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1.  High Dose Rate versus Low Dose Rate Brachytherapy for Oral Cancer – A Meta-Analysis of Clinical Trials 
PLoS ONE  2013;8(6):e65423.
Objective
To compare the efficacy and safety of high dose rate (HDR) and low dose rate (LDR) brachytherapy in treating early-stage oral cancer.
Data Sources
A systematic search of MEDLINE, EMBASE and Cochrane Library databases, restricted to English language up to June 1, 2012, was performed to identify potentially relevant studies.
Study Selection
Only randomized controlled trials (RCT) and controlled trials that compared HDR to LDR brachytherapy in treatment of early-stage oral cancer (stages I, II and III) were of interest.
Data Extraction and Synthesis
Two investigators independently extracted data from retrieved studies and controversies were solved by discussion. Meta-analysis was performed using RevMan 5.1. One RCT and five controlled trials (607 patients: 447 for LDR and 160 for HDR) met the inclusion criteria. The odds ratio showed no statistically significant difference between LDR group and HDR group in terms of local recurrence (OR = 1.12, CI 95% 0.62–2.01), overall mortality (OR = 1.01, CI 95% 0.61–1.66) and Grade 3/4 complications (OR = 0.86, CI 95% 0.52–1.42).
Conclusions
This meta-analysis indicated that HDR brachytherapy was a comparable alternative to LDR brachytherapy in treatment of oral cancer. HDR brachytherapy might become a routine choice for early-stage oral cancer in the future.
doi:10.1371/journal.pone.0065423
PMCID: PMC3677879  PMID: 23762369
2.  Low-dose-rate or high-dose-rate brachytherapy in treatment of prostate cancer – between options 
Purpose
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.
Conclusions
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.
doi:10.5114/jcb.2013.34342
PMCID: PMC3635047  PMID: 23634153
brachytherapy; HDR; LDR; prostate cancer; seeds
3.  High dose rate brachytherapy for oral cancer 
Journal of Radiation Research  2012;54(1):1-17.
Brachytherapy results in better dose distribution compared with other treatments because of steep dose reduction in the surrounding normal tissues. Excellent local control rates and acceptable side effects have been demonstrated with brachytherapy as a sole treatment modality, a postoperative method, and a method of reirradiation. Low-dose-rate (LDR) brachytherapy has been employed worldwide for its superior outcome. With the advent of technology, high-dose-rate (HDR) brachytherapy has enabled health care providers to avoid radiation exposure. This therapy has been used for treating many types of cancer such as gynecological cancer, breast cancer, and prostate cancer. However, LDR and pulsed-dose-rate interstitial brachytherapies have been mainstays for head and neck cancer. HDR brachytherapy has not become widely used in the radiotherapy community for treating head and neck cancer because of lack of experience and biological concerns. On the other hand, because HDR brachytherapy is less time-consuming, treatment can occasionally be administered on an outpatient basis. For the convenience and safety of patients and medical staff, HDR brachytherapy should be explored. To enhance the role of this therapy in treatment of head and neck lesions, we have reviewed its outcomes with oral cancer, including Phase I/II to Phase III studies, evaluating this technique in terms of safety and efficacy. In particular, our studies have shown that superficial tumors can be treated using a non-invasive mold technique on an outpatient basis without adverse reactions. The next generation of image-guided brachytherapy using HDR has been discussed. In conclusion, although concrete evidence is yet to be produced with a sophisticated study in a reproducible manner, HDR brachytherapy remains an important option for treatment of oral cancer.
doi:10.1093/jrr/rrs103
PMCID: PMC3534285  PMID: 23179377
brachytherapy; oral cancer; high dose rate
4.  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.
doi:10.5114/wo.2013.38557
PMCID: PMC3934024  PMID: 24596528
HDR brachytherapy; LDR brachytherapy; prostate cancer; seeds
5.  Low-Dose-Rate Definitive Brachytherapy for High-Grade Vaginal Intraepithelial Neoplasia 
The Oncologist  2011;16(2):182-188.
The efficacy and safety results of treatment with low-dose-rate vaginal brachytherapy for grade 3 vaginal intraepithelial neoplasia over a 25-year period at Gustave Roussy Institute are presented. This treatment was found to be both safe and effective.
Learning Objectives
After completing this course, the reader will be able to: Utilize data supporting the efficacy of low-dose definitive brachytherapy to inform clinical decisions about treating women with high-grade vaginal intraepithelial neoplasia.Implement methods for delivering low-dose definitive brachytherapy that minimize toxicity.Communicate to patients the type and incidence of toxic events associated with low-dose definitive brachytherapy.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
Treatment of high-grade vaginal intraepithelial neoplasia (VAIN) is controversial and could include surgical excision, topical medication, brachytherapy, or other treatments. We report the results of low-dose-rate (LDR) vaginal brachytherapy for grade 3 VAIN (VAIN-3) over a 25-year period at Gustave Roussy Institute.
