EUS-guided fiducial placement before targeted radiation therapyfor prostate cancer

Julie Yang, MD, May Abdel-Wahab, MD, Afonso Ribeiro, MD

Miami, Florida, USA

Background: Image-guided radiation therapy allows the delivery of precisely aimed radiation beams to tumorswhile minimizing radiation to adjacent normal tissue. This is particularly important in the prostate, a movingtarget whose positioning depends on the dynamics of its neighboring bladder and rectum. Targeted radiationtherapy can be achieved by using implantable radiographic markers, or fiducials, which serve as reference pointsto accurately delineate tumors.

Objective: To determine the feasibility and safety of placing fiducials in the prostate under linear array EUSguidance to facilitate targeted radiation therapy.

Design: Retrospective analysis of a prospective database.

Setting: University of Miami Hospital and Clinics, a tertiary cancer referral center.

Patients: Localized prostate cancer patients scheduled to undergo intensity-modulated radiation therapy.

Interventions: A total of 16 patients underwent EUS-guided fiducial placement to delineate the prostate beforeplanned radiation therapy.

Results: Fiducial placement was successful in all patients (100%). A total of 71 gold markers were deployed ina 4-quadrant manner outlining the prostate. Seven of 16 patients had an additional fiducial placed to ensureadequate prostate delineation. Patients tolerated the procedure well with minimal discomfort. No complicationsdeveloped from the procedure.

Limitations: Single-center experience, small sample size.

Conclusions: EUS-guided placement of fiducials to facilitate image-guided radiation therapy for prostate canceris a feasible alternative to transperineal or transrectal US approaches, thereby adding to the expanding list ofindications for linear EUS. This procedure can be safely performed by endosonographers familiar with perirectalanatomy and transrectal FNA technique.

Prostate cancer is the most common cancer diagnosedin men in the United States, excluding skin cancers.1 In lo-calized prostate cancer, external beam radiation is part ofthe treatment armamentarium to which the cancerresponds in a dose-dependent fashion. However, the ben-efits of dose escalation could potentially increase toxicityto surrounding organs if this is pursued without attentionto the advances in localization and treatment techniques.Image-guided radiation therapy provides a solution to thischallenge because it allows the delivery of precisely aimedradiation beams to tumors, while minimizing radiation toadjacent normal tissue. This is particularly important in

Abbreviation: IMRT, intensity-modulated radiation therapy.

DISCLOSURE: All authors disclosed no financial relationships relevant

to this publication.

Copyright ª 2009 by the American Society for Gastrointestinal Endoscopy

0016-5107/$36.00

doi:10.1016/j.gie.2009.03.001

www.giejournal.org

the prostate, a moving target whose positioning dependson the dynamics of its neighboring bladder and rectum.

Intensity-modulated radiotherapy (IMRT) is a techniquethat further optimizes the delivery of radiation. Variable in-tensities within each radiation beam achieve greater dosedistribution control around the defined target. However,this requires defining normal and target tissues. Onemethod of prostate localization before radiation treatmentis through daily transabdominal US, which is not onlytime-consuming but operator dependent and limited bybody habitus. Alternatively, targeted radiation therapycan also be achieved by using implantable radiopaquemarkers, or fiducials, which serve as reference points toaccurately delineate organs or tumors of interest. Pub-lished reports describe prostate fiducials placed by urolo-gists and radiation oncologists through either transrectalor transperineal US guidance, but there have been noreports of gastroenterologists using linear array EUS toguide fiducial placement in the prostate.2-4 This is a retro-spective report of prospectively collected data on fiducial

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EUS-guided fiducial placement Yang et al

placement by linear EUS performed at a tertiary referralcancer center. The article describes the feasibility andsafety of EUS-guided placement of fiducials in patientswith prostate cancer who are scheduled to undergo IMRT.

METHODS

Patient selectionPatients scheduled to undergo IMRT for organ-con-

fined prostate cancer were referred for EUS-guided fidu-cial placement from October 2007 through October2008. Patients with uncorrectable coagulopathy (interna-tional normalized ratio O1.5, platelets !25,000) wereineligible for fiducial placement. Informed consent wasobtained before the procedure, and the study wasapproved by our institutional review board (IRBno. 20080129). All procedures were performed in the en-doscopy unit at the University of Miami Hospital andClinics by one endosonographer and a third-year gastro-enterology fellow.

