Download Implantation of fiducial markers for image guidance in prostate

The British Journal of Radiology, 82 (2009), 941–945
Implantation of fiducial markers for image guidance in prostate
radiotherapy: patient-reported toxicity
1
Ş İĞDEM, MD, 2H AKPINAR, MD, 1G ALÇO, MD, 3F AĞAÇAYAK, MD, 1S TURKAN, MD and 4S OKKAN, MD
1
Department of Radiation Oncology, Florence Nightingale Gayrettepe Hospital, 2Department of Urology, Istanbul Bilim
University, 3Department of Radiology, Florence Nightingale Gayrettepe Hospital and 4Department of Radiation
Oncology, Istanbul Bilim University, Istanbul, Turkey
ABSTRACT. The purpose of this study was to evaluate patient-reported morbidity of
implanted fiducial markers used for image guidance in prostate radiotherapy. Three
fiducial markers were implanted under transrectal ultrasound guidance to 177 patients
who were referred to our department for definitive radiotherapy between June 2005
and January 2008. No local anaesthesia was administered. Patients were asked to
complete a questionnaire about the possible side effects of this invasive procedure. 135
patients completed the questionnaire at a median of 57 weeks after the procedure.
Pain during the procedure was assessed with the Wong–Baker Faces Pain Rating Scale.
Patients were also asked to compare the pain with the diagnostic biopsy. Although
haematuria, rectal bleeding and fever were reported by 15%, 4% and 2% of the 135
patients, respectively, no major toxicity necessitating any intervention was observed.
The mean pain score reported by the patients was 1.7 (range, 0–5). 87% of patients
reported less (or comparable) pain than the diagnostic biopsy. In conclusion,
implantation of fiducial markers for image guidance in prostate radiotherapy is a safe
and well-tolerated procedure.
The development of in-room imaging technologies has
enabled the radiation oncology community to be aware
of organ motion and to implement strategies to deal with
it. Particularly in the radiotherapeutic management of
prostate cancer, where the nature of organ motion [1, 2]
and the potential pitfalls of using bony landmarks as a
surrogate of prostate position have been well established
[3], the importance of target localisation is augmented.
The implantation of fiducial markers and their visualisation with portal imaging before daily treatment is one of
the various methods employed to localise the prostate
gland [4]. The most advantageous part of this image
guidance technique is that no additional treatment unit
modification is required and standard imaging devices
can be used. The disadvantages most often mentioned
include the invasive nature of the procedure with the
potential for possible bleeding and infection, the requirement for an interventional radiologist and/or urologist
and the two-dimensional nature of the system [4, 5].
Although the implantation of radio-opaque fiducials are
widely used for image guidance, detailed data about the
tolerance of this invasive procedure are still limited. The
purpose of this study is to report our own institution’s
experience of fiducial markers and the tolerance of
patients.
Address correspondence to: Şefik İğdem, Department of Radiation
Oncology, Florence Nightingale Gayrettepe Hospital, Cemil Aslan
Güder sok 8, Gayrettepe 34340 Istanbul, Turkey. E-mail:
[email protected]
The British Journal of Radiology, November 2009
Received 15 August 2008
Revised 2 February 2009
Accepted 22 February 2009
DOI: 10.1259/bjr/14201041
’ 2009 The British Institute of
Radiology
Methods and materials
This study was conducted with the approval of our
Institutional Review Board and with written informed
consent from all subjects enrolled. From June 2005 to
January 2008, 177 patients with localised prostate cancer
were referred to our department for high-dose conformal/
intensity-modulated definitive radiotherapy. Each patient
had three intraprostatic gold markers placed transrectally
under ultrasound guidance 3–7 days before CT simulation. For those who were on neoadjuvant hormonal
treatment, the markers were implanted at the time of the
second luteinising hormone-releasing hormone (LHRH)
agonist injection to allow time for prostate shrinkage.
The procedure was performed in the radiology outpatient clinic. On the day of the procedure, an enema
was used to evacuate the rectal contents and standard
antibiotic prophylaxis of 500 mg ciprofloxacin was given
orally and continued for an additional 2 days. All
anticoagulation and antiplatelet medications were withheld 3–7 days before marker implantation.
