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.
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