PreparationProphylactic antibiotics (ciprofloxacin) were intrave-

nously administered to all patients during the procedurewith another 5 days of oral antibiotics after fiducial place-ment. Bowel preparation included a clear liquid diet theday before the procedure and 2 enemas. Anticoagulationand antiplatelet medications were withheld according tothe guidelines for endoscopic procedures.5

TechniqueEUS was performed by using a curvilinear-array echoen-

doscope (GF-UC 0P with an Aloka processor; OlympusAmerica Inc, Central Valley, Pa) with the patient under ti-trated intravenous conscious sedation. The prostate wasidentified by transrectal EUS as a hypoechoic, round struc-ture anterior to the rectum. The base of the prostate wasidentified by the seminal vesicles located at the posteriorsurface of the gland bilaterally, whereas the apex was de-marcated by the midlying urethra, which was seen exitingthe prostate anteriorly and inferiorly. The goal was toplace the fiducials in a 4-quadrant fashion (bilateral baseand apex), equidistant from the center of the prostate,with at least 1 cm of space between fiducials (Fig. 1). Aminimum of 3 fiducials in the prostate was alsoacceptable.

By using a sterile technique, cylindrical gold markers 3or 5 mm long with a 0.8-mm diameter, or fiducials (BestMedical International, Springfield, Va) were backloadedinto a 19-gauge needle (Echotip Ultra; Cook Medical,Bloomington, Ind) after removing the stylet and flushingthe needle with saline solution to avoid air bubbles.The stylet was reintroduced and positioned approximately5 cm proximal to the needle tip with the gold seed inplace. The needle was then inserted in the target area,

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and each fiducial was deployed by advancing the stylet for-ward under real-time EUS (Fig. 2). Fluoroscopy was alsoused in the initial cases. Tumor visualization under EUSwas not necessary for outlining the prostate. Fiducial po-sitioning was confirmed with a postprocedure pelvicradiograph, as well as simulation CT (64-slice pen SeasonCT scanner; Siemens, Forchheim Germany) 7 days aftermarker implantation (Fig. 3). Each patient was called 24hours after the procedure to monitor for complications.

RESULTS

Sixteen consecutive patients with a mean age of 71years (range 57-83 years) and a mean body mass indexof 31 (range 22-48) participated in this study. Fiducialplacement under EUS guidance was successful in all 16 pa-tients. A total of 71 fiducials were deployed in a 4-quadrantmanner outlining the prostate, and 7 of 16 patients had anadditional fiducial placed to ensure adequate prostate de-lineation. One fiducial was lost in the rectum during at-tempted placement. However, an additional fiducial wasimplanted in this patient, for a total of 4 markers. Three-millimeter length markers were used in all cases, exceptfor the last 2 cases, in which 5-mm–length markers wereimplanted. The larger fiducials were easier to visualizeon EUS, but both sizes were effective for IMRT guidance.Furthermore, there was no difference in the level of diffi-culty in deploying the 3- or 5-mm fiducials with the 19-gauge needle.

Patients tolerated the procedure well with minimal dis-comfort. No complications occurred during the recoveryperiod in the endoscopy unit, at 24 hours after the proce-dure, or at 1 week during simulation CT. Patients under-went radiation treatment over an 8-week period. Therewas no reported fiducial migration throughout the course

Figure 1. Cross-sectional rotated illustration of the prostate with 4

implanted fiducials: 2 markers at the base and 2 markers at the posterior

apex of the prostate.

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Yang et al EUS-guided fiducial placement

of therapy because this was monitored daily through thecomparison of the images acquired on each day of therapywith the initial planning CT.

DISCUSSION

As radiation therapy evolves toward higher radiationdoses and greater treatment accuracy, fiducials are re-quired for treatment guidance in prostate cancer IMRT.They provide reliable and accurate position verification,thereby allowing the delivery of higher doses of radiationto the target while minimizing toxicity to surrounding nor-mal tissue.12 Studies have documented a significant bene-fit of increased radiation doses for the treatment oflocalized prostate cancer.6-8 However, dose escalation isassociated with a higher rate of acute and late complica-tions. High-dose IMRT guided by fiducial markers in pros-tate cancer is well tolerated, with a low incidence of acuteand late GI and genitourinary side effects.9 IMRT withposition verification by fiducials also allows the deliveryof increased radiation doses without deterioration in qual-ity of life compared with lower doses using less accurateconformal radiotherapy.10

Studies have also suggested that fiducials are more ac-curate for prostate localization than US-based targetingsystems.11,12 There are several potential reasons for thegreater systematic and random error associated with US.First, the US probe pressure itself may displace the glandand introduce errors in prostate localization.13 Increasedprobe pressure may be needed at times to allow bettervisualization of the prostate, but this may cause more

Figure 2. EUS image demonstrating fiducial deployment in the prostate.

The fiducial marker appears as a hyperechoic, linear structure (arrow)

with an associated hyperechoic shadow.

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anatomic shifts, leading to potential target underdosingand increased bladder or rectal toxicities. Second, accurateprostate localization may not be possible because of theoverlying pubic symphysis. Last, obese patients or patientswith large waist circumferences will likely have suboptimalvisualization of the prostate. Therefore, EUS-guided fidu-cial placement has advantages over transabdominal USlocalization because anatomical barriers are not pertinentowing to the prostate being directly anterior to the rec-tum, and accurate prostate localization can be achievedregardless of the patient’s body habitus. Furthermore,prostate localization with US is more time-consumingcompared with the fast and accurate fiducial positionverification determined automatically by electronic portalimaging devices. Fiducials serving as reference points fortargeted therapy minimize patient setup errors during

Figure 3. Confirmation of fiducial placement in the prostate: pelvic

radiograph (A) and simulation CT showing a fiducial in the prostate (B).