Patients were usually placed in the left lateral
decubitus position with knees and hips flexed at 90 ˚. A
soft-tissue marker kit (Civco, West Lynwood, WA) that
included three 17-gauge 30 cm placement needles with
bone wax at the distal tip and three 1.2 6 3 mm gold
markers was used. The markers were placed by our
urologist under ultrasound guidance (Siemens, Antares,
Germany), with a standard biopsy tool mounted onto the
ultrasound transducer (endocavitary probe, 9–4 MHz).
Local anaesthesia was not administered. The markers
were positioned in the right base, in the left midgland
and in the right apex of the gland to create a triangular
941
Ş İğdem, H Akpınar, G Alço et al
configuration. To avoid the urethra, special care was
taken to place the markers laterally. All implantation
procedures were performed in a 15 min time slot. After
the procedure, the position of the markers was controlled
under fluoroscopy (Figure 1).
To evaluate the tolerance and quality of life, patients
were asked to complete a questionnaire regarding any
complications after the procedure. The most common
complications reported after prostate biopsy (e.g. the
presence of haematuria, rectal bleeding, fever), the
duration of the symptoms and the need for additional
medication were all included.
Pain during the procedure was assessed with the
Wong–Baker Faces Pain Rating Scale [6], where the
patients were asked to rate the pain on a 0–5 scale of six
faces with a range of expressions from smiling to crying.
In our daily practice, we offer our patients a tool to rate
their pain intensity, which is readily available in the
follow-up clinics and shows Wong–Baker faces along
with a visual analogue score (VAS). Our elderly patients
prefer to use the faces scale to VAS most of the time.
Therefore, we chose to use the Wong–Baker Faces Pain
Rating Scale to assess the intensity of pain in a cohort of
elderly prostate cancer patients. Although mainly used
with children, the Faces Pain Scale has proven to be a
reliable tool to assess pain and to make treatment
decisions in a cognitively intact elderly population [7].
Patients were also asked to compare the pain they felt
during the procedure with that in the diagnostic prostate
biopsy.
(a)
(b)
(c)
(d)
Figure 1. (a,b) Fluoroscopic and (c,d) megavoltage anteroposterior and lateral images of set-up fields with three implanted
markers.
942
The British Journal of Radiology, November 2009
Fiducial markers in prostate radiotherapy
Diabetes mellitus, a history of previous transurethral
resection, age, history of colitis, prostatic volume, T
stage, hormonal manipulation and duration of hormonal
treatment were all evaluated as potential risk factors for
any bleeding complications and to identify predisposing
risk factors after marker implantation Fisher exact test
was performed. To analyse the effect of the retrospective
analysis on the patient’s perception of pain, we divided
the patient cohort into early (#6 months) and late
(.6 months) responders and compared their mean pain
scores using a Mann–Whitney U non-parametric test.
(very mild), 36% as 2 (mild), 10% as 3 (moderate), 6% as 4
(severe) and 3% as 5 (worst possible). No statistically
significant difference in the mean pain scores was found
between the patients who completed the questionnaire in
an early period after the procedure and those patients
who completed it later than 6 months (Table 1). 68% of
the patients reported that the procedure was less painful
than the diagnostic biopsy; 19% reported comparable
pain; and 13% noted more pain.
None of the investigated potential risk factors correlated significantly with any bleeding complications.
(Table 2)
Results
The questionnaire was completed by 135 of the 177
patients during their follow-up visits or after the CT
simulation in a median time of 57 weeks (range, 1–
146 weeks) after the procedure. Most of the 42 patients
who were not enrolled into this study were living in a
remote city, and did not appear for their follow-up
clinics during the study period. The median age of the
study population was 72 years (range, 52–83 years). Of
these 135 patients, 73% were staged as T1 and T2, and
27% as T3. 69% of the patients were put on neoadjuvant
hormonal manipulation with an LHRH analogue and
anti-androgen treatment. The median duration of hormone therapy at the time of the procedure was 3 months
(range, 1–12 months). Of the 135 patients, 62 were
receiving anticoagulants. Most of these were on acetylsalicylic acid; however, some were receiving warfarin
(n57) or clopidrogrel (n54). The median prostate
volume was 44 cm3 (range, 22–136 cm3).