Patients and Methods.
We retrospectively reviewed the files of all patients treated at Gustave Roussy Institute for VAIN-3 since 1985. The treatment consisted of LDR brachytherapy using a personalized vaginal mold and delivered 60 Gy to 5 mm below the vaginal mucosa. All patients had at least an annual gynecological examination, including a vaginal smear.
Results.
Twenty-eight patients were eligible. The median follow-up was 41 months. Seven patients had a follow-up <2 years, and the median follow-up for the remaining 21 patients was 79 months. The median age at brachytherapy was 63 years (range, 38–80 years). Twenty-six patients had a history of VAIN recurring after cervical intraepithelial neoplasia and 24 had a previous hysterectomy. The median brachytherapy duration was 4.5 days. Median doses to the International Commission of Radiation Units and Measurements rectum and bladder points were 68 Gy and 45 Gy, respectively. The median prescription volume (60 Gy) was 74 cm3. Only one “in field” recurrence occurred, corresponding to a 5- and 10-year local control rate of 93% (95% confidence interval, 70%–99%). The treatment was well tolerated, with no grade 3 or 4 late toxicity and only one grade 2 digestive toxicity. No second cancers were reported.
Conclusion.
LDR brachytherapy is an effective and safe treatment for vaginal intraepithelial neoplasia.
doi:10.1634/theoncologist.2010-0326
PMCID: PMC3228085  PMID: 21262875
Vaginal neoplasms; Carcinoma in situ; Cervical intraepithelial neoplasia; Brachytherapy
6.  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.
doi:10.1093/jrr/rrt028
PMCID: PMC3766300  PMID: 23559599
primary vaginal cancer; radiation therapy; high-dose-rate brachytherapy; intracavitary brachytherapy; interstitial brachytherapy
7.  The use of nomograms in LDR-HDR prostate brachytherapy 
Purpose
The common use of nomograms in Low Dose Rate (LDR) permanent prostate brachytherapy (BT) allows to estimate the number of seeds required for an implant. Independent dosimetry verification is recommended for each clinical dosimetry in BT. Also, nomograms can be useful for dose calculation quality assurance and they could be adapted to High Dose Rate (HDR). This work sets nomograms for LDR and HDR prostate-BT implants, which are applied to three different institutions that use different implant techniques.
Material and methods
Patients treated throughout 2010 till April 2011 were considered for this study. This example was chosen to be the representative of the latest implant techniques and to ensure consistency in the planning. A sufficient number of cases for both BT modalities, prescription dose and different work methodology (depending on the institution) were taken into account. The specific nomograms were built using the correlation between the prostate volume and some characteristic parameters of each BT modality, such as the source Air Kerma Strength, number of implanted seeds in LDR or total radiation time in HDR.
Results
For each institution and BT modality, nomograms normalized to the prescribed dose were obtained and fitted to a linear function. The parameters of the adjustment show a good agreement between data and the fitting. It should be noted that for each institution these linear function parameters are different, indicating that each centre should construct its own nomograms.
Conclusions
Nomograms for LDR and HDR prostate brachytherapy are simple quality assurance tools, specific for each institution. Nevertheless, their use should be complementary to the necessary independent verification.
doi:10.5114/jcb.2011.24817
PMCID: PMC3551356  PMID: 23346120
nomograms; prostate brachytherapy; quality assurance; independent verification
8.  Suitability of point kernel dose calculation techniques in brachytherapy treatment planning 
Brachytherapy treatment planning system (TPS) is necessary to estimate the dose to target volume and organ at risk (OAR). TPS is always recommended to account for the effect of tissue, applicator and shielding material heterogeneities exist in applicators. However, most brachytherapy TPS software packages estimate the absorbed dose at a point, taking care of only the contributions of individual sources and the source distribution, neglecting the dose perturbations arising from the applicator design and construction. There are some degrees of uncertainties in dose rate estimations under realistic clinical conditions. In this regard, an attempt is made to explore the suitability of point kernels for brachytherapy dose rate calculations and develop new interactive brachytherapy package, named as BrachyTPS, to suit the clinical conditions. BrachyTPS is an interactive point kernel code package developed to perform independent dose rate calculations by taking into account the effect of these heterogeneities, using two regions build up factors, proposed by Kalos. The primary aim of this study is to validate the developed point kernel code package integrated with treatment planning computational systems against the Monte Carlo (MC) results. In the present work, three brachytherapy applicators commonly used in the treatment of uterine cervical carcinoma, namely (i) Board of Radiation Isotope and Technology (BRIT) low dose rate (LDR) applicator and (ii) Fletcher Green type LDR applicator (iii) Fletcher Williamson high dose rate (HDR) applicator, are studied to test the accuracy of the software. Dose rates computed using the developed code are compared with the relevant results of the MC simulations. Further, attempts are also made to study the dose rate distribution around the commercially available shielded vaginal applicator set (Nucletron). The percentage deviations of BrachyTPS computed dose rate values from the MC results are observed to be within plus/minus 5.5% for BRIT LDR applicator, found to vary from 2.6 to 5.1% for Fletcher green type LDR applicator and are up to −4.7% for Fletcher-Williamson HDR applicator. The isodose distribution plots also show good agreements with the results of previous literatures. The isodose distributions around the shielded vaginal cylinder computed using BrachyTPS code show better agreement (less than two per cent deviation) with MC results in the unshielded region compared to shielded region, where the deviations are observed up to five per cent. The present study implies that the accurate and fast validation of complicated treatment planning calculations is possible with the point kernel code package.
