Revised 28 April 2014
LDR - Prostate Brachytherapy
Prostate brachytherapy can be used as a monotherapy for low and intermediate risk, as a monotherapy or in combination with HT for high-tier intermediate risk, or with external beam radiation therapy (EBRT) as a form of dose escalation for selected intermediate and high risk patients.
BCCA Prostate Brachytherapy Program Brachytherapy Eligibility
Low-tier Intermediate risk
High-tier Intermediate risk
<T2a and iPSA < 10 and GS<6
iPSA 10-15 with GS=6
or GS=7 with iPSA<10
iPSA 15-20 and GS=6
or iPSA 10-20 and GS7
iPSA 20-40 or
EBRT 44-46Gy & Brachy boost
Min 3-4 mo neoadjuvant HT, followed by EBRT & brachy boost.
HT duration: 12-36 mo.
(PSA density<0.2, 1-2 cores GS6 on adequate biopsy sampling, and <T2a. Active surveillance is recommended.
1. Brachy & 6 mo HT (3m neoadjuvant & 3m adjuvant)
2. Brachy monotherapy
3. EBRT & Brachy boost & 6-12m HT
CS <T2a, iPSA <10, GS 8-10 in
< 2 cores:
EBRT 44-46GY & Brachy boost, with 6 mo or no HT
Additional general eligibility criteria (1)
Additional notes (informal consultation with brachy doctor if concerns)
Prostate size >50-60cc prior to brachytherapy (which may include anticipated cytoreduction during neoadjuvant ADT)
Cytoreduction prior to Brachy monotherapy: 3 mo neoadjuvant and up to 3 mo adjuvant LHRH agonist/ antagonists or 4-6 month combination of Avodart 0.5 mg with Casodex 50 mg.
Good baseline urinary function. If IPSS score >20, must have suitable flow rates
No, or limited TURP prior to PC treatment
No inflammatory bowel disease if EBRT is recommended. Brachy monotherapy +/- HT may be an option
EBRT may comprise whole pelvis, small pelvis or prostate only.
Low risk and Low-tier intermediate risk PC
Depending on the patient's age, general health, and disease-related parameters several therapeutic options may warrant consideration including; active surveillance for patients with minimal risk disease (recommended), brachytherapy alone, (with or without HT for cytoreduction only), radical prostatectomy, EBRT (with HT in selected patients), watchful waiting (for patients with significant co- morbidity or old age) or HT alone. [See low risk PC under Management]
LDR monotherapy is a standard treatment option for low risk prostate cancer. Good candidate for brachytherapy include men with > 10 years life expectancy, low co- morbidity, good baseline urinary function, prostate size < 60 cc, limited TURP defect.
High-tier intermediate risk and high risk PC
Depending on the patient's age, general health, and disease-related parameters, a variety of therapeutic approaches may be appropriate including: EBRT combined with hormone therapy (HT) (with or without dose escalated radiation using EBRT or brachytherapy), or brachytherapy +/- HT +/- EBRT (high-tier intermediate risk), or radical prostatectomy, EBRT alone, or HT alone. [See also intermediate risk PC and high risk PC under Management].
- Patients with high-tier intermediate risk and selected patients with high risk PCa (CS </=T2a, iPSA<10, and Gleason sum 8-10 provided there are no more than 2 cores with predominate Gleason pattern 4 -5 and the total length of the involvement of pattern 4-5 is </= 10mm) are offered EBRT 44-46Gy directed to the prostate, peri-prostatic tissue and seminal vesicles or small pelvis (or whole pelvis), followed by a LDR prostate brachytherapy boost of 110 Gy or HDR boost. HT in this group of patients is optional, but not mandatory. Patients with high risk disease (PSA <40, GS 8-10 or >T3a) are offered pelvis radiotherapy (44-46Gy) followed with LDR prostate brachytherapy boost of 110 Gy or HDR boost, together with HT(12-36 months). Duration of HT may be modified based on disease and patient and treatment factors (6-36 mo).
