Interventional procedure overview of biodegradable spacer insertion to reduce rectal toxicity during radiotherapy for prostate cancer

Study type

Randomised Controlled Trial

Country

US (multicentre)

Recruitment period

2012 to 2013

Study population and number

n=222 (149 with spacer versus 73 without spacer [control]) patients with clinical stage T1 or T2 prostate cancer (NCCN low or intermediate risk).

Age and sex

Mean age: spacer group 66.4 years; control group: 67.7% years; 100% male

Patient selection criteria

Men with stage T1 and T2 prostate cancer, a Gleason score of <7, PSA concentration of 20 nanograms/ml, and a Zubrod performance status of 0–1, planning to have image guided intensity modulated radiotherapy (IG-IMRT) were included.

Patients with a prostate volume of >80 cm³, extracapsular extension of disease or >50% positivity biopsy scores, metastatic disease, indicated for or had recent androgen deprivation therapy and prior prostate surgery or radiotherapy were excluded.

Technique

Intervention:Injection of a prostate-rectum spacer (polyethylene glycol hydrogel‑SpaceOAR system) during IG-IMRT (total dose of 79.2Gy in 1.8 Gy fractions to the prostate with or without the seminal vesicles delivered 5 days weekly)A planning target volume of 5-10mm was used.

Control – IG-IMRT alone (total dose of 79.2Gy in 1.8 Gy in 44 fractions to the prostate with or without the seminal vesicles delivered 5 days weekly) with no injection.

Patients had CT and MRI scans for treatment planning, followed with fiducial marker placement using transperineal approach. Antibiotic prophylaxis was administered before procedure 95% of time. General anaesthesia in 36%, local in 31%, monitored anaesthesia in 26%, conscious sedation in 6%, other in 10%.

Follow-up

Median 37 months (15 months, Mariados N, 2015; 3 years Hamstra DA 2017, 2018, Karsh 2018)

Conflict of interest/source of funding

The study was supported by research funding from Augmenix. Two authors are shareholders and 1 author received speaking honoraria from the manufacturer. 2 authors have provided consulting services.

Spacer group

Control group

Baseline

1.6±2.2 mm

NR

Post spacer application

12.6±3.9 mm

1.6±2.0 mm

3 months

9.0±5.9 mm

NR

Spacer group (n=148)

Control group (n=72)

p value

Parameter

rV50

rV60

rV70

rV80

rV70

% before spacer

25.7±11.1

18.4±7.7

12.4±5.4

4.6±3.1

12.4

0.95

% after spacer

12.2±8.7

6.8±5.5

3.3±3.2

0.6±0.9

11.7

<0.0001

% of absolute reduction

13.442

11.56

9.078

3.933

% of relative reduction

52.3

62.9

73.3

86.3

p value

<0.0001

<0.0001

<0.0001

<0.0001

Acute toxicity (from procedure to 3‑month visit)^{Mariados 2015}

Rectal toxicity scores (%)

Urinary tract toxicity scores (%)

Grade

Spacer % (n=148)

Control % (n=72)

p value

Spacer % (n=148)

Control % (n=72)

p value

0

73 (108)

68 (49)

0.525

9.5 (14)

9.7 (7)

0.488

1

23 (34)

27.8 (20)

52.7 (78)

45.8 (33)

>2

4.1 (6)*

4.2 (3)*

37.8 (56)*

44.4 (32)*

Late toxicity (between 3 and 15 month visits)^{Mariados 2015}

Grade

Spacer % (n=148)

Control % (n=71)

p value

Spacer % (n=148)

Control % (n=71)

p value

0

98 (145)

93 966)

0.044

90.5 (134)

91.5 (65)

0.622

1

2 (3)+

5.6 (4)+

2.7 (4)

4.2 (3)

>2

0

1.4 (1)+

6.8 (10)

4.2 (3)

Late toxicity (between 15 months and 3 year visits)^{Hamstra 2017}

Rectal toxicity scores (%)

Urinary tract toxicity scores (%)

Grade

Spacer % (n=94)

Control % (n=46)

p value

Spacer % (n=94)

Control % (n=46)

p value

>1

2.0 (95% CI 4-20%)

9.0 (95% CI 1-6%)

0.28

HR 0.24 (95% CI 0.06-0.97)

4 (95% CI 2-10%)

15 (95% CI 8-29%)

0.046

HR 0.36 (95% CI 0.12 -1.1)

>2

0

5.7++ (95% CI 2-17%)

0.012

7

7

0.7

Spacer group %

Control group %

p value

Rates of grade 1 or greater rectal or procedural adverse events at first 6 months

34.2

31.5

0.7

Acute rectal pain

2.7

11.1

0.022

Spacer group %

Control group %

p value

Adverse events

96.6

100

NS

Serious adverse events

13.4

15.1

NS

Systematic review and meta-analysis

USA, UK, Switzerland and Germany

Inception to September 2019; Databases searched: Cochrane Central Register of Controlled Trials, MEDLINE, and Embase; no language or date restrictions applied. Supplemental searches were done in the directory of open access journals, Google scholar, and reference lists of included articles and relevant meta-analyses searched. If outcomes were unclear in studies, authors were contacted.

n=7 studies with 1,011 patients (486 patients who had a perirectal hydrogel spacer injection versus 525 patients who did not receive a spacer [controls] before prostate cancer radiotherapy).

(1 randomised clinical trial [RCT] and 6 cohort studies [1 prospective, 4 retrospective and 1 with prospective enrolment in spacer group and retrospective enrolment in no spacer group])

Clinical stages: localised or locally advanced prostate cancer (T1-T3)

prostate-specific antigen levels ranged from 5.6 to 10.2 nanograms/ml

Mean age of 66 to 77 years.

Inclusion criteria: randomised clinical trials or cohort studies of patients who had the perirectal hydrogel spacer versus patients who had no spacer before radiotherapy for localised or locally advanced prostate cancer. Studies using external-beam RT that reported the percentage volume of the rectum receiving at least 70 Gy radiation (v70).

Exclusion criteria: review articles, commentaries, letters, studies with no control or active control group, studies with fewer than 10 patients, pre-post dosimetric studies, studies that did not report a pre-specified outcome of this review, duplicate publications and unpublished or grey literature.

Intervention: Injection of a prostate-rectum spacer (absorbable polyethylene glycol hydrogel‑SpaceOAR system) between the Denonvilliers fascia and anterior rectal wall before radiotherapy.

Radiotherapy protocols: EBRT with a total therapeutic dose ranging from 76 to 81 Gy (5 studies), BT with or without EBRT (1 study), or combination therapy (1 study).

Median 26 months (range, 3 to 63 months).

The study was funded by Boston Scientific and they were involved in design and interpretation of data, review and approval of manuscript.

Authors served as consultants, and either received personal fees, grants, honoraria, travel expenses, and non-financial support from Boston scientific and other companies.

Mariados 2015

mild and transient complications (did not delay radiotherapy)

10%

Whalley 2016

Inadvertent injection into the rectal lumen (without adverse sequalae)

3% (1/30)

Pinkawa 2017, Taggar 2018

None

0

HTA

Europe

2010 to 2019; Databases searched for existing evidence syntheses (systematic reviews, HTAs) and primary studies include MEDLINE, AMED, Embase, Epistemonikos, and Cochrane Central Register of Controlled Trials.

Also searched trial registry records at ClinicalTrials.gov and WHO ICTRP, Devices@FDA, the American Society of Clinical Oncology conference abstracts, and the Radiation Therapy Oncology Group clinical trials protocols.

Considered information from clinical practice guidelines, information from a general literature search and input from clinical experts, and manufacturers.

