Appendix A. Meta-analysis of biochemical recurrence data ......Comparison: HR=0.43 (95% CI=...

Appendix A. Meta-analysis of biochemical recurrence data from SWOG 8794, EORTC

22911, and ARO 96-02

Appendix B. Outcomes from Randomized Controlled Trials

SWOG 8794 EORTC 22911 ARO 96-02

RP + RT RP only RP + RT RP only RP + RT RP only

Biochemical recurrence Biochemical recurrence-free survival

60/172 (34.9%)

recurrence

5y bRFS:

71.0%

10y bRFS: 53.0%

112/175 (64%)

recurrence

5y bRFS:

44.0%

10y bRFS: 26.0%

198/502

(39.4%)

recurrence

5y bRFS: 74.0%

10y bRFS: 60.6%

311/503 (61.8%)

recurrence

5y bRFS: 54.0%

10y bRFS: 41.1%

38/148

(25.7%)

recurrence

5y bRFS:

72% 10y bRFS: 56%

67/159 (42.1%)

recurrence

5y bRFS:

54%

10y bRFS: 35%

Comparison: HR=0.43 (95% CI= Comparison: HR=0.49 (95% CI= Comparison: HR=0.51 (95% CI=

CU CI+CI:

0.31-0.58; p<0.001) 0.41-0.59; p<0.001) 0.37-0.70; p<0.001)

Local Recurrence Cumulative local relapse

15/190 (8%)

local

recurrence at

median 10.6y

40/184 (22%) 42/502 (8.4%)

with locoregional

failure

10y cumulative local relapse rate: 7.3% (95% CI=4.9-9.8%)

87/503 (17.3%)

locoregional

failure

10y cumulative local relapse rate: 16.6% (95% CI=13.1- 20.1%)

NR NR

local

recurrence at

median 10.6y

Comparison: no HR reported; Comparison: HR=0.45 (95% CI= NR

p<0.01 0.32–0.68; p<0.0001)

Hormone therapy- free survival

5y hTFS:

90.0%

10y hTFS: 84.0%

5y hTFS:

79.0%

10y hTFS: 66.0%

NR NR NR NR

Comparison: HR=0.45 (95% CI= NR NR

0.29 –0.68; p<0.001)

Metastases Metastatic rate Metastases- free survival cumulative

93/214 (43.5%)

had metastases or died of any cause

20/214 (9.3%)

had metastases

5y mRFS: 88%

10y mRFS: 71%

114/211 (54%)

had metastases or died of any cause

37/211 (17.5%)

had metastases

5y mRFS: 84%

10y mRFS:61%

55/502 (11.0%)

had distant metastases

10y cumulative metastatic rate:

10.1% (95% CI=

7.2-13.0%)

57/503 (11.3%)

had distant metastases

10y cumulative metastatic rate:

11% (95% CI=

8.0-14.0%)

4/148 (2.7%)

had distant metastases at median 4.5y 25/148 (16.9%) had distant metastases at median 9.3y

5/159 (3.1%)

had distant metastases at median 4.5y 22/159 (14.9%) had distant metastases at median 9.3y

Comparison: HR=0.71 (95% CI= Comparison: HR=0.99 (95% CI=0.67-

1.44;

0.67 – 1.44; p=0.94)

NR

0.54–0.94; p=0.016) 1 1.44; p=0.94)

Clinical progression and clinical progression- free survival

84/214 (39.3%)

clinical progression or death at median 10.6y

10y cPFS: 70%

111/211

(52.6%) clinical progression or death at median 10.6y

10y cPFS: 49%

157/502

(31.3%) clinical progression or death at median 10.6y

10y cPFS: 70.3%

181/503 (36.0%)

clinical progression or death at median 10.6y

10y cPFS: 64.8%

NR NR

Comparison: HR=0.62 (95% CI=

0.46–0.82; p=0.001)

Comparison: HR=0.81 (95% CI=0.65 –

1.01; p=0.054)

0.65 – 1.01; p=0.054)

NR

Deaths from

cancer

Cancer-

specific

survival

NR NR 25/502 (5.0%)

deaths from

prostate cancer

10y cumulative prostate cancer

mortality rate:

