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1.  Radiation Dose–Volume Effects Of The Urinary Bladder 
An in-depth overview of the normal-tissue radiation tolerance of the urinary bladder is presented. The most informative studies consider whole-organ irradiation. The data on partial-organ/nonuniform irradiation are suspect because the bladder motion is not accounted for, and many studies lack long enough follow-up data. Future studies are needed.
PMCID: PMC3587780  PMID: 20171505
2.  A Novel Low Dose Fractionation Regimen for Adjuvant Vaginal Brachytherapy in Early Stage Endometrial Cancer 
Gynecologic oncology  2012;127(2):351-355.
To evaluate local control, survival and toxicity in patients with early-stage endometrioid adenocarcinoma of the uterus treated with adjuvant high-dose-rate (HDR) vaginal brachytherapy (VB) alone using a novel low dose regimen
We reviewed records of 414 patients with stage IA to stage II endometrial adenocarcinoma treated with VB alone from 2005 to 2011. Of these, 157 patients with endometrioid histology received 24 Gy in 6 fractions of HDR vaginal cylinder brachytherapy and constitute the study population. Dose was prescribed at the cylinder surface and delivered twice weekly in the post-operative setting. Local control and survival rates were calculated by the Kaplan-Meier method.
All 157 patients completed the prescribed course of VB. Median follow-up time was 22.8 months (range, 1.5–76.5). Two patients developed vaginal recurrence, one in the periurethral region below the field and one in the fornix after treatment with a 2.5-cm cylinder. Three patients developed regional recurrence in the para-aortic region. Two patients developed distant metastasis (lung and carcinomatosis). The 2-year rate of vaginal control was 98.6%, locoregional control was 97.9% and disease-free survival was 96.8%. The 2-year overall survival rate was 98.7%. No Grade 2 or higher vaginal, gastrointestinal, genitourinary or skin long-term toxicity was reported for any patient.
Vaginal brachytherapy alone in early-stage endometrial cancer provides excellent results in terms of locoregional control and disease-free survival. The fractionation scheme of 24 Gy in 6 fractions prescribed to the cylinder surface was well-tolerated with minimal late toxicity.
PMCID: PMC3548566  PMID: 22850411
Endometrial cancer; vaginal brachytherapy; high-dose-rate
3.  International Brachytherapy Practice Patterns: A Survey of the Gynecologic Cancer Intergroup (GCIG) 
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.
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).
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.
PMCID: PMC3489266  PMID: 21183288
brachytherapy; cervical cancer; radiation dose
4.  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.
This report presents the 2011 update to the American Brachytherapy Society (ABS) high-dose-rate (HDR) brachytherapy guidelines for locally advanced cervical cancer.
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.
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.
These guidelines update those of 2000 and provide a comprehensive description of HDR cervical cancer brachytherapy in 2011.
PMCID: PMC3489267  PMID: 22265437
5.  3T MR-Guided Brachytherapy for Gynecologic Malignancies 
Magnetic resonance imaging  2012;30(9):1279-1290.
Gynecologic malignancies are a leading cause of death in women worldwide. Standard treatment for many primary and recurrent gynecologic cancer cases includes a combination of external beam radiation, followed by brachytherapy. Magnetic Resonance Imaging (MRI) is benefitial in diagnostic evaluation, in mapping the tumor location to tailor radiation dose, and in monitoring the tumor response to treatment. Initial studies of MR-guidance in gynecologic brachtherapy demonstrate the ability to optimize tumor coverage and reduce radiation dose to normal tissues, resulting in improved outcomes for patients.
In this article we describe a methodology to aid applicator placement and treatment planning for 3 Tesla (3T) MR-guided brachytherapy that was developed specifically for gynecologic cancers. This has been used in 18 cases to date in the Advanced Multimodality Image Guided Operating suite at Brigham and Women’s Hospital. It is comprised of state of the art methods for MR imaging, image analysis, and treatment planning. An MR sequence using 3D-balanced steady state free precession in a 3T MR scan was identified as the best sequence for catheter identification with ballooning artifact at the tip. 3D treatment planning was performed using MR images. Item in development include a software module designed to support virtual needle trajectory planning that includes probabilistic bias correction, graph based segmentation, and image registration algorithms. The results demonstrate that 3T MR has a role in gynecologic brachytherapy. These novel developments improve targeted treatment to the tumor while sparing the normal tissues.
