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Purpose: This report presents an update to the American Brachytherapy Society (ABS) high-dose-rate (HDR) brachytherapy guidelines for locally advanced cervical cancer., Methods: Members of the ABS with expertise in cervical cancer formulated updated guidelines for HDR brachytherapy using tandem and ring, ovoids, cylinder, or interstitial applicators for locally advanced cervical cancer. These guidelines were written based on medical evidence in the literature and input of clinical experts in gynecologic brachytherapy., Results: The ABS 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 before treatment delivery. Applicator placement, dose specification, and dose fractionation must be documented, quality assurance measures must be performed, and followup 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 (normalized therapy dose) is 80-90Gy, 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., (Copyright © 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To present recommendations for the use of interstitial brachytherapy in patients with vaginal cancer or recurrent endometrial cancer in the vagina., Methods: A panel of members of the American Brachytherapy Society reviewed the literature, supplemented that with their clinical experience, and formulated recommendations for interstitial brachytherapy for primary or recurrent cancers in the vagina., Results: Patients with bulky disease (approximately >0.5cm thick) should be considered for treatment with interstitial brachytherapy. The American Brachytherapy Society reports specific recommendations for techniques, target volume definition, and dose-fractionation schemes. Three-dimensional treatment planning is recommended with CT scan and/or MRI. The treatment plan should be optimized to conform to the clinical target volume and should reduce the dose to critical organs, including the rectum, bladder, urethra, and sigmoid colon. Suggested doses in combination with external beam radiation therapy and summated equivalent doses in 2Gy fractions are tabulated., Conclusion: Recommendations are made for interstitial brachytherapy for vaginal cancer and recurrent disease in the vagina. Practitioners and cooperative groups are encouraged to use these recommendations to formulate treatment and dose-reporting policies. Such a process will result in meaningful outcome comparisons, promote technical advances, and lead to appropriate utilization of these techniques., (Copyright © 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To develop a guideline for quality practice of low-dose-rate (LDR) and pulsed-dose-rate (PDR) brachytherapy for locally advanced cervical cancer., Methods: Members of the American Brachytherapy Society (ABS) with expertise in cervical cancer brachytherapy formulated updated guidelines for LDR and PDR brachytherapy for locally advanced (International Federation of Gynecology and Obstetrics [FIGO] Stages IB2-IVA) cervical cancer based on literature review and clinical experience., Results: The ABS strongly recommends the use of brachytherapy as a component of the definitive treatment of locally advanced cervical carcinoma. Precise applicator placement is necessary to maximize the probability of achieving local control without major side effects. The ABS recommends a cumulative delivered dose of approximately 80-90Gy for definitive treatment. Dosimetry must be performed after each insertion before treatment delivery. The dose delivered to point A should be reported for all intracavitary brachytherapy applications regardless of treatment planning technique. The ABS also recommends adoption of the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology guidelines for contouring, image-based treatment planning and dose reporting. Interstitial brachytherapy may be considered for a small proportion of patients whose disease cannot be adequately encompassed by intracavitary application and should be performed by practitioners with special expertise in these procedures. Quality management measures must be performed, and follow-up information should also be obtained., Conclusions: Updated ABS guidelines are provided for LDR and PDR brachytherapy for locally advanced cervical cancer. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their clinical practices and to adopt dose-reporting policies that are critical for outcome analysis., (Copyright © 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To develop brachytherapy recommendations covering aspects of pretreatment evaluation, treatment, and dosimetric issues for locally advanced cervical cancer., Methods: Members of the American Brachytherapy Society (ABS) with expertise in cervical cancer brachytherapy formulated updated recommendations for locally advanced (Federation of Gynecology and Obstetrics Stages IB2-IVA) cervical cancer based on literature review and clinical experience., Results: The ABS recommends the use of brachytherapy as a component of the definitive treatment of locally advanced cervical carcinoma. Precise applicator placement is necessary to maximize the probability of achieving local control without major side effects. The ABS recommends a cumulative delivered dose of approximately 80-90Gy for definitive treatment. The dose delivered to point A should be reported for all brachytherapy applications regardless of treatment-planning technique. The ABS also recommends adoption of the Groupe Européen Curiethérapie-European Society of Therapeutic Radiation Oncology (GEC-ESTRO) guidelines for contouring, image-based treatment planning, and dose reporting. Interstitial brachytherapy may be considered for a small proportion of patients whose disease cannot be adequately encompassed by intracavitary application. It should be performed by practitioners with special expertise in these procedures., Conclusions: Updated ABS recommendations are provided for brachytherapy for locally advanced cervical cancer. Practitioners and cooperative groups are encouraged to use these recommendations to formulate their clinical practices and to adopt dose-reporting policies that are critical for outcome analysis., (Copyright © 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: The objective of the study was to determine the impact of brachytherapy implant quality on outcome among cervical cancer patients treated on Radiation Therapy Oncology Group prospective trials 0116 and 0128., Methods: All enrolled patients received concurrent chemoradiation followed by brachytherapy. Individual brachytherapy parameters, including the symmetry of ovoids in relation to the tandem, displacement of ovoids in relation to the cervical os, tandem bisecting the ovoids, tandem in the midpelvis, and appropriateness of packing, were scored for each implant. Multivariate Cox proportional hazards models were constructed for each parameter for local recurrence (LR), regional recurrence, distant recurrence, disease-free survival (DFS), and overall survival., Results: Records for 103 patients were analyzed. The median follow-up time was 24.5 months. Patients with unacceptable symmetry of ovoids to the tandem had a significantly higher risk of LR than patients in the acceptable group (hazard ratio [HR], 2.67; 95% confidence interval [CI], 1.11-6.45; P = 0.03). Patients with displacement of ovoids in relation to the cervical os had a significantly increased risk of LR (HR, 2.50; 95% CI, 1.05-5.93; P = 0.04) and a lower DFS rate (HR, 2.28; 95% CI, 1.18-4.41; P = 0.01). Inappropriate placement of packing resulted in a lower DFS rate (HR, 2.06; 95% CI, 1.08-3.92; P = 0.03)., Conclusions: Assessment of the quality of a brachytherapy implant is imperative, as proper placement has an impact on patient DFS. If feasible, inappropriate placements should be corrected before treatment initiation. Brachytherapy applicators for cervical cancer should preferably be placed and assessed by experienced practitioners.