Use of Hormone Therapy Together with Prostate Brachytherapy
(HT more information see Medical Castration)
The addition of hormone therapy (HT) to prostate brachytherapy had failed to produce additional benefit to PSA recurrence-free survival (PRFS) with quality brachytherapy (1,3,4). While initial analysis of BCCA data shows small benefit to PRFS with HT(5)(6), recent BCCA 10 year update shows no additional benefit of HT on improving long term PSA outcome in low and low-tier intermediate risk patients with optimal implant dosimetry (good implant quality)(7). Use of HT appears to increase the risk of cardiac morbidity and sudden cardiac death, (this may be restricted to those with other baseline risk factors), and can be associated with a higher risk of diabetes, osteoporosis, glucose intolerance, muscle mass wasting, fatigue, decrease in QOL, decrease in sexual function and cognitive dysfunction(8). Patients with high-risk features being considered for primary EBRT are known to benefit from treatment combined with HT from multiple randomized prospective trials (9,10). Dose escalation using any form of brachytherapy further improves the PSA outcomes, as well as PCa cause specific survival (11)(12). The additional benefit of prolonged HT in combination with dose escalation using EBRT and brachytherapy boost is less significant than with EBRT alone (13,14).(15)(16)
Cytoreduction and Brachytherapy
Hormone therapy (HT) is used in conjunction with PB in order to downsize prostate gland and reduce pubic arch interference (make the implant technically easier/ possible). Cytoreduction can be accomplished by using 3 mo neoadjuvant and up to 3 mo adjuvant LHRH agonist (with antiandrogen given concurrently for one to three months) or LHRH antagonists. Total Androgen Blockade (TAB) has been shown to reduce prostate volume faster and to a greater degree than LHRH agonist alone. Cytoreduction can also be accomplished using combination of Avodart 0.5 mg with Casodex 50 mg daily for at least three months prior to and minimum one month after the implant (17).
Patients with relatively large prostates ( 50 -60cc) may have increased urinary morbidity with prostate brachytherapy (18,19). HT may be used to reduce the prostate volume; however, the morbidity of prostate brachytherapy may be more closely correlated with the pre-cytoreduced volume than the post-cytoreduced volume. Men with median lobes that project superiorly into the bladder are difficult to implant and may have a high risk of acute and prolonged urinary retention. Median lobe resection prior to brachytherapy may be considered and discussed with urologist. The use of peri- and post-operative dexamethasone may reduce the incidence of acute urinary retention in men with large prostates and/or high IPSS scores.
BC Cancer Agency Prostate Brachytherapy Provincial Program
The British Columbia Cancer Agency (BCCA) program started in 1997, and to date has treated over 4500 patients; this is the largest program in Canada and one of the largest in the world. The current volume of over 550 implants per year is shared between 16 Radiation Oncologists. LDR brachytherapy is available at centers in Vancouver, Victoria, Fraser Valley/Abbotsford and Kelowna. All centers use techniques based on the Seattle experience combined with a planning algorithm developed in house and use consistent treatment protocols, selection criteria, and rigorous quality control (20). Numerous series with surgery have shown that the single most important factor affecting surgical outcomes (cure and toxicity) is institutional and individual surgeon experience. Generally a minimum case-volume is 30/year (21). Similar case-volumes exist with brachytherapy (22,23). A large provincial prospective database records baseline disease characteristics, technical (dosimetric) details, as well as follow up PSA and side effect scores on most patients. HDR is offered in context of clinical trial only (Kelowna).
BC Cancer Agency Prostate Brachytherapy Program - Published Outcomes
Low and Low-Tier Intermediate Risk PC
The BC Cancer Agency Brachytherapy Program has recently published10 year biochemical control rates of the first consecutive 1,006 patients (7)(5,6) . With median follow up of 7.5 years (42% intermediate risk and 58% low risk) show 5-year and 10-year disease free survival of 96.7% and 94.1% respectively. (7) Median PSA for the entire group was 0.04 ng/ml, indicating that long-term cancer cure is likely in the majority of patients (24).
Consistent with the PCRSG PC systemic review (25), a recent BC Cancer Agency matched-pair analysis shows that men treated with PB have superior outcomes for PSA control when compared to external beam radiation (EBRT). Five year PSA recurrence free rates are 95% (BT) and 85% (EBRT). After seven years, the BT result was unchanged, but the EBRT had fallen to 75%. Toxicity rates in this study show worse late urinary toxicity with BT, but worse bowel toxicity with EBRT(26).