doi:10.4103/0971-6203.62202
PMCID: PMC2884310  PMID: 20589118
Brachytherapy; cervical cancer; low dose rate; treatment planning system; point kernel code; Monte Carlo
9.  Brachytherapy boost in loco-regionally advanced nasopharyngeal carcinoma: a prospective randomized trial of the International Atomic Energy Agency 
Abstact
Background
The purpose was to determine whether a brachytherapy boost improves outcomes in patients with advanced nasopharyngeal carcinoma treated with standard chemo-radiotherapy.
Methods
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.
Results
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).
Conclusions
The addition of a brachytherapy boost to external beam radiotherapy and chemotherapy did not improve outcome in loco-regionally advanced nasopharyngeal carcinoma.
doi:10.1186/1748-717X-9-67
PMCID: PMC4018980  PMID: 24581393
Nasopharynx; Nasopharyngeal carcinoma; Brachytherapy boost
10.  Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer 
Radiotherapy and Oncology  2011;100(1):116-123.
Background
To analyse the overall clinical outcome and benefits by applying protocol based image guided adaptive brachytherapy combined with 3D conformal external beam radiotherapy (EBRT) ± chemotherapy (ChT).
Methods
Treatment schedule was EBRT with 45–50.4 Gy ± concomitant cisplatin chemotherapy plus 4 × 7 Gy High Dose Rate (HDR) brachytherapy. Patients were treated in the “protocol period” (2001–2008) with the prospective application of the High Risk CTV concept (D90) and dose volume constraints for organs at risk including biological modelling. Dose volume adaptation was performed with the aim of dose escalation in large tumours (prescribed D90 > 85 Gy), often with inserting additional interstitial needles. Dose volume constraints (D2cc) were 70–75 Gy for rectum and sigmoid and 90 Gy for bladder.
Late morbidity was prospectively scored, using LENT/SOMA Score. Disease outcome and treatment related late morbidity were evaluated and compared using actuarial analysis.
Findings
One hundred and fifty-six consecutive patients (median age 58 years) with cervix cancer FIGO stages IB–IVA were treated with definitive radiotherapy in curative intent. Histology was squamous cell cancer in 134 patients (86%), tumour size was >5 cm in 103 patients (66%), lymph node involvement in 75 patients (48%). Median follow-up was 42 months for all patients.
Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 (44%) patients. Total prescribed mean dose (D90) was 93 ± 13 Gy, D2cc 86 ± 17 Gy for bladder, 65 ± 9 Gy for rectum and 64 ± 9 Gy for sigmoid.
Complete remission was achieved in 151/156 patients (97%). Overall local control at 3 years was 95%; 98% for tumours 2–5 cm, and 92% for tumours >5 cm (p = 0.04), 100% for IB, 96% for IIB, 86% for IIIB. Cancer specific survival at 3 years was overall 74%, 83% for tumours 2–5 cm, 70% for tumours >5 cm, 83% for IB, 84% for IIB, 52% for IIIB. Overall survival at 3 years was in total 68%, 72% for tumours 2–5 cm, 65% for tumours >5 cm, 74% for IB, 78% for IIB, 45% for IIIB.
In regard to late morbidity in total 188 grade 1 + 2 and 11 grade 3 + 4 late events were observed in 143 patients. G1 + 2/G3 + 4 events for bladder were n = 32/3, for rectum n = 14/5, for bowel (including sigmoid) n = 3/0, for vagina n = 128/2, respectively.