After the implantation, patients were brought to the
department of Radiation Oncology to check the marker
positions under fluoroscopy. For two patients, it was
noted that one of the markers was missing. During CT
simulation, it was judged that all markers were placed
correctly into the prostate gland in all of the remaining
patients.
Rectal bleeding was reported by five patients and
lasted #1 day and regressed without any intervention.
Haematuria was observed in 20 patients; in 14 of these, it
lasted #1 day. Four patients reported haematuria of
>3 days’ duration. Again, none of the patients required
any other medical intervention. No patient showed
vegetative symptoms such as sweating or hypotonia,
and no urinary retention was reported.
Symptomatic urinary infection with fever, documented by urinary culture, developed in three patients. They
received additional antibiotics and their temperature
normalised within a few days. No admission to hospital
was necessary. In one of these patients, asymptomatic
bacteriuria resistant to antibiotherapy developed during
follow-up and resolved spontaneously after 6 months.
The mean pain score was 1.7 (range, 0–5). Of the 135
patients, 15% scored the pain as 0 (no pain), 30% as 1
Discussion
External skin markers and bony landmarks were
traditionally used as surrogates for prostate position
during the radiotherapeutic management of prostate
cancer. It has been shown that the treatment margins
used to compensate for daily organ motion and set-up
uncertainties could be as large as 1.5–2 cm if these
surrogates were used [8]. These large margins are not
compatible with the delivery of high radiation doses
above 70 Gy that are used in current routine practice.
During recent years, imaging and localisation techniques
prior to and during the daily treatment delivery have
allowed better localisation of the prostate and tighter
margins [9]. Implantation of fiducial markers into the
prostate gland and in-room radiograph based methods
are techniques that are increasingly being used for
targeting. The marker stability, the limited interuser
variability and the fact that there is no need for
additional equipment make this technique more appealing. Although widely used, data on the tolerance of
patients to this invasive procedure are still limited.
In our study, in which 135 of 177 implanted patients
completed the questionnaire, the overall complication
rate reported was 20%. Five patients (3.7%) had mild
rectal bleeding lasting #1 day; 20 patients reported
having had short episodes of haematuria, but only 4 of
these (2.9%) had haematuria for >3 days and none
needed any additional intervention. Only 3 patients
(2.2%) developed urinary tract infection requiring additional antibiotic therapy.
To our knowledge, there is only one study in the
literature reporting in detail marker-induced toxicity in a
large patient group. In that study, Langenhuijsen et al
[10] reported their experience with fiducial markers in
209 patients. After transrectal implantation of four gold
markers, the patients completed a questionnaire about
possible side effects in a mean time of 90 weeks.
Haematuria lasting .3 days and rectal bleeding
occurred in 3.8% and 9.1% of the patients, respectively.
Their rate of fever after implantation was 1.9%. Our
complication rates were consistent with results from this
larger cohort of patients. Only the rectal bleeding rate
Table 1. Correlation of mean pain scores in the early and late responders
Completion of the questionnaire
n
Mean pain score
Mann–Whitney U test
#6 months
.6 months
35
100
1.89
1.63
0.288
The British Journal of Radiology, November 2009
943
Ş İğdem, H Akpınar, G Alço et al
Table 2. Risk factors and complication rates
Any bleeding complication?
T stage
Diabetes
TUR-P
Colitis
Hormones
Age
Prostate volume
Time on hormones
T1–2
T3
Yes
No
Yes
No
Yes
No
Yes
No
,72 years
>72 years
,40 cm3
>40 cm3
,3 months
>3 months
Yes
No
17
8
3
22
5
20
2
23
21
4
15
10
11
14
6
19
82
28
23
87
12
98
1
109
72
38
52
58
58
52
44
66
p-value
0.62
0.4
0.18
0.08
0.09
0.27
0.5
0.17
TUR-P, transurethral resection of the prostate.
was slightly lower in our study, which could be the
result of using three fiducial markers instead of four.
Reducing the number of fiducial markers was also
suggested by the authors as a possible way of lowering
the rates that they reported.
