Bethany M. Anderson

Upper abdominal normal organ contouring guidelines and atlas: A Radiation Therapy Oncology Group consensus

PURPOSE To standardize upper abdominal normal organ contouring guidelines for Radiation Therapy Oncology Group (RTOG) trials. METHODS AND MATERIALS Twelve expert radiation oncologists contoured the liver, esophagus, gastroesophageal junction (GEJ), stomach, duodenum, and common bile duct (CBD), and reviewed and edited 33 additional normal organ and blood vessel contours on an anonymized patient computed tomography (CT) dataset. Contours were overlaid and compared for agreement using MATLAB (MathWorks, Natick, MA). S95 contours, defined as the binomial distribution to generate 95% group consensus contours, and normal organ contouring definitions were generated and reviewed by the panel. RESULTS There was excellent consistency and agreement of the liver, duodenal, and stomach contours, with substantial consistency for the esophagus contour, and moderate consistency for the GEJ and CBD contours using a Kappa statistic. Consensus definitions, detailed normal organ contouring recommendations and high-resolution images were developed. CONCLUSIONS Consensus contouring guidelines and a CT image atlas should improve contouring uniformity in radiation oncology clinical planning and RTOG trials.

Current state of knowledge regarding the use of antiangiogenic agents with radiation therapy

Angiogenesis has been a central theme of oncologic research for several years. Recently, improved understanding of its mechanisms has led to the development of several antiangiogenic agents. Some have demonstrated their effectiveness in large randomized studies; however, no antiangiogenic agent has yet been approved for treatment in combination with radiotherapy. Numerous preclinical studies and a few small clinical trials have recently reported encouraging results. The objective of this article is to review the concept of targeted antiangiogenic agents and the early clinical results of their use in combination with radiation therapy.

The Impact of Hybrid PET-CT Scan on Overall Oncologic Management, with a Focus on Radiotherapy Planning: A Prospective, Blinded Study

Functional imaging using fluorodeoxyglucose positron-emission tomography (FDG-PET) has been increasing incorporated into radiotherapy planning in conjunction with computed tomography (CT). Hybrid FDG-PET/CT scanners allow these images to be obtained in very close temporal proximity without the need for repositioning patients, thereby minimizing imprecision when overlying these images. To prospectively examine the impact of hybrid PET/CT imaging on overall oncologic impact, with a focus on radiotherapy planning, we performed a prospective, blinded trial in 111 patients. Patients with lung cancer (n=38), head-and-neck squamous cell carcinoma (n=23), breast (n=8), cervix (n=15), esophageal (n=9), and lymphoma (n=18) underwent hybrid PET/CT imaging at the time of radiation therapy planning. A physician blinded to the PET dataset designed a treatment plan using all clinical information and the CT dataset. The treating physician subsequently designed a second treatment plan using the hybrid PET/CT dataset. The two treatment plans were compared to determine if a major alteration in overall oncologic management occured. In patients receiving potentially curative radiotherapy the concordance between CT-based and PET/CT-based GTVs was quantified using an index of conformality (CI). In 76/111 (68%) of patients, the PET/CT data resulted in a change in one or more of the following: GTV volume, regional/local extension, prescribed dose, or treatment modality selection. In 35 of these 76 cases (46%; 31.5% of the entire cohort) the change resulted in a major alteration in the oncologic management (dose, field design, or modality change). Thus, nearly a third of all cases had a major alteration in oncologic management as a result of the PET/CT data, and 29 of 105 patients (27.6%) who underwent potentially curative radiotherapy had major alterations in either dose or field design. Hybrid PET/CT imaging at the time of treatment planning may be highly informative and an economical manner in which to obtain PET imaging, with the dual goals of staging and treatment planning.

PET/CT and MRI in the imaging assessment of cervical cancer.

