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1.  Image-based brachytherapy for cervical cancer 
Cervical cancer is the third most common cancer in women worldwide; definitive radiation therapy and concurrent chemotherapy is the accepted standard of care for patients with node positive or locally advanced tumors > 4 cm. Brachytherapy is an important part of definitive radiotherapy shown to improve overall survival. While results for two-dimensional X-ray based brachytherapy have been good in terms of local control especially for early stage disease, unexplained toxicities and treatment failures remain. Improvements in brachytherapy planning have more recently paved the way for three-dimensional image-based brachytherapy with volumetric optimization which increases tumor control, reduces toxicity, and helps predict outcomes. Advantages of image-based brachytherapy include: improved tumor coverage (especially for large volume disease), decreased dose to critical organs (especially for small cervix), confirmation of applicator placement, and accounting for sigmoid colon dose. A number of modalities for image-based brachytherapy have emerged including: magnetic resonance imaging (MRI), computed tomography (CT), CT-MRI hybrid, and ultrasound with respective benefits and outcomes data. For practical application of image-based brachytherapy the Groupe Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology Working Group and American Brachytherapy Society working group guideline serve as invaluable tools, additionally here-in we outline our institutional clinical integration of these guidelines. While the body of literature supporting image-based brachytherapy continues to evolve a number of uncertainties and challenges remain including: applicator reconstruction, increasing resource/cost demands, mobile four-dimensional targets and organs-at-risk, and accurate contouring of “grey zones” to avoid marginal miss. Ongoing studies, including the prospective EMBRACE (an international study of MRI-guided brachytherapy in locally advanced cervical cancer) trial, along with continued improvements in imaging, contouring, quality assurance, physics, and brachytherapy delivery promise to perpetuate the advancement of image-based brachytherapy to optimize outcomes for cervical cancer patients.
doi:10.5306/wjco.v5.i5.921
PMCID: PMC4259954  PMID: 25493230
Cervical cancer; Brachytherapy; Image-based brachytherapy; 3D-planning; Magnetic resonance imaging-based brachytherapy; Groupe Europeen de Curietherapie-European Society for Therapeutic Radiology and Oncology Working Group guidelines
2.  Mapping of dose distribution from IMRT onto MRI-guided high dose rate brachytherapy using deformable image registration for cervical cancer treatments: preliminary study with commercially available software 
Purpose
For patients undergoing external beam radiation therapy (EBRT) and brachytherapy, recommendations for target doses and constraints are based on calculation of the equivalent dose in 2 Gy fractions (EQD2) from each phase. At present, the EBRT dose distribution is assumed to be uniform throughout the pelvis. We performed a preliminary study to determine whether deformable dose distribution mapping from the EBRT onto magnetic resonance (MR) images for the brachytherapy would yield differences in doses for organs at risk (OARs) and high-risk clinical target volume (HR-CTV).
Material and methods
Nine cervical cancer patients were treated to a total dose of 45 Gy in 25 fractions using intensity-modulated radiation therapy (IMRT), followed by MRI-based 3D high dose rate (HDR) brachytherapy. Retrospectively, the IMRT planning CT images were fused with the MR image for each fraction of brachytherapy using deformable image registration. The deformed IMRT dose onto MR images were converted to EQD2 and compared to the uniform dose assumption.
Results
For all patients, the EQD2 from the EBRT phase was significantly higher with deformable registration than with the conventional uniform dose distribution assumption. The mean EQD2 ± SD for HR-CTV D90 was 45.7 ± 0.7 Gy vs. 44.3 Gy for deformable vs. uniform dose distribution, respectively (p < 0.001). The dose to 2 cc of the bladder, rectum, and sigmoid was 46.4 ± 1.2 Gy, 46.2 ± 1.0 Gy, and 48.0 ± 2.5 Gy, respectively with deformable dose distribution, and was significantly higher than with uniform dose distribution (43.2 Gy for all OAR, p < 0.001).
Conclusions
This study reveals that deformed EBRT dose distribution to HR-CTV and OARs in MR images for brachytherapy is technically feasible, and achieves differences compared to a uniform dose distribution. Therefore, the assumption that EBRT contributes the same dose value may need to be carefully investigated further based on deformable image registration.
doi:10.5114/jcb.2014.43240
PMCID: PMC4105642  PMID: 25097559
cervical cancer; deformable image registration; IMRT; MRI
3.  Image guided adaptive brachytherapy for cervical cancer: dose contribution to involved pelvic nodes in two cancer centers 
Purpose
The goal of this study was to determine the dose contributions from image guided adaptive brachytherapy (IGABT) to individual suspicious pelvic lymph nodes (pLNN) in cervical cancer patients. Data were collected in two cancer centers, University of Pittsburgh Cancer Institute (UPCI) and University Medical Center Utrecht (UMCU).