Purpose: To develop recommendations for the use of adjuvant vaginal cuff brachytherapy after hysterectomy and update previous American Brachytherapy Society (ABS) guidelines., Methods and Materials: A panel of members of the ABS performed a literature review, supplemented their clinical experience, and formulated recommendations for adjuvant vaginal cuff brachytherapy., Results: The ABS endorses the National Comprehensive Cancer Network guidelines for indications for radiation therapy for patients with endometrial cancer and cervical cancer and the guidelines on quality assurance of the American Association on Physicists in Medicine. The ABS made specific recommendations for applicator selection, insertion techniques, target volume definition, dose fractionation, and specifications for postoperative adjuvant vaginal cuff therapy. The ABS recommends that applicator selection should be based on patient anatomy, target volume geometry, and physician judgment. The dose prescription point should be clearly specified. Suggested doses were tabulated for treatment with brachytherapy alone, and in combination with external beam radiation therapy, when applicable. A properly fitted brachytherapy applicator should be selected that conforms to the vaginal apex and achieves mucosal contact with optimal tumor and normal tissue dosimetry. Dose prescription points may be individually selected but doses should be reported at the vaginal surface and at 0.5-cm depth., Conclusions: Recommendations are made for adjuvant vaginal cuff brachytherapy. Practitioners and cooperative groups are encouraged to use these recommendations to formulate their treatment and dose reporting policies. These recommendations will permit meaningful comparisons of reports from different institutions and lead to better and more appropriate use of vaginal brachytherapy., (Copyright © 2012 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

