Hydrogel use represents a technical advance in trying to decrease the risk of treatment toxicity in prostate cancer radiation therapy. I presented this talk at the Fall Conference of the Southern NH chapter of Oncology Nursing Society yesterday.

1. Hydrogel Use
in Prostate Cancer
Radiation Therapy
Matthew Katz, MD
November 2021

2. Disclosures
 Partner, Radiation Oncology Associates PA
 Lowell, MA and Manchester, NH
 Own stock in CVS, Dr. Reddy’s Laboratories,
Healthcare Services Group, Quest Diagnostics,
and Pfizer
 Serve as Chair-Elect for ASCO Taxonomy
Committee

3. Learning Objectives
 Understand prostate radiation toxicities
 Comparison to surgery
 Changes over time with technologic advances
 Understand the potential role of hydrogel use
 PIVOT Trial
 Other Data
 Understand the logistics of coordinating
hydrogel use with
 Simulation
 Treatment Planning

4. Background
 External beam radiation therapy is an
excellent treatment option for men with
prostate cancer
 Comparable cancer control to surgery
 Different impact on quality of life and
treatment toxicity profile

5. ProtecT Trial (UK)
 Randomized 1500+
men with low risk
prostate cancer to
 Surgery
 Radiation
 Monitoring
 ~55% received
radiation or surgery in
10 yrs of followup
 85% Gleason 6 (low
grade) disease
Hamdy et al, NEJM 2016

6. ProtecT – Cancer Control
 No difference in
prostate cancer
specific mortality at
10 years
 Monitoring had
higher risk of clinical
progression including
metastatic disease
 Surgery and radiation
equal
Hamdy et al, NEJM 2016

7. ProtecT - Quality of Life
 85% of men
completed patient
reported outcome
measures (PROMS)
Donovan et al, NEJM 2016

8. Urinary PROMS
 Radiation had brief
irritative symptoms
and nocturia but
 Less incontinence
than surgery or
monitoring
 More nocturia than
surgery but less than
monitoring
Donovan et al, NEJM 2016

9. Sexual PROMS
 Radiation has less
negative effect on
sexual PROMs than
surgery
Donovan et al, NEJM 2016

10. Bowel PROMS
 Radiation has more
acute and chronic
bowel toxicity than
surgery
 At 6 years follow up
 Fecal incontinence 4.1%
vs 2.6% monitoring
 Bloody stools ‘half the
time’ 5.6% RT vs 1.3%
monitoring
Donovan et al, NEJM 2016

11. Goals of Prostate Radiotherapy
 Cancer control
 Minimize
 Treatment Toxicity
 Patient inconvenience

12. Higher Doses = More Toxicity
 RTOG 0126
 Randomized 1532 patients to 79.2 Gy in 44
fractions vs 70.2 Gy in 41 fractions
 Higher dose had better PSA control and lower
distant metastases at 8 years without survival
benefit
5-year toxicity 70.2 Gy 79.2 Gy P-value
Grade 2+ GI 15% 21% 0.006
Grade 2+ GU 6% 12% 0.003
Michalski et al, JAMA Oncol 2018

13. Radiation: less time, higher daily dose
Era # of Treatments # of Weeks
1970 – mid 1990s 33-35 6-7
Late 1990s – 2010s 40-45+ 8-9
2010s-Present
20-28 4-5.5
5* 1-2
*stereotactic radiation therapy

14. Potential Advantage of Hydrogel
 Moves anterior rectal wall away from high dose of
radiation
Image: U Wisconsin

15. Polyethylene Hydrogel
 Moves anterior rectal wall away from high dose of
radiation
 Can reduce risk of rectal injury
 Reabsorbed after several months

16. Phase III trial of hydrogel
 Randomized clinical trial 2:1 spacer vs
control
 Single blinded, all patients received 3 gold seeds
in prostate to help align treatment daily
 Patients received 79.2 Gy in 44 treatments
 5-10 mm margin of normal tissue treated
around prostate +/- seminal vesicles
 222 patients enrolled at 20 centers in U.S.
 Low-intermediate risk prostate cancer only
Mariados et al, Int J Radiat Oncol Biol Phys 2015

