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1.  Efficacy and Safety of High-Dose-Rate Brachytherapy of Single Implant with Two Fractions Combined with External Beam Radiotherapy for Hormone-Naïve Localized Prostate Cancer 
Cancers  2011;3(3):3585-3600.
The purpose of this study was to evaluate the efficacy and safety of high-dose-rate (HDR) brachytherapy of a single implant with two fractions plus external beam radiotherapy (EBRT) for hormone-naïve prostate cancer in comparison with radical prostatectomy. Of 150 patients with localized prostate cancer (T1c–T2c), 59 underwent HDR brachytherapy plus EBRT, and 91 received radical prostatectomy. The median follow-up of patients was 62 months for HDR brachytherapy plus EBRT, and 64 months for radical prostatectomy. In patient backgrounds between the two cohorts, the frequency of T2b plus T2c was greater in HDR brachytherapy cohort than in prostatectomy cohort (27% versus 12%, p = 0.029). Patients in HDR brachytherapy cohort first underwent 3D conformal RT with four beams to the prostate to an isocentric dose of 50 Gy in 25 fractions and then, a total of 15–18 Gy in two fractions at least 5 hours apart. We prescribed 9 Gy/fraction for target (prostate gland plus 3 mm lateral outside margin and seminal vesicle) using CT image method for radiation planning. The total biochemical failure-free control rates (BF-FCR) at 3 and 5 years for the HDR brachytherapy cohort, and for the prostatectomy cohort were 92% and 85%, and 72% and 72%, respectively (significant difference, p = 0.0012). The 3-and 5-year BF-FCR in the HDR brachytherapy cohort and in the prostatectomy cohort by risk group was 100 and 100%, and 80 and 80%, respectively, for the low-risk group (p = 0.1418); 92 and 92%, 73 and 73%, respectively, for the intermediate-risk group (p = 0.0492); and 94 and 72%, 45 and 45%, respectively, for the high-risk group (p = 0.0073). After HDR brachytherapy plus EBRT, no patient experienced Grade 2 or greater genitourinay toxicity. The rate of late Grade 1 and 2 GI toxicity was 6% (n = 4). No patient experienced Grade 3 GI toxicity. HDR brachytherapy plus EBRT is useful for treating patients with hormone-naïve localized prostate cancer, and has low GU and GI toxicities.
PMCID: PMC3759211  PMID: 24212968
prostate cancer; high dose rate brachytherapy; external beam radiation therapy; radical prostatectomy
2.  Predictors of distant metastasis after combined HDR brachytherapy and external beam radiation for prostate cancer 
To determine predictors of distant metastases (DM) in prostate cancer patients treated with high dose rate brachytherapy boost (HDR-B) and external beam radiation therapy (EBRT).
Material and methods
From 1991 to 2002, 768 men with localized prostate cancer were treated with HDR-B and EBRT. The mean EBRT dose was 37.5 Gy (range: 30.6-45 Gy), and the HDR-B was 22 or 24 Gy delivered in 4 fractions. Univariate and multivariate analyses using a Cox proportional hazards model including age at diagnosis, T stage, Gleason score (GS), pretreatment PSA, biologically equivalent dose (BED), and use of androgen deprivation therapy (ADT) was used to determine predictors of developing distant metastases.
The median follow-up time for the entire patient population was 4.2 years (range: 1-11.2 years). Distant metastases were identified in 22/768 (3%) of patients at a median of 4.1 years. PSA failure according to the Phoenix definition developed in 3%, 5%, and 14% of men with low, intermediate, and high risk disease with a median time to failure of 3.8 years. Prostate cancer specific mortality was observed in 2% of cases. T stage, GS, and use of ADT were significantly associated with developing DM on univariate analysis. GS, and use of ADT were the only factors significantly associated with developing DM on multivariate analysis (p < 0.01). Patients who received ADT had significantly higher risk features suggesting patient selection bias for higher DM in this group of patients rather than a negative interaction between HDR-B and EBRT.
In men treated with HDR-B and EBRT, GS is a significant factor on multivariate analysis for developing distant metastasis.
PMCID: PMC3797412  PMID: 24143146
brachytherapy; distant metastases; high-dose-rate; prostate cancer
3.  High-dose-rate brachytherapy combined with hypofractionated external beam radiotherapy for men with intermediate or high risk prostate cancer: analysis of short- and medium-term urinary toxicity and biochemical control 
The best management of localized and locally advanced prostate cancer remains controversial, but there are clinical evidences that for patients considered of unfavorable outcome that dose escalation radiotherapy has a significantly better outcome. Methods: Between 2005-2009 a total of 39 unfavorable patients were treated in a phase I-II trial for dose escalation with high-dose rate (HDR)- 30 Gy given by 4 fractions BID, in two separated implants and hypofractionated conformal/tri-dimensional radiotherapy (hEBRT) - 45 Gy (3 Gy per fraction in 3 weeks), at Hospital AC Camargo, Sao Paulo, Brazil. Results: Median age of patients was 69 (range, 58-80) years old. With a median follow up of 42.5 months the highest RTOG acute severe genitourinary toxicity (GU-TX) was grade 3 in two (5.1%) patients. Late severe GU-TX was observed in one (2.6%) patient. On univariate analysis the prostate volume > 45cc (p=0.024), <11 needles per implant (p=0.038) and urethral dose >130% of prescribed dose (p<0,001) were statistical significant predictive factors. Multivariate analysis showed urethral dose >130% as the only predictive factor for late severe GU-TX, p=0.017 (95%CI-1.39-29.49), HR-6.4. The actuarial overall survival, biochemical control and disease specific survival rates for the entire group at 3.5-years were 92.0%, 87.6% and 96.9%, respectively. Conclusion: HDR combined to hEBRT is well tolerated in the short and medium term. Acute toxicity was minimal and improved outcomes in terms of reduced late toxicity can be achieved using at least 11 needles and prostate with no more than 45cc to be implanted. The maximum urethral dose should be kept bellow 130% of prescribed dose.