PMCID: PMC3468320  PMID: 22898699
Brachytherapy; segmentation; bias correction
6.  Combined Chemotherapy and Radiation Improves Survival for Node-Positive Endometrial Cancer 
Gynecologic oncology  2012;127(1):32-37.
To evaluate the clinical outcomes for women with node-positive endometrioid adenocarcinoma of the uterus
Records were reviewed for 66 patients with Stage IIIC endometrioid adenocarcinoma diagnosed between 1/1995 and 12/2009. Study inclusion required TAH, BSO and negative chest imaging. Papillary serous and clear cell histologies were excluded. Adjuvant treatment was external beam radiation (RT) alone in 18 patients (27%), combined chemotherapy and RT in 44 (67%), chemotherapy alone in 1 (2%), and no adjuvant therapy in 3 (5%). The median follow-up was 48 months.
Of 66 patients, 56 (85%) had positive pelvic nodes only, 5 (8%) had positive para-aortic nodes only, and 5 (8%) had both. Of the 62 patients who received adjuvant RT, only 4 (6%) had an in-field recurrence, including 2 with residual disease after surgery. Disease-free (DFS) and overall (OS) survival rates at 5 years were 71% and 81%, respectively. By adjuvant treatment modality, 5-year DFS and OS rates were 63% and 67% for RT alone and 79% and 90% for combined modality therapy (p=0.15 and p<0.01). On multivariate analysis, combined modality therapy significantly improved DFS (HR 0.12, 95% CI 0.03–0.49, p<0.01) and OS (HR 0.20, 95% CI 0.05–0.75, p=0.02) compared to adjuvant RT alone.
Compared to RT alone, combined modality therapy decreased recurrence and improved survival in patients with node-positive endometrioid adenocarcinoma of the uterus. In addition, external beam RT resulted in excellent local and regional control. Future studies are needed to define the optimal chemotherapy regimen, sequencing, and radiation fields.
PMCID: PMC3479633  PMID: 22735786
(5) FIGO IIIC endometrial cancer; node-positive endometrial cancer; radiation therapy; endometrioid histology
7.  Circulating Melatonin And The Risk Of Breast And Endometrial Cancer In Women 
Cancer letters  2008;281(1):1-7.
Several decades of observational data have accumulated to implicate a potential role for melatonin in cancer prevention. Experimental studies suggest that the antineoplastic action of melatonin arises through many different mechanisms, including melatonin’s antioxidant, antimitotic, and antiangiogenic activity, as well as its ability to modulate the immune system and alter fat metabolism. Melatonin interacts with membrane and nuclear receptors, and may be linked to the regulation of tumor growth. Of particular relevance to breast cancer risk, melatonin may also block the estrogen receptor ERα and impact the enzyme aromatase, which produces estradiol. A growing number of epidemiologic studies have evaluated the relationship between night shift work as well as how varying duration of sleep affects peak melatonin secretion at night. While the studies demonstrate lower nightly melatonin levels in night workers, the evidence for an association between sleep duration and melatonin production is less clear. Similarly, both case-control and prospective cohort studies have consistently linked night shift work with breast cancer risk and, more recently, endometrial cancer—another tumor highly sensitive to estrogens. While, to date, the evidence for an association between sleep duration and breast cancer risk is less convincing, overall, there is increasing support for a potentially important link between melatonin and breast cancer risk and perhaps the risk of other tumors. As evidence increases, modifiable factors that have been shown to affect melatonin production, such as night shift work, are likely to gain increasing recognition as potential public health hazards. Additional studies are needed to delineate further the potential of melatonin in cancer prevention.
PMCID: PMC2735793  PMID: 19070424
cancer; treatment; melatonin
8.  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.
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.
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.