Figure: The Fine and Gray’s Competing Risks estimates of disease free survival (DFS) and cause specific survival (CSS), and the Kaplan-Meier estimate for overall survival (OS) for all patients in the cohort (N=1006). (7)
High -Tier Intermediate and High Risk PC- 2012
In November of 2002, BCCA opened a randomized control phase II trial (accrued 41), which was further expanded to a randomized phase III trial in October 2004 (accrued 357) (ASCENDE RT), to compare the efficacy and toxicity of dose escalated radiating using EBRT vs. EBRT plus brachytherapy. Eligibility criteria included patients with ≤ Clinical stage (CS) T3a, any Gleason score (GS) and an initial PSA (iPSA) ≤40 ng/mL. All patients received 12 months HT (8 months neoadjuvant) and elective pelvic nodal irradiation (46Gy/23 fractions 4 field conformal). Randomization was between high dose conformal EBRT (78Gy total dose to prostate) vs. a brachytherapy boost (115Gy, I125 Permanent Prostate Implant)(27). Trial was closed Dec 1, 2011. Results are pending publication. An interim analysis of ASCENDE-RT phases II-III (including all patients started on LHRH injections on or before Aug 31, 2006 N=161 pts) showed superior outcomes with combination of EBRT with brachytherapy boost as compared with an EBRT alone. Single institution reports (14,29, 30, 31) and comprehensive literature review showed excellent long term outcomes in this group of patients treated with EBRT and brachytherapy, without HT (25).
Prostate Brachytherapy - PSA Outcomes
Based on published retrospective cohorts, PSA recurrence free survival for low and intermediate risk disease is exceeding 90%.(7,14,28,29) Patients treated with “triple therapy” for high risk disease also achieve excellent long term disease control (>85%)(30,31). There no randomized control trials to offer insight into comparative treatment effectiveness.
The Prostate Cancer Results Study Group (PCRSG) comprehensive literature review (BJU 2012) (25) identified 18,000 studies involving treatment of prostate cancer published during 2000–2010. Only 848 were included in the analysis (>50.000 patients), based on key criteria: minimum/median follow-up of 5 years; stratification into low, intermediate- and high-risk groups; clinical and pathological staging; accepted standard definitions for PSA failure; minimum patient number of 100 in each risk group (50 for high-risk)(3). Patients treated with any form of brachytherapy had not only superior long term PSA outcome, but also showed remarkable durability of the results with long follow up. Unlike EBRT, high radiation dose delivered with brachytherapy produce durable long term outcomes in all PC risk groups, suggesting luck of metastatic disease at presentation in majority of patients (including high risk pCa) and ablative effect of high radiation dose on prostate tissue (24). Patients with all risk disease have excellent long term outcomes with any form brachytherapy. The potential difference in treatment outcome seen in this study may be attributed to different patient selection.
High-tier intermediate risk prostate cancer is a heterogeneous group. Based on published retrospective cohorts, patients with several disease risk factors may benefit from addition of EBRT and/or HT (6-12 months) to brachytherapy (13,14)(15). Preliminary results of ASCENDE RT phase III trial support this practice (27). RTOG 0815 randomized clinical trial is assessing the role of HT in patients with intermediate risk disease is ongoing.
Dose escalation using EBRT in prostate cancer has been proven to increase long term PSA recurrence free survival (PRFS) and, prostate cancer cause specific survival (CSS) in some series (32) but not in meta-analysis of dose escalation trials (33). It is acknowledged that PSA outcomes in PCa are not a surrogate for OS outcomes, however, dose escalation using any form of brachytherapy has been shown to improve the PSA outcomes, as well as PC cause specific survival (11,12)(25). For example, SEER data on 12,745 patients shows that at a median follow-up of only 6 years, use of brachytherapy improves prostate cancer cause specific survival in patients with high- risk/high Gleason Score (GS) prostate cancer (11). Recent BCCA outcome analysis of 1060 patients treated with EBRT with or without HT shows that patients treated with EBRT with or without HT for intermediate risk and high risk disease and estimated 10 year OS of >90% based on age and luck of co-morbidities had significantly improved OS when PC was biochemically controlled(2). It could be argued that striving for high cure rates in all patients with PC is unnecessary, as most patients with localized prostate cancer will die of other causes. However, younger patients with long life expectancy are those most likely to benefit from curative treatment, avoiding difficult issues with disease recurrence and need for secondary intervention with lifelong androgen suppression.
