1. No category

Radiotherapy and Oncology (2013)
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Radiotherapy and Oncology
journal homepage: www.thegreenjournal.com
Original article
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Low rectal toxicity after dose escalated IMRT treatment of prostate cancer
using an absorbable hydrogel for increasing and maintaining space between
the rectum and prostate: Results of a multi-institutional phase II trial
Matthias Uhl a,⇑, Baukelien van Triest b, Michael J. Eble c, Damien C. Weber d, Klaus Herfarth a,
Theodore L. De Weese e
a
Department of Radiation Oncology, University of Heidelberg, Germany; b Department of Radiation Oncology, NKI-AVL Nederlands Kanker Instituut – Antoni van
Leeuwenhoek, Amsterdam, The Netherlands; c Aachen University Hospital, Germany; d Department of Radiation Oncology, Geneva
University Hospital, Switzerland; e Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, USA
i n f o
Article history:
Received 25 May 2012
Received in revised form 10 October 2012
Accepted 25 November 2012
Available online xxxx
Purpose: To evaluate the safety and efficacy of an absorbable hydrogel when injected between the rectum
and prostate to reduce rectal radiation toxicity in adult men undergoing Intensity Modulated Radiotherapy (IMRT) for treatment of low and intermediate risk prostate cancer.
Methods: This prospective, non-randomized, multi-center, single arm, open-label study included 52 men
with a confirmed diagnosis of prostate cancer. They received transperineal injection of the hydrogel and
3–5 days after injection the simulation scans. All patients received IMRT (78 Gy delivered, 2 Gy per fraction). Space stability was evaluated by using MRI or CT. Gastrointestinal (GI) and genitourinary (GU) toxicity was assessed using RTOG/EORTC scoring system and proctoscopy after 12 months. The median
follow up time was 12 months.
Results: Hydrogel application was straight forward using brachytherapy equipment and techniques, with
minimal patient discomfort. Six patients (12%) experienced acute GI Grade 2 toxicity, with no patients
experiencing Grade 3 or 4 toxicity. In addition, no patients had early late GI toxicity P Grade 2 after
12 months. The gel was stable during the course of radiotherapy and was not detectable in MRI after
9–12 months due to absorption in 42 of 43 patients.
Conclusion: These data demonstrated that the hydrogel is a safe method to displace the rectal wall away
from the prostate therefore substantially reducing toxicity to the rectum.
Ó 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2013) xxx–xxx
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Keywords:
Prostate cancer
Radiotherapy
Rectal toxicity
Hydrogel
a b s t r a c t
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a r t i c l e
levels of radiation [5]. However, the success of primary radiation
therapy of localized prostate cancer is correlated with the given
dose [5–7].
Radiation oncologists must balance the treatment of cancerous
tissue with sparing the radio-sensitive rectum from unacceptable
high side effects. For this reason the rectum is the most doselimiting structure in prostate cancer RT.
Absorbable in situ polymerizing polyethylene glycol (PEG)
based hydrogels have been used as dural [8], vascular [9], and lung
sealants [10]. This paper reports on the clinical outcome of highdose radiation therapy used to treat adenocarcinoma of the prostate cancer and the acute and 12 months side effects when using
a PEG based spacer gel between rectum and prostate in a European
multi-institutional phase II trial.
⇑ Corresponding author. Address: Department of Radiation Oncology, University
of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
E-mail address: [email protected] (M. Uhl).
This was a prospective, non-randomized, multi-center, single
arm, open-label trial involving 52 men with a pathologically confirmed diagnosis of clinical stage T1 or T2 prostate cancer. Patients
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Prostate cancer is a serious threat to the health of men throughout the world. In the European Union (EU) over 345,000 cases of
prostate cancer occurred in 2008 with over 87,000 of these resulting in death [1]. Furthermore, the incidence of new prostate cancer
cases in 2010 was the highest of cancers among men in developed
countries across the globe [2].
For cases of localized prostate cancer, external beam radiation
therapy (RT) is a well-known curative alternative to surgery [3].
Increasingly, men choose radiotherapy for localized prostate cancer due to the perception that the risk of impotence and incontinence is lower than with surgery [4].
One of the risks associated with RT is the potential for rectal injury caused by direct mucosal damage from ionizing radiation.