Interpretation
3D conformal radiotherapy ± chemotherapy plus image (MRI) guided adaptive intracavitary brachytherapy including needle insertion in advanced disease results in local control rates of 95–100% at 3 years in limited/favourable (IB/IIB) and 85–90% in large/poor response (IIB/III/IV) cervix cancer patients associated with a moderate rate of treatment related morbidity. Compared to the historical Vienna series there is relative reduction in pelvic recurrence by 65–70% and reduction in major morbidity. The local control improvement seems to have impact on CSS and OS. Prospective clinical multi-centre studies are mandatory to evaluate these challenging mono-institutional findings.
doi:10.1016/j.radonc.2011.07.012
PMCID: PMC3165100  PMID: 21821305
Cervical cancer; Image guided adaptive brachytherapy; Clinical outcome; GEC-ESTRO recommendations
11.  Sigmoid Dose Using 3D Imaging in Cervical-Cancer Brachytherapy 
Background and Purpose
To evaluate the proximity, variance, predictors of dose, and complications to the sigmoid in cervical-cancer brachytherapy using 3D planning.
Materials and Methods
Over 36 months, 50 patients were treated for cervical cancer with either low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy. The distance from the central tandem to the sigmoid, the D0.1cc and the D2cc to the sigmoid, rectum and bladder doses, and toxicity were analyzed.
Results
The median sigmoid EQD2 D0.1cc and D2cc were 84 Gy and 68.3 Gy for HDR versus 71.1 Gy and 65.9 Gy for LDR (p=0.02 and 0.98, respectively). Twenty percent of the HDR fractions required manipulation of the superior dwell positions to decrease the sigmoid dose. The median distance from the sigmoid to the tandem was 1.7 cm (range [rg], 0.1 – 6.16 cm) for HDR and 2.7 cm (rg, 1.17 – 4.52 cm) for LDR; from the sigmoid to the 100% isodose region the median distances were – 0.1 cm (rg, -1.4 – 2.5 cm) and 0.44 cm (rg. -0.73 – 5.2 cm), respectively. The proximity of the sigmoid to the tandem is significantly related to sigmoid dose (p<0.0001). Within-patient (among-fraction) variation in sigmoid-to-tandem distance during HDR was substantial (coefficient of variation = 40%). No grade 3-4 sigmoid toxicity was seen after a median 31-month follow-up period.
Conclusions
3D imaging in cervical cancer brachytherapy shows the sigmoid in close proximity to the tandem. The sigmoid to tandem distance varies substantially between fractions, indicating the importance of sigmoid dose-volume evaluation with each fraction.
doi:10.1016/j.radonc.2009.06.032
PMCID: PMC2867463  PMID: 19665244
cervical cancer; brachytherapy; normal tissue dose
12.  Salvage brachytherapy in prostate local recurrence after radiation therapy: predicting factors for control and toxicity 
Purpose
To evaluate efficacy and toxicity after salvage brachytherapy (BT) in prostate local recurrence after radiation therapy.
Methods and materials
Between 1993 and 2007, we retrospectively analyzed 56 consecutively patients (pts) undergoing salvage brachytherapy. After local biopsy-proven recurrence, pts received 145 Gy LDR-BT (37 pts, 66%) or HDR-BT (19 pts, 34%) in different dose levels according to biological equivalent doses (BED2 Gy). By the time of salvage BT, only 15 pts (27%) received ADT. Univariate and multivariate analyses were performed to identify predictors of biochemical control and toxicities. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities were graded using Common Terminology Criteria for Adverse Events (CTCv3.0).
Results
Median follow-up after salvage BT was 48 months. The 5-year FFbF was 77%. HDR and LDR late grade 3 GU toxicities were observed in 21% and 24%. Late grade 3 GI toxicities were observed in 2% (HDR) and 2.7% (LDR). On univariate analysis, pre-salvage prostate-specific antigen (PSA) > 10 ng/ml (p = 0.004), interval to relapse after initial treatment < 24 months (p = 0.004) and salvage HDR-BT doses BED2 Gy level < 227 Gy (p = 0.012) were significant in predicting biochemical failure. On Cox multivariate analysis, pre-salvage PSA, and time to relapse were significant in predicting biochemical failure.
HDR-BT BED2 Gy (α/β 1.5 Gy) levels ≥ 227 (p = 0.013), and ADT (p = 0.049) were significant in predicting grade ≥ 2 urinary toxicity.
Conclusions
Prostate BT is an effective salvage modality in some selected prostate local recurrence patients after radiation therapy. Even, we provide some potential predictors of biochemical control and toxicity for prostate salvage BT, further investigation is recommended.
doi:10.1186/1748-717X-9-102
PMCID: PMC4019368  PMID: 24885287
Salvage brachytherapy; Prostate cancer; High-dose-rate-brachytherapy; Low-dose-rate-brachytherapy; Androgen deprivation therapy
13.  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.
doi:10.3390/cancers3033585
PMCID: PMC3759211  PMID: 24212968
prostate cancer; high dose rate brachytherapy; external beam radiation therapy; radical prostatectomy
14.  The relationship between the biochemical control outcomes and the quality of planning of high-dose rate brachytherapy as a boost to external beam radiotherapy for locally and locally advanced prostate cancer using the RTOG-ASTRO Phoenix definition 
Purpose: To evaluated prognostic factors and impact of the quality of planning of high dose rate brachytherapy (HDR-BT) for patients with local or locally advanced prostate cancer treated with external beam radiotherapy (EBRT) and HDR-BT.