No language, design, publication restrictions applied.

n=2 prospective comparative studies including 298 patients with T1 and T2 stage localised prostate cancer)

(1 RCT [SpaceOAR plus radiotherapy versus radiotherapy alone]) including 3 companion studies from the same clinical trial (NCT01538628) and

1 non-randomised control trial (nRCT; hydrogel plus radiotherapy, balloon plus radiotherapy and radiotherapy alone)

RCT: spacer group 66.4 years; control group: 67.7 years

nRCT: not reported

Inclusion criteria: adults (>18yrs) who had prostate cancer (both localised and metastatic undergoing curative treatment); studies on biodegradable rectal spacers for prostate cancer radiotherapy compared with current pathway of care (radiotherapy); RCTs and prospective nRCTs or observational studies with a control group, prospective studies or registry studies, (for effectiveness), including prospective registry-based data (for safety); reporting effectiveness and safety outcomes, in all languages.

Exclusion criteria: study designs other than those specified in inclusion criteria, studies with no outcome of interest, wrong population, no data on patients with spacers, or no full text.

Intervention: biodegradable rectal spacers for prostate cancer radiotherapy.

2 different spacers used: transperineal hydrogel (SpaceOAR) or balloon (BioProtect) plus radiotherapy versus radiotherapy alone (EBRT)

Radiotherapy protocols:

RCT (n=222) IG-IMRT dose of 79.2 Gy at 1.8 Gy fractions, delivered to ≥98% of the planning target volume (PTV) and 100% of the clinical target volume, with the clinical target volume maximum of ≤110% of the prescription dose.

nRCT: IMRT total dose of 75.85 Gy in daily fractional doses of 1.85 Gy prescribed to the 95% isodose using multi-segmental 7-field and shoot IMRT.

RCT: 3,6,12,15 (Mariados 2015) and 36 months (Hamstra 2017).

nRCT: up to 6 months (Wolf 2015)

All authors, and stakeholders involved in the production of this assessment have declared they have no conflicts of interest according to the EUnetHTA declaration of interest (DOI) form.

Outcomes

No of patients

Relative effect (95% CI)

Absolute effect (95% CI)

GRADE

Certainty of evidence

Comments

Spacer+

radiotherapy

Radiotherapy alone

RCT (Mariados 2015, Hamstra 2017)

Rectal toxicity

N=148

Spacer

N=71

no spacer

Acute (grade 1)-3 months

34

20

RR 0.77 (0.50 to 1.19), p=0.42

94 fewer per 1000 (from 204 fewer to 78 more)

Low ^2-3

Acute (grade ≥2) – 3 months

6*

3**

RR 0.91 (0.23 to 3.5), p=0.89

6 fewer per 1000 (from 47 fewer to 152 more)

*no grade 3 or 4 toxicity reported

**1 grade 3 case, no grade 4 reported

Late (grade 1) – 15 months

3

4

RR 0.34 (0.08 to 1.48), p=0.16

40 fewer per 1000 (from 56 fewer to 29 more)

Late (grade≥2)⁴ – 15 months

0

2*

RR 0.15 (0.01 to 3.71), p=0.25

13 fewer per 1000 (from 15 fewer to 41 more)

1 grade 3 case, no grade 4 reported

Cumulative (acute and late, grade 1) – median 3 years

2

4

HR 0.24, 95% CI 0.06 to 0.97, p<0.03

Not able to calculate

Very low ^2,3,5

Loss to follow up 37% (spacer+RT n=54 and RT alone n=25)

Cumulative (acute and late, grade ≥2) – median 3 years

0

3

HR not available

Not able to calculate

nRCT (Wolf 2015)

Acute rectal toxicity (grade 1) – 3 months

5

2

RR 1.58 (0.34 to 7.60), p=0.55

61 more per 1000 (from 69 fewer to 695 more)

Very low

hydrogel versus RT – no grade 2-3 toxicity

5

RR 1.64 (0.35 to 7.60), p=0.52

67 more per 1000 (from 68 fewer to 695 more)

Very Low^3,6

Balloon versus RT – no grade 2-3 toxicity

Outcomes

No of patients

Relative effect (95% CI)

Absolute effect (95% CI)

GRADE

Comments

Spacer+

radiotherapy

Radiotherapy alone

RCT (Mariados 2015, Hamstra 2017)

Urinary toxicity

N=148

N=71

Acute (grade 1)-3 months

78

33

RR 1.03 (0.87 to 1.21), p=0.74

25 more per 1000 (from 107 fewer to 173 more)

Low ^2-3

Acute (grade ≥2) – 3 months

56

32

RR 0.97 (0.81 to 1.18), p=0.79

25 fewer per 1000 (from 156 fewer to 148 more)

*no grade 3 or 4 toxicity reported

Late (grade 1) – 15 months

4

3

RR 0.65 (0.15 to 2.85), p=0.57

15 fewer per 1000 (from 36 fewer to 75 more)

Late (grade ≥2) – 15 months

10*

3*

RR 1.57 (0.44 to 5.53), p=0.47

25 more per 1000 (from 23 fewer to 196 more)

*no grade 3 or 4 toxicity reported

Cumulative (acute and late, grade 1) – median 3 years

4

7

HR 0.36 (0.12 to 1.1), p=0.046

Not able to calculate

Very low ^2,3,5

Loss to follow up 37% (spacer+RT n=54 and RT alone n=25)

Cumulative (acute and late, grade ≥2) – median 3 years

NR

NR

HR 1.22 (0.40 to 3.72), p=0.7

Not able to calculate

Genitourinary toxicity (Wolf 2015)

n=30 hydrogel, n=29 balloon spacer)

n=19 radiotherapy alone

Acute – grade 2

11

5

RR 1.39 (0.57 to 3.38), p=0.46

103 more per 1000 (from 113 fewer to 626 more)

Very Low ^3,6

hydrogel or Balloon versus RT – no grade 3 toxicity

6

6 RR 0.78 (0.27 to 2.12), p=0.64

58 fewer per 1000 (from 192 to 295 more)

Outcomes

No of patients

Relative effect (95% CI)

Absolute effect (95% CI)

GRADE

Comments

Spacer+

radiotherapy

Radiotherapy

RCT (Mariados 2015, Hamstra 2017)

Bowel QoL assessed with EPIC 0-100 – greater values are better

Summary Score: results suggest SpaceOAR +RT may improve bowel QoL (p=0.002) over the entire follow-up period (1 study, 220 participants; very low certainty of evidence) but the evidence is uncertain.

Minimal Clinical Difference – 5-point decline

Bowel QoL 3 months

49% (73/148)

46%(32/71)

RD 0.05, 95% CI -0.09 to 0.19

5 more people in intervention reported 5-point decline

Low ^2,3

Bowel QoL 15 months

24%(36/148)

34% (24/71)

RD -0.09, 95% CI -0.22 to 0.04

9 less people in intervention reported 5-point decline

Bowel QoL 36 months

14% (13/94)

41% (19/46)

OR 0.28, 95% CI 0.13 to 0.63*

27% less patients in the intervention experiencing 5-point decline

Very low ^{2, 3, 5}

Minimal Clinical Difference X2 – 10 point decline

Bowel QoL 3 months

34% (50/148)

32% (23/71)

RD 0.02, 95% CI -0.11 to 0.15

2 more people in the intervention reported 10-point decline

Low

Bowel QoL 15 months

11%(17/148)

21% (15/71)

RD -0.09, 95% CI -0.20 to 0.01

10 fewer people in the intervention reported a 10-point decline

Low ^2,3

Bowel QoL 36 months

5% (5/94)

16% (7/46)

OR 0.30, 95% CI 0.11 to 0.83

16% fewer patients in the intervention reported 10-point decline

Very low ^2,3,5

Urinary QoL - assessed with EPIC 0-100 – greater values are better

Summary Score: Results suggest SpaceOAR may have little to no effect on urinary QoL (p=.13) over the study follow-up period (1 study, 220 participants; very low certainty of evidence); the evidence is very uncertain.