PMCID: PMC2867463  PMID: 19665244
cervical cancer; brachytherapy; normal tissue dose
9.  The Impact of Radiotherapy on Fertility, Pregnancy, and Neonatal Outcomes of Female Cancer Patients 
Radiation has many potential long-term effects on cancer survivors. Female cancer patients may suffer from decreased fertility depending on the site irradiated. Oncologists should be aware of these consequences and discuss options for fertility preservation prior to initiating therapy.
A comprehensive review of the existing literature was conducted. Studies reporting the outcomes for female patients treated with cranio-spinal, abdominal, or pelvic radiation reporting fertility, pregnancy, or neonatal-related outcomes were reviewed.
Cranio-spinal irradiation elicited significant hormonal changes in women that affected their ability to become pregnant later in life. Women treated with abdomino-pelvic radiation have an increased rate of uterine dysfunction leading to miscarriage, preterm labor, low birthweight, and placental abnormalities. Early menopause results from low-dose ovarian radiation. Ovarian transposition may decrease the rates of ovarian dysfunction.
There is a dose-dependent relationship between ovarian radiation therapy (RT) and premature menopause. Patients treated with RT must be aware of the impact of treatment on fertility and explore appropriate options.
PMCID: PMC2865903  PMID: 19306747
Fertility; Pregnancy; Neonatal; Radiation Therapy; Female
10.  Correlation of Point B and Lymph Node Dose in 3D-Planned High-Dose-Rate Cervical Cancer Brachytherapy 
To compare the HDR point B to pelvic lymph node dose using 3D-planned brachytherapy for cervical cancer.
Materials and Methods
Patients with FIGO Stage IB-IIIB cervical cancer received 70 tandem HDR applications using CT-based treatment planning. The obturator, external and internal iliac lymph nodes (LN) were contoured. Per fraction (PF) and combined fraction (CF) right (R), left (L), and bilateral (Bil) nodal doses were analyzed. Point B dose was compared with LN dose-volume histogram (DVH) parameters by a paired t-test and Pearson correlation coefficients.
The mean PF and CF doses to point B were R 1.40 Gy ±0.14 (CF: 7 Gy), L 1.43 ±0.15 (CF: 7.15 Gy), and Bil 1.41 ±0.15 (CF: 7.05 Gy). The correlation coefficients between point B and the D100, D90, D50, D2cc, D1cc, and D0.1cc LN were all less than 0.7. Only the D2cc to the obturator and the D0.1cc to the external iliac nodes were not significantly different from the point B dose. Significant differences between R and L nodal DVHs were seen, likely related to tandem deviation from irregular tumor anatomy.
With HDR brachytherapy for cervical cancer, the per fraction nodal dose approximates a dose equivalent to teletherapy. Point B is a poor surrogate for dose to specific nodal groups. 3D-defined nodal contours during brachytherapy provide a more accurate reflection of delivered dose, and should be part of comprehensive planning of the total dose to the pelvic nodes, particularly when there is evidence of pathologic involvement of nodes.
PMCID: PMC2862357  PMID: 19286328
HDR brachytherapy; cervical cancer; pelvic lymph nodes; point B
11.  Aspirin, NSAID, and Acetaminophen Use and the Risk of Endometrial Cancer 
Cancer research  2008;68(7):2507-2513.
To date, no prospective studies have explored the relationship between the use of aspirin, other non-steroidal anti-inflammatory medications (NSAIDs), and acetaminophen and endometrial adenocarcinoma.
Of the 82,971 women enrolled in a prospective cohort study, 747 developed medical record–confirmed invasive endometrial cancer over a 24-year period. Use of aspirin was queried from 1980 to 2004, and for other NSAIDs and acetaminophen 1990 to 2004. Cox regression models calculated multivariate relative risks (MV RR), controlling for body mass index (BMI), postmenopausal hormone (PMH) use, and other endometrial cancer risk factors.