3.9% (95% CI=

2.0-5.7%)

34/503 (6.8%)

deaths from

prostate cancer

10y cumulative prostate cancer

mortality rate:

5.4% (95% CI=

3.2-7.5%)

NR NR

NR Comparison: HR=0.78 (95% CI=

0.46–1.33; p=0.34)

NR

Overall Survival

88/214 (41.1%) deaths at median 12.7y

10y OS estimate: 74.0%

110/211 (52.1%) deaths at median 12.5y 10y OS estimate: 66.0%

130/502 (25.9%) deaths at median 10.6y 10y OS estimate: 76.9%


10y OS estimate: 80.7%


23/148 (15.5%) deaths at 14y


20/159 (12.6%) deaths at 14y

Comparison: HR=0.72 (95%

CI=0.55–0.96; p=0.023)

Comparison: HR=1.18 (95% CI=

0.91–1.53; p=0.20)

Appendix C. Risk factor subgroup findings from RCTs

SWOG 8794 EORTC 22911 ARO 96-02

Gleason 2-6 Met RFS:

Obs. = RT**

(HR approx. 0.90, CI 0.55-1.50)

Biochem RFS:

Obs < RT****

(HR approx. 0.44; CI 0.26-0.82)

Biochem RFS:

Obs < RT†

(HR 0.42, CI 0.20-0.89)

Obs < RT#

(HR 0.47, CI 0.26-0.83)

Gleason 7-10 Met RFS:

Obs. < RT**

(HR approx. 0.58, CI 0.35-0.92)

Biochem RFS:

Gleason 7: Obs < RT****

but dif n.s. (HR approx.

0.63; CI 0.38-1.00)

-Gleason 8-10: Obs <

RT****

but dif n.s. (HR

approx. 0.52; CI 0.26-

1.20)

Biochem RFS:

Obs < RT†

(HR 0.59, CI 0.37-0.95)

Obs < RT#

(HR 0.52, CI 0.36-0.77)

No SVI Not reported Biochem RFS:

Obs. < RT***

(HR 0.43, CI 0.35-

0.54)

Clin RFS: Obs. =

RT***

(HR 0.8; CI 0.61-1.04)

Overall survival: Obs. =

RT***

(HR 1.30, CI 0.95-

1.77)

Not reported

SVI Biochem RFS:

Obs < RT*

(HR 0.23, CI 0.06 to 0.84)

Met RFS: Obs. < RT**

but dif ns (HR approx. 0.68, CI 0.42-1.07)

Clin RFS: Obs = RT*

(HR 0.76, CI 0.33 to 1.74)

Biochem RFS:

Obs. < RT***

(HR 0.60, CI 0.44-

0.82)

Clin RFS: Obs. = RT***

(HR 0.82; CI 0.58-1.16)


RT***

(HR 1.00, CI 0.66-

1.52)

Biochem RFS:

Obs = RT†

but dif n.s. (pT3c: HR 0.77, CI 0.42-1.40)

SWOG 8794 EORTC 22911 ARO 96-02

Negative margins Not reported Biochem RFS:

Obs. < RT***

(HR 0.61, CI 0.45-

0.81)

Clin RFS:

Obs. = RT***

(HR 1.08;

CI 0.78-1.55)

Overall survival:

Obs. > RT***

(HR 1.68, CI

1.10- 2.56)

Biochem RFS:

Obs = RT†

(HR 0.95, CI 0.47-1.93)

Obs = RT#

(HR 0.80, CI 0.45-1.43)

Positive margins Biochem RFS:

Obs. < RT*

(HR 0.44, CI 0.3 to

0.65))

Clin RFS:

Obs < RT*

(HR 0.64, CI 0.45 to 0.93)

Biochem RFS:

Obs. < RT***

(HR 0.44, CI 0.35-

0.75)

Clin RFS:

Obs. < RT***

(HR 0.69; CI 0.53-0.91)

Overall survival:

Obs. = RT***

(HR 0.98,

CI 0.72-

1.34)

Biochem RFS:

Obs < RT†

(HR 0.41, CI 0.25-0.66)