Unfortunately, most prostate cancers originate in the peripheral
zone of the gland, the area adjacent to the rectum. Therefore, effective treatment of the tumor frequently exposes the rectum to high
Patients and methods
0167-8140/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.radonc.2012.11.009
No responsibility is assumed by Elsevier, its licensors or associates for any injury and/or damage to persons or property as a matter of products
liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.
institutional review board-approved prospective clinical protocol
permitting collection and analysis of de-identified patient data at
baseline and follow-up.
Patients with metastatic disease or planned pelvic lymph node
radiotherapy, history of prostate surgery, prior radiation therapy to
the prostate or pelvis, active bleeding disorder, or history of or active inflammatory bowel disease such as Crohn’s disease were excluded from participation. In addition, patients with a history of
chronic prostatitis or any urogenital anatomic abnormality that
would interfere with the ability to access the injection site were
excluded from the study.
Injection procedure
The SpaceOAR System (Augmenix, Waltham, MA) and procedure is published elsewhere [11]. In brief, when injected into the
perirectal fat, the liquid separates the prostate and the rectum
and then polymerizes (solidifies) within 10 s into a soft hydrogel,
by a reaction of PEG-ester and trilysine amine. The resulting hydrogel contains hydrolysable linkages at each PEG-trilysine junction
whose kinetics is such that the gel remains solid for 3 months
and thereafter liquefies, is absorbed and cleared via renal filtration.
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who were indicated for a course of RT were enrolled in this study at
four sites in Central Europe (University of Heidelberg (n = 21), University of Aachen (n = 20), NKI-AVL Nederlands Kanker Instituut
Amsterdam (n = 7) and University of Geneva (n = 4)).
Most of the patients (96%) were Caucasian and the mean age of
the group was 68.9 years (Table 1). The baseline characteristics
were reflective of a low and intermediate risk prostate cancer population. The mean duration of the initial prostate cancer diagnosis
was 110 days and half of the patients (50%) were classified in the
T1c stage. There was an approximately even distribution of Gleason
Scores 6 and 7. Patient mean PSA levels were 6.9 ± 4.5 ng/ml while
mean prostate volume was 56.9 ± 20.4 cc (±SD).
Part way through the study it was appreciated that less hydrogel would be as effective in space creation, so the injected hydrogel
volume was decreased from 15 ml to 10 ml. Additionally the routine use of stool softeners during radiation therapy was initiated
to address the theoretical concern of rectal wall compression between the spacing gel and the compacted stool. Finally, changes
to the application technique, including the use of side-fire transrectal ultrasound probe, a stepper for probe/image stabilization,
and the use of a stand-off balloon improved needle control and
spacer placement. Patients preceding these changes (Cohort 1,
n = 23) had similar baseline characteristics to those enrolled after
these changes (Cohort 2, n = 29) (Table 1).
About one-fourth (23%) of the patients had a history of gastrointestinal (GI) conditions. (i.e., history of polypectomy or polyps,
diverticulitis, cholecystectomy, appendectomy, stomach resection,
duodenal ulcer, gastric reflux, umbilical hernia, anal fissure, and
hemorrhoids).
Twenty-two patients (42.3%) had pre-existing genitourinary
(GU) conditions, Grade 1 or Grade 2 GU toxicity was reported at
baseline for 10 of the 22 patients with symptoms including hesitation, urgency, dysuria, nocturia, stricture, obstructive micturition,
and irritable bladder.
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Low GI toxicity using spacer in RT of the prostate
Treatment planning and treatment
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Within 3–5 days after hydrogel placement, a CT scan was taken
for Intensity Modulated Radiation Therapy (IMRT) treatment planning. The gross tumor volume (GTV) was defined to be the prostate
(as visualized on the simulation scan).
The clinical target volume (CTV) included the GTV and, per the
treating physician’s discretion, the proximal 2/3 of the seminal vesicles. Primary tumor volume (PTV) included the CTV plus a nonisotropic 4–10 mm margin to compensate for daily setup variability and internal organ motion. Typically, less expansion was performed posteriorly than in other directions. The degree of PTV
expansion was based on individual institutional experience and
image guidance setup accuracy, and was generally 4–7 mm in
the posterior direction.
A dose of 78 Gy (delivered in 39 fractions; 2 Gy per fraction) had
to be delivered to an ICRU reference point within the PTV. At least
99% of the PTV had to receive at least 95% of the prescription dose.