PMCID: PMC3048983  PMID: 21394285
Prostate cancer; radiotherapy; brachytherapy; toxicity; biochemical control
4.  Analysis of prognostic factors in localized high-risk prostate cancer patients treated with HDR brachytherapy, hypofractionated 3D-CRT and neoadjuvant/adjuvant androgen deprivation therapy (trimodality therapy) 
Journal of Radiation Research  2013;55(3):527-532.
Trimodality therapy consisting of high dose rate (HDR) brachytherapy combined with external beam radiation therapy (EBRT), neoadjuvant hormonal therapy (NHT) and adjuvant hormonal therapy (AHT) has been used to treat localized high-risk prostate cancer. In this study, an analysis of patients receiving the trimodality therapy was performed to identify prognostic factors of biochemical relapse-free survival (bRFS). Between May 2005 and November 2008, 123 high-risk prostate cancer patients (D'Amico classification) were treated with NHT prior to HDR brachytherapy combined with hypofractionated EBRT. Among these patients, 121 had completed AHT. The patients were assigned by time to be treated with a low-dose or high-dose arm of HDR brachytherapy with subsequent hypofractionated 3D conformal radiation therapy (3D-CRT). Multivariate analysis was used to determine prognostic factors for bRFS. With a median follow-up of 60 months, the 5-year bRFS for all patients was 84.3% (high-dose arm, 92.9%; low-dose arm, 72.4%, P = 0.047). bRFS in the pre-HDR PSA ≤ 0.1 ng/ml subgroup was significantly improved compared with that in the pre-HDR PSA > 0.1 ng/ml subgroup (88.3% vs 68.2%, P = 0.034). On multivariate analysis, dose of HDR (P = 0.045, HR = 0.25, 95% CI = 0.038–0.97) and pre-HDR PSA level (P = 0.02 HR = 3.2, 95% CI = 1.18–10.16) were significant prognostic factors predicting bRFS. In high-risk prostate cancer patients treated with the trimodality therapy, the dose of HDR and pre-HDR PSA were significant prognostic factors. The pre-HDR PSA ≤ 0.1 subgroup had significantly improved bRFS. Further studies are needed to confirm the relevance of pre-HDR PSA in trimodality therapy.
PMCID: PMC4014157  PMID: 24351458
high-risk prostate cancer; HDR; trimodality therapy; PSA response
5.  High-dose-rate brachytherapy and hypofractionated external beam radiotherapy combined with long-term hormonal therapy for high-risk and very high-risk prostate cancer: outcomes after 5-year follow-up 
Journal of Radiation Research  2013;55(3):509-517.
The purpose of this study was to report the outcomes of high-dose-rate (HDR) brachytherapy and hypofractionated external beam radiotherapy (EBRT) combined with long-term androgen deprivation therapy (ADT) for National Comprehensive Cancer Network (NCCN) criteria-defined high-risk (HR) and very high-risk (VHR) prostate cancer. Data from 178 HR (n = 96, 54%) and VHR (n = 82, 46%) prostate cancer patients who underwent 192Ir-HDR brachytherapy and hypofractionated EBRT with long-term ADT between 2003 and 2008 were retrospectively analyzed. The mean dose to 90% of the planning target volume was 6.3 Gy/fraction of HDR brachytherapy. After five fractions of HDR treatment, EBRT with 10 fractions of 3 Gy was administered. All patients initially underwent ≥6 months of neoadjuvant ADT, and adjuvant ADT was continued for 36 months after EBRT. The median follow-up was 61 months (range, 25–94 months) from the start of radiotherapy. The 5-year biochemical non-evidence of disease, freedom from clinical failure and overall survival rates were 90.6% (HR, 97.8%; VHR, 81.9%), 95.2% (HR, 97.7%; VHR, 92.1%), and 96.9% (HR, 100%; VHR, 93.3%), respectively. The highest Radiation Therapy Oncology Group-defined late genitourinary toxicities were Grade 2 in 7.3% of patients and Grade 3 in 9.6%. The highest late gastrointestinal toxicities were Grade 2 in 2.8% of patients and Grade 3 in 0%. Although the 5-year outcome of this tri-modality approach seems favorable, further follow-up is necessary to validate clinical and survival advantages of this intensive approach compared with the standard EBRT approach.
PMCID: PMC4014151  PMID: 24222312
high-dose-rate brachytherapy; prostate cancer; androgen deprivation therapy; high-risk; very high-risk
6.  Local prostate cancer radiotherapy after prostate-specific antigen progression during primary hormonal therapy 
The outcome of patients after radiotherapy (RT) for localized prostate cancer in case of prostate-specific antigen (PSA) progression during primary hormonal therapy (HT) is not well known.
A group of 27 patients presenting with PSA progression during primary HT for local prostate cancer RT was identified among patients who were treated in the years 2000–2004 either using external-beam RT (EBRT; 70.2Gy; n=261) or Ir-192 brachytherapy as a boost to EBRT (HDR-BT; 18Gy + 50.4Gy; n=71). The median follow-up period after RT was 68 months.
Median biochemical recurrence free (BRFS), disease specific (DSS) and overall survival (OS) for patients with PSA progression during primary HT was found to be only 21, 54 and 53 months, respectively, with a 6-year BRFS, DSS and OS of 19%, 41% and 26%. There were no significant differences between different RT concepts (6-year OS of 27% after EBRT and 20% after EBRT with HDR-BT).
