|Ahead of print publication
Ultrasound-guided transrectal implantation of fiducial markers for image-guided radiotherapy of prostate cancer without local anesthesia: Patient-reported gastrointestinal–genitourinary system complications and pain
Cenk Ahmet Sen
Department of Radiation Oncology, Izmir Medical Park Hospital, Izmir, Turkey
Cenk Ahmet Sen,
Department of Radiation Oncology, Izmir Medical Park Hospital, 1825 St. Yenigirne Boulevard, Karsiyaka 35520, Izmir
Source of Support: None, Conflict of Interest: None
Purpose: The present study evaluates procedure-associated pain and side effects in the gastrointestinal–genitourinary system in patients with early-stage prostate cancer who were treated with image-guided radiotherapy (IGRT), accompanied by an ultrasound-guided transrectal implantation of fiducial markers, without local anesthesia.
Materials and Methods: A total of 46 patients who referred to our clinics between 2012 and 2017 with a diagnosis of early-stage prostate cancer were included in the study. Before undergoing radiotherapy, all patients were implanted with three intraprostatic fiducial markers through the ultrasound-guided transrectal approach without local anesthesia. The patients underwent radiotherapy after the clinical target volumes were established, in accordance with the respective risk groups, and localization of the markers was confirmed before each therapy session. The levels of procedure-associated pain and side effects were graded immediately after the procedure through the use of a patient-based scoring system.
Results: The faces pain scale – revised version was used for the measurement of the severity of procedure-associated pain. Of the total study sample, the facial expressions of 38 patients (35%) corresponded to level 0 in the study, seven (15%) to level 2, and a single patient (2%) to level 4. None of the facial expressions of the patients corresponded to levels 6, 8, or 10. The evaluation of procedure-related genitourinary and gastrointestinal system side effects indicated that nine patients (20%) experienced side effects, while no side effects were reported in 37 patients (80%). The reported side effects included rectal bleeding in two patients (4%), dysuria in three patients (6%), hematuria in five patients (11%), and frequent urination in five patients (11%). None of the patients experienced fever or hematospermia. All side effects were reported by the respondents as “a little,” while only one patient answered positively to the question on the frequency of urination. Among the patients who answered “yes” and “a little” to the questions evaluating genitourinary and gastrointestinal system side effects, the severity of these events was reported as Grade 1, corresponding to mild adverse, in only 9 (20%) patients. None of the patients experienced a Grade 2 or higher severe adverse event. In the comparison of the severity of pain of the patients during the fiducial marker procedure without local anesthesia with the severity of pain during the biopsy, 24 patients (80%) reported “lower” levels of pain, while five patients (20%) reported “equal” levels of pain. None of the patients stated that they had experienced “more” pain.
Conclusion: IGRT accompanied by an ultrasound-guided implantation of fiducial markers without local anesthesia can be considered a safe method, given the associated acceptable levels of pain, low side effect profiles, and high prostate-specific antigen control rates.
Keywords: Fiducial marker, gold marker, image-guided radiotherapy, PEEK marker, prostate cancer
|How to cite this URL:|
Sen CA. Ultrasound-guided transrectal implantation of fiducial markers for image-guided radiotherapy of prostate cancer without local anesthesia: Patient-reported gastrointestinal–genitourinary system complications and pain. J Can Res Ther [Epub ahead of print] [cited 2020 Jul 6]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=263527
| > Introduction|| |
A close relationship exists between high radiotherapy doses and local control, and several randomized trials in patients with localized prostate cancer have reported a dose–response relation ,,,,, although increased doses are accompanied by higher acute and chronic side effect profile. A good radiotherapy plan aims to provide maximum dose efficacy to the target while achieving the lowest dose level outside the target region. The main principle of radiotherapy of “respect of healthy tissue” has always maintained importance, while available radiotherapy devices and application techniques have changed substantially from decade-to-decade. Compared to conventional conformal radiotherapy methods, modern conformal radiotherapy techniques provide a more narrow range of side effects and higher target doses, and intensity-modulated radiotherapy stands out as a technique that much better protects at-risk organs.,,, The image-guided radiotherapy (IGRT) technique, on the other hand, allows confirmation of the correct target localization during therapy by providing orthogonal kilovoltage (kV) portal images and daily evaluations based on bone anatomy. That said, soft tissue cannot be evaluated from kV portal images, although the localization of each target structure can be made through a kV cone beam computed tomography (kV CBCT) before each fraction.