Minimal Clinical Difference – 6-point decline

Urinary QoL 3 months

65%(97/148)

60% (42/71)

RD 0.07, 95% CI -0.07 to 0.21

7 more people in the intervention reported 6 point decline

Low ^2,3

Urinary QoL 15 months

22% (32/148)

21% (15/71)

RD 0.01, 95% CI -0.11 to 0.12

There was no difference in the number of patients reporting 6 point decline

Urinary QoL 36 months

30% (28/94)

17% (8/46)

OR 0.41, 95% CI 0.18 to 0.95

13% fewer participants in the intervention reported 6 point decline

Very low ^2,3,5

Minimal Clinical Difference X2 – 10-point decline

Urinary QoL 3 months

47% (70/148)

49% (34/71)

RD 0.00, 95% CI -0.14 to 0.14*

There was no difference in the number of patients reporting 12-point decline

Urinary QoL 15 months

9% (14/148)

12% (9/71)

RD -0.03, 95% CI -0.12 to 0.06

3 fewer patients in the intervention reported 12-point decline

Urinary QoL 36 months

23% (22/94)

8% (4/46)

OR 0.31, 95% CI 0.11 to 0.85*

15% fewer participants in the intervention reported 12-point decline

Sexual QoL – assessed with EPIC 0-100 – greater values are better

Summary Score: results suggest SpaceOAR may have little to no effect on sexual QoL (p=0.6) over the entire study period (1 study, 140 participants; very low certainty of evidence), but the evidence is very uncertain.

36 months

94

46

Not estimable

Sexual composite over time p=0.59

Very low ^2,3,5

outcomes

No of patients

Relative effect (95% CI)

Absolute effect (95% CI)

GRADE

Comments

Spacer+

radiotherapy

Radiotherapy

RCT (Mariados 2015, Hamstra 2017)

rV70 Mean ± SD

N=148

N=71

-

-

Low ^2,3

97%intervention patients reached ≧25% reduction in rV70

nRCT (Wolf 2015)

Isodose

Hydrogel 30 Balloon 29

radiotherapy alone 19

95% isodose

38% and 63% less

g-gel, b-balloon c control

10.9 cm²-g

17.6 cm²-c

6.6 cm²-b

24% and 42% less

10% and 22% less

Very low ^2,3,5

85% isodose 18.3 cm²-g

24.1 cm²-c

13.2 cm²-b

60% isodose 34.4 cm²-g 38.3 cm²-c 29.7 cm²-b

Distance between rectum and prostate – baseline, post-insertion, 3 months

RCT (Mariados 2015, Hamstra 2017)

Mean perirectal distance (mm)

149

-

Not estimable

Not estimable

Low ^2,3

1.6±2.2 mm, baseline

12.6±3.9 mm, after insertion

9±5.9 mm at 3 months

PSA relapse – baseline, 12 and 15 months

Nanograms/ml – 12 months and 15 months

148

71

Not estimable

Not estimable

Low ^2,3

Values only presented as means (no SD available), no data for 36 months available.

Outcomes

No of patients

Relative effect (95% CI)

Absolute effect (95% CI)

GRADE

Comments

Spacer+

radiotherapy

Radiotherapy alone

1 RCT (Mariados 2015 and 5 companion studies) and 1 nRCT (Wolf 2015)

Deaths related to adverse events, grade 5

207

91

There was no (device) death related to adverse events reported in these studies

1 RCT and 1 nRCT

Adverse events, grades 3-4

207

91

There was no (device) grade 3-4 related to adverse events reported in these studies

Adverse events grades 1-2 ¹

148

71

Procedural adverse events

no unanticipated SpaceOAR related adverse events.

10% of the spacer patients had mild transient procedural adverse events (perineal discomfort and others)

n=10 events requiring no medication*

grade 2 events treated with medication included mild lower urinary tract symptoms and hypotension, and moderate perineal pain.

no implant infections, rectal wall ulcerations or other more serious complications.

SpaceOAR Hydrogel procedural rectal wall infiltration in 6% (n=9).

2/149 spacer patients had no SpaceOAR Hydrogel present after application: hydrogel injected beyond the prostate in 1 patient, no hydrogel injected in the other due to inadvertent needle penetration of the rectal wall requiring study-mandated termination of the procedure.

Low ^2,3

The information reported in the RCT and companions studies: Mariados 2015, Pieczonka 2015, Karsh and Fisher Valuck 2017

Systematic review

UK, USA and Germany

Search period: inception to May 2020; databases searched: MEDLINE, Embase, PubMed, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database (HTA), KSR Evidence, Econlit (EBSCO), and NHS EED (CRD). HTA agency websites, clinical trials registers, conference abstracts databases and reference lists of included articles were also searched. No restrictions on language or publication status were applied.

19 studies (3,622 patients who had a perirectal hydrogel spacer versus patients who did not receive a spacer [controls] before prostate cancer radiotherapy).

1 RCT (10 references), 18 comparative nRCTs.

patients between 65 to 75 years

Inclusion criteria: RCTs and nRCTs with patients receiving radiotherapy (all types) for localised or locally advanced prostate cancer with or without rectal hydrogel spacer; reporting a number of outcomes including radiation dose, toxicity and QoL.

Intervention: Injection of a prostate-rectum spacer (absorbable polyethylene glycol hydrogel‑SpaceOAR system) between the Denonvilliers fascia and anterior rectal wall before RT.

Comparator (control):no spacer

Radiotherapy protocols: different RT modalities used.

1. EBRT- IG-IMRT- 1 RCT

2. EBRT, BT and combinations thereof (in 18 comparative nRCTs):

Varied across studies

4 authors worked for a company which received funding for the project from Boston Scientific, few authors are employed by Boston Scientific, some received honoraria for advisory boards, travel expenses to medical meetings and 1 served as a consultant for different companies.

Measures of dosimetry

With spacer

Without spacer

Absolute reduction

Relative reduction

Rectum

V50

9.6

20.8

11.2

53.9

V60

5.3

15.4

10.1

65.6

V70

2.3

10.5

8.2

78.0

V80

0.1

4.0

3.9

97.3

Measures of dosimetry

Baseline dose Gy (mean±SD)

Post spacer dose Gy (mean±SD)

% Change in dose from baseline, p value

Bladder

V70

11.3

11

NR

Rectum

V50

25.7±11.1

12.2±8.7

52.3, p=<0.0001

V60

18.4±7.7

6.8±5.5

62.9, p<0.0001

V70

12.4±5.4

3.3±3.2

73.3, p<0.0001

V80

4.6±3.1

0.6±0.9

86.3, p<0.0001

Pinkawa 2017 IMRT (n=167)

T1-T3

Low to high risk

V70 %

20

32

<0.01

V90 %

4

13

<0.01

Te Velde 2019 IMRT (n=125)

T1-T3

Low to high risk

V40 %

25.9

33.3

<0.0001

V75%

2.1

7.4

<0.0001

V65%

5.2

12.6

<0.0001

Whalley 2016 IMRT (n=140)

T1-T3

Intermediate/ high risk

V40 %

22.9

32

<0.01

V65%

5.3

13.5

<0.01

Navaratnam 2020

PBT (n=72)

T-1-T3

V70 %

NR

NR

-

V75 %

NR

NR

-

Fried 2017

SBRT (n=94)

Low/intermediate risk

D10 Gy

26.66

30.44

0.000

D50 Gy

10.9

11.4

0.47

BT

Baghwala 2019

HDR BT (n=36)

Low/intermediate risk

V75 cc

0.02

0.7

<0.05

V90 cc

>92

NR

<0.05

HDR BT in combination with EBRT

Chao 2019 HDR BT+IG-IMRT (n=97)

T1-T3 Intermediate/

high risk

V40%

4.6

10.7

<0.001

V75%

0

0.55

<0.001

V80%

0

0.21

<0.001

Wu 2018 HDR BT +/- EBRT (n=54)

T-T3

V40 cc

8.11

9.38

0.16

V75

<0.005

0.12

<0.0005

V80

<0.005

0.01

0.007

V90

NR

<0.005

0.1

Saigal 2019

HDR BT + EBRT (n=117)

NR

D1 Gy

35.3

54.6

<0.05

D90

100.1

101.3

0.354

LDR BT in combination with EBRT

Morita 2020 LDR BT+IMRT (n=300)

