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1.  Comparison and Consensus Guidelines for Delineation of Clinical Target Volume for CT- and MR-Based Brachytherapy in Locally Advanced Cervical Cancer 
To create and compare consensus clinical target volume (CTV) contours for computed tomography (CT) and 3 Tesla (3T) magnetic resonance (MR) image-based cervical-cancer brachytherapy
Twenty-three gynecologic radiation oncology experts contoured the same 3 cervical-cancer brachytherapy cases: one Stage IIB near-complete response (CR) case with a tandem and ovoid, one Stage IIB partial response (PR) case with ovoid with needles and one Stage IB2 CR case with a ring applicator. CT contours were completed before MRI contours. These were analyzed for consistency and clarity of target delineation using an expectation maximization algorithm for simultaneous truth and performance level estimation (STAPLE), with kappa statistics as a measure of agreement between participants. The conformity index (CI) was calculated for each of the six data sets. Dice coefficients were generated to compare CT and MR contours of the same case.
For all 3 cases, the mean tumor volume was smaller on MR than on CT (p<0.001). Kappa and CI estimates were slightly higher for CT, indicating a higher level of agreement on CT. DICE coefficients were 89% for the Stage IB2 case with a CR, 74% for the Stage IIB case with a PR, and 57% for the Stage IIB case with a CR.
When comparing MR- to CT-contoured CTV volumes, the higher level of agreement on CT may be due to the more distinct contrast visible on the images at the time of brachytherapy. The largest difference at the time of brachytherapy was in the case with parametrial extension at diagnosis that had a near-complete response, due to the appearance of the parametria on CT but not on MR. Based on these results, a 95% consensus volume was generated for CT and for MR. Online contouring atlases are available for instruction at
PMCID: PMC4194192  PMID: 25304792
Radiation; brachytherapy; CT; MR; cervical cancer
2.  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
3.  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
4.  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
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.
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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  Real-time active MR-tracking of metallic stylets in MR-guided radiation therapy 
To develop an active MR-tracking system to guide placement of metallic devices for radiation therapy.
An actively tracked metallic stylet for brachytherapy was constructed by adding printed-circuit micro-coils to a commercial stylet. The coil design was optimized by electromagnetic simulation, and has a radio-frequency lobe pattern extending ~5 mm beyond the strong B0 inhomogeneity region near the metal surface. An MR-tracking sequence with phase-field dithering was used to overcome residual effects of B0 and B1 inhomogeneities caused by the metal, as well as from inductive coupling to surrounding metallic stylets. The tracking system was integrated with a graphical workstation for real-time visualization. 3T MRI catheter-insertion procedures were tested in phantoms and ex-vivo animal tissue, and then performed in three patients during interstitial brachytherapy.
The tracking system provided high-resolution (0.6 × 0.6 × 0.6 mm3) and rapid (16 to 40 frames per second, with three to one phase-field dithering directions) catheter localization in phantoms, animals, and three gynecologic cancer patients.
This is the first demonstration of active tracking of the shaft of metallic stylet in MR-guided brachytherapy. It holds the promise of assisting physicians to achieve better targeting and improving outcomes in interstitial brachytherapy.
PMCID: PMC4257908  PMID: 24903165
Active MR-tracking; metallic device; radiation therapy; phase-field dithering
14.  The risk of lymphedema after postoperative radiation therapy in endometrial cancer 
Lower extremity lymphedema adversely affects quality of life by causing discomfort, impaired mobility and increased risk of infection. The goal of this study is to investigate factors that influence the likelihood of lymphedema in patients with endometrial cancer who undergo adjuvant radiation with or without chemotherapy.
A retrospective chart review identified all stage I–III endometrial cancer patients who had a hysterectomy with or without complete staging lymphadenectomy and adjuvant radiation therapy between January 2006 and February 2013. Patients with new-onset lymphedema after treatment were identified. Logistic regression was used to find factors that influenced lymphedema risk.
Of 212 patients who met inclusion criteria, 15 patients (7.1%) developed new-onset lymphedema. Lymphedema was associated with lymph-node dissection (odds ratio [OR], 5.6; 95% CI, 1.01 to 105.5; p=0.048) and with the presence of pathologically positive lymph nodes (OR, 4.1; 95% CI, 1.4 to 12.3; p=0.01). Multivariate logistic regression confirmed the association with lymph-node positivity (OR, 3.2; 95% CI, 1.0007 to 10.7; p=0.0499) when controlled for lymph-node dissection. Median time to lymphedema onset was 8 months (range, 1 to 58 months) with resolution or improvement in eight patients (53.3%) after a median of 10 months.