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)., Methods and Materials: 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%) used HDR. The three most common HDR brachytherapy fractionation regimens for Stage IB-IIA patients were 6 Gy for five fractions (18%), 6 Gy for four fractions (15%), and 7 Gy for three fractions (11%); for Stage IIB-IVA patients they were 6 Gy for five fractions (19%), 7 Gy for four fractions (8%), and 7 Gy for three fractions (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 as follows: 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 doses administered for cervical cancer are 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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To identify prognostic and predictive factors of overall survival (OS), relapse-free survival (RFS) and toxicity for patients with uterine papillary serous carcinoma (UPSC)., Materials and Methods: Patient, tumor, treatment and relapse characteristics of 135 women with Stages I-IVA UPSC treated between 1980 and 2006 at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) were analyzed using Cox regression models to determine prognostic and predictive factors for OS, RFS and toxicity., Results: Mean follow-up was 5.5 years (range, 0.01-25.2). Median 5-year OS was 52%, and RFS was 42% for all patients. On Cox regression analysis, increasing age, stage, and myometrial invasion were prognostic factors associated with shorter OS and RFS. A paclitaxel-platinum chemotherapy regimen was significantly associated with longer OS (hazard ratio [HR]=0.34, 95% confidence interval [CI] 0.15-0.74, p=0.007) and RFS (HR=0.45, 95% CI 0.22-0.92, p=0.03). RFS was improved for patients treated with RT (HR=0.44, 95% CI 0.25-0.77, p=0.004). The 5-year grade 3+ toxicity rate was 3.5% for those who received RT and was 2.9% for those who did not (p=NS)., Conclusion: Uterine papillary serous cancer can be an aggressive tumor type with a poor prognosis. RFS was improved by radiation and chemotherapy with few grade 3 or higher complications. Using radiation and paclitaxel-platinum chemotherapy should be attempted whenever feasible for patients with UPSC who do not have distant metastases at diagnosis., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To assess the dose to the organs at risk (OARs) and utility of repeated OAR dose-volume histogram calculations in multifraction high-dose-rate vaginal cylinder brachytherapy using 3-dimensional imaging., Methods and Materials: Thirty-eight patients (125 fractions) received high-dose-rate brachytherapy to the vaginal vault between January 2005 and October 2005. All patients emptied their bladders before insertion. After each insertion, a CT scan with 2.5-mm slices and contours of the bladder, rectum, and sigmoid was performed. Dose-volume histograms were generated for the D(0.1cc) and D(2cc) for the OAR using a software program created at our institution. Variance component models estimated the within-patient variance of the dose to the OAR between fractions. Predictors of dose to the OAR were identified using linear mixed models., Results: The within-patient coefficients of variation of total D(0.1cc) dose were bladder 14.0%, rectum 7.9%, and sigmoid 27.6%; for D(2cc), these were 8.1%, 5.9%, and 20.3%, respectively. Intraclass correlations ranged from 0.27 to 0.79. Larger OAR predicted greater total D(0.1cc) and D(2cc). Other predictors of total D(0.1cc) and D(2cc) dose included the size of the cylinder and the length of the treatment field for rectum., Conclusions: CT simulation provides a noninvasive assessment of the dose to the bladder, rectum, and sigmoid. The small within-patient variation in doses to the bladder and rectum do not support reporting doses to the OARs beyond the initial fraction., (Copyright © 2011 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Objective: To compare outcomes in patients with squamous cell carcinoma (SCC) of the vulva treated with radiation (RT) and concurrent weekly platinum-based or every-3-4-week regimens containing 5-fluorouracil (5-FU)., Methods: Records of 44 patients with vulvar SCC treated with concurrent chemotherapy and radiation (chemoRT) from 1988 to 2008 were reviewed. Rates of disease-free survival (DFS), overall survival (OS), locoregional recurrence (LRR), and distant metastases (DM) were estimated using the Kaplan-Meier method., Results: The median age was 63 years (range, 44-90), 84.1% of patients had ECOG performance status 0-1, and patients had FIGO Stage II (n=6), III (n=31), or IVA (n=7) disease. Patients were treated preoperatively (n=10), postoperatively (n=10), or without surgery (n=24). The median RT dose to the vulva was 50.2 Gray (range, 22-75). Concurrent chemotherapy regimens included weekly platinum (n=16) or every 3-4 week regimens with 5-FU as the backbone (n=28). With a median follow-up of 31.5 months, there was no significant difference in 2-year OS (74.5% vs. 70.0%; p=0.65), DFS (61.9% vs. 56.0%; p=0.85), LRR (31.3% vs. 32.9%; p=0.93), or DM (6.3% vs. 10.6%; p=0.81) between the weekly platinum and every-3-4-week 5-FU regimens. Twenty patients (45.4%) recurred: 16 LRR, 2 DM, and 2 with both. The clinical and pathologic complete response rates were 58.8% (20/34), and 53.8% (14/26), respectively. There was a higher proportion of grade 3 or higher acute non-skin toxicities in patients receiving every-3-4-week 5-FU (46.1% vs. 13.3%; p=0.07), but more grade 3 or higher skin toxicity in patients receiving weekly platinum (62.5% vs. 32.0%; p=0.01)., Conclusion: OS, response rates, and recurrence rates were not significantly different after RT with concurrent weekly platinum-based versus every-3-4-week regimens containing 5-FU for vulvar SCC., (Copyright © 2010 Elsevier Inc. All rights reserved.)