Material and methods
27 and 15 patients with node positive cervical cancer treated with HDR (high dose rate) or PDR (pulsed dose rate)-IGABT were analyzed. HDR-IGABT (UPCI) was delivered with CT/MRI compatible tandem-ring applicators with 5.0-6.0 Gy × five fractions. PDR-IGABT (UMCU) dose was delivered with Utrecht tandem-ovoid applicators with 32 × 0.6 Gy × two fractions. Pelvic lymph nodes with short axis diameter of ≥ 5 mm on pre-treatment MRI or PET-CT were contoured for all BT-plans. Dose contributions to individual pLNN expressed as D90 (dose to 90% of the volume) were calculated from dose-volume histograms as absolute and relative physical dose (% of the reference dose) for each fraction. For each node, the total dose from all fractions was calculated, expressed in EQD2 (equivalent total dose in 2 Gy fractions).
Results
Fifty-seven (UPCI) and 40 (UMCU) individual pLNN were contoured. The mean D90 pLNN was 10.8% (range 5.7-25.1%) and 20.5% (range 6.8-93.3%), respectively, and therefore different in the two centers. These values translate into 2.7 Gy (1.3-6.6 Gy) EQD2 and 7.1 Gy (2.2-36.7 Gy) EQD2, respectively. Differences are caused by the location of the individual nodes in relation to the spatial dose distribution of IGABT, differences in total dose administered and radiobiology (HDR versus PDR).
Conclusions
The IGABT dose contribution to individual pelvic nodes depends on patient and treatment related factors, and varies considerably.
doi:10.5114/jcb.2014.42021
PMCID: PMC4003428  PMID: 24790618
brachytherapy; cervical cancer; dosimetry; HDR; MRI-guidance; PDR
4.  Pretreatment SUVmax predicts progression-free survival in early-stage non-small cell lung cancer treated with stereotactic body radiation therapy 
Background
This retrospective study aims to assess the usefulness of SUVmax from FDG-PET imaging as a prognosticator for primary biopsy-proven stage I NSCLC treated with SBRT.
Methods
This study includes 95 patients of median age 77 years, with primary, biopsy-confirmed peripheral stage IA/IB NSCLC. All patients were treated with 60Gy in 3 fractions with a median treatment time of six days. Local, regional, and distant failures were evaluated independently according to the terms of RTOG1021. Local, regional, and distant control, overall- and progression-free survival were estimated by the Kaplan-Meier method. Cox proportional hazards regression was performed to determine whether SUVmax, age, KPS, gender, tumor size/T stage, or smoking history influenced outcomes. SUVmax was evaluated as both a continuous and as a dichotomous variable using a cutoff of <5 and ≥5.
Results
Median follow-up for the cohort was 16 months. Median OS and PFS were 25.3 and 40.3 months, respectively. SUV with a cutoff value of 5 predicted for OS and PFS (p = .024 for each) but did not achieve significance for LC (p = .256). On Cox univariate regression analysis, SUV as a dichotomous variable predicted for both OS and PFS (p = .027 and p = .030, respectively). Defined as a continuous variable, SUVmax continued to predict for OS and PFS (p = .032 and p = .003), but also predicted LC (p = .045) and trended toward significance for DC (p = .059).
SUVmax did not predict for OS as a dichotomous or continuous variable. It did, however, predict for PFS as a continuous variable (p = .008), neared significance for local control (p = .057) and trended towards, significance for distant control (p = .092).
Conclusions
SUVmax appears to be a statistically and clinically significant independent prognostic marker for progression-free survival in patients with stage I NSCLC treated with SBRT. Prospective studies to more accurately define the role of tumor FDG uptake in the prognosis of NSCLC are warranted.
doi:10.1186/1748-717X-9-41
PMCID: PMC3922961  PMID: 24479954
5.  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
6.  Is there an advantage to delivering breast boost in the lateral decubitus position? 
Background
The purpose of this study was to compare the change in depth of target volume and dosimetric parameters between the supine and lateral decubitus positions for breast boost treatment with electron beam therapy.
Methods
We analyzed 45 patients who were treated, between 2009–2010, with whole breast radiation (WBRT) followed by a tumor bed boost in the lateral decubitius position. Tumor bed volume, distance from skin to the maximal depth of the tumor bed, D90 (dose covering 90% of the tumor bed volume), maximal dose, electron energy and doses to heart and lungs were compared. Additional variables of body mass index (BMI) and tumor bed location were also analyzed to see if there was a benefit limited to any subgroup.
Results
Median BMI for the 45 patients treated was 30.6 (20.6-42.4). When comparing the supine scan to the lateral decubitus scan, there was no significant difference in the tumor bed volume (p = 0.116). There was a significant difference between depth to the tumor bed in the supine scan and lateral decubitus scan (p < 0.001). The mean maximum doses and D90 between the two scans were 110.7 (100.0-133.0)% vs 106.1 (95.1-116.9)% (p < 0.05) and 93.9 (81.3-01.0-101.0)% vs. 98.2 (89.1-108.0)% (p = 0.004) respectively. There was no difference in dose delivered to the lungs or heart between the two scans (p = 0.848 and p = 0.992 respectively). On subset analysis, there was a difference in depth to tumor that was seen across all BMI classes, including normal (p ≤ 0.001, overweight (p ≤ 0.001) and obese (p ≤ 0.001). The majority of patients had a tumor in the upper outer quadrant (77.8%) and on subset analysis, there was a significant difference in tumor bed volume (p < 0.01), depth to tumor (p < 0.01), tumor bed coverage [D90] (p < 0.05), maximum dose (p < 0.05) and energy (p < 0.001) for this location.