Prostate Brachytherapy Side Effects:
LDR brachytherapy is an hour long surgical day-care procedure where radioactive seeds are implanted permanently into the prostate. Most implants are done with general or spinal anaesthesia. Patients are discharged 2-3 hours later and resume normal daily activities in a few days. Severe long term side effects are uncommon. Side effects present in here are based on BCCA Prostate Brachytherapy Program peer review publications.
Urinary Side Effects:
Most men will experience some urinary symptoms after the procedure; about 50% will have moderate obstructive and/or irritative urinary symptoms lasting 6-12 months. Median time for IPSS to return to baseline is 12 months. At seven years after PB, the majority of patients (92.5%) will have very little or no urinary symptoms (18,34). Patients with larger prostate volume, worse baseline urinary function, and those given hormone therapy are more likely to have more irritative and obstructive urinary symptoms after PB(18,19). Five to ten percent of patients will require a Foley catheter for urinary obstruction (most for <1 week, 3% of all patients for several weeks or months; again this is more often seen in patients with worse baseline urinary function, protruding median lobes, and those with larger prostate size before implant (19). Long-term, < 3% of men will require urethral dilatation or a TURP (transurethral resection of the prostate) to relieve obstructive urinary symptoms. With greater experience in the program, the overall acute rate of urinary side effects has declined. (19).
Rectal Side Effects:
Mild self-limiting rectal irritation affects 20%-30% of patients in the first 1-2 years after the implant. Rectal bleeding is reported in 2-7% of patients (1-5% will require a laser photocoagulation procedure) (35). Serious rectal injury (requiring major surgical intervention such as colostomy) occurres in 1/500 men treated with brachytherapy at the BCCA.
Inflammatory bowel disease and biopsies of the anterior rectal wall had been a major culprit of this serious complication. Anterior rectal wall biopsies are strongly discouraged as even relatively minor tissue trauma can precipitate development of a rectal fistula due to the poor vascular supply to this tissue after an implant. Similarly, laser coagulation for rectal bleeding is only undertaken when conservative measures have failed, and is best performed by a specialist who is familiar with managing post-brachytherapy complications.
A recent BC study of >1400 patients showed that the 8 year potency preservation rate is 60-80% in men age <60, 55-60% in those 60-69 and 20-30% in those >70. Loss of erectile function is most prominent in the first 3 years after the treatment, with little additional deterioration in potency rates at 5 and 8 years after brachytherapy. For the entire BC cohort, erectile function preservation was reported in 50% at 8 years (with 30 % of man using phosphodiesterase -5 inhibitors) (36). This is consistent with results published by others (37).Younger patients and those with better pre-treatment erectile function are likely to do better after the treatment (36,38) Many patients will have improvement in their function with oral GMP-specific phosphodiesterase inhibitors (PDE5 inhibitors: Sildenafil, Verdanefil, Tadalafil).
Brachytherapy in combination with EBRT - side effects
Despite EBRT and PB boost being a standard of care in the USA for over a decade, there has been surprisingly little written about the long terms side effects of the combined treatment vs. brachytherapy alone. A recent report of 585 men with high risk PCa treated with EBRT, brachytherapy and HT (median of 5 years, range, 2-11), showed 6.2% urinary retention, 4.3% incontinence (associated with a post implant TURP), 54.7% potency preservation and, 10.6% Grade 1-2 proctitis and 0.7% Grade 3-4 proctitis (2 ulcers and 2 fistulas)(39). Above toxicity profile is consisted with our brachytherapy monotherapy program results.(18,19,34-36). Toxicity analysis of ADCENDE RT study is pending. Preliminary analysis shows no grade 4 toxicity. Late urinary grade 3 toxicity was higher in brachytherapy arm (5.4% vs.1.2%). Late GI grade 3 toxicity was the same in both arms (1.8 and 1.2%).