Imaging plays a central role in the evaluation of patients with cervical cancer and helps guide treatment decisions. The purpose of this pictorial review is to describe magnetic resonance (MR) imaging and positron emission tomography (PET)/computed tomography (CT) assessment of cervical cancer, including indications for imaging, important findings that may result in management change, as well as limitations of both modalities. The International Federation of Gynecology and Obstetrics cervical cancer staging system does not officially include imaging; however, the organization endorses the use of MR imaging and PET/CT in the management of patients with cervical cancer where these modalities are available. MR imaging provides the best visualization of the primary tumor and extent of soft tissue disease. PET/CT is recommended for assessment of nodal involvement, as well as distant metastases. Both MR imaging and PET/CT are used to follow patients post-treatment to assess for recurrence. This review focuses on the current MR imaging and PET/CT protocols, the utility of these modalities in assessing primary tumors and recurrences, with emphasis on imaging findings which change management and on imaging pitfalls to avoid. It is important to be familiar with the MR imaging and PET/CT appearance of the primary tumor and metastasis, as well as the imaging pitfalls, so that an accurate assessment of disease burden is made prior to treatment.

Predictive factors of recurrence following adjuvant vaginal cuff brachytherapy alone for stage I endometrial cancer

PURPOSE The purpose of this study is to identify risk factors for recurrence in a cohort of stage I endometrial cancer patients treated with vaginal cuff brachytherapy at a single academic institution. METHODS AND MATERIALS From 1989 to 2011, 424 patients with stage I endometrial cancer underwent total hysterectomy and bilateral salpingo-oophorectomy, with or without lymphadenectomy (LND), followed by high-dose-rate vaginal cuff brachytherapy (VCB) to patients felt to be high or intermediate risk FIGO stage IA and IB disease. Covariates included: 2009 FIGO stage, age, grade, histology, presence of lymphovascular space invasion, LND, and receipt of chemotherapy. RESULTS With a median follow-up of 3.7years, the 5 and 10-year disease free survival were 98.4% and 95.9%, respectively. A total of 30 patients developed recurrence, with the predominant pattern of isolated distant recurrence (57.0%). On multivariate analysis, grade 3 (p=0.039) and LND (p=0.048) independently predicted of increased recurrence risk. χ(2) analysis suggested that higher-risk patients were selected for LND, with significant differences in age, stage, and grade noted between cohorts. Distant metastatic rate was significantly higher for patients who qualified for GOG 0249 at 23.1% (95% CI 10.7-35.5%) compared to those who did not at 6.8% (95% CI 1.8-11.8%, p<0.001). CONCLUSION Overall disease-free survival for this cohort of patients was >95% at 10years. Univariate analysis confirmed previously identified risk factors as predictors for recurrence. Multivariate analysis found that grade 3 and LND correlated with risk for recurrence. Of those that did recur, the initial site of relapse included distant metastasis in most cases.

Adjuvant and definitive radiation therapy for primary carcinoma of the vagina using brachytherapy and external beam radiation therapy

Purpose To report the outcomes of patients receiving vaginal brachytherapy and/or external beam radiation therapy (EBRT) for primary vaginal cancer. Material and methods Between 1983 and 2009, 63 patients received brachytherapy and/or EBRT for primary tumors of the vagina at a single tertiary center. Patient data was collected via chart review. The Kaplan-Meier method was used to calculate actuarial pelvic local control (LC), disease-free survival (DFS), overall survival (OS), and severe late toxicity rates. Acute and late toxicities were scored according to the Common Terminology Criteria for Adverse Events version 3 (CTCAE v3.0). Results Median follow up was 44.2 months. Patients with early stage disease (stages I and II) had significantly improved 5-year OS when compared to patients with locally advanced disease (stages III and IVA) (73.3 vs. 34.4%, p = 0.032). Patients with greater than 1/3 vaginal involvement had significantly worse prognosis than patients with tumors involving 1/3 or less of the vagina, with the later having superior DFS (84.0 vs. 52.4%, p = 0.007) and LC (86.9 vs. 60.4%, p = 0.018) at 5-years. Age, histology, and brachytherapy technique did not impact treatment outcomes. The 5-year actuarial grade 3 or higher toxicity rate was 23.1% (95% CI: 10.6-35.6%). Concurrent chemotherapy had no impact on outcomes or toxicity in this analysis. Conclusions Success of treatment for vaginal cancer depends primarily on disease stage, but other contributing factors such as extent of vaginal involvement and tumor location significantly impact outcomes. Treatment of vaginal cancer with primary radiotherapy yields acceptable results with reasonable toxicity rates. Management of this rare malignancy requires a multidisciplinary approach to appropriately optimize therapy.

