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DOE OSTI2021

Hierarchical median narrow band for level set segmentation of cervical cell nuclei

This paper presents a novel hierarchical nuclei segmentation algorithm for isolated and overlapping cervical cells based on a narrow band level set implementation. Our method applies a new multiscale analysis algorithm to estimate the number of clusters in each image region containing cells, which turns into the input to a narrow band level set algorithm. We assess the nuclei segmentation results on three public cervical cell image databases. Overall, our segmentation method outperformed six state-of-the-art methods concerning the number of correctly segmented nuclei and the Dice coefficient reached values equal to or higher than 0.90. We also carried out classification experiments using features extracted from our segmentation results and the proposed pipeline achieved the highest average accuracy values equal to 0.89 and 0.77 for two-class and three-class problems, respectively. Furthermore, these results demonstrated the suitability of the proposed segmentation algorithm to integrate decision support systems for cervical cell screening.

47 OTHER INSTRUMENTATION↗

DOE OSTI2019

Paravertebral Collateral Arteries in Patients with Carotid Stenosis: Is There a Safe Space for Transforaminal Cervical Nerve Root Injections?

Aim: Image-guided cervical nerve root injections can cause serious complications including spinal cord infarction. This risk may be increased in patients with carotid stenosis who develop collateral arteries. The aim of this study is to describe the prevalence, and anatomical location, of arterial collateral vessels in relation to the optimal needle tip position in cervical nerve root injections. Materials and Methods: This retrospective study included 25 patients who had > 70% stenosis on a carotid CT angiogram. For each foramen the position of collateral arteries and the most anterior point of the facet joint were recorded, as Cartesian coordinates, by two independent observers. Descriptive statistics were used to analyse and present the results. Results: 14 patients had unilateral and 11 had bilateral stenoses. A total of 85 collaterals were identified at all levels, the most common being C2/3. The median distance from collateral to optimal needle tip placement was 9.6 mm (95% CI median: 6.7–12.4, IQR: 5.6–15.6). The minimum distance was 2.9 mm. Inter-observer reliability was “substantial” (ICC 0.78, 95% CI 0.71–0.83). Conclusion: Collateral arteries were common in our cohort of patients with carotid artery stenosis and half lay within 10 mm of the optimal position for transforaminal cervical nerve root injection.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2016

microRNA-146a inhibits proliferation, migration and invasion of human cervical and colorectal cancer cells

microRNAs (miRNAs) play significant roles in diverse biological processes and their deregulation is implicated in carcinogenesis. miR-146a executes tumour suppressive or oncogenic functions depending on the cancer type, but its effect on human cervical (CaCx) and colorectal (CRC) cancers have not been examined thus far. In this study, miR-146a exhibited high expression in CaCx but poor expression in CRC, in comparison to corresponding normal tissues. Nevertheless, ectopic expression of miR-146a inhibited proliferation in both CaCx and CRC cells and curbed their migration and invasion. When the expression of endogenous miR-146a was suppressed, proliferative, migratory and invasive capacities of CaCx and CRC cells increased, suggesting an anti-tumourigenic function for miR-146a. Re-expression of miR-146a down-regulated the expression of crucial signalling intermediates: CTNNB1, STAT3, RELA, CCND1 and SNAI1, and enhanced TP53 and CDH1 expression. Thus, the present study reveals a hitherto unknown tumour suppressive role for miR-146a providing a plausible mechanistic basis for it. - Highlights: • miR-146a inhibits proliferation in human cervical and colorectal cancer cells. • miR-146a retards migratory and invasive potentials of cancer cells. • AntimiR-146a enhances growth and motility. • miR-146a modulates the expression of a few genes related to growth and motility. • miR-146a is highly expressed in cervical but poorly so in colorectal tumours.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2013

Chemoradiation With Paclitaxel and Carboplatin in High-Risk Cervical Cancer Patients After Radical Hysterectomy: A Korean Gynecologic Oncology Group Study

Purpose: To evaluate the efficacy and toxicity of concurrent chemoradiation with paclitaxel and carboplatin in patients with high-risk cervical cancer. Methods and Materials: Patients after radical hysterectomy for cervical cancer, with at least 1 high-risk characteristic, were administered paclitaxel 135 mg/m{sup 2}, carboplatin area under the curve = 5 every 3 weeks for 3 cycles concomitant with radiation therapy as adjuvant treatment. Results: This prospective study enrolled 71 consecutive patients. Sixty-six patients (93%) completed the planned treatment. The majority of grade 3/4 neutropenia or nonhematologic toxicities were usually self-limited. Diarrhea grades 3/4 were observed in 4 patients (5.6%). One patient developed anaphylactic shock after infusion of paclitaxel. With a median follow-up of 57 months, recurrences occurred in 16 patients. Multivariable analysis indicated that common iliac lymph node involvement is an independent risk factor for disease recurrence (odds ratio 13.48; 95% confidence interval 2.93-62.03). In the intent-to-treat population (n=71), the estimated 5-year disease-free survival and overall survival rates were 77.3% and 80.3% respectively. In the per-protocol population (n=62), disease-free survival was 78.9% and overall survival was 83.9%. Conclusions: Concurrent chemoradiation with paclitaxel/carboplatin is well tolerated and seems to be effective for patients who undergo radical hysterectomy. Therefore, a prospective, randomized controlled study should be designed to evaluate efficacy of this approach for patients with high-risk cervical cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2013