It is a challenging process to ensure an identical lying position on the table of the therapy device, thus matching the reference simulation position, every day, although this in itself can contribute greatly to the success of treatment. In cases of prostate radiotherapy, the daily changes in the contents of the rectum adjacent to the posterior wall of the prostate, and in the bladder, as the superior neighbor of the prostate, lead to significant anatomical changes in target organ mobility.
The present study evaluates procedure-associated pain and postprocedure side effects through the use of patient-based scales and assesses late-term treatment outcomes in 46 patients who referred with early-stage prostate cancer and received IGRT accompanied by an ultrasound-guided transrectal implantation of fiducial markers without local anesthesia.
| > Materials and Methods|| |
In total, 46 patients who referred to our clinics between 2012 and 2017 with a diagnosis of early-stage prostate cancer were included in the study. The clinical characteristics of the patients are summarized in [Table 1]. All patients underwent external radiotherapy using the IGRT technique at a dose of 7800 cGy. The study made use of two different types of fiducial markers, with 41 patients implanted with a gold marker and five patients with a PEEK marker.
One week after the implantation of fiducial markers, patients who referred for CT simulation procedures completed questionnaires evaluating the intensity of procedure-associated pain and other side effects through the use of patient-based scales. These patient-oriented measurement tools have been recommended by several researchers based on their use of criteria that combine both clinician- and patient-based questions., The aim is to combine and confirm the rates of side effects as predicted by the clinicians with those reported by the patients, and to this end, questions with patient-oriented subjective response criteria were used in this study.
The Turkish translation of the faces pain scale – revised version was used to measure the intensity of procedure-associated pain, as a tool that can be used in all age groups and that is not affected by cross-cultural differences., This evaluation scales the intensity of pain from 0 to 10 in an order of 0, 2, 4, 6, 8, and 10, with each score is represented by a facial expression of pain. As recommended by the guideline, extremities were marked clearly using “no pain” and “very much pain” statements and avoiding the use of such words as “happy” or “sad.” The patients were informed that this evaluation aims to measure their feelings and were asked the following question “show me how you feel.”
To evaluate procedure-related genitourinary and gastrointestinal system side effects, patients were asked questions relating to the presence of such symptoms as fever, rectal bleeding, dysuria, hematuria, hematospermia, and frequency of urination. Each question was answered “yes,” “a little,” or “no.”
In order to rate the severity of the side effects in patients who responded with “yes” and “a little” to the questions on genitourinary and gastrointestinal system side effects, the events were evaluated based on the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, US Dep. of Health and Human Services, general definitions system. The grades of severity for each adverse event were defined as follows: Grade 1: mild adverse event, Grade 2: moderate adverse event, Grade 3: severe adverse event, Grade 4: life-threatening adverse event, and Grade 5: death related to the adverse event.
Patients were also asked to compare the severity of pain experienced after the fiducial marker implantation procedure without local anesthesia with the pain experienced during the diagnostic prostate biopsy performed with the use of local anesthesia, being asked to express this comparison as less, equal, or more.
Fiducial marker procedure
The fiducial marker implantation technique was previously described by Shinohara and Roach  and Linden et al. Transrectal or transperineal routes are preferred and generally under local anesthesia. The protocol followed for this procedure in our clinics is as follows: bowel cleaning is carried out by a rectal enema before the procedure in each patient who is to be implanted with fiducial markers. Immediately after the procedure, a single dose of third-generation cephalosporin is administered intramuscularly, and an ofloxacin 400 mg tablet 1 × 1 peroral and ornidazole 500 mg tablet 2 × 1 peroral are prescribed for the patients. Patients are informed about hematuria, rectal bleeding, pelvic pain, and similar urinary symptoms. In lithotomy position, and under the guidance of an ultrasound probe, three cylindrical fiducial markers of 1 mm diameter and 3 mm length are placed into the prostate base, central zone, and apex using 18–20 mm gauges. The procedure is performed through the transrectal route and without the use of local anesthesia. There are several gold marker designs of different lengths and widths, needle sizes, and appearances; and carbon and PEEK markers have also been produced to reduce the CT artifact caused by gold. In our clinics, we use gold and PEEK as fiducial markers.