Considering all 332 patients in multivariate Cox regression analysis, PSA progression during initial HT, Gleason score>6 and patient age were found to be predictive for lower OS (p<0.001). The highest hazard ratio resulted for PSA progression during initial HT (7.2 in comparison to patients without PSA progression during primary HT). PSA progression and a nadir >0.5 ng/ml during initial HT were both significant risk factors for biochemical recurrence.
An unfavourable prognosis after PSA progression during initial HT needs to be considered in the decision process before local prostate radiotherapy. Results from other centres are needed to validate our findings.
PMCID: PMC3551819  PMID: 23227960
Prostate cancer; Radiotherapy; Brachytherapy; Ir-192; Prostate-specific antigen; Hormone therapy
7.  Brachytherapy in the therapy of prostate cancer – an interesting choice 
Contemporary Oncology  2013;17(5):407-412.
Brachytherapy is a curative alternative to radical prostatectomy or external beam radiation [i.e. 3D conformal external beam radiation therapy (CRT), intensity-modulated radiation therapy (IMRT)] with comparable long-term survival and biochemical control and the most favorable toxicity. HDR brachytherapy (HDR-BT) in treatment of prostate cancer is most frequently used together with external beam radiation therapy (EBRT) as a boost (increasing the treatment dose precisely to the tumor). In the early stages of the disease (low, sometimes intermediate risk group), HDR-BT is more often used as monotherapy. There are no significant differences in treatment results (overall survival rate – OS, local recurrence rate – LC) between radical prostatectomy, EBRT and HDR-BT. Low-dose-rate brachytherapy (LDR-BT) is a radiation method that has been known for several years in treatment of localized prostate cancer. The LDR-BT is applied as a monotherapy and also used along with EBRT as a boost. It is used as a sole radical treatment modality, but not as a palliative treatment. The use of brachytherapy as monotherapy in treatment of prostate cancer enables many patients to keep their sexual functions in order and causes a lower rate of urinary incontinence. Due to progress in medical and technical knowledge in brachytherapy (“real-time” computer planning systems, new radioisotopes and remote afterloading systems), it has been possible to make treatment time significantly shorter in comparison with other methods. This also enables better protection of healthy organs in the pelvis. The aim of this publication is to describe both brachytherapy methods.
PMCID: PMC3934024  PMID: 24596528
HDR brachytherapy; LDR brachytherapy; prostate cancer; seeds
8.  Radiation therapy for primary vaginal carcinoma 
Journal of Radiation Research  2013;54(5):931-937.
Brachytherapy plays a significant role in the management of cervical cancer, but the clinical significance of brachytherapy in the management of vaginal cancer remains to be defined. Thus, a single institutional experience in the treatment of primary invasive vaginal carcinoma was reviewed to define the role of brachytherapy. We retrospectively reviewed the charts of 36 patients with primary vaginal carcinoma who received definitive radiotherapy between 1992 and 2010. The treatment modalities included high-dose-rate intracavitary brachytherapy alone (HDR-ICBT; two patients), external beam radiation therapy alone (EBRT; 14 patients), a combination of EBRT and HDR-ICBT (10 patients), or high-dose-rate interstitial brachytherapy (HDR-ISBT; 10 patients). The median follow-up was 35.2 months. The 2-year local control rate (LCR), disease-free survival (DFS), and overall survival (OS) were 68.8%, 55.3% and 73.9%, respectively. The 2-year LCR for Stage I, II, III and IV was 100%, 87.5%, 51.5% and 0%, respectively (P = 0.007). In subgroup analysis consisting only of T2–T3 disease, the use of HDR-ISBT showed marginal significance for favorable 5-year LCR (88.9% vs 46.9%, P = 0.064). One patient each developed Grade 2 proctitis, Grade 2 cystitis, and a vaginal ulcer. We conclude that brachytherapy can play a central role in radiation therapy for primary vaginal cancer. Combining EBRT and HDR-ISBT for T2–T3 disease resulted in good local control.
PMCID: PMC3766300  PMID: 23559599
primary vaginal cancer; radiation therapy; high-dose-rate brachytherapy; intracavitary brachytherapy; interstitial brachytherapy
9.  Early observed transient prostate-specific antigen elevations on a pilot study of external beam radiation therapy and fractionated MRI guided High Dose Rate brachytherapy boost 
To report early observation of transient PSA elevations on this pilot study of external beam radiation therapy and magnetic resonance imaging (MRI) guided high dose rate (HDR) brachytherapy boost.
Materials and methods
Eleven patients with intermediate-risk and high-risk localized prostate cancer received MRI guided HDR brachytherapy (10.5 Gy each fraction) before and after a course of external beam radiotherapy (46 Gy). Two patients continued on hormones during follow-up and were censored for this analysis. Four patients discontinued hormone therapy after RT. Five patients did not receive hormones. PSA bounce is defined as a rise in PSA values with a subsequent fall below the nadir value or to below 20% of the maximum PSA level. Six previously published definitions of biochemical failure to distinguish true failure from were tested: definition 1, rise >0.2 ng/mL; definition 2, rise >0.4 ng/mL; definition 3, rise >35% of previous value; definition 4, ASTRO defined guidelines, definition 5 nadir + 2 ng/ml, and definition 6, nadir + 3 ng/ml.
Median follow-up was 24 months (range 18–36 mo). During follow-up, the incidence of transient PSA elevation was: 55% for definition 1, 44% for definition 2, 55% for definition 3, 33% for definition 4, 11% for definition 5, and 11% for definition 6.
We observed a substantial incidence of transient elevations in PSA following combined external beam radiation and HDR brachytherapy for prostate cancer. Such elevations seem to be self-limited and should not trigger initiation of salvage therapies. No definition of failure was completely predictive.