Obs < RT#

(HR 0.39, CI 0.27-0.57)

No EPE Not reported Biochem RFS: Obs. <

RT***

(HR 0.51, CI 0.35-

0.75)


(HR 0.78; CI 0.49-1.24)


RT***

(HR= 1.21, 95%

CI=0.70-2.08)

1.21, CI 0.70-

2.08)

Not reported

EPE Not reported Biochem RFS: Obs. <

RT***

(HR 0.49, CI 0.40-

0.60)


(HR 0.83; CI 0.65-1.05)


RT***

(HR 1.16, CI 0.88-

1.54)

Biochem RFS:

Obs < RT†

(pT3a/b: HR 0.34, CI 0.19-0.64)

Obs < RT#

(pT3a/b: HR 0.37, CI 0.24-0.58)

SWOG 8794 EORTC 22911 ARO 96-02

EPE or Positive margins Met RFS: Obs. < RT**

but dif n.s. (HR approx. 0.73, CI 0.52-1.08)

Not reported Not reported

SVI and Positive margins

Biochem RFS: Obs < RT*

(HR 0.40, CI 0.20-0.77)

Clin RFS: Obs < RT*

(HR

0.47, CI 0.27-0.81)

Not reported Not reported

Age Not reported Biochem RFS:

-<65 y: Obs. < RT***

(HR 0.43, CI 0.33-0.56)

-65-69 y: Obs. < RT***

(HR 0.46, CI 0.34-0.61)

-≥70 y: Obs. < RT***

but dif n.s. (HR 0.75, CI 0.52-1.08)

Clin RFS:

-<65 y: Obs. < RT***

(HR 0.57, CI 0.40-0.79)

-65-69 y: Obs. = RT***

(HR 0.81, CI 0.57-1.15)

-≥70 y: Obs. > RT***

(HR 1.78, CI 1.14-2.78) Overall survival:

-<65 y: Obs. = RT***

(HR 0.91, CI 0.60-1.39)

-65-69 y: Obs. = RT***

(HR 0.97, CI 0.65-1.44)

-≥70 y: Obs. < RT***

(HR 2.94, CI 1.75-4.93)

Not reported

* Thompson23 median 10.6 years follow-up; all bRFS analyses conducted in patient subset of 348 who

had post-RP PSA </= 0.4 ng/ml **

Thompson24 median 12.7 years follow-up for RT group; median 12.5 years follow-up for Observ group; all bRFS analyses conducted in patient subset of 348 who had post-RP PSA </= 0.4 ng/ml ***

Bolla25 median 10.6 years follow-up ****

Van der Kwast322 patient subset (n=552) of total eligible sample (n=972) who had central pathology review; included here are data from Fig. 2 which consists of only patient with post-RP PSA ≤ 0.2 ng/ml †

Wiegel26 median 4.5 years follow-up; 1992 AJCC – pT3a/b – EPE; pT3c – SVI #

Wiegel27 median 9.3 years follow-up

Appendix D. Hormone therapy RCT data

GETUG-AFU 16 (Carrie 2016) RTOG 9601 (Shipley 2017)

Country France North America (USA/Canada)

Funding source French Ministry of Health, Astra

Zeneca and La Ligue Contre le

Cancer

National Cancer Institute and Astra

Zeneca

Study period 2006 - 2010 1998 – 2003

Overall sample

size

743 760

Inclusion criteria - men aged 18y or older

- pathological T2-T4a prostate

adenocarcinoma with N0/NX

disease

- had undergone radical

prostatectomy

- must have PSA level < 0.1

ng/ ml for at least 6 months

after surgery and then rose to

0.2 to less than 2.0 ng/ml,

confirmed by two consecutive

tests without evidence of

clinical disease

- Eastern Cooperative Oncology

Group performance status of

0 to 1

- Have adequate cardiac

function including controlled

hypertension

- life expectancy of 10 years or

more

- men who had undergone

radical prostatectomy +

lymphadenectomy

- pathological T2 or T3 disease

without nodal involvement

(N0)