Attention must be paid not to damage the urethra during the procedure, as this may result in hematuria or the unintended loss of the markers. It is also necessary to ensure that the markers are not placed on the same plane in the spatial dimension. Different coordinates should be defined in x, y, and z axis, and the necessary adjustments should be made during radiotherapy by detecting the dislocation of the prostate on each axis. It is preferable to allow the patient to recover for 1 week after the procedure and to wait for the resolution of the iatrogenic prostate edema, as this will allow the differences between the reference CT simulator images and the treatment device images to be reduced for all fiducial markers. After this recovery period, serial tomographic images are obtained from a simulation device; after which, the clinician contours the fiducial markers, along with the target structures and the surrounding organs, through the use of special planning software. Treatment planning is carried out by medical physics specialists who make use of sophisticated calculation algorithms to select the appropriate planning technique and to finalize the plan, and the proposed plan is approved by the physician. The application of the selected plan from theory to practice and quality control are checked by a medical physics specialist; after which, the patient is invited to therapy. Immediately before initiating radiotherapy on the patient positioned on the treatment table, it is confirmed that the prostate is at the planned location by checking the obtained CBCT and/or kV image pairs. The coordinates of the fiducial markers on the reference tomographic images provided by the treatment planning system and/or digitally reconstructed radiograph are directly paired with the coordinates of the fiducial markers in kV CBCT and/or the orthogonal kV portal images obtained during treatment. In this way, target localization is identified and confirmed in three dimensions.
| > Results|| |
The Turkish translation of the faces pain scale – revised version was used to measure the severity of procedure-associated pain. The facial expressions of 38 patients (83%) corresponded to level 0 in the study, seven (15%) to level 2, and a single patient (2%) to level 4. None of the facial expressions of the patients corresponded to levels 6, 8, or 10 [Figure 1].
An evaluation of procedure-related genitourinary and gastrointestinal system side effects assessed symptoms including fever, rectal bleeding, dysuria, hematuria, hematospermia, and frequency of urination, with each question being answered by the patient as “yes,” “a little,” or “no.” In total, nine patients (20%) experienced side effects, while no side effects were reported in 37 patients (80%). Reported side effects included rectal bleeding in two patients (4%), dysuria in three patients (6%), hematuria in five patients (11%), and frequency of urination in five (11%) patients. None of the patients experienced fever or hematospermia. All side effects were graded as “a little,” and only one patient answered “yes” to the question on the frequency of urination [Table 2].
To identify the severity of the side effects in patients responding “yes” and “a little” to the questions on genitourinary and gastrointestinal system side effects, the events were evaluated based on an NCI, CTCAE version 5.0, general definitions system, and the severity of the side effects in the nine patients (20%) who responded with “a little” and “yes” was found to be Grade 1, corresponding to a mild adverse event. None of the patients experienced a Grade 2 or higher severe adverse event.
When the patients were asked to compare the severity of the pain experienced after fiducial marker implantation procedure without local anesthesia with the pain experienced during the diagnostic prostate biopsy performed using local anesthesia, 24 patients (80%) described “less” and five patients (20%) described “equal” levels of pain during fiducial marker implantation procedure without local anesthesia than during the diagnostic prostate biopsy. None of the patients reported that the pain experienced during fiducial marker implantation was “more” than pain experience during the biopsy [Figure 2].
|Figure 2: Comparison of pain severity between the fiducial marker implantation procedure performed without local anesthesia and the biopsy performed with local anesthesia|
Click here to view
| > Discussion|| |
Fiducial markers can be useful in identifying the prostate, which can dislocate as a result of the above changes, and such markers, when implanted into the prostate, can be easily evaluated through orthogonal kV imaging and so have a well-established role in prostate radiotherapy.,,
The level of pain experienced after the fiducial marker implantation procedure, as measured by the faces pain scale, was very low despite being conducted without anesthesia.
Biopsy procedure is much more invasive technique than fiducial marker procedure. To allow the patients to better define the intensity of pain they experienced, they were asked to compare it with the pain experienced during the biopsy, and although the procedure was carried out without local anesthesia, the patients stated that the severity of pain was “lower” than in the biopsy procedure performed under local anesthesia.
An evaluation of postprocedural side effects revealed no side effects in the majority of patients, and none of those that did experience side effects reported anything other than Grade 1. In total, 15 patients (23%) developed a Grade 1 complication, with no Grade 2, 3, or 4 complications observed in any patient. The most commonly noted complications were hematuria and frequency of urination, each of which was reported by 11% of the patients, which may be associated with the prostatic urethra damage that occurred during the procedure. All complications resolved spontaneously in a short period of time without the need for medical treatment.
Control prostate-specific antigen values were found to be significantly lower in all patients when compared to the values recorded before RT.
| > Conclusion|| |
The ultrasound-guided transrectal implantation of fiducial markers' technique is a safe and well-tolerated method that accurately pinpoints the prostate position. Performing the procedure without local anesthesia is important, as it eliminates the need for additional invasive procedures, shortens the total duration of the procedure, and decreases the risk of side effects. When compared to the pain experienced during the biopsy procedure, the patients reported much lower levels of pain despite the procedure being carried out with no anesthesia. The rates of procedure-related complications were also low, acceptable, and transient.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Pollack A, Zagars GK, Starkschall G, Antolak JA, Lee JJ, Huang E, et al.