PMCID: PMC1564026  PMID: 16914054
10.  Evaluation of the Response of Concurrent High Dose Rate Intracavitary Brachytherapy with External Beam Radiotherapy in Management of Early Stage Carcinoma Cervix 
To evaluate local disease control and early complications of concomitant brachytherapy with external beam-radiotherapy in early stage carcinoma cervix.
Fifty patients of early stage carcinoma cervix (FIGO-IB/IIA) were randomly divided into study group concomitant external beam irradiation (EBRT) and HDR-ICBT (intra-cavitary brachytherapy, xrt = 50 Gy/25 Fr, HDR 5.2 Gy*5 Fr) and the control group EBRT followed by HDR-ICBT (xrt = 50 Gy/25 Fr, HDR 7.5 Gy*3 Fr). Acute reactions and local disease response were compared between treatment and at 6-month follow up.
Median overall treatment times were 38 and 61 days in the study and the control groups, respectively. Acute skin reactions and diarrhea were more in the study but manageable. At the completion of the study, there were 80 and 68 % complete responses, 16 and 20 % partial responses, 0 and 8 % stable diseases in the study group and the control group, respectively.
Response was better in the study group but statistically insignificant. Larger number of patients and longer follow up are required to arrive at concrete conclusion.
PMCID: PMC3526703  PMID: 24082559
Concurrent; High dose rate intracavitary brachytherapy; Carcinoma cervix; External beam radiotherapy
11.  High-dose-rate intraluminal brachytherapy during preoperative chemoradiation for locally advanced rectal cancers 
AIM: To determine the feasibility and safety of high dose rate intraluminal brachytherapy (HDR-ILBT) boost during preoperative chemoradiation for rectal cancer.
METHODS: Between 2008 and 2009, thirty-six patients with locally advanced rectal cancer (≥ T3 or N+), were treated initially with concurrent capecitabine (825 mg/m2 oral twice daily) and pelvic external beam radiotherapy (EBRT) (45 Gy in 25 fractions), then were randomized to group A; HDR-ILBT group (n = 17) to receive 5.5-7 Gy × 2 to gross tumor volume (GTV) and group B; EBRT group (n = 19) to receive 5.4 Gy × 3 fractions to GTV with EBRT. All patients underwent total mesorectal excision.
RESULTS: Grade 3 acute toxicities were registered in 12 patients (70.6%) in group A and in 8 (42.1%) in group B. Complete pathologic response of T stage (ypT0) in group A was registered in 10 patients (58.8%) and in group B, 3 patients (15.8%) had ypT0 (P < 0.0001). Sphincter preservation was reported in 6/9 patients (66.7%) in group A and in 5/10 patients (50%) in group B (P < 0.01). Overall radiological response was 68.15% and 66.04% in Group A and B, respectively. During a median follow up of 18 mo, late grade 1 and 2 sequelae were registered in 3 patients (17.6%) and 4 patients (21.1%) in the groups A and B, respectively.
CONCLUSION: HDR-ILBT was found to be effective dose escalation technique in preoperative chemoradiation for rectal cancers, with higher response rates, downstaging and with manageable acute toxicities.
PMCID: PMC2941067  PMID: 20845511
High dose rate; Intraluminal brachytherapy boost; Locally advanced rectal cancer; Preoperative chemoradiation
12.  Dosimetry and toxicity outcomes in postoperative high-dose-rate intracavitary brachytherapy for endometrial carcinoma 
The optimal dosimetric parameters and planning techniques for high-dose-rate vaginal brachytherapy (HDR-VB) are unclear. Our aim was to evaluate the utility of bladder and rectal dosimetry for patients receiving HDR-VB for postoperative treatment of endometrial carcinoma.
Material and methods
Patients with endometrial cancer who underwent postoperative HDR-VB from January 1, 2004 through December 31, 2010 were included. All patients underwent primary surgery consisting of total hysterectomy and bilateral salpingo-oophrectomy (TH-BSO) with or without lymph node dissection and were treated with HDR-VB without pelvic external beam radiotherapy (EBRT) or chemotherapy. Demographic, pathologic, dosimetric and clinical data were collected.
One hundred patients were identified with the majority of patients receiving HDR-VB in 700 cGy × 3 fractions (45%) or 550 cGy x 4 fractions (53%). No plan was altered based on bladder dosimetry at the time of planning. The rate of acute urinary reactions (< 90 days from beginning of RT) grades 1 and 2 were 14% and 2%, respectively. The rate of late urinary reactions (> 90 days after RT) grades 1 and 2 were 7% and 3%, respectively. Dose to the bladder point did not correlate with urinary toxicity. No rectal toxicity was reported by patients receiving HDR-VB.
In the setting of HDR-VB without EBRT, the measured dose to the bladder point does not predict urinary toxicity and is very unlikely to indicate the need to change the treatment plan. The treatment of endometrial carcinoma utilizing HDR-VB alone is associated with very low rates of high-grade acute or late bladder toxicity.