T1-T4

Very low to very high

V100 cc

0.026

0.318

<0.001

V150

0.001

0.025

<0.001

Patel 2018

LDR BT + EBRT (n=57)

NR

V50

0.53

.21

<0.001

V100

0.0001

0.25

<0.001

Taggar 2018

LDR BT+EBRT (n=210)

T1-T3

V100

0.01

0.07

0

Liu 2020

LDR BT +/- EBRT (n=81)

Low/intermediate

risk

D2 Gy

-25.1

5

<0.0001

D0.1

-65.7

-1

<0.0001

Type of adverse event

Follow up

With spacer

Without spacer

P value

OR (95% CI)

Rectal or procedure related adverse events

6 months

34.2%

31.5%

0.7

Rectal toxicity late

3 to 15 months

Grade 1+

2.03 (3/148)

6.94 (5/71)

0.044

0.28 (0.06,1.19)

Grade 2+

0

1.39 (1/71)

NE

1

2.03 (3/148)

5.63 (4/71)

0.35 90.08, 1.59)

2

0

0

NE

3

0

1.41 (1/71)

4

0

0

Grade>1

36 months

2.0%

9.2%

0.028

Grade>2

36 months

0

5.7%

0.012

Rectal toxicity acute

3 months

Grade 1+

27.03 (40/148)

31.94 (23/72)

0.525

0.79 (0.43,1.46)

Grade 2+

4.05 (6/148)

4.17 (3/72)

0.97 (0.24,4)

1

22.97 (34/148)

27.78 (20/72)

0.78 (0.41,1.47)

2

4.05 (6/148)

2.78 (2/72)

1.48 (0.29, 7.52)

3

0

1.39 (1/72)

NE

4

0

0

Urinary toxicity late

3 to 15 months

Grade 1+

9.46 (14/148)

8.33 (6/71)

0.622

1.15 (0.42, 3.13)

Grade 2+

6.76 (10/148)

4.17 (3/71)

1.67 (0.44, 6.25)

1

2.70 94/148)

4.23 (3/71)

0.63 (0.14, 2.89)

2

6.76 (10/148)

4.23 (3/71)

1.64 90.44, 6.16)

3

0

0

NE

4

0

0

Urinary toxicity acute

3 months

Grade 1+

90.54 (134/148)

90.28 (65/72)

0.488

1.03 (0.4, 2.68)

Grade 2+

37.84 (56/148)

44.44 (32/72)

0.76 (0.43, 1.35)

1

52.70 (78/148)

45.83 (33/72)

1.32 (0.75, 2.32)

2

37.84 (56/148)

44.44 (32/72)

0.76 (0.43, 1.35)

3

0

0

NE

4

0

0

Te Velde 2019 IMRT (n=125)

Diarrhoea (grade 1)

During radiotherapy

13.8% (9/65)

31.7 (19/60)

0.02

0.34 (0.14,0.84)

3 months

4.6%

5%

1

0.92 (0.18,4.72)

36 months

1.7%

7.3%

0.192

0.22 (0.03,1.86)

Proctitis (grade 1)

During radiotherapy

9.2

13.3

0.6

0.66 (0.22,2.03)

3 months

1.5

5

0.3

0.29 (0.03,2.86)

36 months

1.7

3.6

0.606

0.46 (0.04,4.88)

Proctitis Grade (2)

During radiotherapy

4.6

1.7

0.6

2.79 (0.28,27.56)

3 months

0

0

1

36 months

0

3.6

0.227

Faecal incontinence (grade 1)

During radiotherapy

3.1

3.3

1

0.94 (0.13,6.87)

3 months

0

1.7

0.5

36 months

0

0

Haemorrhoids (grade 1)

During radiotherapy

23.1

20

0.8

1.2 (0.51,2.83)

3 months

3.1

11.7

0.09

0.24 (0.05,1.21)

36 months

5

7.3

0.708

0.67 (0.15,2.98)

Haemorrhoids (grade 2)

During radiotherapy

4.6

3.3

1

3 months

0

0

36 months

1.7

1.8

1

0.94 (0.06,14.5)

Whalley 2016

IMRT (n=140)

Rectal toxicity late -grade 1

Median 26-28 months

16.6 (5/30)

41.8 (46/110)

0.04

0.28 (0.1,0.78)

Grade 2

3.3 (1/30)

3.6 (4/110)

NR

0.91 (0.1,8.49)

Rectal toxicity acute -grade 1

43 (13/30)

50.6 (56/110)

0.74 (0.33,1.66)

Grade 2

0

4.5 (5/110)

Wolf 2015

IMRT (n=78)

Rectal toxicity acute-grade 1

NR

16.6

9

NR

Genitourinary toxicity- grade 1

12.5

21

Grade 2

36.6

28.5

Any toxicity acute -grade 3

0

0

Navaratnam 2020

PBT (n=72)

Rectal toxicity-any -grade 1

During radiotherapy

35.3 (18/51)

9.5 (2/21)

0.061

5.2 (1.09,24.89)

Median 8.7 to 10.3 months

7.7 (3/39)

0 (0/14)

NR

Grade 2

During radiotherapy

2 (1/51)

0 (0/21)

NR

Median 8.7 to 10.3 months

0 (0/39)

7.1 (1/14)

Zelefsky 2019

SBRT (n=551)

GI toxicity acute (grade 2+)

NR

1 (269)

2 (282)

0.09

0.33 (0.07,1.55)

GI toxicity late (grade 2+)

1

6

0.01

0.16 (0.05,0.48)

GU toxicity acute (grade 2+)

9

12

0.19

0.73 (0.42,1.26)

GU toxicity late (grade 2+)

15

32

<0.001

0.38 (0.25,0.57)

HDR BT in combination with EBRT

Chao 2019

BT+IG-IMRT (n=97)

GI toxicity acute (grade 2)

3 months

0 (0/32)

1.5 (1/65)

0.48

Grade1+

13.3

30.8

0.05

0.34 (0.11,1.11)

GI toxicity late (grade 1)

0

7.7

0.11

GU toxicity acute (grade 2)

0

1.5

0.48

Grade 1+

83.3

92.3

0.22

0.42 (0.11,1.56)

GU toxicity late (grade 3)

3.3

6.2

0.57

0.52 (0.06,4.82)

Grade 1+

46.7

43.1

0.74

1.16 (0.49,2.71)

Grade 2+

3.3

7.7

0.4

0.41 (0.05,3.66)

LDR BT alone or in combination with EBRT

Taggar 2018

LDR BT/LDR BT+/- EBRT (n=210)

Any rectal GI toxicity

NR

20.3 (15/74)

24.3 (33/136)

0.95

0.79 (0.4,1.58)

Taggar 2018

LDR BT monotherapy

Diarrhoea

7.7 (2/26)

15.9 (7/44)

NR

0.44 (0.08,2.31)

Proctitis

0 (/26)

0 (/44)

NR

Rectal bleeding

0 (/26)

6.8 (/44)

NR

Rectal discomfort

15.7 (/26)

0 (/44)

NR

Taggar 2018

LDR BT monotherapy (salvage for recurrent PC)

Diarrhoea

NR

12.5 (1/11)

5.3 (1/19)

NR

2.55 (0.14,45.36)

Proctitis

0

0

NR

Rectal bleeding

0

5.3

NR

Rectal discomfort

0

0

NR

Taggar 2018

LDR BT+EBRT combination therapy

Diarrhoea

NR

12.5 (5/42)

4.1 (3/73)

NR

3.34 (0.76,14.76)

Proctitis

0

5.5

Rectal bleeding

5

19.2

0.22 (0.05,1.03)

Rectal discomfort

5

0

EPIC dimension

Follow up (months)

With spacer

Without spacer

Mean difference

P value

Bowel domain

3

-7.5

-6.2

NR

36

0.5

-5.3

5.8, p<0.05

Urinary domain

3

-11.5

-11.2

NR

36

0.6

-3.3

3.9, p=0.04

Authors definition

OR (95% CI), p value

10-point decline in bowel QoL

15

11.6

21.6

0.49 (0.21, 1.11)