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., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: To determine current practice patterns with regard to three-dimensional (3D) imaging for gynecologic brachytherapy among American Brachytherapy Society (ABS) members., Methods and Materials: Registered physician members of the ABS received a 19-item survey by e-mail in August 2007. This report excludes physicians not performing brachytherapy for cervical cancer., Results: Of the 256 surveys sent, we report results for 133 respondents who perform one or more implantations per year for locally advanced cervical cancer. Ultrasound aids 56% of physicians with applicator insertion. After insertion, 70% of physicians routinely obtain a computed tomography (CT) scan. The majority (55%) use CT rather than X-ray films (43%) or magnetic resonance imaging (MRI; 2%) for dose specification to the cervix. However, 76% prescribe to Point A alone instead of using a 3D-derived tumor volume (14%), both Point A and tumor volume (7%), or mg/h (3%). Those using 3D imaging routinely contour the bladder and rectum (94%), sigmoid (45%), small bowel (38%), and/or urethra (8%) and calculate normal tissue dose-volume histogram (DVH) analysis parameters including the D2cc (49%), D1cc (36%), D0.1cc (19%), and/or D5cc (19%). Respondents most commonly modify the treatment plan based on International Commission on Radiation Units bladder and/or rectal point dose values (53%) compared with DVH values (45%) or both (2%)., Conclusions: More ABS physician members use CT postimplantation imaging than plain films for visualizing the gynecologic brachytherapy apparatus. However, the majority prescribe to Point A rather than using 3D image based dosimetry. Use of 3D image-based treatment planning for gynecologic brachytherapy has the potential for significant growth in the United States.

Adenocarcinoma in situ (AIS) of the endocervix is typically confined to the cervix, but may be extensive. We report 2 cases of extensive AIS-one with intraendometrial spread-that recurred after cone biopsy and were associated with ovarian metastases. In both cases, primary and metastatic tumors were positive for human papillomavirus 16. Both patients are currently disease-free and one has had no recurrence after a follow-up period of 145 months. Extensive, recurring AIS is a rare variant that may be unique for its risk of coincident ovarian involvement. However, ovarian spread, albeit rare, does not invariably result in an adverse outcome.

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 D0.1 cc and the D2 cc to the sigmoid, rectum and bladder doses, and toxicity were analyzed., Results: The median sigmoid EQD2 D0.1 cc and D2 cc 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 to 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.

Purpose: To compare high dose rate (HDR) point B to pelvic lymph node dose using three-dimensional-planned brachytherapy for cervical cancer., Methods and Materials: 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 paired t test and Pearson correlation coefficients., Results: 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., Conclusions: With HDR brachytherapy for cervical cancer, per fraction nodal dose approximates a dose equivalent to teletherapy. Point B is a poor surrogate for dose to specific nodal groups. Three-dimensional 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.

Purpose: To evaluate factors affecting survival and toxicity in patients with stage IIIB cervical cancer treated with external-beam radiotherapy and low-dose-rate brachytherapy., Materials and Methods: Seventy patients with stage IIIB cervical cancer treated between 1980 and 2000 were identified. A total of 51 patients had a tandem placed; 19 had interstitial brachytherapy only with no tandem placed. Univariate and multivariate analyses assessed factors potentially associated with survival and long-term complications., Results: Kaplan-Meier estimates for overall survival (OS) for the entire population at 2, 3, and 4 years were 43%, 29%, and 27%, respectively. Overall survival differed significantly between those treated with a tandem versus those treated without (log rank P < 0.0001). Significant predictors of OS on univariate Cox regression were presence of a tandem (hazards ratio [HR], 0.31; P = 0.0001) and cumulative dose to point A (HR, 0.95; P = 0.0001). Multivariate regression showed that the presence of a tandem was the only significant predictor of OS (HR, 0.46; P = 0.04). There were no significant predictors of complications., Conclusions: The dose to point A of approximately 85 Gy as associated with tandem use was a significant predictor of survival in patients with stage IIIB cervical carcinoma, indicating the significance of the central location of the high dose provided by the tandem. Patients selected for interstitial brachytherapy alone must receive sufficient dose, and a tandem should be placed whenever feasible for all patients with an intact uterus treated for locally advanced cervical cancer.

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 ERalpha 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.