Prostate cancer radiation dose response: Results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002;53:1097-105.
Zietman AL, DeSilvio ML, Slater JD, Rossi CJ Jr., Miller DW, Adams JA, et al.
Comparison of conventional-dose vs. high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: A randomized controlled trial. JAMA 2005;294:1233-9.
Peeters ST, Heemsbergen WD, van Putten WL, Slot A, Tabak H, Mens JW, et al.
Acute and late complications after radiotherapy for prostate cancer: Results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys 2005;61:1019-34.
Zelefsky MJ, Fuks Z, Hunt M, Lee HJ, Lombardi D, Ling CC, et al.
High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urol 2001;166:876-81.
Pollack A, Zagars GK, Smith LG, Lee JJ, von Eschenbach AC, Antolak JA, et al.
Preliminary results of a randomized radiotherapy dose-escalation study comparing 70 Gy with 78 Gy for prostate cancer. J Clin Oncol 2000;18:3904-11.
Lyons JA, Kupelian PA, Mohan DS, Reddy CA, Klein EA. Importance of high radiation doses (72 Gy or greater) in the treatment of stage T1-T3 adenocarcinoma of the prostate. Urology 2000;55:85-90.
Storey MR, Pollack A, Zagars G, Smith L, Antolak J, Rosen I, et al.
Complications from radiotherapy dose escalation in prostate cancer: Preliminary results of a randomized trial. Int J Radiat Oncol Biol Phys 2000;48:635-42.
Zelefsky MJ, Fuks Z, Happersett L, Lee HJ, Ling CC, Burman CM, et al.
Clinical experience with intensity modulated radiation therapy (IMRT) in prostate cancer. Radiother Oncol 2000;55:241-9.
Gill S, Thomas J, Fox C, Kron T, Rolfo A, Leahy M, et al.
Acute toxicity in prostate cancer patients treated with and without image-guided radiotherapy. Radiat Oncol 2011;6:145.
Sveistrup J, Rosenschöld PM, Deasy JO, Oh JH, Pommer T, Petersen PM, et al.
Improvement in toxicity in high risk prostate cancer patients treated with image-guided intensity-modulated radiotherapy compared to 3D conformal radiotherapy without daily image guidance. Radiat Oncol 2014;9:44.
Valicenti R, Lu J, Pilepich M, Asbell S, Grignon D. Survival advantage from higher-dose radiation therapy for clinically localized prostate cancer treated on the radiation therapy oncology group trials. J Clin Oncol 2000;18:2740-6.
Palombarini M, Mengoli S, Fantazzini P, Cadioli C, Degli Esposti C, Frezza GP, et al.
Analysis of inter-fraction setup errors and organ motion by daily kilovoltage cone beam computed tomography in intensity modulated radiotherapy of prostate cancer. Radiat Oncol 2012;7:56.
Basch E, Bennett A, Pietanza MC. Use of patient-reported outcomes to improve the predictive accuracy of clinician-reported adverse events. J Natl Cancer Inst 2011;103:1808-10.
Farnell DJ, Mandall P, Anandadas C, Routledge J, Burns MP, Logue JP, et al.
Development of a patient-reported questionnaire for collecting toxicity data following prostate brachytherapy. Radiother Oncol 2010;97:136-42.
Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The faces pain scale-revised: Toward a common metric in pediatric pain measurement. Pain 2001;93:173-83.
Kim EJ, Buschmann MT. Reliability and validity of the faces pain scale with older adults. Int J Nurs Stud 2006;43:447-56.
Shinohara K, Roach M 3rd
. Technique for implantation of fiducial markers in the prostate. Urology 2008;71:196-200.
Linden RA, Weiner PR, Gomella LG, Dicker AP, Suh DB, Trabulsi EJ, et al.
Technique of outpatient placement of intraprostatic fiducial markers before external beam radiotherapy. Urology 2009;73:881-6.
Schallenkamp 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.
Van den Heuvel F, Fugazzi J, Seppi E, Forman JD. Clinical application of a repositioning scheme, using gold markers and electronic portal imaging. Radiother Oncol 2006;79:94-100.
Scarbrough TJ, Golden NM, Ting JY, Fuller CD, Wong A, Kupelian PA, et al.
Comparison of ultrasound and implanted seed marker prostate localization methods: Implications for image-guided radiotherapy. Int J Radiat Oncol Biol Phys 2006;65:378-87.
[Figure 1], [Figure 2]
[Table 1], [Table 2]