Methods and Materials: Between 1997 and 2005, 209 patients with biopsy proven prostate adenocarcinoma were treated with localized EBRT and HDR-BT at the Department of Radiation-Oncology, Hospital A. C. Camargo, Sao Paulo, Brazil. Patient's age, Gleason score (GS), clinical stage (CS), initial PSA (iPSA), risk group for biochemical failure (GR), doses of EBRT and HDR-BT, use of three-dimensional planning for HDR-BT (3DHDR) and the Biological Effective Dose (BED) were evaluated as prognostic factors for biochemical control (bC).
Results: Median age and median follow-up time were 68 and 5.3 years, respectively. Median EBRT and HDR-BT doses were 45 Gy and 20 Gy. The crude bC at 3.3 year was 94.2%. For the Low, intermediate and high risk patients the bC rates at 3.3 years were 91.5%, 90.2% and 88.5%, respectively. Overall survival (OS) and disease specific survival rates at 3.3 years were 97.8% and 98.4%, respectively. On univariate analysis the prognostic factors related bC were GR (p= 0.040), GS ≤ 6 (p= 0.002), total dose of HDR-BT ≥ 20 Gy (p< 0.001), 3DHDR (p< 0.001), BED-HDR ≥ 99 Gy1.5 (p<0.001) and BED-TT ≥ 185 (p<0.001). On multivariate analysis the statistical significant predictive factors related to bC were RG (p< 0.001), HDR-BT ≥ 20 Gy (p=0.008) and 3DHDR (p<0.001).
Conclusions: we observed that the bC rates correlates with the generally accepted risk factors described in the literature. Dose escalation, evaluated through the BED, and the quality of planning of HDR-BT are also important predictive factors when treating prostate cancer.
PMCID: PMC2424177  PMID: 18566673
high-dose rate brachytherapy; external beam radiotherapy; prostate cancer; RTOG-ASTRO Phoenix; biochemical failure; biochemical control
15.  Radical Radiotherapy for Locally Advanced Cancer of Uterine Cervix 
Purpose
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).
Results
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%).
Conclusion
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.
doi:10.4143/crt.2004.36.4.222
PMCID: PMC2843887  PMID: 20368838
Radiotherapy; Advanced cancer of the uterine cervix; High-dose rate brachytherapy
16.  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.
doi:10.4103/0971-6203.62201
PMCID: PMC2884303  PMID: 20589121
Brachytherapy; conformity; intensity modulated radiotherapy; prostate
17.  Acute complications following intracavitary high-dose-rate brachytherapy in uterine cancer 
Purpose
Almost 30% of malignancies in women of developing countries are gynecological and brachytherapy is an integral part of management of these patients. Reports of complications (both acute and late) of high-dose-rate (HDR) intracavitary brachytherapy are sparse in world literature due to relatively small number of gynecological malignancies, particularly in advanced stage, in developed countries. High-dose-rate brachytherapy is gaining popularity in developing countries due to scientific and economic reasons. Here we are reporting our experience regarding acute complications of intracavitary brachytherapy (events occurring within 30 days of insertion needing hospitalization or death) and their causes to improve the quality of management, so that the already low incidence of acute complications can be further reduced.
Material and methods
From February 2004 to December 2012, a total of 1947 patients with uterine cancer were treated by HDR intracavitary brachytherapy in the Department of Radiotherapy, of a tertiary cancer centre of a developing country, 86% of them were cervical cancer and 14% endometrial cancer. Excluding the post-operative patients, a total of 4285 insertions were done in 1527 patients with intact uterus (eligible for analysis) and acute complications were analyzed.
Results
Out of 4285 intracavitary brachytherapy insertions in gynecological malignancy patients, only 12 mortality and 239 morbidity instances needing hospitalization were documented and most of them were in cervical carcinoma patients.