MR Imaging of Cervical Cancer

Cervical cancer is a significant cause of morbidity and mortality worldwide despite advances in screening and prevention. Although cervical cancer remains clinically staged, the 2009 International Federation of Gynecology and Obstetrics committee has encouraged the use of advanced imaging modalities, including MR imaging, where available, to increase the accuracy of staging, guide treatment, and detect recurrence. Understanding the multiple roles of advanced imaging in the evaluation of cervical cancer will help radiologists provide an accurate and useful report to the referring clinicians.

Outcomes of Node-positive Breast Cancer Patients Treated With Accelerated Partial Breast Irradiation Via Multicatheter Interstitial Brachytherapy: The Pooled Registry of Multicatheter Interstitial Sites (PROMIS) Experience.

Objectives: To report outcomes for breast-conserving therapy using adjuvant accelerated partial breast irradiation (APBI) with interstitial multicatheter brachytherapy in node-positive compared with node-negative patients. Materials and Methods: From 1992 to 2013, 1351 patients (1369 breast cancers) were treated with breast-conserving surgery and adjuvant APBI using interstitial multicatheter brachytherapy. A total of 907 patients (835 node negative, 59 N1a, and 13 N1mic) had >1 year of data available and nodal status information and are the subject of this analysis. Median age (range) was 59 years old (22 to 90 y). T stage was 90% T1 and ER/PR/Her2 was positive in 87%, 71%, and 7%. Mean number of axillary nodes removed was 12 (SD, 6). Cox multivariate analysis for local/regional control was performed using age, nodal stage, ER/PR/Her2 receptor status, tumor size, grade, margin, and adjuvant chemotherapy/antiestrogen therapy. Results: The mean (SD) follow-up was 7.5 years (4.6). The 5-year actuarial local control (95% confidence interval) in node-negative versus node-positive patients was 96.3% (94.5-97.5) versus 95.8% (87.6-98.6) (P=0.62). The 5-year actuarial regional control in node-negative versus node-positive patients was 98.5% (97.3-99.2) versus 96.7% (87.4-99.2) (P=0.33). The 5-year actuarial freedom from distant metastasis and cause-specific survival were significantly lower in node-positive versus node-negative patients at 92.3% (82.4-96.7) versus 97.8% (96.3-98.7) (P=0.006) and 91.3% (80.2-96.3) versus 98.7% (97.3-99.3) (P=0.0001). Overall survival was not significantly different. On multivariate analysis age 50 years and below, Her2 positive, positive margin status, and not receiving chemotherapy or antiestrogen therapy were associated with a higher risk of local/regional recurrence. Conclusions: Patients who have had an axillary lymph node dissection and limited node-positive disease may be candidates for treatment with APBI. Further research is ultimately needed to better define specific criteria for APBI in node-positive patients.

Locoregional recurrence risk for women with various molecular subtypes of breast cancer treated with multicatheter interstitial accelerated partial-breast irradiation: Results from Pooled Registry of Multicatheter Interstitial Sites (PROMIS).

