David K. Gaffney

Ten-Year Multi-Institutional Results of Breast-Conserving Surgery and Radiotherapy in BRCA1/2-Associated Stage I/II Breast Cancer

PURPOSE We compared the outcome of breast-conserving surgery and radiotherapy in BRCA1/2 mutation carriers with breast cancer versus that of matched sporadic controls. METHODS A total of 160 BRCA1/2 mutation carriers with breast cancer were matched with 445 controls with sporadic breast cancer. Primary end points were rates of in-breast tumor recurrence (IBTR) and contralateral breast cancers (CBCs). Median follow-up was 7.9 years for mutation carriers and 6.7 years for controls. RESULTS There was no significant difference in IBTR overall between carriers and controls; 10- and 15-year estimates were 12% and 24% for carriers and 9% and 17% for controls, respectively (hazard ratio [HR], 1.37; P = .19). Multivariate analyses for IBTR found BRCA1/2 mutation status to be an independent predictor of IBTR when carriers who had undergone oophorectomy were removed from analysis (HR, 1.99; P = .04); the incidence of IBTR in carriers who had undergone oophorectomy was not significantly different from that in sporadic controls (P = .37). CBCs were significantly greater in carriers versus controls, with 10- and 15-year estimates of 26% and 39% for carriers and 3% and 7% for controls, respectively (HR, 10.43; P < .0001). Tamoxifen use significantly reduced risk of CBCs in mutation carriers (HR, 0.31; P = .05). CONCLUSION IBTR risk at 10 years is similar in BRCA1/2 carriers treated with breast conservation surgery who undergo oophorectomy versus sporadic controls. As expected, CBCs are significantly increased in carriers. Although the incidence of CBCs was significantly reduced in mutation carriers who received tamoxifen, this rate remained significantly greater than in controls. Additional strategies are needed to reduce contralateral cancers in these high-risk women.

Consensus Guidelines for Delineation of Clinical Target Volume for Intensity-Modulated Pelvic Radiotherapy for the Definitive Treatment of Cervix Cancer

PURPOSE Accurate target definition is vitally important for definitive treatment of cervix cancer with intensity-modulated radiotherapy (IMRT), yet a definition of clinical target volume (CTV) remains variable within the literature. The aim of this study was to develop a consensus CTV definition in preparation for a Phase 2 clinical trial being planned by the Radiation Therapy Oncology Group. METHODS AND MATERIALS A guidelines consensus working group meeting was convened in June 2008 for the purposes of developing target definition guidelines for IMRT for the intact cervix. A draft document of recommendations for CTV definition was created and used to aid in contouring a clinical case. The clinical case was then 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. RESULTS Nineteen experts in gynecological radiation oncology generated contours on axial magnetic resonance images of the pelvis. Substantial STAPLE agreement sensitivity and specificity values were seen for gross tumor volume (GTV) delineation (0.84 and 0.96, respectively) with a kappa statistic of 0.68 (p < 0.0001). Agreement for delineation of cervix, uterus, vagina, and parametria was moderate. CONCLUSIONS This report provides guidelines for CTV definition in the definitive cervix cancer setting for the purposes of IMRT, building on previously published guidelines for IMRT in the postoperative setting.

American Brachytherapy Society consensus guidelines for locally advanced carcinoma of the cervix. Part II: high-dose-rate brachytherapy.

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.

Pelvic Normal Tissue Contouring Guidelines for Radiation Therapy: A Radiation Therapy Oncology Group Consensus Panel Atlas

PURPOSE 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. RESULTS 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. CONCLUSIONS 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.

Elevated cyclooxygenase-2 expression correlates with diminished survival in carcinoma of the cervix treated with radiotherapy

PURPOSE The purpose of this study was to examine the relationship between overall survival and prognostic factors in carcinoma of the cervix treated with radiation therapy. A clinicopathologic study was performed on 24 patients. METHODS AND MATERIALS Formalin-fixed, paraffin-embedded tumor biopsies were stained for Cyclooxygenase-2 (COX-2), Topoisomerase I, Topoisomerase II, and p53. Clinical factors such as stage, grade, tumor size, pre- and post-treatment hemoglobin level, and radiotherapy dose were also evaluated. RESULTS Median follow-up was 75 months for living patients. The only immunohistochemical or clinical factor that was associated with improved survival was decreased COX-2 distribution staining. High COX-2 distribution staining was associated with decreased overall survival (p = 0.021) and decreased disease-free survival (p = 0.015) by log-rank comparison of Kaplan-Meier survival curves. The 5-year overall survival rates for tumors with low vs. high COX-2 distribution values were 75% and 35%, respectively. COX-2 staining intensity was found to correlate positively with tumor size (p = 0.022). CONCLUSION These findings indicate that increased expression of COX-2 portends a diminished survival in patients with invasive carcinoma of the cervix treated with radiotherapy. Because COX-2 is an early-response gene involved in angiogenesis and inducible by different stimuli, these data may indicate opportunity to intervene with specific inhibitors of COX-2 in carcinoma of the cervix.