Radiation Dose and Subsequent Risk for Stomach Cancer in Long-term Survivors of Cervical Cancer

Purpose: To assess the dose–response relationship for stomach cancer after radiation therapy for cervical cancer. Methods and Materials: We conducted a nested, matched case–control study of 201 cases and 378 controls among 53,547 5-year survivors of cervical cancer diagnosed from 1943 to 1995, from 5 international, population-based cancer registries. We estimated individual radiation doses to the site of the stomach cancer for all cases and to corresponding sites for the matched controls (overall mean stomach tumor dose, 2.56 Gy, range 0.03-46.1 and after parallel opposed pelvic fields, 1.63 Gy, range 0.12-6.3). Results: More than 90% of women received radiation therapy, mostly with external beam therapy in combination with brachytherapy. Stomach cancer risk was nonsignificantly increased (odds ratio 1.27-2.28) for women receiving between 0.5 and 4.9 Gy to the stomach cancer site and significantly increased at doses ≥5 Gy (odds ratio 4.20, 95% confidence interval 1.41-13.4, P{sub trend}=.047) compared with nonirradiated women. A highly significant radiation dose–response relationship was evident when analyses were restricted to the 131 cases (251 controls) whose stomach cancer was located in the middle and lower portions of the stomach (P{sub trend}=.003), whereas there was no indication of increasing risk with increasing dose for 30 cases (57 controls) whose cancer was located in the upper stomach (P{sub trend}=.23). Conclusions: Our findings show for the first time a significant linear dose–response relationship for risk of stomach cancer in long-term survivors of cervical cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2014

Dosimetrically Triggered Adaptive Intensity Modulated Radiation Therapy for Cervical Cancer

Purpose: The widespread use of intensity modulated radiation therapy (IMRT) for cervical cancer has been limited by internal target and normal tissue motion. Such motion increases the risk of underdosing the target, especially as planning margins are reduced in an effort to reduce toxicity. This study explored 2 adaptive strategies to mitigate this risk and proposes a new, automated method that minimizes replanning workload. Methods and Materials: Thirty patients with cervical cancer participated in a prospective clinical study and underwent pretreatment and weekly magnetic resonance (MR) scans over a 5-week course of daily external beam radiation therapy. Target volumes and organs at risk (OARs) were contoured on each of the scans. Deformable image registration was used to model the accumulated dose (the real dose delivered to the target and OARs) for 2 adaptive replanning scenarios that assumed a very small PTV margin of only 3 mm to account for setup and internal interfractional motion: (1) a preprogrammed, anatomy-driven midtreatment replan (A-IMRT); and (2) a dosimetry-triggered replan driven by target dose accumulation over time (D-IMRT). Results: Across all 30 patients, clinically relevant target dose thresholds failed for 8 patients (27%) if 3-mm margins were used without replanning. A-IMRT failed in only 3 patients and also yielded an additional small reduction in OAR doses at the cost of 30 replans. D-IMRT assured adequate target coverage in all patients, with only 23 replans in 16 patients. Conclusions: A novel, dosimetry-triggered adaptive IMRT strategy for patients with cervical cancer can minimize the risk of target underdosing in the setting of very small margins and substantial interfractional motion while minimizing programmatic workload and cost.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2014

National Cancer Data Base Analysis of Radiation Therapy Consolidation Modality for Cervical Cancer: The Impact of New Technological Advancements

Purpose: To utilize the National Cancer Data Base to evaluate trends in brachytherapy and alternative radiation therapy utilization in the treatment of cervical cancer, to identify associations with outcomes between the various radiation therapy modalities. Methods and Materials: Patients with International Federation of Gynecology and Obstetrics stage IIB-IVA cervical cancer in the National Cancer Data Base who received treatment from January 2004 to December 2011 were analyzed. Overall survival was estimated by the Kaplan-Meier method. Univariate and multivariable analyses were performed to identify factors associated with type of boost radiation modality used and its impact on survival. Results: A total of 7654 patients had information regarding boost modality. A predominant proportion of patients were Caucasian (76.2%), had stage IIIB (48.9%) disease with squamous (82.0%) histology, were treated at academic/research centers (47.7%) in the South (34.8%), and lived 0 to 5 miles (27.9%) from the treating facility. A majority received brachytherapy (90.3%). From 2004 to 2011, brachytherapy use decreased from 96.7% to 86.1%, whereas intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT) use increased from 3.3% to 13.9% in the same period (P<.01). Factors associated with decreased brachytherapy utilization included older age, stage IVA disease, smaller tumor size, later year of diagnosis, lower-volume treatment centers, and facility type. After controlling for significant factors from survival analyses, IMRT or SBRT boost resulted in inferior overall survival (hazard ratio, 1.86; 95% confidence interval, 1.35-2.55; P<.01) as compared with brachytherapy. In fact, the survival detriment associated with IMRT or SBRT boost was stronger than that associated with excluding chemotherapy (hazard ratio, 1.61′ 95% confidence interval, 1.27-2.04′ P<.01). Conclusions: Consolidation brachytherapy is a critical treatment component for locally advanced cervical cancer; however, there has been declining utilization of brachytherapy. Increased use of IMRT and SBRT boost coupled with increased mortality risk should raise concerns about utilizing these approaches over brachytherapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2014