Conclusions
Our results have indicated that acute complications can be minimized by pre-treatment management of co-morbidities, decreasing the time of operative lithotomy position and bed rest, avoidance of ‘conscious sedation’ in selected cases etc. Routine post insertion CT scan if done in all patients in all insertions, then only, uterine perforations can be detected early and prompt management can reduce both the mortality and morbidity to a great extent.
doi:10.5114/jcb.2014.45493
PMCID: PMC4200184  PMID: 25337129
acute complications; cervical cancer; HDR brachytherapy; intracavitary brachytherapy; uterine cancer
18.  Canadian prostate brachytherapy in 2012 
Prostate brachytherapy can be used as a monotherapy for low- and intermediate-risk patients or in combination with external beam radiation therapy (EBRT) as a form of dose escalation for selected intermediate- and high-risk patients. Prostate brachytherapy with either permanent implants (low dose rate [LDR]) or temporary implants (high dose rate [HDR]) is emerging as the most effective radiation treatment for prostate cancer. Several large Canadian brachytherapy programs were established in the mid- to late-1990s. Prostate brachytherapy is offered in British Columbia, Alberta, Manitoba, Ontario, Quebec and New Brunswick. We anticipate the need for brachytherapy services in Canada will significantly increase in the near future. In this review, we summarize brachytherapy programs across Canada, contemporary eligibility criteria for the procedure, toxicity and prostate-specific antigen recurrence free survival (PRFS), as published from Canadian institutions for both LDR and HDR brachytherapy.
doi:10.5489/cuaj.218
PMCID: PMC3650818  PMID: 23671495
19.  High-dose rate brachytherapy (HDRB) for primary or recurrent cancer in the vagina 
Purpose
The purpose of this study was to evaluate the efficacy of HDR brachytherapy for primary or recurrent vaginal cancer.
Methods
Between the years 2000 to 2006, 18 patients with primary or recurrent vaginal cancer were treated with brachytherapy (HDRB). Six patients had primary vaginal cancer (stage II to IVA) while 12 were treated for isolated vaginal recurrence (primary cervix = 4, vulva = 1 and endometrium = 7). Five patients had previous pelvic radiation therapy. All except one patient received external beam radiation therapy to a median dose of 45 Gy (range 31.2–55.8 Gy). The HDRB was intracavitary using a vaginal cylinder in 5 patients and interstitial using a modified Syed-Nesblett template in 13 patients. The dose of interstitial brachytherapy was 18.75 Gy in 5 fractions delivered twice daily. The median follow-up was 18 months (range 6–66 months).
Results
Complete response (CR) was achieved in all but one patient (94%). Of these 17 patients achieving a CR, 1 had local recurrence and 3 had systemic recurrence at a median time of 6 months (range 6–22 months). The 2-year actuarial local control and cause-specific survival for the entire group were 88% and 82.5%, respectively. In subset analysis, the crude local control was 100% for primary vaginal cancer, 100% for the group with recurrence without any prior radiation and 67% for group with recurrence and prior radiation therapy. Two patients had late grade 3 or higher morbidity (rectovaginal fistula in one patient and chronic vaginal ulcer resulting in bleeding in one patient). Both these patients had prior radiation therapy.
Conclusion
Our small series suggests that HDRB is efficacious for primary or recurrent vaginal cancer. Patients treated with primary disease and those with recurrent disease without prior irradiation have the greatest benefit from HDRB in this setting. The salvage rate for patients with prior radiation therapy is lower with a higher risk of significant complications. Additional patients and follow-up are ongoing to determine the long-term efficacy of this approach.
doi:10.1186/1748-717X-3-7
PMCID: PMC2270281  PMID: 18271958
20.  A Phase II Trial of Brachytherapy Alone Following Lumpectomy for Select Breast Cancer: tumor control and survival outcomes of RTOG 95-17 
Purpose:
RTOG 95-17 is a prospective Phase II cooperative group trial of APBI alone using multicatheter brachytherapy following lumpectomy in select early stage breast cancers. Tumor control and survival outcomes are reported.
Materials and Methods:
Eligibility criteria included stage I/II breast carcinoma confirmed to be <3cm, unifocal, invasive non-lobular histology with 0-3 positive axillary nodes without extracapsular extension. APBI treatment was delivered with either Low Dose Rate (LDR) (45 Gy in 3.5-5 days) or High Dose Rate (HDR) (34 Gy in 10 BID fractions over 5 days). Endpoints evaluated included in-breast control, regional control, mastectomy-free rate, mastectomy-free survival, disease-free survival and overall survival. The study was designed to analyze the HDR and LDR groups separately and without comparison.
Results:
Between 1997 and 2000, 100 patients were accrued and 99 were eligible; 66 treated with HDR and 33 treated with LDR. Eighty seven patients had T1 lesions and 12 had T2 lesions. Seventy nine were pathologically N0 and 20 were N1. Median follow-up in the HDR group is 6.14 years with the 5-year estimates of in-breast, regional and contralateral failure rates of 3%, 5% and 2%, respectively. The LDR group experienced similar results with a median follow-up of 6.22 years. The 5-year estimates of in-breast, regional and contralateral failure rates of 6%, 0% and 6%, respectively.