17. Patient Characteristics
 Baseline CT and MRI
 All patients received
fiducials, 2/3 had spacer
placed
 Repeat CT scan for radiation
planning
 MRI repeated after procedure
 Excluded patients with
 prostate >80 mL
 extracapsular extension or
>50% + cores
 Prior prostate surgery/RT
 Use of ADT Mariados et al, Int J Radiat Oncol Biol Phys 2015

18. Phase III Hydrogel Trial
 Endpoints
 Reduced % volume of
rectum receiving
moderate to high doses
 No increase in
procedure-related
adverse events
 Urinary, bowel, and
sexual quality of life
monitored both by
physician and with some
patient reported
outcomes
Mariados et al, Int J Radiat Oncol Biol Phys 2015

19. Acute Toxicity
 No differences seen at 3 months in urinary or
bowel toxicity
Mariados et al, Int J Radiat Oncol Biol Phys 2015

20. Longer Term Follow-up
 Median follow up 37 months
 MD reported patient toxicity
3-Year Endpoint Control Hydrogel P-value
Grade 1 Rectal 9% 2% <0.03
Grade 2 Rectal 6% 0% <0.015
Grade 3 Rectal 1.3% 0% NS
Grade 1 Urinary
Incontinence
15% 4% 0.046
Other urinary NS
Hamstra et al, Int J Radiat Oncol Biol Phys 2017

21. Patient Reported Quality of Life
 Assessing minimally important differences (MID) in EPIC
QoL scores
 Assessed detectable decline in QoL
3-Year Endpoint Control Hydrogel P-value
Bowel, 5-point decline 41% 14% 0.002
Bowel, 10-point decline 21% 5% 0.02
Urinary, 6-point decline 30% 17% <0.05
Urinary, 12-point decline 23% 8% <0.03
Hamstra et al, Int J Radiat Oncol Biol Phys 2017

22. Seminal Vesicles Matter
 Larger radiation fields, more bowel irradiated
Hamstra et al, Int J Radiat Oncol Biol Phys 2017

23. Meta-Analysis
 7 studies, 1011 patients
 Early rectal toxicity: no difference
 Late grade 2 rectal toxicity reduced from 5.7% to 1.5% (p<0.05)
 Any late rectal toxicity reduced from 16.2% to 4.5% (P<0.001)
Miller et al, JAMA Network Open 2020

24. Who Really Benefits?
Quinn et al, Practical Rad Oncol 2020
 Trial helps, but not
definitive
 Selection bias
 Less diabetes in study
compared to U.S. population
>65 (26.8%)?
 High volume centers
 Benefit may be more for
younger, heavier, smoking
men

25. Complications of Hydrogel
 Up to 6% had asymptomatic rectal wall
infiltration in randomized trial
 Not associated with toxicity in trial
 Acute symptoms
 Tenesmus, perineal tenderness
 Risk of infection
Fischer-Valuk et al, Pract Radiation Oncol 2017

26. Manufacturer and User Facility Device
Experience (MAUDE) database
Aminsharifi et al, J Endourol 2019

27. Severe Complications Rare but Serious
 Developed
rectovesical fistula
 Required major
surgery for repair McLaughlin et al, Advances Radiat Oncol 2021

28. Complications
 Unknown how many procedures performed
to give an estimated risk
 Corporate reporting indicates use in 70,000
patients as of 2021
 Likelihood of injury may vary based upon
 Physician experience
 Technique
 Location of Procedure

29. Physician Experience
 Learning curve may be relatively small as
simple procedure
 Reported improved symmetry after 15
patients
 No report on complications
 Did not look at difference between urologists
and radiation oncologists
Pinkawa et al, Urology 2013

30. Location
 Performed in OR with anesthesia or in office
with local
 No data on differences
 ? Ease of accurate, safe placement with
patient conscious