The prostate brachytherapy implant is a surgical day-care procedure taking about 1 hour. Patients are discharged home two to three hours later. The radiation oncologist places the radioactive seeds into the prostate through the perineum, using between 20-28 needles, each carrying two to six seeds. The seeds are 0.5 cm titanium shells that contain I125 (Iodine 125) radioactive gas. The half life of I125 is 60 days. As radioactive decay is an exponential function, 50% of the radioactivity is released by two months, 88% by six months, 99% by 12 months.
The procedure is done using a real-time ultrasound guidance and fluoroscopy. Seed placement is guided using three-dimensional co-ordinates predetermined by a customized planning algorithm using computer modeling leaving 90-150 seeds permanently in the prostate. Most implants are done with general or spinal anesthesia (occasionally under local anesthesia). After the procedure a CT scan of the prostate is performed to ensure accurate position of the seeds and adequate radiation dose distribution within the prostate. This is a rigorous QA procedure that was built into our program as a standard practice from the outset. Very rarely, (1 in 200) men may be asked to come and have a second procedure done, where additional seeds may be placed in the prostate.
BCCA Prostate Brachytherapy Program: clinical trials
BCCA Prostate Brachytherapy Program is actively participating in several multi-institutional clinical trials, results of which are expected to further refine the treatment of intermediate and high risk PC. In particular, participation in RTOG 0815 and RTOG 0924 is encouraged. Degarelix trial for prostate downsizing and HDR trial for intermediate risk PC is offered in Kelowna. High risk PC registration trial of surgery vs. radiation and HT is pending, and will be offered initially in Vancouver.
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(2) Herbert C, Liu M, Tyldesley S, Morris WJ, Joffres M, Khaira M, et al. Biochemical control with radiotherapy improves overall survival in intermediate and high-risk prostate cancer patients who have an estimated 10-year overall survival of >90%. Int J Radiat Oncol Biol Phys 2012 May 1;83(1):22-27.
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(14) Merrick GS, Butler WM, Galbreath RW, Lief J, Bittner N, Wallner KE, et al. Prostate cancer death is unlikely in high-risk patients following quality permanent interstitial brachytherapy. BJU Int 2011 Jan;107(2):226-232.
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(17) Merrick GS, Butler WM, Wallner KE, Galbreath RW, Allen ZA, Kurko B. Efficacy of neoadjuvant bicalutamide and dutasteride as a cytoreductive regimen before prostate brachytherapy. Urology 2006 Jul;68(1):116-120.
(18) Keyes M, Miller S, Moravan V, Pickles T, McKenzie M, Pai H, et al. Predictive factors for acute and late urinary toxicity after permanent prostate brachytherapy: long-term outcome in 712 consecutive patients. Int J Radiat Oncol Biol Phys 2009 Mar 15;73(4):1023-1032.
(19) Keyes M, Schellenberg D, Moravan V, McKenzie M, Agranovich A, Pickles T, et al. Decline in urinary retention incidence in 805 patients after prostate brachytherapy: the effect of learning curve? Int J Radiat Oncol Biol Phys 2006 Mar 1;64(3):825-834.
(20) Keyes M, LaPointe V, Pickles T, Crook J, Spadinger I, McKenzie M, et al. Radiation Oncologists Quality Assurance Program In BC Cancer Agency Provincial Prostate Brachytherapy Program. Brachytherapy, Volume 10, Supplement 1, May-June 2011, Page S78 2011;10(May-June):s78.
(21) Barocas DA, Mitchell R, Chang SS, Cookson MS. Impact of surgeon and hospital volume on outcomes of radical prostatectomy. Urol Oncol 2010 May-Jun;28(3):243-250.
(22) Chen AB, D'Amico AV, Neville BA, Steyerberg EW, Earle CC. Provider case volume and outcomes following prostate brachytherapy. J Urol 2009 Jan;181(1):113-8; discussion 118.
(23) Keyes M, Morris WJ, Spadinger I, Araujo C, Cheung A, Chng N, et al. Radiation oncology and medical physicists quality assurance in British Columbia Cancer Agency Provincial Prostate Brachytherapy Program. Brachytherapy 2012 Jun 21.