Background: Inactivation of the PTEN suppressor gene has been shown to occur in the majority of endometrial cancer cases. Somatic PTEN inactivation by deletion and/or mutation, the first detectible change of endometrial carcinogenesis, has been reported to occur at a high frequency in the endometrium of normal premenopausal women, although few of these cases progress to cancer. It was hypothesized that the 50% to 60% reduced cancer risk attributed to oral contraceptives (OCPs) and intrauterine devices (IUDs) occurred in part through their activity as negative selection factors for these subclinical mutated glands., Methods: A total of 71 women with a history of OCP use and 80 with a history of IUD use were age matched with 191 and 119 controls, respectively. Endometrial biopsy specimens were immunostained for PTEN, and each was scored for the presence or absence of PTEN-null glands (latent precancer)., Results: The frequency of latent precancers was found to be significantly reduced in OCP-exposed (13%; odds ratio [OR], 0.19 [P < .001]) and IUD-exposed (18%; OR, 0.42 [P = .015]) women compared with respective matched controls (43% and 34%). The presence or absence of endometritis did not appear to be significantly correlated with PTEN status within the IUD-exposed group (P = .24)., Conclusions: 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 reported to diminish the incidence of endometrial cancer 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.

Purpose: Radiation has many potential long-term effects on cancer survivors. Female cancer patients may experience decreased fertility depending on the site irradiated. Oncologists should be aware of these consequences and discuss options for fertility preservation before initiating therapy., Methods and Materials: 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., Results: 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 birth weight, and placental abnormalities. Early menopause results from low-dose ovarian radiation. Ovarian transposition may decrease the rates of ovarian dysfunction., Conclusions: 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.

Purpose: To investigate the effect of bladder filling on dosimetry and to determine the best bladder dosimetric parameter for vaginal cuff brachytherapy., Methods and Materials: In this prospective clinical trial, a total of 20 women underwent vaginal cylinder high-dose-rate brachytherapy. The bladder was full for Fraction 2 and empty for Fraction 3. Dose-volume histogram and dose-surface histogram values were generated for the bladder, rectum, and urethra. The midline maximal bladder point (MBP) and the midline maximal rectal point were recorded. Paired t tests, Pearson correlations, and regression analyses were performed., Results: The volume and surface area of the irradiated bladder were significantly smaller when the bladder was empty than when full. Of the several dose-volume histogram and dose-surface histogram parameters evaluated, the bladder maximal dose received by 2 cm(3) of tissue, volume of bladder receiving >/=50% of the dose, volume of bladder receiving >/=70% of the dose, and surface area of bladder receiving >/=50% of the dose significantly predicted for the difference between the empty vs. full filling state. The volume of bladder receiving >/=70% of the dose and the maximal dose received by 2 cm(3) of tissue correlated significantly with the MBP. Bladder filling did not alter the volume or surface area of the 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., Conclusions: Patients undergoing vaginal cuff brachytherapy treated with an empty bladder have a lower bladder dose than those treated with a full bladder. The MBP correlated well with the volumetric assessments of bladder dose and provided a noninvasive method for reporting the MBP dose using three-dimensional imaging. The MBP can therefore be used as a surrogate for complex dosimetry in the clinic.

To date, no prospective studies have explored the relationship between the use of aspirin, other nonsteroidal anti-inflammatory medications (NSAID), 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 ascertained from 1980 to 2004, and for other NSAIDs and acetaminophen, from 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, >or=30 kg/m(2)) 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 that 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 PMHs; these subgroup findings require further confirmation.

Background: Endometriosis, a major cause of pelvic pain in women, is driven by estrogen. Ovarian remnant irradiation may alleviate pelvic pain by eliminating estrogen production in appropriately selected women with endometriosis., Case: Three patients with endometriosis causing incapacitating pelvic pain received 3D-imaging-based external beam radiation to doses of 1,500 to 2,100 cGy. All had pre-irradiation premenopausal follicle stimulating hormone levels and imaging evidence of ovarian remnants. None were candidates for further medical or surgical interventions. By 3 months after radiation, follicle stimulating hormone levels reached postmenopausal levels in all three patients, with complete resolution of the severe pelvic pain., Conclusion: Radiation therapy effectively induced menopause and relieved refractory pain from endometriosis. Careful selection of patients is necessary, given the potential for an increased long-term risk of radiation-related complications.