Lymph-node positivity was associated with an increased risk of lymphedema in endometrial cancer patients who received adjuvant radiation. Future studies are needed to explore whether node-positive patients may benefit from early lymphedema-controlling interventions.
PMCID: PMC4695454  PMID: 26463430
Endometrial Neoplasms; Lymphedema; Positive Lymph Nodes
15.  Pilot study assessing 18F-fluorothymidine PET/CT in cervical and vaginal cancers before and after external beam radiation☆ 
The role of F-18-fluorothymidine (FLT) PET-CT imaging in the evaluation of gynecologic cancers has not been established. We sought to evaluate (FLT) PET-CT imaging in gynecologic cancers by comparing standard uptake values (SUVs) of FLT with F-18-fluorodeoxyglucose (FDG) PET in the primary tumor at diagnosis, and assess FLT uptake immediately following concurrent chemoradiotherapy (chemoRT).
In this pilot study, patients treated for cervical (5) or vaginal (1) cancer underwent FLT-PET and FDG-PET scanning at diagnosis (FLT1 and FDG1). Five patients (4 cervical and 1 vaginal) also underwent FLT-PET within 1–3 weeks after chemoRT before brachytherapy (FLT2). Wilcoxon rank-sum test was used to compare the FLT1 and FDG1 parameters.
Median age at diagnosis was 61-years (range, 33–72). Cervical cancers were staged as IB2 (n = 1, 20%), IIB (n = 1, 20%), IIIB (n = 1, 20%) and IVA (n = 2, 40%) and the single vaginal cancer was staged IIIB. The most common histology was squamous cell carcinoma (n = 3, 50%) followed by adenocarcinoma (n = 2, 33%) and clear-cell adenosquamous carcinoma (n = 1, 17%). Median tumor SUVmax at diagnosis was 7.8 on FLT1-PET (3.9–14.2) versus 11.6 (5.9–23.2) on FDG1-PET (p = 0.15). Tumor SUVmax of FLT declined 54%–100% after chemoRT.
The tumor SUV of FLT at diagnosis was lower than that of FDG-PET. FLT uptake was markedly decreased after chemoRT. Results indicate that there may not be a significant effect of inflammation on FLT uptake in gynecologic cancers. FLT may be a useful tool when assessing the effects of chemoRT on gynecologic malignancies and planning for postchemoRT brachytherapy treatments.
•Standard uptake values of FLT were compared with FDG-PET in GYN cancer patients.•FLT tracer uptake markedly decreased after chemoradiation therapy (chemoRT).•There may not be a significant effect of inflammation on FLT uptake after RT.
PMCID: PMC4688880  PMID: 26793770
Gynecologic malignancies; Radiotherapy; External-beam radiation therapy; FLT-PET
16.  Dietary insulin index and insulin load in relation to endometrial cancer risk in the Nurses’ Health Study 
While unopposed estrogen exposure is considered the main driver of endometrial carcinogenesis, factors associated with states of insulin resistance and hyperinsulinemia are independently associated with endometrial cancer risk. We used dietary insulin load and insulin index scores to represent the estimated insulin demand of overall diets and assessed their association with endometrial cancer risk in the prospective Nurses’ Health Study.
We estimated incidence rate ratios (RRs) and 95% confidence intervals (CI) for risk of invasive endometrial cancer using Cox proportional hazards models. Between the baseline dietary questionnaire (1980) and 2010, we identified a total of 798 incident invasive epithelial endometrial adenocarcinomas over 1,417,167 person-years of follow-up.
Dietary insulin scores were not associated with overall risk of endometrial cancer. Comparing women in the highest to the lowest quintile, the multivariable-adjusted RRs of endometrial cancer were 1.07 (95% CI: 0.84, 1.35) for cumulative average dietary insulin load and 1.03 (95% CI: 0.82, 1.31) for cumulative average dietary insulin index. Findings did not vary substantially by alcohol consumption, total dietary fiber intake, or BMI and/or physical activity (Pheterogeneity ≥ 0.10).
Intake of a diet predicted to stimulate a high postprandial insulin response was not associated with endometrial cancer risk in this large prospective study. Considering the complex interplay of diet, lifestyle and genetic factors contributing to the hyperinsulinemic state, dietary measures alone may not sufficiently capture absolute long-term insulin exposure.