A maximum dose less than 107% of the prescription dose was
required.
Patient eligibility
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Patients with pathologically confirmed clinical stage T1 or T2
invasive adenocarcinoma of the prostate; prostate size < 80 cc;
PSA 6 20 ng/mL; Gleason Score 6 6 or Gleason Score 7 with a grade
3 predominant pattern were eligible for participation. Androgen
deprivation therapy was not an exclusion criterion. Informed consent was obtained from every patient. In accordance with institutional guidelines, all research was conducted under an
Table 1
Patient baseline characteristics.
Characteristic
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Age (years)
Mean ± SD (N)
T stage
T1
T2
N Stage, radiologic
Nx
No
PSA level (ng/mL)
64
>4–10
P10–20
Gleason score
6
7
Prostate volume (cc)
Mean ± SD (n)
Prior/Current hormone therapy
a
Values are n (%) unless otherwise noted.
Cohort 1
Cohort 2
Total no. (%)a
71.3 ± 6.0 (23)
67.0 ± 9.0 (29)
68.9 ± 8.0 (52)
12 (52%)
11 (48%)
16 (54%)
13 (44%)
28 (54%)
24 (46%)
9 (39%)
14 (61%)
2 (7%)
27 (93%)
11 (21%)
41 (79%)
5 (22%)
14 (61%)
4 (17%)
6 (21%)
17 (59%)
6 (21%)
11 (21%)
31 (60%)
10 (19%)
13 (57%)
10 (43%)
14 (48%)
15 (52%)
27 (52%)
25 (48%)
55.5 ± 19.3 (22)
9 (39.1%)
58.0 ± 21.4 (29)
5 (17.2%)
56.9 ± 20.4 (51)
14 (27%)
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Treatment toxicity
Following the last fraction, subjects underwent another MRI or
CT scan for evaluation of the maintenance of the created space between rectum and prostate. Another CT or MRI was performed
90 days following completion of the IMRT (or approximately
6 months following hydrogel injection), with a final MRI performed
6 months after completion of IMRT treatment.
Symptoms of radiation proctitis were assessed via the Radiation
Therapy Oncology Group/ European Organization for Research and
Treatment of Cancer (RTOG/EORTC) GI toxicity score (acute and
late). Genitourinary (GU) toxicity was assessed using an adapted
RTOG/EORTC scoring system [12]. Weekly and at the completion
of IMRT, patients were evaluated for acute rectal and genitourinary
toxicity. During follow-up toxicity assessments were performed
90 days, 6 and 12 months after end of radiation therapy (RTOG/
EORTC).
All events (GI, GU, and otherwise) captured from the hydrogel
injection through the 12 months follow-up visit were identified
using CTCAE V. 4.0. The incidence of adverse events (AEs) was summarized by body system and preferred term in accordance with
Medical Dictionary for Regulatory Activities (MedDRA) term as
appropriate.
All patients were planned to have a proctoscopy at the end of
the follow-up period (12 months after end of radiation therapy).
This proctoscopy was performed to evaluate the rectal mucosa
reactions (Vienna Rectoscopy Score). The median follow up time
was 12 months.
The image guided radiotherapy modalities utilized included
cone beam guidance (8 patients), ultrasound (21 patients) and
megavoltage CT guidance (21 patients). All patients completed
their course of IMRT. The Independent Medical Monitor (IMM)
adjudicated 1 subject as experiencing a device-related event (G1
proctitis) and 3 subjects as experiencing procedure-related events
(focal rectal mucosal necrosis due to inadvertent injection of
hydrogel into the rectal wall, bladder pierced during injection with
hydrogel leak into bladder and urinary retention). All of these
events resolved with no further sequelae. These events occurred
early on in the study and were addressed with procedural and protocol modifications previously mentioned. With these modifications, no patients in Cohort 2 experienced a device or procedural
related event. The IMM was unable to determine the procedure
or device relatedness for 5 events in 5 subjects. Four of these
events occurred in Cohort 1 (a G1 proctitis, a localized mucosal defect appearing 6 weeks post RT, a G1 constipation and one patient
with a G2 dysuria/weak stream) with one event in Cohort 2 (G1
rectal urgency 3 weeks following start of RT). All of these events resolved with no further sequelae.