Melatonin has several oncostatic properties, including possible anti-estrogenic and anti-aromatase activity, and seems to be linked with fat metabolism. Night workers have lower levels of melatonin, which may predispose them to develop cancer. Endometrial cancer risk is influenced significantly by hormonal and metabolic factors; therefore, we hypothesize that night workers may have an increased risk of endometrial cancer. Of the 121,701 women enrolled in a prospective cohort study, 53,487 women provided data on rotating night shift work in 1988 and were followed through on June 1, 2004. A total of 515 women developed medical record-confirmed invasive endometrial cancer. We used Cox regression models to calculate multivariate relative risks (MVRRs), controlling for endometrial cancer risk factors. Women who worked 20+ years of rotating night shifts had a significantly increased risk of endometrial cancer [MVRR, 1.47; 95% confidence interval (95% CI), 1.03-1.14]. In stratified analyses, obese women working rotating night shifts doubled their baseline risk of endometrial cancer (MVRR, 2.09; 95% CI, 1.24-3.52) compared with obese women who did no night work, whereas a nonsignificant increase was seen among non-obese women (MVRR, 1.07; 95% CI, 0.60-1.92). Women working rotating night shifts for a long duration have a significantly increased risk of endometrial cancer, particularly if they are obese. We speculate that this increased risk is attributable to the effects of melatonin on hormonal and metabolic factors. Our results add to growing literature that suggests women who work at night may benefit from cancer prevention strategies.

Purpose: To compare the contours and dose-volume histograms (DVH) of the tumor and organs at risk (OAR) with computed tomography (CT) vs. magnetic resonance imaging (MRI) in cervical cancer brachytherapy., Methods and Materials: Ten patients underwent both MRI and CT after applicator insertion. The dose received by at least 90% of the volume (D(90)), the minimal target dose (D(100)), the volume treated to the prescription dose or greater for tumor for the high-risk (HR) and intermediate-risk (IR) clinical target volume (CTV) and the dose to 0.1 cm3, 1 cm3, and 2 cm3 for the OARs were evaluated. A standardized approach to contouring on CT (CT(Std)) was developed, implemented (HR- and IR-CTV(CTStd)), and compared with the MRI contours., Results: Tumor height, thickness, and total volume measurements, as determined by either CT or CT(Std) were not significantly different compared with the MRI volumes. In contrast, the width measurements differed in HR-CTV(CTStd) (p = 0.05) and IR-CTV(CTStd) (p = 0.01). For the HR-CTV(CTStd), this resulted in statistically significant differences in the volume treated to the prescription dose or greater (MRI, 96% vs. CT(Std), 86%, p = 0.01), D(100) (MRI, 5.4 vs. CT(Std), 3.4, p <0.01), and D(90) (MRI, 8.7 vs. CT(Std), 6.7, p <0.01). Correspondingly, the IR-CTV DVH values on MRI vs. CT(Std), differed in the D(100) (MRI, 3.0 vs. CT(Std), 2.2, p = 0.01) and D(90) (MRI, 5.6 vs. CT(Std), 4.6, p = 0.02). The MRI and CT DVH values of the dose to 0.1 cm3, 1 cm3, and 2 cm3 for the OARs were similar., Conclusion: Computed tomography-based or MRI-based scans at brachytherapy are adequate for OAR DVH analysis. However, CT tumor contours can significantly overestimate the tumor width, resulting in significant differences in the D(90), D(100), and volume treated to the prescription dose or greater for the HR-CTV compared with that using MRI. MRI remains the standard for CTV definition.

Background: Vulvar synovial cell sarcomas are rare, with only four previously published cases in the literature. Traditionally, the primary management for these tumors has been surgery alone., Case: We report a case of a large vulvar synovial cell sarcoma in a 50-year-old woman treated with comprehensive combined multimodality management, including preoperative intensity-modulated radiation therapy, radical hemivulvectomy, flap reconstruction, interstitial low-dose-rate brachytherapy boost, and adjuvant chemotherapy., Conclusion: Based on this case and the limited data in the literature, multimodality treatment of advanced soft tissue sarcoma of the vulva may optimize local control and minimize toxicity while preserving sexual function.