P=0.087

36

5

21

0.3 (0.11, 0.83)

P=0.02

10-point decline in urinary QoL

6

8.8

22.2

0.27 (0.11, 0.64)

P=0.003

12-point decline in urinary QoL

36

8

23

0.31 (0.11, 0.85)

P<0.03

5-point decline in bowel QoL

14

41

0.28 90.13, 0.63)

P=0.002

6-point decline in urinary QoL

17

30

0.41 (0.18, 0.95)

P<0.05

Patients experiencing MID declines in all 3 QoL domains (bowel, urinary, sexual)

36

2.5

20

NR

P=0.002

Decline of all 11 or more points in EPIC sexual score

53

75

NR, P=0.064

Potent patients at baseline retaining erections sufficient for intercourse

66.7

37.5

NR, =0.046

Study

EPIC outcome

Follow up (months)

With spacer,

Mean change from baseline

Without spacer, mean change from baseline

p value

Patel 2018

EBRT + LDR BT (n=57)

Bowel function score

3 months

Median: 0.00, IQR: -8.93 to 0.89

Median: -6.25, IQR: -12.95 to 0

0.312

6 months

Median: 0.00, IQR: -8.92 to 0

Median: -3.57, IQR: -9.82 to 0

0.650

Pinkawa 2012

IMRT (n=72)

Urinary function

Last day radiotherapy

-10

-10

NR

2-3 months

-1

-5

Urinary bother score

Last day radiotherapy

-17

-18

2-3 months

-4

-6

Bowel function

Last day radiotherapy

-15

-14

2-3 months

-3

-3

Bowel bother score

Last day radiotherapy

-16

-17

2-3 months

-2

-6

Sexual function

Last day radiotherapy

-15

-10

2-3 months

-5

-9

Sexual bother score

Last day radiotherapy

-20

-18

2-3 months

-11

-15

Hormonal function

Last day radiotherapy

-3

-6

2-3 months

-1

-2

Hormonal bother score

Last day radiotherapy

-3

-2

2-3 months

-2

-1

Pinkawa 2016

IMRT (n=202)

Bowel bother score

Last day radiotherapy

-14

-18

NR

2 months

-3

-6

17 months

0

-7

Sexual bother score

Last day radiotherapy

-6

-9

2 months

-12

-19

17 months

-12

-17

Urinary bother score

Last day radiotherapy

-18

-21

2 months

-14

-17

17 months

1

2

Pinkawa 2017

IMRT (n=167)

Urinary function

End of radiotherapy

-10

-13

NR

2 months

-2

-4

>12 months

1

-

Bowel function

End of radiotherapy

-11

-14

NR

2 months

-4

-5

>12 months

0

-5

<0.01

Sexual function

End of radiotherapy

-12

-10

NR

2 months

-6

-8

>12 months

-6

-

Hormone function

End of radiotherapy

-5

-7

NR

2 months

-3

-4

>12 months

2

-

Bowel bother score

18 months

-1

-7

0.13

60 months

-1

-6

0.99

Sexual bother score

18 months

-13

-18

0.28

60 months

-21

-28

0.77

Urinary bother score

18 months

2

3

0.49

60 months

0

3

0.22

Systematic review

UK

Search period: January 2013 to December 2019; databases searched: MEDLINE, Embase, PubMed, CINAHL, and Cochrane library Google scholar, and reference lists of included articles were also searched.

13 studies: (9 retrospective case series and 4 case reports of less than 10 patients)

n=1208 patients (671 patients who had a perirectal hydrogel spacer injection versus 537 patients who did not receive a spacer [controls] before prostate cancer brachytherapy).

Not reported

Inclusion criteria: English-language articles, randomised and non-randomised studies of patients with localised or locally advanced prostate cancer receiving brachytherapy with or without PEG hydrogel spacer (salvage and primary treatment); reporting a number of outcomes including radiation dose, prostate-rectum separation, toxicity and technique for hydrogel insertion.

Studies of more than 10 patients evaluated for efficacy and less than 10 patients reviewed for only procedure related complications.

Exclusion criteria: case reports, review articles and editorials, non-English-language studies, animal and laboratory studies.

Intervention: under ultrasound guidance a needle is inserted into perineum. Hydrodissection of the potential space is done first and then a prostate-rectum spacer (absorbable polyethylene glycol hydrogel) is injected posterior to the Denonvilliers fascia and anterior to the rectal wall at the level between mid-gland and apex of the prostate (4 studies used DuraSeal off label and 5 used SpaceOAR since 2017).

Comparator (control):no hydrogel spacer(in 6 studies)

Radiotherapy protocols: LDR or HDR BT alone or in combination with EBRT

All LDR or HDR BT start with seed insertion followed by spacer insertion and subsequent IMRT.

Varied across studies (range 6 to 60 months)

Authors state that there is no potential conflict of interest.

Study details

Mean follow up/scoring system

Mean prostate-rectum separation (mm)

Rectal dosimetric reduction/percentage dose reduction^

Acute GI toxicity (spacer versus no spacer)

Late GI toxicity (spacer versus no spacer)

Failure rate

Mahal 2014

Salvage LDR BT; prior pelvic irradiation (n=11)

DuraSeal spacer

15.7 months/

EPIC questionnaire

10.9 in patients with prior BT

7.7 in patients with prior EBRT

Median V75% (cc): 0.07

Grade 1: 0%

Grade 2: 9% (n=1 fistula)

Grade >3: 0

Grade 1 or 2:

36% (4/11)

Grade 3 or 4: 9% (n=1 patient developed prostatorectal

fistula requiring a diverting colostomy and an interposition rotational gracilis muscle

flap)

16 months: 26% (3/11)

bowel QoL change

27.2%

Heikkila 2014

LDR BT

(n=10)

DuraSeal spacer

-

10

Rectal D2 cc

64±13 Gy with gel versus

95±13 Gy without gel

(p=0.005)/

(32.6%)

1 patient reported a sensation of pressure in the rectum.

1 patient felt a sudden need for defecation.

-

0%

Wu 2017 HDR BT: HDR BT+EBRT

Salvage HDR BT

(n=18 with spacer and 36 without spacer)

(SpaceOAR)

-

-

Median V75%

(cc): <0.005

versus 0.12

(p≤0.0005)/

(100%)

1 patient developed a rectal abscess.

-

0%

Chao 2019

HDR BT+IMRT

(n=32 with spacer and 65 without spacer) (SpaceOAR)

60 months

NCICTCAE v4.0

10

Median V75% (cc) 0.0 versus 0.45 (p≤0.001)/ (100%)

Grade 1 12.5% versus 30.8% (p=0.05)

Grade 1: 0% versus 7.7% (p=0.11)

-

Chao 2019

HDR BT+IMRT or VMAT

(n=30 with spacer and 65 without spacer) (SpaceOAR)

58 months

NCICTCAE v4.0

-

Median V75% (cc) 0.0 versus 0.45 (p≤0.001)/ (100%)

Grade 1 13.3% versus 30.8% (p=0.05)

Grade 2 0% versus 1.5% (p=0.48)

Grade 1: 0% versus 7.7% (p=0.11)

-

Storm 2014

HDR BT +IMRT (n=100 with spacer and 100 without spacer) (DuraSeal)

8.7 months

12

Rectal D2 cc

47±9% versus

60±8%

(p<0.001)/

(21.6%)

-

-

0%

Yeh 2016

HDR BT +IMRT

(n=326)

(DuraSeal)

16 months

NCICTCAE v4.0

16

maximum dose to rectum 78% versus 95%

(SD=11.9%)/

(17.3%)

Grade 1: 37.4%

Grade 2: 2.8% Most commonly diarrhoea

Grade 1:12.7% Grade 2: 1.4% Grade 3: 0.7%

1 case of severe proctitis

1 case of fistula and necrotising fasciitis requiring a diverting colostomy.