Henry et al [11] demonstrated minimal morbidity in
terms of haematuria, rectal bleeding and prolonged pain
or discomfort in 12 patients. They implanted the markers
via a transperineal route using local anaesthesia and
concluded that most patients found this invasive
procedure acceptable. Dehnad et al [12] reported
transitory haematuria in the first 24 h after transrectal
insertion of the markers in 3 of 10 patients and an
episode of rectal bleeding by the first defecation in 7
patients.
Compared with diagnostic biopsy data, where multiple biopsy cores are taken, our complication rates seem
to be acceptable. Two large European screening programs noted haematuria in 23–63% of men after sextant
biopsy, rectal bleeding in 2.1–21.7% and urinary tract
infection in 3.5–10.9% [13, 14].
Shinohara and Roach [15] described their technique for
implanting fiducial markers in 705 patients, which is
similar to ours except for the administration of local
anaesthesia. The patients in their study were instructed to
contact the clinic with unexpectedly severe or prolonged
adverse effects. Only one patient developed urinary tract
infection requiring additional antibiotic therapy. There
were no instances of severe rectal bleeding or gross
haematuria requiring further intervention.
Periprostatic nerve block (PPNB) is widely used for
minimising prostatic biopsy pain with lidocaine local
anaesthesia. Many studies evaluated and conclusively
proved the benefit of PPNB, especially if extended
biopsy techniques are used [16–18]. The need for PPNB
during marker implantation for prostate immobilisation
has not yet been addressed in a prospective fashion. In
the technique described by Shinohara and Roach [15],
whereby they used PPNB routinely before marker
implantation, the tolerance to pain is not mentioned in
detail, probably because it was out of the scope of the
study. The mean pain scores reported in our study and
944
by Langenhuijsen et al [10] without using PPNB were
comparable: 1.7 (in a scale ranging from 0 to 5) and 3.2
(in a scale ranging from 0 to 10), respectively. 9% of our
patients and 15% of their patients scored the pain during
implantation of the markers as ‘‘severe’’ or ‘‘worst
possible’’, and the large majority of both study populations (87% and 90%) noted less (or comparable) pain than
the diagnostic procedure. Our results, as well as those by
Langenhuijsen et al [10], suggest that the use of PPNB is
not warranted before implantation of fiducial markers.
None of the investigated potential risk factors was
found to be a significant predictor for bleeding complications in our study. Inflammatory disease is cited
among the contraindications to gold marker implantation in the paper by Shinohara and Roach [15]. In our
study, rectal bleeding was observed in two of three
patients who reported a history of colitis. The difference
was not statistically significant, but there was a trend
towards more bleeding complications in patients with
colitis. Colitis in the population is indicated by frequent
changes in bowel habits but the hospital records of these
patients did not show any biopsy-proven inflammatory
bowel disease. Because of the indolent appearance of the
rectal bleeding, we believe that marker implantation
seems to be reasonable for these patients unless
inflammatory disease is proven by biopsy.
We could not demonstrate any detrimental effects of
advanced tumour stage or shorter duration of hormonal
treatment on bleeding complications, as shown by
Langenhuijsen et al [10]. A possible explanation could
be that our longer median time on hormonal treatment
(12 weeks vs 7 weeks) at the time of implantation
allowed maximal shrinkage in tumour volume and
decreased vascularisation.
Conclusions
Implanting three fiducial markers under transrectal
ultrasound guidance for prostate localisation during
radiotherapy is a safe and well-tolerated procedure.
Although haematuria, rectal bleeding and fever were
The British Journal of Radiology, November 2009
Fiducial markers in prostate radiotherapy
reported by 15%, 4% and 2% of our study population,
respectively, no major toxicity necessitating any intervention was observed. The mean pain scores reported by
patients were very low and a great majority of the
patients reported comparable or less pain compared with
diagnostic biopsy. Therefore, PPNB does not seem to be
justified.
References
1. KupelianPA, Langen KM, Willoughby TR, Zeidan OA,
Meeks SL. Image guided radiotherapy for localized prostate
cancer: Treating a moving target. Semin Radiat Oncol
2008;18:58–66.
