supports the radiobiological assumption upon which the rationale for prostate

cancer hypofractionation is based. Continued pursuit of this trial seems warranted but

with reasonable caution however, as longer follow-up will be necessary to confirm

durable biochemical control rates and low late toxicity profiles.

14
 FIGURE CAPTIONS

Figure 1. Dose volume histogram achieved with the Cyberknife for a typical prostate

cancer patient. Dose is normalized to cover the 95% of the PTV.

Figure 2. PSA response plotted as median PSA as a function of time after SBRT. The

error bar is +/- one standard deviation from the mean (SEM).

Figure 3. Benign PSA bounce as seen in three representative patients. Note that a PSA

bounce can occur several times during the available follow-up.

15
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11. Demanes DJ, Rodrihuez RR, Schour L, et al. High-dose rate intensity-modulated

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13. Yoshioka Y, Nose T, Yoshida K, et al. High-dose rate brachytherapy as monotherapy

for localized prostate cancer: a retrospective analysis with special focus on tolerance and

chronic toxicity. Int J Radiat Oncol Biol Phys 2003;56:213-220.

14. Fowler JF, Ritter MA, Chappell RJ, and Brenner DJ. What hypofractionated

protocols should be tested for prostate cancer? Int J Radiat Oncol Biol Phys.

2003;56:1093-104.

15. Greene FL, Page DL, Flemming ID, et al. AJCC Manual for staging cancer. 6th ed.

New York: Springer Verlag 2002;309-13.

16. Barry MJ, Fowler FJ Jr, O’Leary MP, et al. The American Urological Association

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19. Kuban DA, Tucker SL, Dong L, et al. Long-term results of the M. D. Anderson

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20. Guerrero M, Li XA. Halftime for repair of sublethal damage in normal bladder and

rectum: an analysis of clinical data from cervix brachytherapy. Phys Med Biol. 2006

Aug 21;51(16):4063-71.

21. Crook J, Gillan C, Yeung I, et al. PSA kinetics and PSA bounce following permanent

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22. Horwitz EM, Levy LB, Thames HD, et al. Biochemical and clinical significance of

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19
Figure 1
Click here to download Figure: Figure-1.pdf

Figure 1
100

80
PTV
Bladder
% Volume

60

Rectum
40

Rt femur
20
Lt femur

0
0 20 40 60 80 100 120

% Normalized Dose
Figure 2
Click here to download Figure: Figure-2.pdf

Figure 2

10
Median PSA ± SEM

0
0 6 12 18 24 30 36 42 48

Months after RT
Figure 3
Click here to download Figure: Figure-3.pdf

8
Figure 3

6
PSA (ng/mL)

0
0 6 12 18 24 30 36 42 48

Months after RT
Table

Table 1: Proportion of patients achieving a given PSA nadir threshold as a function of

time after radiotherapy

% achieving PSA nadir by follow-up time

PSA nadir At 1 year At 2 years At 3 years

(32 pts) (17 pts) (15 pts)
1 ng/mL 53% 70% 93%

0.6 ng/mL 31% 70% 87%

0.4 ng/mL 19% 53% 67%

0.2 ng/mL 9% 6% 40%

PSA: prostate specific antigen

SBRT: stereotactic body radiotherapy
Table 2: Urinary QOL from IPSS and rectal QOL from EPIC, as a function of time after
SBRT

% with given QOL score, Urinary*

QOL score (IPSS) Baseline 3 months 1 year 2 years

0-1 51% 37% 44% 92%

2-3 41% 58% 52% 8%

4-5 8% - 4% -

6 - 5% - -

*Urinary QOL (IPSS) scale: 0-1 (delighted/pleased); 2-3 (mostly satisfied/mixed);

4-5 (mostly dissatisfied/unhappy); 6 (terrible)

% with given QOL score, Rectal**

QOL score (EPIC) Baseline 3 months 1 year 2 years
1 89% 37% 46% 45%

2-3 11% 48% 50% 45%

4 - 16% 4% 9%

5 - - - -

**Rectal QOL (EPIC) scale:1 (no problem); 2-3 (very small/small problem);
4 (moderate problem); 5 (big problem)

QOL: quality of life

IPSS: international prostate symptom score
EPIC: expanded prostate cancer index composite
SBRT: stereotactic body radiotherapy
Table 3: Late urinary and rectal toxicity on the RTOG scale, compared with results from
the Univ. of Texas MD Anderson (MDA) dose-escalation trial (78 Gy at 2 Gy per
fraction group)

RTOG grade
Urinary 0 I II III IV
This trial, % (no. pts) 30% (11) 41% (15) 24% (9) 5% (2) -

MDA dose-escalation trial, 76% (114) 14% (21) 7% (11) 3% (5) -

% (no. pts)
RTOG grade
Rectal 0 I II III IV
This trial, % (no. pts) 51% (20) 33% (13) 15% (6) - -

MDA dose-escalation trial, 47% (71) 28% (42) 19% (28) 7% (10) -
% (no. pts)
RTOG: Radiation therapy Oncology Group
Table 4: Comparison of late urinary and late rectal toxicity from EPIC between
consecutive daily treatments (QD) and those delivered three times a week (QOD)

URINARY

QD QOD p-value***

Overall urinary QOL 19% (4/21) 5% (1/20) p=0.34

score 4-6 (‘Mostly
Dissatisfied’ or
‘Unhappy’ or ‘Terrible’)
Baseline urinary QOL 38% (8/21) 15% (3/20) p=0.16
score 3 (‘Mixed’)
RECTAL

Any item* score 4-5 38% (8/21) 0% (0/20) p=0.0035

(‘Moderate’ or ‘Big
problem’)
Overall rectal QOL** 24% (5/21) 0% (0/20) p=0.048
score 4-5 (‘Moderate’ or
‘Big problem’)
Baseline rectal QOL 19% (4/21) 0% (0/20) p=0.11
score 2 (‘Very small
problem’)
*urgency, frequency, control, bloody stool, pain
**bowel habits (at 6 months or later)
***Fisher’s exact test (two-tailed)

QOL: quality of life

EPIC: expanded prostate cancer index composite