PMCID: PMC3551376  PMID: 23346142
endometrial cancer; high-dose-rate; brachytherapy
13.  Low-dose-rate or high-dose-rate brachytherapy in treatment of prostate cancer – between options 
Permanent low-dose-rate (LDR-BT) and temporary high-dose-rate (HDR-BT) brachytherapy are competitive techniques for clinically localized prostate radiotherapy. Although a randomized trial will likely never to be conducted comparing these two forms of brachytherapy, a comparative analysis proves useful in understanding some of their intrinsic differences, several of which could be exploited to improve outcomes. The aim of this paper is to look for possible similarities and differences between both brachytherapy modalities. Indications and contraindications for monotherapy and for brachytherapy as a boost to external beam radiation therapy (EBRT) are presented. It is suggested that each of these techniques has attributes that advocates for one or the other. First, they represent the extreme ends of the spectrum with respect to dose rate and fractionation, and therefore have inherently different radiobiological properties. Low-dose-rate brachytherapy has the great advantage of being practically a one-time procedure, and enjoys a long-term follow-up database supporting its excellent outcomes and low morbidity. Low-dose-rate brachytherapy has been a gold standard for prostate brachytherapy in low risk patients since many years. On the other hand, HDR is a fairly invasive procedure requiring several sessions associated with a brief hospital stay. Although lacking in significant long-term data, it possesses the technical advantage of control over its postimplant dosimetry (by modulating the source dwell time and position), which is absent in LDR brachytherapy. This important difference in dosimetric control allows HDR doses to be escalated safely, a flexibility that does not exist for LDR brachytherapy.
Radiobiological models support the current clinical evidence for equivalent outcomes in localized prostate cancer with either LDR or HDR brachytherapy, using current dose regimens. At present, all available clinical data regarding these two techniques suggests that they are equally effective, stage for stage, in providing high tumor control rates.
PMCID: PMC3635047  PMID: 23634153
brachytherapy; HDR; LDR; prostate cancer; seeds
14.  Radical Radiotherapy for Locally Advanced Cancer of Uterine Cervix 
This study was performed to evaluate the treatment results, prognostic factors and complication rates in patients with locally advanced cancer of uterine cervix after radiotherapy with high-dose rate (HDR) brachytherapy.
Materials and Methods
One hundred and twenty patients with a locally advanced (stages IIB~IVA according to FIGO classification) carcinoma of the uterine cervix were treated with radiotherapy at the Department of Radiation Oncology, Samsung Medical Center between September 1994 and December 2001. The median age of the patients was 61 years (range 29 to 81). Sixty-one, 56 and 3 patients had FIGO stage IIB, III, and IV diseases, respectively. All patients were given external beam radiotherapy over the whole pelvis (median 50.4 Gy) and HDR intracavitary brachytherapy, with a median of 4 Gy per fraction, to point A. Twenty-one patients received chemotherapy, of which 13 and 21 received neoadjuvant chemotherapy and concurrent chemotherapy, respectively, during the first and fourth weeks of external beam radiotherapy. The chemotherapy was not randomly assigned and the median follow-up time was 28.5 months (range: 6~100 months).
The three- and 5-year overall survival (OS) and disease-free survival (DFS) rates were 64.4 and 57.0%, and 63.7 and 60.2%, respectively. The 5-year OS and DFS rates of the patients at stages IIB, III and IV were 60.2, 57.9 and 33.3%, and 57.4, 65.4 and 33.3%, respectively. Univariate analysis indicated that the FIGO stage, overall treatment time (OTT) and treatment response were significant variables for the OS (p=0.035, p=0.0649 and p=0.0009) and of the DFS (p=0.0009, p=0.0359 and p=0.0363). Multivariate analysis showed that the treatment response was the only significant variable for the OS (p=0.0018) and OTT for the DFS (p=0.0360). The overall incidence of late complications in the rectum and bladder were 11.7 and 6.7%, respectively. In addition, insufficiency fractures were observed in 7 patients (5.8%).
The results of this study suggest that radical radiotherapy with HDR brachytherapy was appropriate for the treatment of locally advanced uterine cervix cancer. Also, the response after treatment and OTT are significant prognostic factors.
PMCID: PMC2843887  PMID: 20368838
Radiotherapy; Advanced cancer of the uterine cervix; High-dose rate brachytherapy
15.  Tri-Modality therapy with I-125 brachytherapy, external beam radiation therapy, and short- or long-term hormone therapy for high-risk localized prostate cancer (TRIP): study protocol for a phase III, multicenter, randomized, controlled trial 
BMC Cancer  2012;12:110.
Patients with high Gleason score, elevated prostate specific antigen (PSA) level, and advanced clinical stage are at increased risk for both local and systemic relapse. Recent data suggests higher radiation doses decrease local recurrence and may ultimately benefit biochemical, metastasis-free and disease-specific survival. No randomized data is available on the benefits of long-term hormonal therapy (HT) in these patients. A prospective study on the efficacy and safety of trimodality treatment consisting of HT, external beam radiation therapy (EBRT), and brachytherapy (BT) for high-risk prostate cancer (PCa) is strongly required.
This is a phase III, multicenter, randomized controlled trial (RCT) of trimodality with BT, EBRT, and HT for high-risk PCa (TRIP) that will investigate the impact of adjuvant HT following BT using iodine-125 (125I-BT) and supplemental EBRT with neoadjuvant and concurrent HT. Prior to the end of September 2012, a total of 340 patients with high-risk PCa will be enrolled and randomized to one of two treatment arms. These patients will be recruited from more than 41 institutions, all of which have broad experience with 125I-BT. Pathological slides will be centrally reviewed to confirm patient eligibility. The patients will commonly undergo 6-month HT with combined androgen blockade (CAB) before and during 125I-BT and supplemental EBRT. Those randomly assigned to the long-term HT group will subsequently undergo 2 years of adjuvant HT with luteinizing hormone-releasing hormone agonist. All participants will be assessed at baseline and every 3 months for the first 30 months, then every 6 months until 84 months from the beginning of CAB.
The primary endpoint is biochemical progression-free survival. Secondary endpoints are overall survival, clinical progression-free survival, disease-specific survival, salvage therapy non-adaptive interval, and adverse events.
To our knowledge, there have been no prospective studies documenting the efficacy and safety of trimodality therapy for high-risk PCa. The present RCT is expected to provide additional insight regarding the potency and limitations of the addition of 2 years of adjuvant HT to this trimodality approach, and to establish an appropriate treatment strategy for high-risk PCa.