Conclusion:
Patients treated with multicatheter partial breast brachytherapy on this trial experienced excellent in-breast control rates and overall outcome that compare to reports from APBI studies with similar extended follow-up.
doi:10.1016/j.ijrobp.2007.12.056
PMCID: PMC2604132  PMID: 18294778
Brachytherapy; breast cancer; breast cancer trials; radiation therapy for breast cancer; accelerated partial breast irradiation
21.  International Brachytherapy Practice Patterns: A Survey of the Gynecologic Cancer Intergroup (GCIG) 
Purpose
To determine current practice patterns with regard to gynecologic high-dose-rate (HDR) brachytherapy among international members of the Gynecologic Cancer Intergroup (GCIG) in Japan/Korea (Asia), Australia/New Zealand (ANZ), Europe (E) and North America (NAm).
Materials and Methods
A 32-item survey was developed requesting information on brachytherapy practice patterns and standard management for Stage IB-IVA cervical cancer. The chair of each GCIG member cooperative group selected radiation oncology members to receive the survey.
Results
A total of 72 responses were analyzed; 61 respondents (85%) utilized HDR. The three most common HDR brachytherapy fractionation regimens for Stage IB-IIA patients were 6 Gy for 5 fractions (18%), 6 Gy × 4 (15%), 7 Gy × 3 (11%), and for Stage IIB-IVA patients were 6 Gy for 5 fractions (19%), 7 Gy × 4 (8%), and 7 Gy × 3 (8%). Overall, the mean combined external-beam and brachytherapy equivalent dose (EQD2) was 81.1 (standard deviation [SD], 10.16). The mean EQD2 recommended for Stage IB-IIA patients was 78.9 Gy (SD, 10.7) and for Stage IIB-IVA was 83.3 Gy (SD, 11.2) (p=0.02). By region, the mean combined EQD2 was: Asia, 71.2 Gy (SD, 12.65); ANZ, 81.18 (SD, 4.96); E, 83.24 (SD, 10.75); and NAm, 81.66 (SD, 6.05; p=0.02 for Asia vs. other regions). The ratio of brachytherapy to total prescribed dose was significantly higher for Japan (p=0.0002).
Conclusion
Although fractionation patterns may vary, the overall mean dose administered for cervical cancer is similar in Australia/New Zealand, Europe and North America, with practitioners in Japan administering a significantly lower external-beam dose but higher brachytherapy dose to the cervix. Given common goals, standardization should be possible in future clinical trials.
doi:10.1016/j.ijrobp.2010.10.030
PMCID: PMC3489266  PMID: 21183288
brachytherapy; cervical cancer; radiation dose
22.  Reirradiation of recurrent head and neck cancer using high-dose-rate brachytherapy 
SUMMARY
The aim of the present study was to evaluate the results of hypofractionated accelerated CT-guided interstitial HDR-BRT using 2.5 Gy per fraction. From December 2008 to March 2010, 30 patients were treated for recurrence of previously-irradiated head and neck cancer. Thirteen patients underwent surgical resection followed by HDR-BRT to the tumour bed. Seventeen patients were treated with HDR-BRT only. All patients received 2.5 Gy twice per day for a total dosage of 30 Gy. The overall survival rate (OS) for the entire group at 1 and 2-years was 63% and 47%, while local control (LC) was 73% and 67%, and disease-free survival (DFS) was 60% and 53%, respectively. Patients treated with surgical resection and HDR-BRT showed an improvement in both 2-year LC (77% vs. 47%, p = 0.013) and 2-year OS (62% vs. 35%, p = 0.035) compared to patients treated with HDR-BRT only. Median OS for pre-treatment tumour volumes ≤ 36 cm3 was 22 months and 9.2 months for those > 36 cm3 (p = 0.038). Grade III and IV late complications occurred in 3% of patients. There were no grade V complications. The interstitial HDR brachytherapy regimen using 2.5 Gy twice daily fractions at a total dose of 30 Gy offers an effective treatment option for patients with recurrent previously-irradiated head and neck cancer with a low rate of late high grade toxicity. Surgical resection had a positive effect on survival and local control in management of patients with recurrent head and neck cancer.
PMCID: PMC3546407  PMID: 23326008
Head and neck cancer; HDR brachytherapy; Reirradiation
23.  Outcomes of Gleason Score ≤8 among High Risk Prostate Cancer Treated with 125I Low Dose Rate Brachytherapy Based Multimodal Therapy 
Yonsei Medical Journal  2013;54(5):1207-1213.
Purpose
To investigate the role of low dose rate (LDR) brachytherapy-based multimodal therapy in high-risk prostate cancer (PCa) and analyze its optimal indications.
Materials and Methods
We reviewed the records of 50 high-risk PCa patients [clinical stage ≥T2c, prostate-specific antigen (PSA) >20 ng/mL, or biopsy Gleason score ≥8] who had undergone 125I LDR brachytherapy since April 2007. We excluded those with a follow-up period <3 years. Biochemical recurrence (BCR) followed the Phoenix definition. BCR-free survival rates were compared between the patients with Gleason score ≥9 and Gleason score ≤8.