Currency, duration, and quantity of aspirin were not associated with endometrial cancer risk overall (current use MV RR 1.03, 95% confidence interval [CI] 0.83–1.27; >10 years of use, MV RR 1.01, 95% CI 0.78–1.30; and cumulative average > 7 tablets per week MV RR 1.10, 95%CI 0.84–1.44). However, stratified analyses showed that a lower risk of endometrial cancer among obese (BMI ≥ 30 kg/m2) women was seen with current aspirin use (MV RR 0.66, 95% CI 0.46–0.95) The greatest risk reduction for current aspirin users was seen in postmenopausal obese women who had never used PMH (MV RR 0.43, 95% CI 0.26–0.73). The use of other NSAIDs or acetaminophen was not associated with endometrial cancer.
Our data suggest use of aspirin or other NSAIDs does not play an important role in endometrial cancer risk overall. However, risk was significantly lower for current aspirin users who were obese or who were postmenopausal and had never used postmenopausal hormones; these subgroup findings require further confirmation.
PMCID: PMC2857531  PMID: 18381460
endometrial cancer; aspirin; prospective cohort
12.  Pelvic Normal Tissue Contouring Guidelines for Radiation Therapy: A Radiation Therapy Oncology Group Consensus Panel Atlas 
To define a male and female pelvic normal tissue contouring atlas for Radiation Therapy Oncology Group (RTOG) trials.
Methods and Materials
One male pelvis computed tomography (CT) data set and one female pelvis CT data set were shared via the Image-Guided Therapy QA Center. A total of 16 radiation oncologists participated. The following organs at risk were contoured in both CT sets: anus, anorectum, rectum (gastrointestinal and genitourinary definitions), bowel NOS (not otherwise specified), small bowel, large bowel, and proximal femurs. The following were contoured in the male set only: bladder, prostate, seminal vesicles, and penile bulb. The following were contoured in the female set only: uterus, cervix, and ovaries. A computer program used the binomial distribution to generate 95% group consensus contours. These contours and definitions were then reviewed by the group and modified.
The panel achieved consensus definitions for pelvic normal tissue contouring in RTOG trials with these standardized names: Rectum, AnoRectum, SmallBowel, Colon, BowelBag, Bladder, UteroCervix, Adnexa_R, Adnexa_L, Prostate, SeminalVesc, PenileBulb, Femur_R, and Femur_L. Two additional normal structures whose purpose is to serve as targets in anal and rectal cancer were defined: AnoRectumSig and Mesorectum. Detailed target volume contouring guidelines and images are discussed.
Consensus guidelines for pelvic normal tissue contouring were reached and are available as a CT image atlas on the RTOG Web site. This will allow uniformity in defining normal tissues for clinical trials delivering pelvic radiation and will facilitate future normal tissue complication research.
PMCID: PMC3904368  PMID: 22483697
Radiation therapy atlas; Pelvic contouring atlas; Normal tissue volumes; Male pelvis; Female pelvis
13.  Concurrent Chemoradiation for Vaginal Cancer 
PLoS ONE  2013;8(6):e65048.
It is not known whether the addition of chemotherapy to radiation therapy improves outcomes in primary vaginal cancer. Here, we review clinical outcomes in patients with primary vaginal cancer treated with radiation therapy (RT) or concurrent chemoradiation therapy (CRT).
Seventy-one patients with primary vaginal cancer treated with definitive RT with or without concurrent chemotherapy at a single institution were identified and their records reviewed. A total of 51 patients were treated with RT alone; 20 patients were treated with CRT. Recurrences were analyzed. Overall survival (OS) and disease-free survival (DFS) rates were estimated using the Kaplan-Meier method. Cox regression analysis was performed.
The median age at diagnosis was 61 years (range, 18–92 years) and the median follow-up time among survivors was 3.0 years. Kaplan-Meier estimates for OS and DFS differed significantly between the RT and CRT groups (3-yr OS = 56% vs. 79%, log-rank p = 0.037; 3-yr DFS = 43% vs. 73%, log-rank p = 0.011). Twenty-three patients (45%) in the RT group had a relapse at any site compared to 3 (15%) in the CRT group (p = 0.027). With regard to the sites of first relapse, 10 patients (14%) had local only, 4 (6%) had local and regional, 9 (13%) had regional only, 1 (1%) had regional and distant, and 2 (3%) had distant only relapse. On univariate analysis, the use of concurrent chemotherapy, FIGO stage, tumor size, and date of diagnosis were significant predictors of DFS. On multivariate analysis, the use of concurrent chemotherapy remained a significant predictor of DFS (hazard ratio 0.31 (95% CI, 0.10–0.97; p = 0.04)).
