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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. 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