Trial registration
PMCID: PMC3350387  PMID: 22439742
Prostate cancer; Trimodality; Radiation therapy; Brachytherapy; External beam radiation therapy; Hormone therapy; Randomized controlled trial; Biochemical progression-free survival
16.  Optimizing parametrial aperture design utilizing HDR brachytherapy isodose distribution 
Treatment of cervical cancer includes combination of external beam radiation therapy (EBRT) and brachytherapy (BRT). Traditionally, coronal images displaying dose distribution from a ring and tandem (R&T) implant aid in construction of parametrial boost fields. This research aimed to evaluate a method of shaping parametrial fields utilizing contours created from the high-dose-rate (HDR) BRT dose distribution.
Eleven patients receiving HDR-BRT via R&T were identified. The BRT and EBRT CT scans were sent to FocalSim (v4.62)® and fused based on bony anatomy. The contour of the HDR isodose line was transferred to the EBRT scan. The EBRT scan was sent to CMS-XIO (v4.62)® for planning. This process provides an automated, potentially more accurate method of matching the medial parametrial border to the HDR dose distribution. This allows for a 3D-view of dose from HDR-BRT for clinical decision-making, utilizes a paperless process and saves time over the traditional technique.
PMCID: PMC3635048  PMID: 23634156
brachytherapy; cervical cancer; combined modality
17.  Dosimetric analysis and comparison of IMRT and HDR brachytherapy in treatment of localized prostate cancer 
Radical radiotherapy is one of the options for the management of prostate cancer. In external beam therapy, 3D conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT) are the options for delivery of increased radiation dose, as vital organs are very close to the prostate and a higher dose to these structures leads to an increased toxicity. In brachytherapy, low dose rate brachytherapy with permanent implant of radioactive seeds and high dose rate brachytherapy (HDR) with remote after loaders are available. A dosimetric analysis has been made on IMRT and HDR brachytherapy plans. Ten cases from each IMRT and HDR brachytherapy have been taken for the study. The analysis includes comparison of conformity and homogeneity indices, D100, D95, D90, D80, D50, D10 and D5 of the target. For the organs at risk (OAR), namely rectum and bladder, V100, V90 and V50 are compared. In HDR brachytherapy, the doses to 1 cc and 0.1 cc of urethra have also been studied. Since a very high dose surrounds the source, the 300% dose volumes in the target and within the catheters are also studied in two plans, to estimate the actual volume of target receiving dose over 300%. This study shows that the prescribed dose covers 93 and 92% of the target volume in IMRT and HDR brachytherapy respectively. HDR brachytherapy delivers a much lesser dose to OAR, compared to the IMRT. For rectum, the V50 in IMRT is 34.0cc whilst it is 7.5cc in HDR brachytherapy. With the graphic optimization tool in HDR brachytherapy planning, the dose to urethra could be kept within 120% of the target dose. Hence it is concluded that HDR brachytherapy may be the choice of treatment for cancer of prostate in the early stage.
PMCID: PMC2884303  PMID: 20589121
Brachytherapy; conformity; intensity modulated radiotherapy; prostate
18.  Combined brachytherapy and external beam radiotherapy without adjuvant androgen deprivation therapy for high-risk prostate cancer 
To report the outcomes of patients treated with combined iodine-125 (I-125) brachytherapy and external beam radiotherapy (EBRT) for high-risk prostate cancer.
Between 2003 and 2009, I-125 permanent prostate brachytherapy plus EBRT was performed for 206 patients with high-risk prostate cancer. High-risk patients had prostate-specific antigen ≥ 20 ng/mL, and/or Gleason score ≥ 8, and/or Stage ≥ T3. One hundred and one patients (49.0%) received neoadjuvant androgen deprivation therapy (ADT) but none were given adjuvant ADT. Biochemical failure-free survival (BFFS) was determined using the Phoenix definition.
The 5-year actuarial BFFS rate was 84.8%. The 5-year cause-specific survival and overall survival rates were 98.7% and 97.6%, respectively. There were 8 deaths (3.9%), of which 2 were due to prostate cancer. On multivariate analysis, positive biopsy core rates and the number of high-risk factors were independent predictors of BFFS. The 5-year BFFS rates for patients in the positive biopsy core rate <50% and ≥50% groups were 89.3% and 78.2%, respectively (p = 0.03). The 5-year BFFS rate for patients with the any single high-risk factor was 86.1%, compared with 73.6% for those with any 2 or all 3 high-risk factors (p = 0.03). Neoadjuvant ADT did not impact the 5-year BFFS.
At a median follow-up of 60 months, high-risk prostate cancer patients undergoing combined I-125 brachytherapy and EBRT without adjuvant ADT have a high probability of achieving 5-year BFFS.
PMCID: PMC3904455  PMID: 24401540
Prostate cancer; Brachytherapy; High risk; Androgen deprivation therapy
19.  Expanded risk groups help determine which prostate radiotherapy sub-group may benefit from adjuvant androgen deprivation therapy 
To assess whether an expanded (five level) risk stratification system can be used to identify the sub-group of intermediate risk patients with prostate cancer who benefit from combining androgen deprivation therapy (ADT) with external beam radiotherapy (EBRT).
Materials and methods
Using a previously validated 5-risk group schema, a prospective non-randomized data set of 1423 men treated at the British Columbia Cancer Agency was assessed for the primary end point of biochemical control (bNED) with the RTOG-ASTRO "Phoenix" definition (lowest PSA to date + 2 ng/mL), both with and without adjuvant ADT. The median follow-up was 5 years.