-

Taggar 2017

LDR BT.

LDR BT+EBRT

Salvage LDR BT (74 with spacer 136 without spacer)

(SpaceOAR)

6 months

RTOG

11.2

Rectal D2 cc

20.47% versus

43.16%

(p=0.000)/

(52.6%)

Grade 1 or 2 20.3% (n=15) versus 24.3% (n=33) (p= 0.95)

Diarrhoea: LDR BT alone 7.7% versus 15.9%

LDR BT +EBRT 12.5% versus 4.1%

Salvage 12.5% versus 5.3% Proctitis: LDR BT alone 0% versus 0%, LDR BT+EBRT 0% versus 5.5% Salvage 0% versus 0%

Rectal discomfort -8% (n=7) versus 0

Rectal bleeding 5% (n=2) versus 21.3% (n=18).

No grade 3 or 4 complications

-

6.8%

(2 aborted due to unsuccessful hydro dissections)

Morita 2019

LDR BT; LDR BT+EBRT

(100 with spacer 200 without spacer) (SpaceOAR)

-

11.6

Median V100% 0.026±0.14 versus 0.318+/1 0.34 (p≤0.001)/ (91.8%)

-

-

4%

(1 aborted due to operator inexperience and premature coagulation of the solution during injection)

Study

N

Complications

n

Procedure related complications

Teh 2014

1 spaceOAR

Rectal ulcer (1 month after hydrogel spacer insertion, resolved without further intervention)

1

Beydoun 2013 (BT)

5 spaceOAR

Perineal pain or rectal discomfort (resolved without intervention within 1 week)

3

Heikkila 2014 (LDR BT)

10 DuraSeal

Sensation of pressure/fullness in the rectum (self-limiting symptoms, resolved by 3 months with medication)

1

Heikkila 2014 (LDR BT)

10 DuraSeal

Sudden need for defecation (self-limiting, symptoms resolved by 3 months with medication)

1

Storm 2014

(HDR BT with IMRT)

100 with DuraSeal versus 100 without

Infection (bacterial prostatitis and epididymitis), adjusted antibiotic prophylaxis before

procedure

6% (n=3)

Wu 2018

(HDR BT boost to EBRT)

18 with spaceOAR versus 36 without spacer)

Rectal perineal abscess (1 month after SpaceOAR insertion. required incision, drainage and antibiotics)

1

Mahal 2014 (salvage LDR BT)

Yeh 2016 (HDR BT +IMRT)

11 DuraSeal

326 (SpaceOAR)

Prostatorectal fistula requiring diverting colostomy and an interposition rotational gracilis muscle flap

Fistula and necrotising fasciitis requiring a diverting colostomy.

1

1

Yeh 2016 (HDR BT +IMRT)

326 (SpaceOAR)

Severe proctitis

1

Other complications at follow up

Taggar 2018

LDR BT

LDR BT+EBRT

Salvage LDR BT

(74 with spacer 136 without spacer)

(SpaceOAR)

Diarrhoea

LDR BT alone 7.7% versus 15.9%

LDR BT +EBRT 12.5% versus 4.1%

Salvage 12.5% versus 5.3%

Rectal discomfort

8% (n=7) versus 0

Rectal bleeding

5% (n=2) versus 21.3 (n=18)

Study type

Systematic review and meta-analysis

Country

USA, UK, Switzerland and Germany

Study search details

Inception to August 2020; Databases searched: Cochrane Central Register of Controlled Trials, MEDLINE, and Embase; no language or date restrictions applied. Supplemental searches were done in the directory of open access journals, Google scholar, and reference lists of included articles and relevant meta-analyses searched. Unpublished or grey literature was also included.

Study population and number

n=11 studies (14 papers) with 780 people having SpaceOAR hydrogel spacer before SBRT for localised prostate cancer.

(5 prospective and 6 retrospective studies)

Clinical stages: localised or locally advanced prostate cancer (T1-T3), Risk category: varied but intermediate risk

PSA levels median 8.2 (range 6.3 to 9.8 nanograms/ml)

Age and sex

Median age 70 years (range 69 to 73 years).

Study selection criteria

Inclusion criteria: randomised clinical trials or observational studies of people who had the perirectal hydrogel spacer versus patients who had no spacer before SBRT for localised or locally advanced prostate cancer.

Exclusion criteria: review articles, commentaries, letters, studies with fewer than 5 patients, studies of other rectal spacers such as hyaluronic acid and rectal balloons, studies that did not report an outcome specified in this review and duplicate publications.

Technique

Intervention: Injection of a prostate-rectum spacer (absorbable polyethylene glycol hydrogel‑SpaceOAR system) between the Denonvilliers fascia and anterior rectal wall before radiotherapy.

Radiotherapy protocols: SBRT (≥5.0 Gy fractions) protocols varied and ranged from 7 Gy to 10 Gy per fraction with total dose ranging from 19 to 45 Gy. 561/780 had dose-escalated SBRT regimens (37.5 GY to 45Gy in 5 fractions).

Follow up

Median 20 months (range, 9 to 24 months).

Conflict of interest/source of funding

The study was funded by Boston Scientific and they were involved in design and interpretation of data, review and approval of manuscript.

Authors served as consultants, and either received personal fees, grants, honoraria, travel expenses, and non-financial support from Boston scientific and other companies.

Study

Early grade 2

Early grade 3

Late grade 2

Late grade 3

Freedom from biochemical failure

Alongi (2013) (n=8)

-

0

0

0

8/8 (100%)

Chen (2020) (n=250)

18/250

(7.2%)

0

10/250

(4%)

1/250

(0.4%)

241/250 (96%)

Cuccia (2020) (n=10)

0

0

-

-

-

Hwang (2019, 2018) (n=50)

2/50 (4%)

0

0

0

50/50 (100%)

Jones 2017 (Folkert 2017) (n=44)

1/44

0

-

0

44/44 (100%)

King 2018 (n=6)

0

0

-

-

-

Ogita 2019 (n=40)

7/40 (18%)

0

-

-

-

Pryor 2019

Wilton 2017 (n=80)

-

0/80

-

-

-

Ruggeri 2014 (n=11)

-

-

-

-

-

Saito 2020 (n=20)

-

-

-

-

-

Zelefsky 2019 (n=269)

-

-

-

3/269 (1.1%)

-

Systematic review

UK

Search period: not reported; databases searched: MEDLINE

11 studies (reported within 12 articles), n=346 patients

Not reported

Inclusion criteria: published articles and conference abstracts from preclinical and clinical studies; prostate cancer patients in whom PR spaces were implanted

Exclusion criteria: not provided.

Intervention: Prostate-rectum spacers compared to each other: PEG spacers (4 studies), hyaluronic acid spacers (5 studies), biodegradable balloons (1 study), and collagen implants (1 study).

An additional 3 preclinical studies were included (2 used PEG spacers and 1 used a biodegradable balloon spacer).

Radiotherapy protocols: different treatment techniques used (IMRT, VMAT, IMPT, 3D-CRT, and HDR monotherapy) in the primary studies.

EBRT (6 studies) and BT (5 studies).

3 to 72 months

None; Review funded by an institute for a health technology assessment report.

Study

Spacer type (ml injected)

Radiation technique

Mean prostate-rectum distance (mm)

Mean rectal Vxx Gy/% without spacer/ with spacer

Relative reduction of rectal Vxx Gy/%

Acute or late toxicity

Weber 2012

N=8

PEG hydrogel (10)

IMRT (78 Gy)

VMAT (78 Gy)

IMPT (78 Gy)

7-10

7-10

7-10

V70Gy: 9.8%/5.3% V70Gy: 10.1%/3.9% V70Gy: 9.7%/5.0%

V70Gy: 46% V70Gy: 61% V70Gy: 49%

-

Pinkawa 2011

N=18

PEG hydrogel (10)

IMRT (78 Gy) 3D-CRT (78 Gy)

10

10

V70Gy:17.2%/7.5% V70Gy:14.4%/6.1%

V70Gy: 56% V70Gy: 58%

-

Song 2013

N=48

PEG hydrogel (10)

IMRT (78 Gy)

9.7

V70Gy:13.0%/5.1%

V70Gy: 60%

Focal rectal mucosal necrosis and bladder perforation (n=3, self-limiting) (Uhl 2014)

Acute GI toxicity

grade 1 39.6%

grade 2 toxicity 12.5%. No grade 3 or 4 toxicities.