The radiation toxicity data are summarized in Table 2. Six patients experienced Grade 2 Acute GI toxicity. No patients experienced Grade 3 or 4 toxicity. In addition, no patients had early
late GI or GU toxicity P Grade 2.
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Endpoint stability of the space and radiation toxicity
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Stability
Statistics
GI and GU Toxicity was evaluated using frequency distributions.
Based on technical changes of the protocol (see section Patients
and methods), the evaluation is separated into two cohorts (23 patients in Cohort 1 and 29 patients in Cohort 2).
Results
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Patient disposition
A total of 52 patients were included within this study. As described previously, twenty-three (23) of these patients were included in Cohort 1 and 29 in Cohort 2. Four patients (all from
Cohort 1) were excluded from the Per-Protocol Population. Reasons
for exclusion include no hydrogel injection (n = 2), inadvertent rectal wall injection (n = 1) and improper polymer reconstitution
(n = 1).
After IMRT the created space for both cohorts was nearly unchanged in all patients, demonstrating that the perirectal space
was maintained during the course of radiotherapy. At the end of
the acute phase (6 months after implantation), the space remaining for Cohorts 1 and 2 was 5 mm and 2 mm, respectively, suggesting space reduction due to hydrogel absorption at the implant site
(Fig. 1).
To date, T2w MR images for 43 patients approximately
9 months after gel injection have been evaluated. There was no
hydrogel presence in 42 patients. Only one subject presented with
a small amount of hydrogel after 9 months.
Proctoscopy
At present time there are proctoscopy data from 29 patients (19
from Cohort 1 and 10 from Cohort 2) at the end of the follow-up
period (12 months after end of radiation therapy) available. The
proctoscopy was evaluated by using the Vienna rectoscopy score
Table 2
Acute and late GI and GU toxicity (maximum score).a
GI toxicity scores (n%)
Per-Protocol Population (n = 48)
0
1
2
3
4
Grade 1 or more
Grade 2 or more
GU toxicity scores (n%)
Acute (n = 48)
Late (n = 27)
Acute (n = 48)
Late (n = 27)
23 (48%)
19 (40%)b
6 (12%)
0 (0%)
0 (0%)
25 (52%)
6 (12%)
25 (93%)
2 (7%)c
0 (0%)
0 (0%)
0 (0%)
2 (7%)
0 (0%)
10 (21%)
20 (42%)d
17 (35%)f
1 (2%)
0 (0%)
38 (79%)
18 (37%)
21 (78%)
6 (22%)e
0 (0%)
0 (0%)
0 (0%)
6 (22%)
0 (0%)
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Grade
a
Acute GI/GU = Up to and including the end of acute study phase visit. Late GI/GU = 6 and 12 months follow-up visits. Toxicity score reported is the maximum score
experienced by the subject across all intervals using the RTOG/EORTC scoring criteria.
b
1 subject was Grade 1 at Baseline.
c
1 subject was Grade 1 at Baseline.
d
4 subjects were Grade 1 at Baseline.
e
4 subjects were Grade 1 at Baseline.
f
3 subjects were Grade 1 at Baseline, 1 subject was Grade 2 at Baseline.
In this trial, we demonstrated that a PEG based gel could successfully create a space between the prostate and the rectum
which remained stable for the entire course of radiation therapy.
The rate of acute Grade 1 and Grade 2 rectal toxicity in this study
was only 40% and 12% (early late toxicity after 12 months 7% and
0%) with patients receiving a dose of 78 Gy. We believe this low
toxicity rate can be ascribed to a reduction in rectal V70 due to
spacer application. The corresponding data are evaluated separately. Since it is a multi-center study there is a possibility of
PTV variability, which could influence the rectal toxicity data.
However this risk exists in almost every clinical radiooncology trial
even if the treatment is within the same department [15]. We tried
to reduce the variability by giving requirements for contouring.
Other groups used hyaluronic acid or collagen for creating space
between the rectum and the prostate [16–18]. In those studies, the
number of patients was lower (1–27 patients) compared to our
study and only the reduction of dose to the rectum was reported.
Only Wilder et al. reported of a toxicity reduction in 10 patients
[18]. While each technique reduces the volume of the rectum that
is exposed to radiation, they also have characteristics that can prevent them from optimal performance. Hyaluronic acid can undergo
partial degradation upon exposure to radiation [9], while human
based collagen can be challenging to use. In addition, the hyaluronic acid showed a stability of the volume and shape for close
to one year, and showed only a slow regression thereafter [18].