31. Technique
 Key factors for success
 Create perirectal space
before inserting hydrogel
 Hydrodissection with 10-20
mL saline w/18 gauge needle
 Limit hydrogel to 10 mL or
less
 Proper needle angle
 Parallel to ultrasound probe
or slight angle toward
prostate apex
Müller et al, Radiat Oncol 2016

32. Contraindications
 Absolute
 Locally advanced prostate cancer
 Active bleeding disorder or coagulopathy
 Relative
 Anticoagulation (should be reversed)
 Active GU/GI infection or inflammation
 Prostatitis
 Crohn’s/Ulcerative Colitis
 Prior prostate treatment or pelvic adhesions
 Radiation
 HIFU
 Cryotherapy
Müller et al, Radiat Oncol 2016

33. Workflow and Coordination
 Requires collaboration within departments
and between departments
 Varies significantly based upon practice
setting

34. Who, What, Where, When, & How
 Who Decides?
 Urology, Radiation Oncology, Patient involvement
 Decision Support
 Who Does it?
 What Hydrogel used?
 Original (requires MRI for planning)
 Iodinated (visible on CT, no MRI needed)
 Where: Office vs. Operating Room?
 How to Coordinate
 Communication and Timing

35. Who Decides?
 Shared decision making is essential
 Decision for hydrogel is contingent on patient
choice for radiation therapy
 Individualize balancing potential toxicity of
radiation therapy vs. added risk/benefit of hydrogel
use
 Asking about tolerance of prostate biopsy can be
helpful

36. Selecting Higher Risk Men
 Larger radiation fields, more rectum/bowel irradiated
 Can select men at higher risk of rectal toxicity with
predictive models, like nomograms
Valdagni et al, Int J Radiat Oncol Biol Phys 2008

37. Who Does the Procedure?
 Urology or Radiation Oncology?
 Unless radiation oncologist very experienced
with brachytherapy, likely best done by
urology

38. What Hydrogel?
 Gives more anatomic
detail with MRI
 Can identify and protect
the urethra
 ? Help with GU toxicity
 Requires selecting
fiducials that can be
identified on both MRI
and linear accelerators
 Cannot identify urethra
 Use for men who can’t
have an MRI (e.g.
pacemaker)
 Iodine is bound, no
allergic issues
 More expensive (but no
MRI needed)
Original Iodine-bound

39. What Fiducials to Use?
 Larger gold
fiducials
work across
all imaging
modalities
Chan et al, Technol Cancer Res Treat 2016

40. Where is the Procedure Performed?
 Office setting
 Convenient, no general anesthesia risk
 Operating room
 Better patient comfort
 Impact on technique, complications?
 No current data on this issue

41. When: Timing for Simulation
 Original hydrogel
 CT simulation for radiation and MRI for planning should
be 7+ days after procedure
 Permits time for
 Resolution of edema
 Fiducial migration risk decreased
 Iodinated hydrogel
 No need for MRI but may benefit to wait for simulation
for same reasons
 If using androgen deprivation therapy, do
procedure closer to time of radiation therapy

42. How: Coordination
 Deciding on Radiation
 Discussion of all treatment options (surgery, active
surveillance)
 Consent for radiation obtained first
 Hydrogel is separate discussion
 Once Decided
 If patient wants hydrogel, coordinate with urology to
evaluate for fiducial/hydrogel placement
 If using hormone therapy, make sure procedure done ~8
weeks after starting LHRH agonist
 May require cardiac clearance if done in OR

43. How: Coordination
 Communication
 After hydrogel procedure scheduled, urology notifies
radiation oncology of date
 Radiation oncology can then
 Schedule MRI if needed
 Send report to urologist placing fiducials so they can review how the
procedure went
 Schedule simulation, patient education
 Treatment planning
 Requires accurate fusion of fiducials from MRI to
planning CT scan to ensure accurate targeting

44. Summary
 Hydrogel can lessen the toxicity of prostate
radiation treatment
 Some people may benefit more than others
 Requires shared decision making to use it
 Patient preferences play important role
 Quality & Safety
 Monitor toxicities of hydrogel placement
 More research needed on optimal location, other factors
 Coordination of Care is essential

45. Thank you