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EUS-guided fiducial placement Yang et al

treatment, which leads to less rectal and bladderirradiation.14

Endoscopic placement of fiducial markers for radiationtherapy guidance is a relatively newer application of EUSin pancreatic and thoracic tumors. One recent report de-scribed the successful use of fiducials placed under linearEUS guidance only in patients with abdominal and medias-tinal tumors, but not in the prostate.15 Placement of pros-tate fiducials is less technically challenging than placementin deeper periduodenal and perigastric structures becauseof the relatively straighter position of the echoendoscopeand short distance from the anal verge.

Urologists and radiation oncologists use either a trans-perineal or transrectal approach to place fiducial markersin the prostate with larger–caliber needles (14-, 17-, and18-gauge needles) and use rigid US probes with topical an-esthesia.2,3 Gastroenterologists can play an important roleby providing an alternative technique for implanting fidu-cials through transrectal flexible EUS with the patient un-der conscious sedation that may be better tolerated,although the focus of this study was not to compare itwith other techniques. EUS-guided fiducial placementmay also provide the opportunity for prostate cancer pa-tients to undergo fiducial-based IMRT if they are at centerswhere this is not routinely performed, as was the case atour institution.

The learning curve for EUS-guided fiducial placement isnot as steep as it is for other EUS interventional tech-niques. However, one must be aware of potential areasof technical difficulty. To prevent the fiducials from fallingout of the needle after backloading, we simply kept theneedle tip facing straight up during transport into theechoendoscope channel rather than using a sealing agentat the needle tip. The alternative method of frontloadingthe fiducial and then pushing it down the needle channelwith the stylet is not ideal. This could potentially result inthe infusion of air into the prostate, which would makefiducial visualization during deployment more difficult.Fiducials should not be deployed in areas in the prostatethat are significantly calcified because of their similarhyperechogenicity, although a distinction can be madebecause fiducials produce a characteristic bright, whiteshadow. Radiographic confirmation of the overall fiducialspatial configuration by pelvic x-ray is recommendedbefore patient discharge. Fluoroscopy, however, was notnecessary for EUS-guided fiducial placement. We also rec-ommend the use of prophylactic antibiotics. However,there is currently no consensus on the appropriate dura-tion of antibiotics in the studies of fiducial placement byurologists and radiation oncologists.2-4 As this is our initialexperience, we chose 5 days of treatment to avoid anyinfectious complications.

There are still unknown variables with regard to themethodology of placing fiducials in said targets. For in-stance, the optimal number and size of implanted markersremain to be determined. In previous studies, 1 to as

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many as 6 fiducials have been implanted, with sizes rang-ing from 0.7 to 1.6 mm in diameter and 3 to 7 mm inlength.2-4 It is unclear whether the accuracy of targeted ra-diation therapy is improved by placing additional or largerfiducials. One study suggests that implantation of 4markers is better than 3 with particular prostate localiza-tion systems.11 Overall, the more important placed fidu-cials are at the base because this accounts for most ofthe gland’s volume and defines the critical prostate/rectalinterface.

Limitations of this study include the small number ofpatients and single-center experience. This study wasalso not designed to evaluate the impact of EUS-guidedplacement of fiducials and IMRT on survival or quality oflife. Future studies will evaluate clinical outcome whenusing this technique by assessing biochemical responseswith pre- and post-IMRT prostate specific antigen levels.In addition, it will be important to ascertain whetherEUS-guided placement of fiducials is cost-effective com-pared with alternative methods of fiducial placement.

In summary, we have demonstrated successful place-ment of fiducials in the prostate for IMRT guidance by us-ing a linear flexible echoendoscope. This technique isa feasible alternative to traditional US-guided transrectaland transperineal approaches, thereby adding to the ex-panding list of indications for linear EUS.

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Received November 24, 2008. Accepted March 2, 2009.

Current affiliations: Division of Gastroenterology (J.Y., A.R.), Department of

Radiation Oncology (M.A.), University of Miami, Miller School of Medicine,

Miami, Florida.

Presented at the 16th International Symposium on Endoscopic

Ultrasonography, September 12–13, 2008, San Francisco, CA, and the

American Society for Gastrointestinal Endoscopy, Digestive Disease Week,

May 17–22, 2008, San Diego, California (Gastrointest Endosc

2008;67:AB202-3).

Reprint requests: Afonso Ribeiro, MD, Division of Gastroenterology,

University of Miami, PO Box 016960, Miami, FL 33101.

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