- detectable PSA at least 8

weeks after surgery ranging

from 0.2-4.0 ng/ml

- Karnofsky performance status

score of ≥80

- no previous use of hormone

therapy unless for short-term

pre-operative indication; 2-6

months prior to surgery (6.4%

of enrollees)

- life expectancy of more than

10 years

Exclusion criteria - have pituitary adenoma

- history of receiving previous

androgen deprivation therapy

or pelvic radiation therapy

- history of invasive cancer in

the past 5 years

- receiving other cancer

treatment at the time of

enrollment

- had evidence of distant

metastasis

- had evidence of liver disease

- had history of previous

chemotherapy or radiation for

prostate cancer

- had persistent urinary

extravasation after

prostatectomy


Intervention arm SRT + goserelin (n=369)

Hormone therapy protocol:

Goserelin acetate 10.8 mg was

given by subcutaneous injection

on the first day of radiation.

Another subcutaneous injection

of goserelin acetate 10.8 mg was

given 3 months later (duration of

hormone therapy: 6 months)

SRT protocol:

- All received 3D conformal

radiotherapy (3D-CRT) or

intensity modulated

radiotherapy (IMRT)

- Total dose: 66 Gy in 33

fractions, 5 days a week (SRT

duration = 7 weeks)

- Seminal vesicles received up

to 50 Gy for T3b disease only

- Those who did not have node

dissection and at least 15%

risk of nodal involvement

received pelvic irradiation, up

to a dose of 46 Gy (2

Gy/fraction)

SRT + bicalutamide (n=376)

Hormone therapy protocol:

- Oral bicalutamide 150mg OD

- First dose at initiation of

radiotherapy and then

provided daily for the next 24

months

SRT protocol:

- Radiation initiated within 12

weeks after randomization;

targeted toward original

prostatic site, tumor bed and

membranous urethra

- Total dose: 64.8 Gy in 36 daily

fractions of 1.8 Gy at five

sessions per week (SRT

duration = 7.2 weeks)

- No one received pelvic

irradiation

Control arm SRT alone (n=373)

SRT protocol:

- Same as above

SRT + placebo (n=384)

Placebo protocol:

One placebo tablet given daily

from day one of radiation and

for the next 24 months (same

as hormone therapy protocol

above)

SRT protocol:

Same as above

Type of hormone

therapy

Goserelin is a GnRH agonist Bicalutamide is an anti-androgen

Median follow-up

duration

5.3y 13y


Follow-up

protocol

Initial staging for baseline

information included

measurement of PSA

concentration and clinical exam.

PSA measured every 6 months

for five years and every year

thereafter.

Radiographical assessment was

only performed where evidence

of clinical or biochemical

progression was present.

Definition of biochemical

recurrence: confirmed by 2

consecutive tests at 2-month

intervals; PSA above nadir of

more than 0.5 ng/ml or clinical

evidence of disease

Quality of life and functional

dependence evaluated at

randomization, 1 year and 5

years follow up after end of

radiotherapy using QLQ-C30 and

QLQ-PR25 questionnaires.

At initiation and end of

radiotherapy, every 3 months

after radiotherapy for fist 2 years

and every 6 months for 3 years,

then yearly: clinical history,

physical exam, Karnofsky

performance-status score, CBC,

PSA level, serum ALT, serum

bilirubin, adverse effects were

measured.

At subsequent biochemical

recurrence after randomization,

bone and CT scans were

performed.

Definition of biochemical

recurrence: second recurrence

was defined as an increase of at

least 0.3 ng/ml above the lowest

detectable PSA after protocol

treatment. The lowest detectable

PSA decreased from 0.5 ng/ml to

0.2 ng/ml during the years of

enrollment. Third biochemical

recurrence occurred when PSA

reached 0.5 ng/ml or higher or

when there was disease

progression after the start of

salvage hormone therapy.

If metastatic disease was

discovered or if serum PSA >4.0

ng/ml, maximum androgen

blockade was instituted.


Outcomes

measured and

definitions

Primary outcome: Progression-

free survival defined as time from

randomization to documented

biochemical or clinical

progression, or both; death from

any cause, or censoring at date

of last follow-up.