Vaginal cancer results in poor outcomes. Adequate radiation dose is essential to ensure curative management. Concurrent chemotherapy should be considered for vaginal cancer patients.
PMCID: PMC3676389  PMID: 23762284
14.  A Prospective Clinical Trial of Bladder Filling and 3D-Dosimetry in High-Dose-Rate Vaginal-Cuff Brachytherapy 
To investigate the impact of bladder filling state on dosimetry and determine the best bladder dosimetric parameter in vaginal-cuff brachytherapy.
Materials and Methods
Twenty women received vaginal cylinder high-dose-rate (HDR) brachytherapy with each fraction followed by a planning CT scan on a prospective clinical trial. The bladder was full for fraction 2 and empty for fraction 3. Dose volume histogram (DVH) and dose surface histogram (DSH) values were generated for the bladder, rectum, and urethra. The midline maximum bladder point (MBP) and the midline maximum rectal point (MRP) were recorded. Paired t-tests, Pearson correlations, and regression analyses were performed.
The volume and surface area of bladder irradiated were significantly smaller when the bladder was empty than when full. Of several DVH and DSH parameters evaluated, the bladder D2cc, V50, V70 and SA50 significantly predicted the difference in empty versus full filling states. The V70 and D2cc were significantly correlated with the MBP. Bladder filling did not alter the volume or surface area of rectum irradiated. However, an empty bladder did result in the nearest point of bowel being significantly closer to the vaginal cylinder than when the bladder was full.
In order to minimize radiation dose to the bladder, patients receiving vaginal-cuff HDR brachytherapy should be treated with an empty bladder if feasible. The MBP correlates well with the volumetric assessments of bladder dose and provides a non-invasive method for reporting maximum bladder point dose using 3D imaging. The MBP can therefore be used as a surrogate for complex dosimetry in the clinic.
PMCID: PMC2877499  PMID: 18395360
Vaginal cuff brachytherapy; CT bladder dosimetry
15.  Involution of latent endometrial precancers by hormonal and non hormonal mechanisms 
Cancer  2009;115(10):2111-2118.
Inactivation of the PTEN suppressor gene occurs in the majority of endometrial cancer cases. Somatic PTEN inactivation by deletion and/or mutation, the first detectible change of endometrial carcinogenesis, occurs at a high frequency in the endometrium of normal premenopausal women, though few of these progress to cancer. We hypothesized that the 50–60% reduced cancer risk of oral contraceptives (OCP) and intrauterine devices (IUD) occurs in part through their activity as negative selection factors for these subclinical mutated glands.
71 women with a history of oral contraceptive use and 80 with a history of IUD use were age matched with 191 and 119 controls, respectively. Endometrial biopsies were immunostained for PTEN and each scored for presence or absence of PTEN null glands (latent precancer).
The frequency of latent precancers was significantly reduced in OCP (13%, OR 0.19, p<0.001) and IUD (18%, OR 0.42, p=0.015) exposed women compared to respective matched controls (43 and 34%). Presence or absence of endometritis did not significantly correlate with PTEN status within the IUD exposed group (p=0.24).
Normal appearing PTEN mutated endometrial glands, which are highly prevalent in the normal population, may be targets of endometrial cancer risk modulating exposures. Some exposures known to diminish endometrial cancer occurrences in epidemiologic outcome studies, including OCP and IUD use, are associated with a proportionate decline in the frequency of latent precancers. Involution of pre-existing endometrial latent precancers, as evaluated by PTEN analysis, may provide an accessible surrogate marker for long term endometrial cancer risk.
PMCID: PMC2745907  PMID: 19280590
endometrium; latent precancer; PTEN; oral contraceptive; intrauterine device

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