(24) Hayden AJ, Morris JW, Keyes M, LaPointe V, McKenzie M, Pickles T, et al. The PSA Value at 4-5 years After Permanent Prostate Brachytherapy Predicts for Biochemical Failure Free Survival. Radiotherapy and Oncology 2010;96(Supplement 2, September 25):s2.
(25) Grimm PD, Billiet I, Bostwick DG, Dicker A. P., Frank SJ, Immerzeel J, et al. Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group. BJU Int 2012;109(supp 1):22-29.
(26) Pickles T, Keyes M, Morris WJ. Brachytherapy or conformal external radiotherapy for prostate cancer: a single-institution matched-pair analysis. Int J Radiat Oncol Biol Phys 2010 Jan 1;76(1):43-49.
(27) Morris WJ. ASCENDE-RT: Androgen suppression combined with elective nodal and dose escalated radiation therapy. ;http://clinicaltrials.gov/show/NCT00175396..
(28) Sylvester JE, Grimm PD, Wong J, Galbreath RW, Merrick G, Blasko JC. Fifteen-year biochemical relapse-free survival, cause-specific survival, and overall survival following i(125) prostate brachytherapy in clinically localized prostate cancer: Seattle experience. Int J Radiat Oncol Biol Phys 2011 Oct 1;81(2):376-381.
(29) Taira AV, Merrick GS, Butler WM, Galbreath RW, Lief J, Adamovich E, et al. Long-term outcome for clinically localized prostate cancer treated with permanent interstitial brachytherapy. Int J Radiat Oncol Biol Phys 2011 Apr 1;79(5):1336-1342.
(30) Bittner N, Merrick GS, Wallner KE, Butler WM, Galbreath R, Adamovich E. Whole-pelvis radiotherapy in combination with interstitial brachytherapy: does coverage of the pelvic lymph nodes improve treatment outcome in high-risk prostate cancer? Int J Radiat Oncol Biol Phys 2010 Mar 15;76(4):1078-1084.
(31) Fang LC, Merrick GS, Butler WM, Galbreath RW, Murray BC, Reed JL, et al. High-Risk Prostate Cancer With Gleason Score 8-10 and PSA Level 32) Kuban DA, Levy LB, Cheung MR, Lee AK, Choi S, Frank S, et al. Long-term failure patterns and survival in a randomized dose-escalation trial for prostate cancer. Who dies of disease? Int J Radiat Oncol Biol Phys 2011 Apr 1;79(5):1310-1317.
(33) Viani GA, Stefano EJ, Afonso SL. Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials. Int J Radiat Oncol Biol Phys 2009 Aug 1;74(5):1405-1418.
(34) Keyes M, Miller S, Moravan V, Pickles T, Liu M, Spadinger I, et al. Urinary Symptom Flare in 712 (125)I prostate brachytherapy patients: Long-Term Follow-Up. Int J Radiat Oncol Biol Phys 2009 Feb 9.
(35) Keyes M, Spadinger I, Liu M, Pickles T, Pai H, Hayden A, et al. Rectal toxicity and rectal dosimetry in low-dose-rate (125)I permanent prostate implants: a long-term study in 1006 patients. Brachytherapy 2012 May-Jun;11(3):199-208.
(36) Hayden AJ, Keyes M, Moravan V, McKenzie M, Pickles T. Erectile Function Following I125 Permanent Prostate Brachytherapy: 5 and 8 years Results in 1411 men. Radiotherapy and Oncology 2010;96(Supplememt 2, September 25):S3.
(37) Alemozaffar M, Regan MM, Cooperberg MR, Wei JT, Michalski JM, Sandler HM, et al. Prediction of erectile function following treatment for prostate cancer. JAMA 2011 Sep 21;306(11):1205-1214.
(38) Macdonald AG, Keyes M, Kruk A, Duncan G, Moravan V, Morris WJ. Predictive factors for erectile dysfunction in men with prostate cancer after brachytherapy: Is dose to the penile bulb important? International Journal of Radiation Oncology, Biology, Physics 2005;63(1):155-163.
(39) Stone NN, Cesaretti JA, Rosenstein B, Stock RG. Do high radiation doses in locally advanced prostate cancer patients treated with 103Pd implant plus external beam irradiation cause increased urinary, rectal, and sexual morbidity? Brachytherapy 2010 Apr-Jun;9(2):114-118.