Secondary outcomes:

Overall survival

Acute and late toxicities

Metastasis-free survival

Time from randomization to

nadir PSA

Changes in quality of life

Changes in functional

dependence among men older

than 75y

Primary outcome: Overall survival

Secondary outcomes:

Disease-specific death: all

death from prostate cancer or

treatment complications, or

unknown cause in a patient

with active prostate cancer

Non-disease-specific death:

death from any other cause

but the above

Distant metastasis: requires

radiographic confirmation from

bone or CT scans

Local disease progression:

development of palpable mass

in prostatic fossa, determined

by clinical exam

Any disease progression

including biochemical

recurrence

Acute and late toxicities


Baseline

characteristics

Median age = 67y

Race & ethnicity: NR

Disease stage T3a/3b = 342

(46.0%); N0 = 547 (74%)

ECOG performance status 0 =

674 (90.8%)

Gleason score ≥8 = 81 (11%)

Positive surgical margins = 371

(50%)

No seminal vesicle involvement =

630 (85%)

Median PSA at randomization =

0.3 ng/ ml

Median interval between surgery

and recurrence = 2.5y (control) -

2.8y (intervention)

Median age = 65y

Race & ethnicity: White = 668

(87.9%); Black = 68 (8.9%);

Hispanic = 9 (1.2%); Other = 15

(2.0%)

Disease stage: T2 = 248 (32.6%)

and T3 = 512 (67.4%)

Karnofsky performance status

score of 100 = 576 (75.8%)

Gleason score: 2-6 = 214

(28.2%); 7 = 413 (54.5%); 8-10

= 131 (17.3%)

Positive surgical margin = 569

(74.9%)

Neoadjuvant hormone use = 49

(6.4%)

Median PSA at trial entry = 0.6

ng/ml

PSA nadir after surgery of <0.5

ng/ml = 670 (88.2%)


and first detectable PSA = 1.4y


and trial entry = 2.1y

BMI = NR

Comorbidities = NR


Primary outcome Progression-free survival

At median follow up of 63 months

(5.3 years):

Number with disease progression:

SRT + Goserelin = 66/369 (18%)

SRT alone = 124/373 (33%)

Median duration between

randomization and disease

progression:

SRT+Goserelin = 32 months

(IQR=26-44)

SRT alone = 22 months (IQR=14-

38)

5-year progression-free survival:

SRT+Goserelin = 80% (95%

CI=75-84)

SRT alone = 62% (95% CI=57-67)

HR for progression = 0.50, 95% CI

= 0.38-0.66; P<0.0001 – favoring

SRT + Goserelin

Overall survival

At 12 years follow-up:

Bicalutamide = 76.3%

Placebo = 71.3%

Overall survival at 12 years by

subgroups (bicalutamide vs.

placebo):

a) Gleason 2-6 = 79.5% vs. 79.2%

b) Gleason 7 = 78.5% vs. 70.9%

c) Gleason 8-10 = 63.9% vs. 58.4%

d) PSA of <0.7 ng/ml at trial entry =

76.8% vs. 80.7%

e) PSA of 0.7-1.5 ng/ml at trial entry

= 77.0% vs. 67.5%

f) PSA of >1.5 ng/ml at trial entry =

73.5% vs. 48.9%

g) Negative surgical margin = 73.5%

vs. 72.9%

h) Positive surgical margin = 77.3%

vs. 70.7%

HR for death for all patients = 0.77;

95% CI = 0.59 – 0.99; P=0.04)

HR for death in each of these

subgroups:

a) Gleason 2-6 = 0.95; 95% CI =

0.57 - 1.59; P=0.84

b) Gleason 7 = 0.69; 95% CI = 0.49

– 0.98; P=0.04

c) Gleason 8-10 = 0.76; 95% CI =

0.44 – 1.30; P=0.32

d) PSA of <0.7 ng/ml at trial entry =

1.13; 95% CI = 0.77 – 1.65; P=0.53

e) PSA of 0.7-1.5 ng/ml at trial entry

= 0.61; 95% CI = 0.39 – 0.95;

P=0.03

f) PSA of >1.5 ng/ml at trial entry =

0.45; 95% CI = 0.25 – 0.81;

P=0.007

g) Negative surgical margin = 0.87;

95% CI = 0.53 – 1.41; P=0.56)

h) Positive surgical margin = 0.73;

95% CI = 0.54 – 0.98; P=0.04

On multivariable analysis (Cox),

significant negative prognostic

factors were: being assigned to

placebo, age ≥65 years,

PSA>1.5ng/ml at trial entry, Gleason

score of 8-10, and Karnofsky performance status score of 80-90.