Acute GU toxicity grade 1 41.7% grade 2 35.4% grade 3 2.1%.

No grade 4 toxicities

Late grade 1 GI toxicity 4.3% (2) no grade 2 or worse toxicity.

Late GU toxicity grade 1 in 17.0% grade 2 toxicity 2.1%. No grade 3 or worse GU toxicity.

Chapet 2013

n-16

Hyaluronic acid (10)

IMRT (62 Gy, 3.1 Gy/fx)

11.5

V90%: 7.7 cc/2.1 cc

V70%: 13.3 cc/7.6 cc

V90%: 74% V70%: 43%

Rectal toxicity 0% versus 30% in historical controls

Chapet 2014

N=10

Hyaluronic acid (10)

SBRT (32.5 Gy, 6.5 Gy/fx) (42.5 Gy, 8.5 Gy/fx)

10.1

V90% 3.2 cc/0.3 cc

V90% 3.5 cc/0.3 cc

V90%: 90% V90%: 91%

-

Noyes 2012

N=11

Collagen (20)

IMRT (75.6 Gy)

12.7

V40Gy:

7%-15% in collagen group

20 to 25% without collagen

V40Gy: 40%-65%

No GI toxicities

Melchert 2013

N=22

Balloon (16)

IMRT/3D-CRT (74 Gy)

19.2

V60Gy: 30% pre-implant /15% post implant

V60Gy: 50% (Gez 2013)

V90%: 72%

Acute dysuria grade 1 or 2 (58%)

Urinary retention needing catheter (n=1)

Diarrhoea (grade 1 17%)

Proctitis (grade 1 8%)

Study

Spacer type (ml injected)

Radiation technique

Mean prostate-rectum distance (mm)

Mean rectal Vxx Gy/% without spacer/ with spacer

Acute and late toxicity

Storm 2014 (n=100 hydrogel versus no hydrogel)

PEG hydrogel (15)

HDR BT monotherapy (13.5-14.0 Gy x 2 fx)

IMRT (45 Gy) + HDR BT boost (9.5-11.5 Gy x 2 fx)

12

D2cc = 60%/47%

Bacterial peritonitis 2 (had prophylactic treatment).

Prada 2007 (n=27)

Hyaluronic acid (3-7)

3D-CRT (46 Gy) + HDR BT boost (11.5 Gy x 2 fx)

20

Dmax = 7.1Gy/5.1Gy

Dmean = 6.1 Gy/4.4 Gy

None related to HA implant

Prada 2009

(n=36)

Hyaluronic acid (6-8)

LDR BT ¹²⁵I 145 Gy

20

NA

Rectal mucosal damage 5%

Prada 2012 (n=40)

Hyaluronic acid (NA)

HDR BT ¹⁹²Ir 19 Gy x 1 fx

20

NA

None related to HA implant

GI toxicity: asymptomatic anal mucositis (grade 1) 12.5%

GU toxicity -urinary obstruction grade 1 requiring catheterisation in 1 (2.5%).

At 6 months 27.5% had mild grade 1 urinary obstruction.

Wilder 2010 (n=10)

Hyaluronic acid (9)

IMRT (50.4 Gy) + HDR BT boost (5.4 Gy x 4 fx)

13

V70Gy = 4% in HA group

25% in controls

None related to HA implant

Grade 1-3 diarrhoea 0% versus 29.7%

Study

Complications

% (n)

Noyes 2012

n=11

Collagen

Acute urinary obstruction

5/11

Self-limiting light rectal pressure

3/11

Temporary catheterisation for acute urinary retention (presumed to be secondary to pudendal nerve blocking)

1/11

Gez 2013

n=2013

ERB

During balloon insertion

n=26

Pain at the perineal skin/scar (ranging 1–7, VAS score)

27 (7/26)

Acute pain in the anus (ranging 2–9, VAS score)

15 (4/26)

Acute urinary retention (needed catheterisation, resolved within few hours)

12 (3/26)

Dysuria and nocturia (grade 1–2)

12 (3/26)

Penile bleeding

4 (1/26)

Balloon failure after implantation (needing removal)

4 (1/26)

Premature balloon deflation

3

During radiotherapy

n=23

Proctitis

8 (2/23)

Diarrhoea (grade 1)

17 (4/23)

Signs of blood in faeces (grade 1)

4 (1/23)

Constipation (grade1)

4 (1/23)

Erectile dysfunction

4 (1/23)

Fatigue

4 (1/23)

Decreased urine flow

4 (1/23)

Systematic review

USA, Netherlands, UK, Germany,

Search period: January 2000 to December 2019; databases searched: PubMed; Additionally, a further search was done from January 2010 to December 2019 for abstracts. Reference lists of articles were also reviewed for relevant articles.

21 studies of patients with prostate cancer who had a rectal spacer during radiation therapy (n=287).

Age not reported

Inclusion criteria: studies in English, in humans, full text articles specifically investigating the impact of rectal displacement devices on prostate motion.

Exclusion criteria: review articles, case reports, animal studies, lack of relevant outcome data, non-English articles, editorials and commentaries.

Rectal spacers used during EBRT for prostate cancer. Different radiotherapy techniques (IMRT, 3DCRT, VMAT, PT) were used.

12 studies evaluated role of ERBs, 4 evaluated polyethylene glycol hydrogel spacers (SpaceOAR)

4 studies assessed rectal retractors (RR), and 1 study assessed ProSpare.

Not reported

None reported

Study

No of patients

Radiotherapy technique

Results

Wacher 2002

10 with 40ml air filled ERB and 10 without

3DCRT

AP displacement: >5mm in 20% of ERB patients.

>5mm in 80% of non-ERB patients.

ERB significantly reduces maximum AP displacement of prostate (p=0.008).

Hung 2011

14 with 120ml water filled balloon and 15 without

IMRT

AP displacement: mean 5.4±3.4 mm in ERB.

mean 7.3± 4.8 mm in non-ERB

ERB reduces inter-fractional prostate motion but not statistically significant (p=0.22–0.38)

Van lin 2005

22 with an 80ml air filled ERB and 30 without

IMRT

AP displacement: mean 0.4±4.7mm ERB.

0.6±4.3mm in non-ERB

ERB does not decrease the inter-fractional prostate motion (p=NR)

Smeenk 2012

15 with an 100ml air filled ERB and 15 without

IMRT

AP displacement: 3.9 mm ERB, 3.8 mm non-ERB

ERB does not significantly reduce the inter-fractional variation (p=0.06–0.92).

Takayama 2011

7 with a double ERB and 7 without

3DCRT or IMRT

AP displacement: 1.3 ± 0.9mm ERB; 2.8 ± 1.8mm non-ERB. ERB only reduces inter-fractional prostate motion in the AP direction (p=0.014)

Teh 2002

10 with an 100ml air filled ERB

Combined radioactive seed implant and IMRT

AP displacement: 1mm

ERB can reduce inter-fractional prostate motion.

Mc Gary 2002

10 with an 100ml air filled ERB

IMRT

AP displacement: 0.42 ± 0.35mm

Most improvements observe in AP displacement.

El-Bassiouni 2006

15 with a 60ml air filled ERB

3DCRT

AP displacement: 3.8±4.0mm; ERB does not eliminate prostate motion in anterior rectal wall.

Study

No of patients

Radiotherapy technique

Results

Juneja 2015

12 with hydrogel spacer versus 14 without spacer

VMAT

Mean prostate motion was 1.5 ± 0.8mm with spacer and 1.1 ± 0.9mm without spacer (p< 0.05). No significant difference in the average time of motion >3mm between group with and without hydrogel, which were 7.7 ± 1.1% and 4.5 ± 0.9% (p> 0.05), respectively. Therefore, hydrogel spacer has no effect on intra-fractional prostate motion.