This study is the first to investigate dietary insulin scores in relation to endometrial cancer risk.
PMCID: PMC4119561  PMID: 24859872
endometrial cancer; diet; hyperinsulinemia; body mass index; prospective cohort
17.  Dosimetric Consequences of Interobserver Variability in Delineating the Organs at Risk in Gynecologic Interstitial Brachytherapy 
To investigate the dosimetric variability associated with interobserver organ-at-risk delineation differences on computed tomography in patients undergoing gynecologic interstitial brachytherapy.
Methods and Materials
The rectum, bladder and sigmoid of 14 patients treated with gynecologic interstitial brachytherapy were retrospectively contoured by 13 physicians. Geometric variability was calculated using κ statistics, conformity index (CIgen), and coefficient of variation (CV) of volumes contoured across physicians. Dosimetric variability of the single-fraction D0.1cc and D2cc was assessed through CV across physicians, and the standard deviation of the total EQD2 (equivalent dose in 2 Gy per fraction) brachytherapy dose (SDTOT) was calculated.
The population mean ± 1 standard deviation of κ, CIgen and volume CV were, respectively: 0.77 ± 0.06, 0.70 ± 0.08 and 20% ± 6% for bladder; 0.74 ± 06, 0.67 ± 0.08 and 20% ± 5% for rectum, and 0.33 ± 0.20, 0.26 ± 0.17 and 82% ± 42% for sigmoid. Dosimetric variability was: for bladder, CV = 31% ± 19% (SDTOT = 72 ± 64 Gy) for D0.1cc and CV = 16% + 10% (SDTOT = 9 ± 6 Gy) for D2cc; for rectum, CV = 11% ± 5% (SDTOT = 16 ± 17 Gy) for D0.1cc and CV = 7% ± 2% (SDTOT = 4 ± 3 Gy) for D2cc; for sigmoid, CV = 39% ± 28% (SDTOT = 12 ± 18 Gy) for D0.1cc and CV = 34% ± 19% (SDTOT = 4 ± 4 Gy) for D2cc.
Delineation of bladder and rectum by 13 physicians demonstrated substantial geometric agreement and resulted in good dosimetric agreement for all dose-volume histogram parameters except bladder D0.1cc. Small delineation differences in high-dose regions by the posterior bladder wall may explain these results. The delineation of sigmoid showed fair geometric agreement. The higher dosimetric variability for sigmoid compared with rectum and bladder did not correlate with higher variability in the total brachytherapy dose but rather may be due to the sigmoid being positioned in low-dose regions in the cases analyzed in this study.
PMCID: PMC4180236  PMID: 24803035
18.  A novel intracavitary applicator design for the treatment of deep vaginal fornices: preliminary dose metrics and geometric analysis 
To investigate the dose distributions associated with a novel balloon sleeve placed over a standard cylinder applicator.
Material and methods
A computed tomography (CT) scan of a sleeve balloon shaped to inflate into the vaginal fornices was used to digitize 1-, 3-, and 5-catheter configurations. Point doses for rectum, apex, and fornix were calculated and compared to the values associated with a standard cylinder plan not targeting the vaginal fornices. Inflation of the sleeve balloon in the vaginal fornices and dose coverage with constraints to the rectum, bladder, and sigmoid D2cc were evaluated.
Rectum, apex, and fornix doses were respectively 76%, 119%, and 44% for a standard cylinder; 190%, 310%, and 93% for a 1-catheter configuration; 98%, 109%, and 109% for a 3-catheter configuration; and 91%, 107%, and 96% for the 5-catheter configuration. In a patient analysis, expansion of the sleeve balloon into the vaginal fornices was confirmed. The 5-catheter configurations were associated with best coverage of the fornices and acceptable doses to rectum, bladder, and sigmoid.
A 1-catheter configuration cannot be used clinically due to high rectal and apex dose. In theoretical analysis, the 3- and 5-catheter configurations showed > 96% coverage to the vaginal fornices with a clinically acceptable rectal dose. In a treatment simulation in a patient, a 5-catheter configuration showed 90% coverage of the fornices with acceptable doses to the organs at risk. The treatment of deep vaginal fornices results in an increased rectal dose compared to a standard cylinder plan.
PMCID: PMC4371065  PMID: 25829937
brachytherapy; intracavitary; vaginal fornices; multi-channel; applicator
19.  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
20.  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
21.  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
22.  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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