Other outcomes Median duration from randomization to nadir PSA was 3.0 months (IQR=2.3-7.6) in

intervention arm and 9.4 months (IQR=7.3-17.5) in the control arm

Total number died at 5 years:

SRT+Goserelin = 17/369 (5%) SRT alone = 26/374 (7%)

5-year OS SRT+Goserelin = 96% (93-98) SRT alone = 95% (92-97)

HR = 0.70; 95% CI 0.40-1.2; P=0.18

Quality of life scores

Number of respondents at baseline=615 (83%) Number of respondents at 1 year=403 (55%) Number of respondents at 5

years=163 (22%) QLQ-C30 global QoL score (at 5y compared to baseline) SRT+Goserelin: improved = 18%; worsened = 31%

SRT alone: improved = 20%;

worsened = 30%

Changes in functional dependence among men older than 75 years of age Number of men >75 years = 71;

only 44 (62%) returned IADL questionnaire at inclusion, 16 (23%) at 1 year, and 13 (18%) at 5 years, not allowing for analysis

*No data for metastasis-free survival was available

12-year disease-specific death: Bicalutamide = 5.8% Placebo = 13.4%

HR for death = 0.49 (95% CI = 0.32 – 0.74); P<0.001 12-year non-disease-specific

death: Bicalutamide = 17.9% Placebo = 15.3%

HR for death = 1.10 (95% CI = 0.79 – 1.53); P=0.53 12-year cumulative incidence of

metastatic disease: Bicalutamide = 14.5%

Placebo = 23.0% HR for metastases = 0.63 (95% CI = 0.46 – 0.87); P=0.005 Subgroup analysis for incidence of metastases: a) Gleason 8-10: HR = 0.35 (95% CI =

0.18-0.67); P=0.001 b) PSA>1.5 ng/ml at trial entry: HR = 0.36 (95% CI = 0.15 – 0.84); P=0.01 c) Positive surgical margin: HR = 0.56 (95% CI = 0.38 – 0.84); P=0.005

12-year cumulative incidence of

second biochemical recurrence: Bicalutamide = 44.0% Placebo = 67.9% HR for second biochemical recurrence = 0.48 (95% CI = 0.40 – 0.58); P<0.001


third biochemical recurrence: Bicalutamide = 84.2% Placebo = 80.7% HR for third biochemical recurrence = 1.11 (95% CI = 0.85 – 1.46); P=0.43

12-year cumulative incidence of local progression:

Bicalutamide = 1.8% Placebo = 4.7% HR for local progression = 0.36 (95% CI = 0.15 – 0.85); P=0.02


any disease progression: Bicalutamide = 47.1% Placebo = 69.2% HR for any disease progression = 0.51

(95% CI = 0.42 -0.61); P<0.001


Early toxicity Grade 2 or worse genitourinary

toxicity: Goserelin = 13%; SRT

alone = 11%

Grade 2 or worse gastrointestinal


alone = 14%

From text: no difference in rates of

early urinary, bowel, hematologic,

skin or other toxicities. Toxicities

were primarily Grade 1-2 toxicities.