Results
The mean initial PSA was 22.1 ng/mL, and mean D90 was 244.3 Gy. During a median follow-up of 39.2 months, biochemical control was obtained in 72% (36/50) of the total patients; The estimated 3-year BCR-free survival was 92% for the patients with biopsy Gleason scores ≤8, and 40% for those with Gleason scores ≥9 (p<0.001). In Cox multivariate analysis, only Gleason score ≥9 was observed to be significantly associated with BCR (p=0.021). Acute and late grade ≥3 toxicities were observed in 20% (10/50) and 36% (18/50) patients, respectively.
Conclusion
Our results showed that 125I LDR brachytherapy-based multimodal therapy in high-risk PCa produced encouraging relatively long-term results among the Asian population, especially in patients with Gleason score ≤8. Despite small number of subjects, biopsy Gleason score ≥9 was a significant predictor of BCR among high risk PCa patients after brachytherapy.
doi:10.3349/ymj.2013.54.5.1207
PMCID: PMC3743192  PMID: 23918571
Prostate cancer; brachytherapy; high risk group; biochemical recurrence
24.  Age is not a limiting factor for brachytherapy for carcinoma of the node negative oral tongue in patients aged eighty or older 
Background
To examine the role of brachytherapy for aged patients 80 or more in the trend of rapidly increasing number.
Methods
We examined the outcomes for elderly patients with node negative oral tongue cancer (T1-3N0M0) treated with brachytherapy. The 21 patients (2 T1, 14 T2, and 5 T3 cases) ranged in age from 80 to 89 years (median 81), and their cancer was pathologically confirmed. All patients underwent definitive radiation therapy, with low dose rate (LDR) Ra-226 brachytherapy (n = 4; median 70Gy), with Ir-192 (n = 12; 70Gy), with Au-198 (n = 1) or with high dose rate (HDR) Ir-192 brachytherapy (n = 4; 60 Gy). Eight patients also underwent external radiotherapy (median 30 Gy). The period of observation ranged from 13 months to 14 years (median 2.5 years). We selected 226 population matched younger counterpart from our medical chart.
Results
Definitive radiation therapy was completed for all 21 patients (100%), and acute grade 2-3 mucositis related to the therapy was tolerable. Local control (initial complete response) was attained in 19 of 21 patients (90%). The 2-year and 5-year local control rates were 91%, (100% for T1, 83% for T2 and 80% for T3 tumors after 2 years). These figures was not inferior to that of younger counterpart (82% at 5-year, n.s.). The cause-specific survival rate was 83% and the regional control rate 84% at the 2-years follow-up. However, 12 patients died because of intercurrent diseases or senility, resulting in overall survival rates of 55% at 2 years and 34% at 5 years.
Conclusion
Age is not a limiting factor for brachytherapy for appropriately selected elderly patients, and brachytherapy achieved good local control with acceptable morbidity.
doi:10.1186/1748-717X-5-116
PMCID: PMC3016284  PMID: 21143904
25.  The American Brachytherapy Society Treatment Recommendations for Locally Advanced Carcinoma of the Cervix Part II: High Dose-Rate Brachytherapy 
Brachytherapy  2012;11(1):47-52.
Purpose
This report presents the 2011 update to the American Brachytherapy Society (ABS) high-dose-rate (HDR) brachytherapy guidelines for locally advanced cervical cancer.
Methods
Members of the American Brachytherapy Society (ABS) with expertise in cervical cancer brachytherapy formulated updated guidelines for HDR brachytherapy using tandem and ring, ovoids, cylinder or interstitial applicators for locally advanced cervical cancer were revised based on medical evidence in the literature and input of clinical experts in gynecologic brachytherapy.
Results
The Cervical Cancer Committee for Guideline Development affirms the essential curative role of tandem-based brachytherapy in the management of locally advanced cervical cancer. Proper applicator selection, insertion, and imaging are fundamental aspects of the procedure. Three-dimensional imaging with magnetic resonance or computed tomography or radiographic imaging may be used for treatment planning. Dosimetry must be performed after each insertion prior to treatment delivery. Applicator placement, dose specification and dose fractionation must be documented, quality assurance measures must be performed, and follow-up information must be obtained. A variety of dose/fractionation schedules and methods for integrating brachytherapy with external-beam radiation exist. The recommended tumor dose in 2 Gray (Gy) per fraction radiobiologic equivalence (EQD2) is 80–90 Gy, depending on tumor size at the time of brachytherapy. Dose limits for normal tissues are discussed.
Conclusion
These guidelines update those of 2000 and provide a comprehensive description of HDR cervical cancer brachytherapy in 2011.
doi:10.1016/j.brachy.2011.07.002
PMCID: PMC3489267  PMID: 22265437

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