2. Chen J, Lee RJ, Handrahan D, Sause WT. Intensity
modulated radiotherapy using implanted fiducial markers
with daily portal imaging: assessment of prostate organ
motion. Int J Radiat Oncol Biol Phys 2007;68:912–9.
3. Shallenkamp JM, Herman MG, Kruse JJ, Pisansky TM.
Prostate position relative to pelvic bony anatomy based on
intraprostatic gold markers and electronic portal imaging.
Int J Radiat Oncol Biol Phys 2005;63:800–11.
4. Van Herk M. Different styles of image guided radiotherapy.
Semin Radiat Oncol 2007;17:258–67.
5. Moseley DJ, White EA, Wiltshire KL, Rosewall T, Sharpe
MB, Siewerdsen JH, et al. Comparison of localization
performance with implanted fiducial markers and cone
beam computed tomography for on-line image guided
radiotherapy of the prostate. Int J Radiat Oncol Biol Phys
2007;67:942–53.
6. Wong D, Baker C. Pain in children: comparison of
assessment scales. Pediat Nurs 1988;14:9–17.
7. Miro J, Huguet A, Nieto R, Parades S, Baos J. Evaluation of
reliability, validity, and preference for a pain intensity scale
for use with the elderly. J Pain 2005;6:727–35.
8. Poli ME, Parker W, Patrocinio H, Souhami L, Shenouda G,
Campos LL, et al. An assessment of PTV magrin definitions
for patients undergoing conformal 3D external beam
radiation therapy for prostate cancer based on an analysis
of 10327 pretreatment daily ultrasound localizations.
Int J Radiat Oncol Biol Phys 2007;67:1430–7.
The British Journal of Radiology, November 2009
9. Melancon AD, O’Daniel JC, Zhang L, Kudchadker RJ,
Kuban DA, Lee AK, et al. Is a 3 mm intrafractional margin
sufficient for daily image guided intensity modulated
radiation therapy of prostate cancer? Radiother Oncol
2007;85:251–9.
10. Langenhuijsen JF, van Lin ENJT, Kiemeney LA, van der
Vight LP, McColl G, Visser AD, et al. Ultrasound guided
transrectal implantation of gold markers for prostate
localization during external beam radiotherapy: complication rate and risk factors. Int J Radiat Oncol Biol Phys
2007;69:671–6.
11. Henry AM, Wikinson C, Wylie JP, Loque JP, Price P, Khoo
VS. Trans-perineal implantation of radio opaque treatment
verification markers into the prostate: an assessment of
procedure related morbidity, patient acceptability and
accuracy. Radiother Oncol 2004;73:57–9.
12. Dehnad H, Nederveen AJ, van der Heide UA, van
Moorselaar RJ, Hofman P, Lagendijk JJ. Clinical feasibility
study for the use of implanted gold seeds in the prostate as
reliable positioning markers during megavoltage irradiation. Radiother Oncol 2003;67:295–302.
13. Raaijmakers R, Kirkels WJ, Roobol MJ, Wildhagen MF,
Schröder FH. Complication rates and risk factors of 5802
transrectal ultrasound guided sextant biopsies of the
prostate within a population-based screening program.
Urology 2002;60:826–30.
14. Djavan B, Waldert M, Zlotta A, Dobronski P, Seitz C, Remzi
M, et al. Safety and morbidity of first and repeat transrectal
ultrasound guided prostate needle biopsies: results of a
prospective European prostate cancer detection study.
J Urol 2001;166:856–60.
15. Shinohara K, Roach M. Technique for implantation of
fiducial markers in the prostate. Urology 2008;71:196–200.
16. Nash PA, Bruce JE, Indudhara R, Shinohara K. Transrectal
ultrasound guided prostatic nerve blockade eases systemic
needle biopsy of the prostate. J Urol 1996;155:607–9.
17. Soloway MS, Obek C. Periprostatic local anaesthesia before
ultrasound guided prostate biopsy. J Urol 2000;163:172–3.
18. Trucchi A, De Nunzio C, Mariani S, Palleschi G, Miano L,
Tubaro A. Local anesthesia reduces pain associated with
transrectal prostatic biopsy. A prospective randomized
study. Urol Int 2005;77:209–13.
945