Late toxicity Grade 3 or worse genitourinary


alone = 8%

Grade 3 or worse gastrointestinal


alone = 1%

Grade 3 or worse sexual disorder:

Goserelin = 8%; SRT alone = 5%

Grade 1-3 hot flashes: Goserelin

= 45%; SRT alone = 1%

Grade 1-3 sweating: 13%; SRT

alone = 0%

Genitourinary toxicity:-

Grade 3: Bicalutamide = 2.4%;

Placebo = 1.3%


Placebo = 0.8%

Gastrointestinal toxicity:-


Placebo = 6.0%


Placebo = 0.3%

Liver toxicity:-


Placebo = 0.8%


Placebo = 0.3%

Hematologic toxicity:-


Placebo = 0.5%


Placebo = 0.5%

Gynecomastia:-


Placebo = 2.1%


Placebo = 0.0%

Cardiac:-


Placebo = 0.3%


Placebo = 1.3%

Appendix E. RTOG Acute and RTOG/EORTC Late Radiation Morbidity Scoring Criteria

Acute Late

Gastrointestinal Genitourinary Gastrointestinal Genitourinary

Grade 0 No change No change None None

Grade 1 Anorexia with ≤5% weight loss; nausea, abdominal discomfort, increased frequency or change in bowel habits,

rectal discomfort; no need for medications

urinary frequency or nocturia that is twice pre- treatment levels, dysuria, urgency; no need for medications

mild diarrhea, mild cramping, bowel movement 5/day, slight rectal discharge or

bleeding

slight bladder epithelial atrophy, minor telangiectasia (microscopic

hematuria)

Grade 2 anorexia with ≤15% weight loss, nausea and/or

vomiting or abdominal pain requiring medication, diarrhea requiring parasympatholytics, mucus discharge not requiring sanitary pads, rectal/abdominal pain

requiring analgesics

urinary frequency or nocturia that is <1/hour,

dysuria, urgency, bladder spasm requiring local anesthetic (e.g., Pyridium)

moderate diarrhea and colic, bowel

movement >5/day, excessive mucus or intermittent bleeding

moderate frequency,

generalized telangiectasia, intermittent macroscopic hematuria

Grade 3 anorexia with >15% weight loss or nausea/vomiting or diarrhea requiring nasogastric (NG) tube or

parenteral support; abdominal pain that is severe despite medications, hematemesis or melena, abdominal distension; severe

mucus/blood discharge requiring sanitary pads

urinary frequency with urgency and nocturia hourly or more frequently with dysuria, pelvis pain or bladder spasm

requiring regular frequent narcotics or gross hematuria with/without clot passage

Obstruction or bleeding requiring surgery

Severe frequency and dysuria, severe generalized telangiectasia

(often with petechiae), frequent hematuria, reduction in bladder capacity

(<150 cc)

Grade 4 ileus, subacute or acute obstruction, fistula,

perforation, GI bleeding requiring transfusion, abdominal pain requiring tube decompression or bowel diversion

hematuria requiring transfusion, acute bladder

obstruction not secondary to clot passage; ulceration or necrosis

Necrosis, perforation, fistula

Necrosis, contracted

bladder (capacity <100 cc), severe hemorrhage, cystitis

Appendix F: Acute Toxicity Effects of Radiotherapy After Prostatectomy

(Ranges based on RTOG or CTCAE Grading Systems)

Genitourinary Gastrointestinal

Study Arm Type Grade 1-2 Grade 3-4 Grade 1-2 Grade 3-4

Adjuvant 10.5 - 26% 2.0 - 8.0% 22.0 – 25.0% 0.0 – 2.0%

Salvage 3.0 - 82.0% 0.0 – 6.0% 2.9 – 96.0% 0.0 – 2.2%

Mixed 5.0 – 92.0% 0.0 – 3.0% 4.3 – 87.0% 0.0 – 1.3%

Appendix G. Late Toxicity Effects of Radiotherapy After Prostatectomy

(Ranges based on RTOG/EORTC or CTCAE Grading Systems)

Genitourinary Gastrointestinal

Study Arm Type Grade 1-2 Grade 3-4 Grade 1-2 Grade 3-4

Adjuvant 2.0 – 22.0% 0.0 - 10.6% 1.0 – 12.7% 0.0 – 6.7%

Salvage 1.0 – 49.0% 0.0 – 6.0% 0.0 – 66.0% 0.0 – 18.0%

Mixed 1.3 – 79.0% 0.0 – 17.0% 2.0 – 59.0% 0.0 – 4.3%

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Appendix A. Meta-analysis of biochemical recurrence data ......Comparison: HR=0.43 (95% CI=...

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