Hedrick 2017

10 with ERB versus 16 with hydrogel spacer

IGRT-PBT

The mean vector shift was 0.9mm with hydrogel and 0.6mm with ERB (p< 0.001). These results were not clinically significant because the minimum robust evaluation tolerance was 3mm. Prostate vector shifts were similar between ERB and hydrogel for shifts >3mm (p=0.13) and >5mm (p=0.36). Prostate displacements were clinically comparable for both ERB and hydrogel spacer groups.

Picardi 2016

10 with hydrogel spacer and 10 without

IGRT-VMAT

Overall mean inter-fraction prostate displacements >5mm in AP and SI direction were similar between with and without spacer (AP direction p=0.78; SI direction p=0.47). Prostate displacements 45mm in the AP and SI directions were similar for both groups. Systematic and random setup errors were similar for both groups.

Pinkawa 2013

15 with hydrogel spacer and 30 without

IMRT

Prostate position displacement >5mm were similar for both groups (no statistically significant difference p>0.05), but posterior prostate displacement could be decreased in group with hydrogel spacer (p=0.03).

Study

No of patients

Radiotherapy technique

Toxicity results

Van lin 2017

Prospective randomised study

24 with an 80ml air filled ERB versus 24 non-ERB

3D-CRT

Acute rectal toxicity ERB versus non-ERB Grade 1: 46% versus 50%, NS

Grade 2: 29.2% versus 29.2%, NS

Late rectal toxicity ERB versus non-ERB

Grade ≥1: 21% versus 58.3%, p=0.003

No grade 2–3 in ERB

Goldner 2007

Prospective study

166 with a 40ml air filled ERB

3D-CRT

Late rectal toxicity Grade 0: 57%; Grade 1: 11% Grade 2: 28%; Grade 3: 3%

VRS Grade 0: 32%; Grade 1: 22% Grade 2: 32%; Grade 3: 14%

Deville 2012

Retrospective study

100 with a 100ml water filled ERB

IMRT

Acute GI toxicity Grade 0: 69% 1: 23% Grade 2: 8% Grade 3–4: 0%

Wortel 2017

Prospective phase III trial

85 with an 80–100ml air filled ERB versus 242 without ERB

IMRT

Acute mucous loss: 28.4% in non-ERB versus 16.8% in ERB, p< 0.001.

Acute rectal discomfort: 59.9% in non-ERB versus 41.0% in ERB, p=0.003.

Late rectal complaints in the ERB group were statistically significantly lower than in the non-ERB group.

Teh 2018

Retrospective study

596 with a 100ml air filled ERB

IMRT

Late GI toxicity

Grade ≥2: 8.5%

Grade ≥3: 1.2%

Study

No of patients

Radiotherapy technique

Toxicity results

Uhl 2013

Prospective study

52

IMRT

Presented under study 3, 6

Mariados 2015, Hamstra 2017

Prospective RCT

149 with hydrogel spacer versus 79 without

IMRT

Presented under study 1, 2, 3,4

Pinkawa 2017

Retrospective study

101 with spacer versus 66 without

IMRT/VMAT

Presented under study 2, 4

Te Velde 2017

Retrospective study

65 with spacer versus 56 without

IMRT

Presented under study 2, 4

Hwang 2019

Retrospective study

50

SBRT

GI toxicity 1 month after RT

Grade 1: 8% Grade 2: 4% No acute or late rectal toxicity was reported.

Dinha 2020

Retrospective study

92 with a 90ml water filled ERB versus 75 with hydrogel spacer

PBT

At 2 years

actuarial rate of grade ≥2 late rectal bleeding was 19% in ERB arm and 3% in spacer arm; p=0.003.

EPIC-bowel QoL composite scores were less diminished in spacer arm (absolute mean difference 5.5; p=0.030).

Review

USA

Search period: January 2015 to March 2019, in the MAUDE database.

N=25 patients

Not reported

Not reported

Injection of a prostate-rectum spacer (absorbable polyethylene glycol hydrogel SpaceOAR) posterior to the Denonvilliers fascia and anterior to the rectal wall at the level between mid-gland and apex of the prostate before radiotherapy.

Varied across studies (range 6 to 60 months)

Authors state that there is no potential conflict of interest and no funding was received.

Study

Year of report

Reported adverse event

N=25

Level I*

2015, 2017

Venous injection—No sequelae

2

2017

Tenesmus with air in rectal wall—No sequelae

1

2018

Venous injection—No sequelae

1

2018

Rectal wall erosion—No sequelae

1

Level II*

2018

Purulent drainage from perineum requiring antibiotics

1

2018

Pulmonary embolism requiring anticoagulant

4

Level III*

2016,2018, 2019

Perineal abscess requiring drainage^

3

2016

Proctitis requiring colostomy^

1

2017, 2018, 2019

Recto-urethral fistula requiring diverting colostomy^

4

2018

Rectal ulcer and haemorrhage requiring surgery^

1

2018

Perirectal fistula requiring surgical intervention^

1

2019

Urinary tract infection and prostatic abscess requiring drainage^

1

Level IV*

2018

Perineal abscess^—subsequent death from alcoholic cardiomyopathy

1

2018

Severe urosepsis—ICU admission

1

2018

Severe anaphylactic reaction

1

2019

Dizziness/nausea post-procedure leading to unresponsiveness and death (cause of death unclear)

1

Commentary

USA, UK

Search period: May 1, 2015, to May 1, 2020, MAUDE database.

N=85 patients

Not reported

Not reported

Commentary including data from MAUDE database, not primary data.

The project was supported by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, UK.

Authors received some research and travel funding from companies, outside of this work. One author reports personal fees from The Institute of Cancer Research, during the conduct of the study and a patent for a prostate location and stabilisation device.

Study type

Case series

Country

France

Recruitment period

2010–12

Study population and number

n=36 patients with low-risk to intermediate-risk localised prostate cancer

Mean prostate volume: 45.9 cc

Tumour classification: 1c (n=18), 2a (n=10), 2b (n=8).

Gleason score: 6 (n=22), 7 (n=14)

PSA: mean 9.46 nanograms/ml

Age and sex

Mean age: 71 years; 100% male

Patient selection criteria

patients aged between 18-80 years, adenocarcinoma of the prostate histologically proven, low- to intermediate-risk cancer according to the D'Amico classification (T1c to T2b, Gleason score <7, and PSA <20 nanograms/ml) and Karnofsky performance score >60 were included.

Patients with metastases, regional lymph nodes1.5 cm on CT scan or MRI, inflammatory disease of the digestive tract, previous pelvic irradiation, and previous malignant disease other than basal cell carcinoma were excluded.

Technique

Injection of 10 ml hyaluronic acid during hypofractionated intensity modulated radiation therapy (IMRT) (with 20 fractions of 3.1 Gy, up to 62 Gy total dose over 4 weeks)

Injection was done under local anaesthesia (10 ml lidocaine 1%). All patients had daily prostate repositioning on the 3 gold markers implanted. Antibiotics were given before and after injection.

Follow up

3 months

Conflict of interest/source of funding

None

Overall toxicity

% (n)

Grade 0 (no toxicity)

6 (2/35)

Grade 1

40 (14/35)

Grade 2

54 (19/35)

Grade 3 or 4 toxicity

0

During radiotherapy

Acute GU toxicity^ (at least 1)

94.3 (33/35)

Grade 2 toxicity (at least 1): urinary obstruction, frequency*

54.2 (19/35)

Acute GI toxicity^^

57.1 (20/35)

Grade 1 (at least 1)

54.2 (19/35)

Grade 2

2.8 (1/35): proctitis

3‑month follow up (n=34)

GU toxicity

41.2 (14/34)

4 patients had grade 2 obstruction or frequency

GI toxicity: grade 1

2.9 (1/34)