Conclusions
Delivering a tumor bed boost in the lateral decubitus position reduces the distance to the tumor bed allowing for a lower energy treatment to be used to treat breast cancer. It improves coverage and decreases maximal dose to the target volume, all of which would help reduce skin morbidities and should be considered for patients with upper outer quadrant disease, irrespective of BMI status.
doi:10.1186/1748-717X-7-163
PMCID: PMC3508826  PMID: 23006598
Breast cancer; Body mass index; Electron beam therapy
7.  Changes in lower urinary tract symptoms after prostate brachytherapy 
Purpose
To further define the bothersome lower urinary tract symptoms that occur after prostate brachytherapy (PB) by evaluating patient's responses to the individual questions of the urinary portion of the Expanded Prostate Cancer Index Composite (EPIC) survey and the AUA symptoms score in men undergoing PB.
Material and methods
A longitudinal, prospective study of 170 patients who have undergone PB at a single institution was performed. All patients were asked to complete the EPIC survey pre-operatively and at 2 weeks, 4 weeks, 3 months, and 6 months post-operatively. Starting with the 75th patient in the cohort, patients were also asked to complete the AUA symptom score.
Results
The pattern of changes for each question is similar for both the EPIC survey and the AUA symptom score, with a marked worsening of symptoms at 2 and 4 weeks and an improvement to baseline by 3 to 6 months. Hematuria questions had the quickest and dysuria questions had the longest return to baseline. The dysuria questions had the greatest change and the incontinence questions had the smallest change in magnitude. Obstructive symptoms had a greater magnitude of change when compared to irritative symptoms, but the irritative symptoms took longer to return to baseline.
Conclusions
The present study adds to the fund of knowledge regarding the bothersome lower urinary tract symptoms which occur after PB by analyzing the individual questions of both the urinary portion of the EPIC survey and the AUA symptom score.
doi:10.5114/jcb.2011.24816
PMCID: PMC3551359  PMID: 23346119
brachytherapy; cesium-131; EPIC; quality of life
8.  Comparison of Locoregional Recurrence with Mastectomy vs. Breast Conserving Surgery in Pregnancy Associated Breast Cancer (PABC) 
Cancers  2009;1(1):12-20.
We have compared outcomes, including the locoregional recurrence, between mastectomy and breast conserving therapy in PABC. Patients were divided into those who were treated with mastectomies (group 1) and those with breast conserving surgery (group 2). The groups were comparable except for lower mean age in group 2 and more patients with stage III disease and higher number of nodes positive in the group 1. Five-year actuarial LRR, distant metastases free survival and overall survival in group 1 vs. 2 were 10% vs. 37%, 73% vs. 81% and 57% vs. 59% respectively. The patients with PABC treated with breast conserving therapy, despite having lower stage disease, have a higher risk of local regional recurrence in comparison with those treated with mastectomy.
doi:10.3390/cancers1010012
PMCID: PMC3757348  PMID: 24280969
pregnancy; cancer; surgery; mastectomy; breast conserving surgery
9.  Prevalence, Morphologic Features and Proliferation Indices of Breast Carcinoma Molecular Classes Using Immunohistochemical Surrogate Markers 
There is dearth of studies that provide a practical working formulation of breast cancer gene expression analysis for the surgical pathologist. ER, PR, HER2 were used as surrogate markers to classify 205 breast carcinomas into molecular classes. Ki-67 labeling index was calculated using an image analysis system. The data was analyzed for molecular class prevalence, and inter-relationships amongst morphologic parameters, Ki-67 index, and molecular classes. Of the 205 tumors, 113 (55%) were classified as luminal A (strong ER+, HER2 negative), 34 (17%) as luminal B (weak to moderate ER+, HER2 negative), 32 (15%) as triple negative (negative for ER/PR and HER2), 8 (4%) as ERBB2 (negative for ER/PR but HER2+), 10 (5%) as luminal A-HER2 hybrid (strong ER+ and HER2+), and 8 (4%) as luminal B-HER2 hybrid (weak to moderate ER+ and HER2+). The average Ki-67 index was lowest in luminal A (15.8%), intermediate for ERBB2 (27.8%) and highest for triple negative tumors (>50%). Multivariate logistic regression analyses found the following associations: ERBB2 tumors with apocrine differentiation (p=0.0031); Triple negative tumors with high Ki-67 index (p<0.0001) and CK5 positivity (p<0.0001); HER2 negative-low receptor positive tumors (luminal B) with increased lymph node involvement (p=0.0141). The immunohistologic criteria were validated on a different set of 359 cases treated with neoadjuvant chemotherapy, which showed a pathologic complete response predominantly in ERBB2 and triple negative tumors. Immunohistochemistry is a reliable surrogate tool to classify breast carcinoma according to the gene expression profile classification.
PMCID: PMC2655155  PMID: 19294003
Molecular classes; breast carcinoma; immunohistochemical surrogate markers; Ki-67
10.  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

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