There was no bNED benefit for ADT in the low or low intermediate groups but there was a statistically significant bNED benefit in the high intermediate, high and extreme risk groups. The 5-year bNED rates with and without ADT were 70% and 73% respectively for the low intermediate group (p = non-significant) and 72% and 58% respectively for the high intermediate group (p = 0.002).
There appears to be no advantage to ADT where the Gleason score is 6 or less and PSA is 15 or less. ADT is beneficial in patients treated to standard dose radiation with Gleason 6 disease and a PSA greater than 15 or where the Gleason score is 7 or higher.
PMCID: PMC2358899  PMID: 18423030
20.  The role of the maximum involvement of biopsy core in predicting outcome for patients treated with dose-escalated radiation therapy for prostate cancer 
To evaluate the influence of the maximum involvement of biopsy core (MIBC) on outcome for prostate cancer patients treated with dose-escalated external beam radiotherapy (EBRT).
Methods and materials
The outcomes of 590 men with localized prostate cancer treated with EBRT (≥75 Gy) at a single institution were retrospectively analyzed. The influence of MIBC on freedom from biochemical failure (FFBF), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival (OS) was compared to other surrogates for biopsy tumor volume, including the percentage of positive biopsy cores (PPC) and the total percentage of cancer volume (PCV).
MIBC correlated with PSA, T-stage, Gleason score, NCCN risk group, PPC, PCV, and treatment related factors. On univariate analysis, MIBC was prognostic for all endpoints except OS; with greatest impact in those with Gleason scores of 8–10. However, on multivariate analysis, MIBC was only prognostic for FFBF (hazard ratio [HR] 1.9, p = 0.008), but not for FFM (p = 0.19), CSS (p = 0.16), and OS (p = 0.99).
In patients undergoing dose-escalated EBRT, MIBC had the greatest influence in those with Gleason scores of 8–10 but provided no additional prognostic data as compared to PPC and PCV, which remain the preferable prognostic variables in this patient population.
PMCID: PMC3484035  PMID: 22852797
Prostate cancer; Biopsy; prognostic factors; Maximum involvement; Tumor in Core; Radiotherapy
21.  Oxidative Stress Markers in Prostate Cancer Patients after HDR Brachytherapy Combined with External Beam Radiation 
Assessment of oxidative stress markers was perfomed in prostate cancer (PCa) patients subjected to high-dose brachytherapy (HDR) with external beam radiotherapy (EBRT). Sixty men with PCa were subjected to combined two-fraction treatment with HDR (tot. 20 Gy) and EBRT (46 Gy). Blood samples were taken before treatment, immediately afterwards, after 1.5–3 months, and approx. 2 years. Control group consisted of 30 healthy men. Erythrocyte glutathione peroxidase activity in the patients was lower than in healthy subjects by 34% (P < 0.001), 50% (P < 0.001), 30% (P < 0.05), and 61% (P < 0.001), respectively, at all periods. No significant differences were found by comparing superoxide dismutase and catalase activity in PCa patients with that of the controls. After 2 years of the end of treatment, the activity of studied enzymes demonstrated a decreasing tendency versus before therapy. Blood plasma thiobarbituric acid reactive substances (TBARS) concentration was higher than in the controls at all periods, while erythrocyte TBARS decreased after 2 years to control levels. The results confirm that in the course of PCa, imbalance of oxidant-antioxidant processes occurs. The therapy did not alter the levels of oxidative stress markers, which may prove its applicability. Two years is too short a period to restore the oxidant-antioxidant balance.
PMCID: PMC3533485  PMID: 23365695
22.  High dose rate brachytherapy before external beam irradiation in inoperable oesophageal cancer. 
British Journal of Cancer  1996;74(9):1452-1457.
To induce fast relief of dysphagia in patients with oesophageal cancer high dose rate (HDR) brachytherapy was applied before external radiotherapy in a prospective study. Seventy-four patients with inoperable oesophageal cancer (36 squamous cell, 38 adenocarcinoma) were treated with a combination of 10 Gy HDR brachytherapy, followed by 40 Gy in 4 weeks external beam radiotherapy (EBRT), starting 2 weeks later. Tumour response, as measured by endoscopy and/or barium swallow, revealed complete remission in 21 and partial response in 38 patients (overall response rate 80%). Improvement of dysphagia was induced by brachytherapy within a few days in 39%, and achieved at the end of treatment in 70% of patients. Further weight loss was prevented in 39 of the 59 patients who presented with weight loss. Pain at presentation improved in 12 out of 25 patients. Median survival was 9 months. No differences in either response rate or survival were found in squamous cell or adenocarcinoma. Side-effects were either acute with minimal discomfort in 32 (42%) or late with painful ulceration in five patients (7%), occurring after a median of 4 months. A fistula developed in six patients, all with concurrent tumour. In conclusion, brachytherapy before EBRT was a safe and effective procedure to induce rapid relief of dysphagia, especially when combined with EBRT.
PMCID: PMC2074787  PMID: 8912544
23.  Role of Isotope Selection in Long-term Outcomes in Patients With Intermediate-risk Prostate Cancer Treated With a Combination of External Beam Radiotherapy and Low-dose-rate Interstitial Brachytherapy 
Urology  2012;79(5):1098-1104.
To examine the rates of long-term biochemical recurrence-free survival (BRFS) with respect to isotope in intermediate-risk prostate cancer treated with external beam radiotherapy (EBRT) and brachytherapy.
A total of 242 consecutive patients with intermediate-risk prostate cancer were treated with iodine-125 (125I) or palladium-103 (103Pd) implants after EBRT (range 45.0–50.4 Gy) from 1996 to 2002. Of the 242 patients, 119 (49.2%) were treated with 125I and 123 (50.8%) with 103Pd. Multivariate Cox regression analysis was used to analyze BRFS, defined according to the Phoenix definition (prostate-specific antigen nadir plus 2 ng/mL) with respect to Gleason score, stage, pretreatment prostate-specific antigen level, and source selection. Late genitourinary/gastrointestinal toxicities were assessed using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale.