Purpose: To evaluate the feasibility and to describe the acute toxicity of a real-time intraoperative magnetic resonance (MR)-image guided interstitial approach to treating vaginal recurrence of endometrial cancer., Methods and Materials: From February 2004 to April 2005, 10 patients with recurrent endometrial cancer underwent MR-guided interstitial brachytherapy. Parameters evaluated included needle placement, dose-volume histograms (DVH), and complications., Results: Magnetic resonance-image guidance resulted in accurate needle placement. Tumor DVH values included median volume, 47 cc; V100, 89%; V150, 61%; V200, 38%; D90, 71 Gy; and D100, 60 Gy. DVH of organs at risk resulted in a median D2cc of external beam and brachytherapy dose (% of brachytherapy prescription): bladder, 75Gy(3) (88%); rectum, 70Gy(3) (87%); and sigmoid, 56Gy(3) (41%). All patients experienced either a Grade 1 or 2 acute toxicity related to the radiation; only 1 patient had Grade 3 toxicity. No toxicities were attributable to the use of MR guidance., Conclusions: Real-time MR guidance during the insertion of interstitial needles reduces the likelihood of an inadvertent insertion of the needles into the bladder and the rectum. Three-dimensional dosimetry allows estimation of the dose to organs at risk. Toxicities are limited.

The use of brachytherapy in the treatment of cervical cancer has increased worldwide since its initial introduction over 100 years ago. However, certain aspects of the use of high-dose-rate (HDR) versus low-dose-rate (LDR) brachytherapy continue to be controversial, particularly the role of HDR in FIGO Stage III cervical cancer and the use of HDR with concurrent chemotherapy. This study represents a systematic literature review of prospective and retrospective series of patients with cervical carcinoma treated with external-beam radiation (EBRT) followed by either HDR or LDR radiation. The local control rates, survival rates, and treatment-related complications in patients with Stage III cervical cancer treated with HDR or LDR and those treated with concomitant chemotherapy are examined. Patients with Stage III cervical cancer treated with EBRT and brachytherapy have a local control rate of >50% in most series. Randomized prospective and retrospective studies show overall statistically equivalent local control, overall survival, and complication rates between HDR and LDR. However, LDR may be preferable for large, bulky tumors at the time of brachytherapy. Retrospective studies of HDR and concurrent chemotherapy are limited but have demonstrated toxicity rates similar to those with LDR. Selected patients with Stage III cervical carcinoma who have an adequate response to EBRT and concomitant chemotherapy may be treated with HDR brachytherapy. The existing literature shows no significant increase in complications in patients treated with HDR and concurrent chemotherapy; however, sufficient tumor shrinkage prior to HDR and careful monitoring of the dose to the normal tissues are imperative.

Purpose: To examine the relationship between margin status and local recurrence (LR) or any recurrence after radical hysterectomy (RH) in women treated with or without radiotherapy (RT) for Stage IB cervical carcinoma., Methods and Materials: This study included 284 patients after RH with assessable margins between 1980 and 2000. Each margin was scored as negative (> or =1 cm), close (>0 and <1 cm), or positive. The outcomes measured were any recurrence, LR, and relapse-free survival., Results: The crude rate for any recurrence was 11%, 20%, and 38% for patients with negative, close, and positive margins, respectively. The crude rate for LR was 10%, 11%, and 38%, respectively. Postoperative RT decreased the rate of LR from 10% to 0% for negative, 17% to 0% for close, and 50% to 25% for positive margins. The significant predictors of decreased relapse-free survival on univariate analysis were the depth of tumor invasion (hazard ratio [HR] 2.14/cm increase, p = 0.007), positive margins (HR 3.92, p = 0.02), tumor size (HR 1.3/cm increase, p = 0.02), lymphovascular invasion (HR 2.19, p = 0.03), and margin status (HR 0.002/increasing millimeter from cancer for those with close margins, p = 0.03). Long-term side effects occurred in 8% after RH and 19% after RH and RT., Conclusion: The use of postoperative RT may decrease the risk of LR in patients with close paracervical margins. Patients with other adverse prognostic factors and close margins may also benefit from the use of postoperative RT. However, RT after RH may increase the risk of long-term side effects.