The results of the current study demonstrated that the material
was effective at displacing the rectal wall away from the prostate.
The 1 cm space created between the prostate (mid gland) and
anterior rectum was maintained throughout the course of IMRT
in all patients. In addition, at 6 months post implantation the space
had decreased due to hydrogel absorption (Fig. 2). After 9 months
there was no presence of hydrogel in 42 of 43 patients. Only in one
patient there was a small amount of gel left.
The procedural modifications implemented for the patients in
Cohort 2 provided a number of clinical benefits. Use of a TRUS
probe improved visibility of the perirectal space. Use of the stepper
increased TRUS probe stability and allowed both hands to be free
to control the applicator. The optional stand-off balloon improved
visibility of the perirectal space. Reducing the volume per kit from
15 mL to 10 mL decreased the total spacer volume and should result in decreased rectal wall stress. The implementation of stool
softeners would also be expected to reduce stool-induced stress
to the rectal wall by contents of the bowel.
The cohort analysis demonstrated that the procedural, product,
and patient care enhancements implemented in Cohort 2 improved
safety resulting in a marked reduction in device and procedure-related events.
The effectiveness of a temporary, absorbable spacer between
rectum and the prostatic gland has important clinical implications
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Fig. 1. Space maintenance by Cohort.
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(VRS). The score range is 0–5 and the highest grade of any one
parameter qualifies for the attribution to one of the given score levels regardless of the grade achieved in any other parameter.
Parameters are congested mucosa, telangiectasia, necrosis, stricture and ulceration. 69% of the patients had no pathological findings on the rectal mucosa (VRS score 0). 10% presented Grade 1
telangiectasia (VRS score 1). VRS score 2 (telangiectasia and/or
congested mucosa) was found in 17% of the patients and VRS score
3 (telangiectasia) only in one patient (3%). No incidence of ulceration, stricture or necrosis in these patients.
Discussion
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The success of radiation therapy in the treatment of prostate
cancer is dependent on the radiation dose. The MD Anderson dose
escalation trial randomized 70 Gy vs. 78 Gy and showed a benefit
of the higher dose for intermediate risk patients [5]. This trial also
showed the increased risk of rectal toxicity with the increased dose
(46% grade 2 rectal toxicity of more than 25% of the rectum received more than 70 Gy). Kuban et al. published, that the amount
of rectum treated can significantly affect the GI complication rate
[5]. Technical advances like IMRT can reduce the amount of rectum
irradiation without compromising the results [7,13]. Zietman et al.
also documented a benefit of dose escalation also for low risk prostate cancer patients using a proton boost in the RTOG 95–09 trial
[6]. However, even with advanced radiation techniques like protons, they reported of 63% acute grade 2 GI toxicity and 24% late
grade 2 GI toxicity in the 79.2 GyE treatment arm [6]. Heemsbergen et al. examined the correlation between acute and late toxicity
in 553 prostate patients from the Dutch dose escalation trial and
could show that acute GI toxicity was an independent significant
predictor of late GI toxicity [14].
Fig. 2. Axial images from the same patient at (a) pre implant baseline (T2w MRI), (b) post implant/pre IMRT (CT), (c) post IMRT (T2w MRI), and (d) 6 months post-implant
showing hydrogel absorption (T2w MRI).
Conclusion
These data suggest that creating a PEG based spacer between
the prostate and the rectum results in a clinically meaningful
reduction of rectal toxicity during and after IMRT of prostate cancer. The gel used in this study persists during the time of radiation
therapy and was absorbed within one year. Given these important
biochemical properties, Phase III studies are underway.
Financial and material support
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This study was supported by Augmenix, Inc.
Research funding
This study was partially (Dr. K. Herfarth) funded by German Research foundation DFG (KFO214; He2499/3-1).
Financial disclosures
Dr. De Weese served as medical monitor for this study and received compensation for this activity.
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Honoraria
BrainLab (Dr. Weber).
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for prostate RT, including dose escalation and hypofractionation.
The advantages of these evolving radiation therapy treatments,
including increased patient convenience and decreased overall
costs, are potentially constrained by the potential increased rectal
toxicity. Indeed, the report of the ASTRO Emerging Technology
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This reprint is provided by Augmenix.
email: [email protected]
CPC D032113