The risk of secondary malignancies over 30 years after the treatment of non‐Hodgkin lymphoma

Survivors of non‐Hodgkin lymphoma (NHL) are at increased risk for developing secondary malignancies. For the current study, the authors quantitated this risk in a group of NHL survivors over 30 years of follow‐up.

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) negatively affect overall survival in carcinoma of the cervix treated with radiotherapy.

PURPOSE The purpose of this study was to examine a variety of biomarkers in carcinoma of the cervix to better characterize (1). the natural history of the disease, (2). response to radiotherapy (RT), and (3). potential for new therapeutic strategies. MATERIALS AND METHODS Fifty-five patients with Stage IB-IVA carcinoma of the cervix, treated with definitive intent RT, and on whom tumor tissue blocks were available were included in this study. Charts were reviewed for clinical parameters and disease status. Immunohistochemistry was performed for epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), CD34, topoisomerase II alpha (topo-II), and cyclooxygenase-2 (COX-2). Univariate and multivariate Cox proportional hazards modeling was performed with disease-free survival (DFS) and overall survival (OS) as the end points. Biomarkers were evaluated for correlation between various prognostic factors. RESULTS In this series of 55 patients with carcinoma of the cervix treated with definitive RT, only stage was significant on univariate analysis for DFS (p < 0.0001). On univariate analysis, increasing FIGO stage (p < 0.0001) and membranous staining of EGFR (p < 0.037) indicated diminished OS. On multivariate analysis for DFS, COX-2, VEGF, and stage were significant (p = 0.012, p = 0.014, and p = 0.03, respectively), with increased expression indicating a worse prognosis. For OS, multivariate analysis revealed that VEGF, EGFR, and FIGO stage were significant (p = 0.005, p = 0.011, and p < 0.0001, respectively). Significant direct correlations were identified between VEGF and CD34 (p = 0.04), COX-2 and topo-II (p = 0.04), COX-2 and grade (p = 0.04), and tumor size and clinical stage (p = 0.04). CONCLUSION Multivariate analysis revealed that increased staining for VEGF and COX-2 indicated diminished DFS, and VEGF and EGFR identified patients at increased risk of death. A significant direct correlation between VEGF and CD34 implicates the process of angiogenesis. Topo-II is a proliferative marker and it correlated directly with COX-2, indicating that expression of COX-2 may be greater in more proliferative tumors. Increased expression of EGFR, VEGF, and COX-2 has identified patients with a worse prognosis in cancer of the cervix. These data support the investigation of therapeutics that target these proteins in carcinoma of the cervix.

Malignant phyllodes tumor of the female breast: Association of primary therapy with cause-specific survival from the Surveillance, Epidemiology, and End Results (SEER) Program

Malignant phyllodes tumor is a rare and potentially aggressive breast neoplasm. Little information is available regarding the optimal management of these lesions and rarer still are data regarding survival. The current study used a large population database to determine prognostic factors that predict cause‐specific survival (CSS).

Response to radiation therapy and prognosis in breast cancer patients with BRCA1 and BRCA2 mutations

BACKGROUND AND PURPOSE The purpose of this study is to evaluate overall survival in BRCA1 or BRCA2 breast cancer patients, describe presenting stage, review histologic findings and evaluate response to radiotherapy. MATERIALS AND METHODS A retrospective study was performed evaluating breast cancer patients with known mutations of BRCA1 or BRCA2. Patients from 12 different pedigrees were cross-referenced with the Utah Cancer Registry (UCR), histologic findings were verified and radiotherapy records were reviewed for acute response to treatment. Actuarial survival calculations were performed and patients were matched for age, date of diagnosis and tumor size. RESULTS Thirty breast cancer patients with BRCA1 mutations were found to have 34 breast cancers (four had bilateral metachronous lesions) and 20 breast cancer patients with BRCA2 mutations were found to have 22 breast cancers (two had bilateral metachronous disease). The median age at diagnosis was 49 years (range 21-77 years) and 42 years (range 23-83 years), respectively, for BRCA1 and BRCA2 patients. Unusual histologic types of breast cancers were represented with 7% (4/56) medullary and 5% (3/56) lobular carcinomas. Complete staging was possible for 63% (35/56) of cancers. Stages I, II, III and IV represented 26, 63, 6 and 6% of cancers, respectively. The most severe radiation reaction was moist desquamation which was self-limiting and developed in 29% (6/21) of irradiated patients. The mean follow-up was 9.8 and 7.5 years for BRCA1 and BRCA2 cancers, respectively. Kaplan-Meier survival analysis demonstrated 5-year survival values of 75% for BRCA1 patients, 73% for BRCA2 patients, 70% for matched controls and 69% for UCR controls. No statistically significant differences were evident between the groups at 5 or 10 years. CONCLUSIONS Despite their younger age at presentation, breast cancer patients harboring BRCAI or BRCA2 mutations present at a similar stage, display a normal acute reaction to radiotherapy and have a similar prognosis when compared with sporadic breast cancer patients.

American Brachytherapy Society consensus guidelines for adjuvant vaginal cuff brachytherapy after hysterectomy

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.