An inverse association between smoking and endometrial cancer has generally been observed, primarily among current smokers. To assess this association, we analyzed data from the prospective Nurses' Health Study. From 1976 to 2000, 702 cases of invasive endometrial cancer were identified during 1.8 million person-years of follow-up. Smoking status was assessed in 1976 and updated every 2 years. Cox proportional hazards models were used to calculate multivariate relative risks (RRs), controlling for endometrial cancer risk factors. Compared to never smokers, the multivariate RR of endometrial cancer was significantly lower among both current smokers (RR = 0.63; 95% CI = 0.50-0.79) and past smokers (RR = 0.73; 95% CI = 0.62-0.87). When additionally adjusting for body mass index (BMI), the RR for current smokers was attenuated (RR = 0.72; 95% CI = 0.57-0.90), but the RR for past smokers did not change. Risk was lower among women who smoked 35 or more cigarettes a day (RR = 0.60; 95% CI = 0.39-0.91) and among those who smoked for 40 or more years (RR = 0.63; 95% CI = 0.45-0.87). Tests for trend, which excluded never smokers, were not statistically significant for any of the smoking variables analyzed. These data indicate that both current and past smoking are associated with a lower risk of endometrial cancer. The findings provide insight into disease etiology and suggest that the influence of smoking on endometrial cancer risk occurs even in early adulthood, is long-lasting, and may not be attributed solely to short-term hormonal modulation.

Objectives: To analyze the sites of relapse and overall survival in women with neuroendocrine marker-positive small cell carcinoma of the cervix., Methods: The records of all women who had their initial treatment for cervical cancer at The University of Texas M.D. Anderson Cancer Center between 1980 and 2000 were reviewed. Fifty-one patients had stages I-III cancers that were originally described as "small cell" or "neuroendocrine." Histological material was available for reexamination in 45 cases; of these, 21 were found to have small cell neuroendocrine carcinoma (SCNEC) as indicated by positive staining for chromogranin, synaptophysin, or CD56. Local treatment consisted of a radical hysterectomy in six patients and radiation therapy in 15. Thirteen patients received chemotherapy as part of their initial treatment. The median follow-up for surviving patients was 83 months (range, 25-209 months)., Results: Fourteen (66%) of the 21 patients had a relapse. The median time to first relapse from the initiation of treatment was 8.4 months (range, 3.6-28 months). Most patients developed hematogenous distant metastases before their death. Only 2 of 15 patients who were treated with radiation therapy had a recurrence within the radiation fields. However, five patients had a recurrence above the radiation fields in the paraaortic lymph nodes, and two patients had a recurrence distal to the pelvic fields in the vagina. No patient had brain metastases as the sole site of first recurrence. However, two patients developed brain metastases concurrently with lung metastases. The overall survival rate was 29% at 5 years; none of the patients who had disease more extensive than stage IB1 or clinical evidence of lymph node metastases survived their disease., Conclusions: Patients with small cell neuroendocrine cervical cancer have a poor prognosis. Their course is frequently characterized by the development of widespread hematogenous metastases; locoregional recurrence outside irradiated fields is also frequent. Brain metastases were seen only in patients who also had lung metastases, suggesting that prophylactic cranial irradiation would be of little benefit.

Purpose: To analyze the sites of relapse, relapse-free survival, and overall survival in children with Group III rhabdomyosarcoma treated with or without radiotherapy (RT)., Methods and Materials: The outcomes of 48 children with Group III rhabdomyosarcoma treated between 1980 and 1997 were evaluated. The median overall survival follow-up was 7.3 years. Of the 48 patients, 65% had embryonal histology. Local treatment after induction chemotherapy included complete surgical resection (CSR) alone in 9 (19%), CSR plus RT in 13 (27%), partial resection or rebiopsy plus RT in 10 (21%), and RT alone in 15 patients (31%). One child developed distant disease before completing local therapy., Results: Of the 48 patients, 12 developed relapse at local (n = 3), regional (n = 4), or distant (n = 5) sites. All 9 patients treated with CSR after induction chemotherapy had embryonal/botryoid histology. Only 1 of these 9 patients developed relapse. No statistically significant difference was found in overall survival (p = 0.95) or relapse-free survival (p = 0.67) between patients treated with or without RT. The Kaplan-Meier estimate of 5-year overall survival and relapse-free survival was 76% +/- 7% and 74% +/- 7%, respectively. Significant predictors of relapse-free survival on univariate analysis included CSR (p = 0.03), nodal positivity (p = 0.001), and embryonal histology (p = 0.0003). On multivariate analysis, embryonal histology was the most significant predictor of relapse-free (p = 0.001) and overall (p = 0.01) survival., Conclusion: The overall survival for children with Group III rhabdomyosarcoma in this series was favorable. Embryonal/botryoid histology was the most significant predictor of both overall and relapse-free survival. We found that for a selected subgroup of children with embryonal histology, induction chemotherapy followed by complete surgical resection alone may be adequate local therapy.