73 Background: This study was performed to determine in breast tumor recurrence (IBTR) and regional nodal recurrence (RNR) rates for women with different subtypes of invasive ductal breast cancer treated with multicatheter interstitial accelerated partial breast irradiation (mAPBI). METHODS Data from 5 institutions was collected for patients treated from 1992-2013. We report the outcomes of 821 women with 830 breast cancers, all with ≥ 1 year of follow-up after completion of mAPBI. Molecular subtype analysis was performed for 582 women in whom ER, PR, Her-2, and grade were known. The Kaplan-Meier method was used to calculate overall survival (OS), IBTR and RNR. A univariate proportional hazard model was performed to estimate the risk of IBTR based upon molecular subtype, age, grade, N-stage, T-stage, margin status, tumor size, dose rate, endocrine therapy, and chemotherapy. RESULTS The median age of our patient cohort was 60 years. 50.0% (n = 415) of women had luminal A, 6.9% (n = 57) luminal B, 5.7% (n = 47) luminal Her-2, 1.8% (n = 15) Her-2, and 5.8% (n = 48) triple negative breast cancer (TNBC); an additional 29.8% (n = 248) could not be subtyped. With a median follow-up time of 6.5 years, the 5-year OS of our patient cohort was 94.8%. The 5-year IBTR was 3.5% for luminal A, 4.1% for luminal B, 5.1% for luminal Her-2, 13.3% for Her-2, 11.3% for TNBC, and 1.7% for non-subtyped women. Positive surgical margins and high grade correlated with risk for IBTR; molecular subtype and other variables did not. The 5-year RNR rates were 0.3% for luminal A, 4.6% for luminal B, 2.6% for luminal Her-2, 34.5% for Her-2, and 2.3% for TNBC. RNR risk was significantly higher for women with Her-2 compared to the other 4 subtypes. In addition, risk of RNR was significantly higher for women with luminal B compared to those of luminal A. CONCLUSIONS Women with Her-2 and luminal B breast cancer may have higher RNR but not IBTR risk after mAPBI, as compared with women with luminal A subtype. Further follow-up, correlation with use of trastuzumab, and comparison of outcomes with whole breast irradiation will be valuable.

Abstract A110: EGFRvIII expression is associated with shorter progression-free and overall survival in glioblastoma patients treated with standard-of-care temozolomide and radiation: A report from the RTOG-0525 trial.

Background: Glioblastomas (GBMs) are aggressive primary brain tumors with high levels of genomic heterogeneity impacting prognosis and treatment response. A recurrent in-frame deletion within the extracellular domain of the epidermal growth factor receptor (EGFR variant III, or vIII) is found in a substantial fraction of GBMs. Methods: The Radiation Therapy Oncology Group (RTOG) 0525 trial of temozolomide dosing in newly-diagnosed GBM enrolled 1174 patients. Of these, 494 eligible GBMs were analyzed for EGFRvIII expression by RT-PCR. The Kaplan-Meier method was used to compare the progression free survival (PFS) and overall survival (OS) of GBMs expressing EGFRvIII with those not expressing EGFRvIII. Results: 142 of 494 tested GBMs (29%) had expressed EGFRvIII. There were no significant differences in PFS or OS between patients whose tumors did (494) or did not (631) undergo EGFRvIII expression analysis. EGFRvIII expression was significantly associated with age (p=0.005), Karnofsky performance status (p=0.02), and RTOG recursive partitioning analysis (RPA) class (p=0.005). EGFRvIII expression analyzed in the entire study population did not reveal an association with PFS or OS. In a univariate subgroup analysis of patients treated on the standard-of-care arm of RTOG-0525, EGFRvIII expression was was significantly associated with worse PFS (HR=1.43, 95% CI: [1.05, 1.96], p=0.025), and worse OS (HR 1.45, 95% CI:[1.03, 2.05], p=0.032). However, in multivariate models, when adjusted for RPA class and MGMT methylation status, EGFRvIII was not an independent predictor of either PFS or OS. Conclusion: For GBMs treated with standard-of-care therapy in RTOG-0525, EGFRvIII expression was associated with worse PFS and OS. However, well-established stratification metrics such as age, KPS, and RPA override this prognostic association, suggesting that trials of therapeutic modalities directed against EGFRvIII should utilize these standard prognostic variables when survival is being analyzed or compared. Project Support: This project was supported by RTOG grant U10 CA21661, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and Schering-Plough Corporation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A110. Citation Format: Daniel P. Cahill, Asha George, Mark R. Gilbert, Arnab Chakravarti, Roger Stupp, Monika Hegi, Paul Brown, Kurt A. Jaeckle, Benjamin Corn, Erik P. Sulman, Luis Souhami, Maria Werner-Wasik, Bethany M. Anderson, Minesh Mehta, Kenneth D. Aldape. EGFRvIII expression is associated with shorter progression-free and overall survival in glioblastoma patients treated with standard-of-care temozolomide and radiation: A report from the RTOG-0525 trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A110.