At a median follow-up of 10 years, the BRFS rate was 77.3%. A statistically significant difference was found in the 10-year BRFS rate between the 125I- and 103Pd-treated groups (82.7% and 70.6%, respectively; P = .001). The addition of hormonal therapy did not improve the 10-year BRFS rate (77.6%) compared with RT alone (77.1%; P = .22). However, a statistically significant difference in the BRFS rate was found with the addition of hormonal therapy to 103Pd, improving the 10-year BRFS rate for (73.8%) compared with 103Pd alone (69.1%; P = .008). On multivariate analysis, isotope type (103Pd vs 125I), pretreatment prostate-specific antigen level > 10 ng/mL, and greater tumor stage increased the risk of recurrence by 2.6-fold (P = .007), 5.9-fold (P < .0001), and 1.7-fold (P = .14), respectively.
125I renders a superior rate of BRFS compared with 103Pd when used with EBRT. Hormonal therapy does not provide additional benefit in patients with intermediate-risk prostate cancer treated with a combination of EBRT and brachytherapy, except for the addition of hormonal therapy to 103Pd.
PMCID: PMC3623292  PMID: 22546388
24.  Early results of prostate cancer radiation therapy: an analysis with emphasis on research strategies to improve treatment delivery and outcomes 
BMC Cancer  2013;13:23.
There is scant data regarding disease presentation and treatment response among black men living in Africa. In this study we evaluate disease presentation and early clinical outcomes among Ghanaian men with prostate cancer treated with external beam radiotherapy (EBRT).
A total of 379 men with prostate cancer were referred to the National Center for Radiotherapy, Ghana from 2003 to 2009. Data were collected regarding patient-and tumor-related factors such as age, prostate specific antigen (PSA), Gleason score (GS), clinical stage (T), and use of androgen deprivation therapy (ADT). For patients who received EBRT, freedom from biochemical failure (FFbF) was evaluated using the Kaplan-Meier method.
Of 379 patients referred for treatment 69.6% had initial PSA (iPSA) > 20 ng/ml, and median iPSA was 39.0 ng/ml. A total of 128 men, representing 33.8% of the overall cohort, were diagnosed with metastatic disease at time of referral. Among patients with at least 2 years of follow-up after EBRT treatment (n=52; median follow-up time: 38.9 months), 3- and 5-year actuarial FFbF was 73.8% and 65.1% respectively. There was significant association between higher iPSA and GS (8–10 vs. ≤7, p < 0.001), and T stage (T3/4 vs. T1/2, p < 0.001).
This is the largest series reporting on outcomes after prostate cancer treatment in West Africa. That one-third of patients presented with metastatic disease suggests potential need for earlier detection to permit curative-intent therapy. Data from this study will aid in the strategic development of prostate cancer research roadmap in Ghana.
PMCID: PMC3558339  PMID: 23324165
African men; Prostate cancer; External beam RT; Biochemical failure
25.  Brachytherapy boost in loco-regionally advanced nasopharyngeal carcinoma: a prospective randomized trial of the International Atomic Energy Agency 
The purpose was to determine whether a brachytherapy boost improves outcomes in patients with advanced nasopharyngeal carcinoma treated with standard chemo-radiotherapy.
Patients with nasopharyngeal carcinoma WHO grades I-III and TNM stages III or non-metastatic stage IV were eligible for this phase III study. Patients were randomized to either arm (A) induction chemotherapy, followed by external beam radiotherapy (EBRT) with concomitant cisplatin (n = 139) or arm (B), the same schedule plus a brachytherapy boost to the nasopharynx (n = 135). The EBRT doses given were 70 Gy to the primary tumour and positive lymph nodes and 46 Gy to the negative neck. The additional brachytherapy boost in arm (B) was given by either low dose-rate (LDR – 11 Gy) or high dose-rate (HDR – 3 fractions of 3.0 Gy) brachytherapy. The primary endpoint was 3-year overall survival (OS) and secondary endpoints were: local control, regional control, distant metastasis and grade 3–4 adverse events.
274 patients were randomized between September 2004 and December 2008. The two arms were comparable with regard to age, gender, stage and grade. 273 patients completed treatment. Median follow-up was 29 months (0.2-67 months). The effect of treatment arm, country, age, gender, WHO pathology, stage (T3-4, N2-3 versus other) and chemotherapy on overall survival (OS), disease-free survival (DFS) and local recurrence-free survival (LRFS) was studied. Stage significantly affected OS (p = 0.024) and DFS (p = 0.018) while age significantly affected OS (p = 0.014). None of the other factors studied were significant. The 3-year LRFS was 60.5% and 54.4% in arms A and B respectively (p = 0.647). The 3-year regional control rate in the neck was 59.7% and 54.3% respectively (p = 0.7). Distant metastasis developed in 59.7% of patients in arm A and 55.4% in arm B (p = 0.377). Patients with T1/T2 N + had a 3 year LRFS of 51.8% in Arm A (62 patients) versus 57.9% in Arm B (67 patients) (p = 0.343). The grade 3–4 toxicity rate was 21.6% (30/139) and 24.4% (33/135) respectively (p = 0.687).
The addition of a brachytherapy boost to external beam radiotherapy and chemotherapy did not improve outcome in loco-regionally advanced nasopharyngeal carcinoma.
PMCID: PMC4018980  PMID: 24581393
Nasopharynx; Nasopharyngeal carcinoma; Brachytherapy boost

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