Extended Field Intensity Modulated Radiation Therapy With Concomitant Boost for Lymph Node–Positive Cervical Cancer: Analysis of Regional Control and Recurrence Patterns in the Positron Emission Tomography/Computed Tomography Era

Purpose: Positron emission tomography/computed tomography (PET/CT) is commonly used for nodal staging in locally advanced cervical cancer; however the false negative rate for para-aortic disease are 20% to 25% in PET-positive pelvic nodal disease. Unless surgically staged, pelvis-only treatment may undertreat para-aortic disease. We have treated patients with PET-positive nodes with extended field intensity modulated radiation therapy (IMRT) to address the para-aortic region prophylactically with concomitant boost to involved nodes. The purpose of this study was to assess regional control rates and recurrence patterns. Methods and Materials: Sixty-one patients with cervical cancer (stage IBI-IVA) diagnosed from 2003 to 2012 with PET-avid pelvic nodes treated with extended field IMRT (45 Gy in 25 fractions with concomitant boost to involved nodes to a median of 55 Gy in 25 fractions) with concurrent cisplatin and brachytherapy were retrospectively analyzed. The nodal location was pelvis-only in 41 patients (67%) and pelvis + para-aortic in 20 patients (33%). There were a total of 179 nodes, with a median number of positive nodes of 2 (range, 1-16 nodes) per patient and a median nodal size of 1.8 cm (range, 0.7-4.5 cm). Response was assessed by PET/CT at 12 to 16 weeks. Results: Complete clinical and imaging response at the first follow-up visit was seen in 77% of patients. At a mean follow-up time of 29 months (range, 3-116 months), 8 patients experienced recurrence. The sites of persistent/recurrent disease were as follows: cervix 10 (16.3%), regional nodes 3 (4.9%), and distant 14 (23%). The rate of para-aortic failure in patients with pelvic-only nodes was 2.5%. There were no significant differences in recurrence patterns by the number/location of nodes, largest node size, or maximum node standardized uptake value. The rate of late grade 3+ adverse events was 4%. Conclusions: Extended field IMRT was well tolerated and resulted in low regional recurrence in node-positive cervical cancer. The dose of 55 Gy in 25 fractions was effective in eradicating disease in involved nodes, with acceptable late adverse events. Distant metastasis is the predominant mode of failure, and the OUTBACK trial may challenge the presented paradigms.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2015

Relationship Between Low Hemoglobin Levels and Outcomes After Treatment With Radiation or Chemoradiation in Patients With Cervical Cancer: Has the Impact of Anemia Been Overstated?

Purpose: Previous reports have suggested that anemia increases rates of recurrence after radiation therapy for cervical cancer. However, these studies may not have fully corrected for confounding risk factors. Using a well-characterized cohort of cervical cancer patients, we examined the association between anemia and outcomes before and after the introduction of chemoradiation as standard of care. Methods and Materials: We reviewed the records of 2454 patients who underwent definitive radiation therapy from 1980 through 2011. Minimum hemoglobin level (Hgb{sub min}) was recorded for 2359 patients (96%). Endpoints included freedom from central recurrence (FFCR), freedom from distant metastasis (FFDM), and disease-specific survival (DSS). Results: For the entire cohort, hemoglobin concentrations of 9, 10, and 12 g/dL before and during radiation were all significantly associated with FFCR, FFDM, and DSS (all P<.001) on univariate analysis. However, on multivariate analysis, only Hgb{sub min} less than 10 g/dL during RT (RT-Hgb{sub <10}) remained significant, and it was correlated with lower DSS (P=.02, hazard ratio [HR] = 1.28) and FFDM (P=.03, HR = 1.33) but not with FFCR. In a subset analysis of patients receiving chemoradiation (n=678), RT-Hgb{sub <10} was associated only with DSS (P=.008, HR = 1.49), not with FFCR or FFDM. In this subgroup, despite an association between RT-Hgb{sub <10} and DSS, the use of transfusion was not correlated with benefit. Conclusions: No evidence was found supporting anemia as an independent predictor of central recurrence in patients treated with definitive radiation therapy with or without chemotherapy. Less emphasis on correcting anemia in cervical cancer patients may be warranted.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2015

Trends in the Quality of Treatment for Patients With Intact Cervical Cancer in the United States, 1999 Through 2011

Purpose: High-quality treatment for intact cervical cancer requires external radiation therapy, brachytherapy, and chemotherapy, carefully sequenced and completed without delays. We sought to determine how frequently current treatment meets quality benchmarks and whether new technologies have influenced patterns of care. Methods and Materials: By searching diagnosis and procedure claims in MarketScan, an employment-based health care claims database, we identified 1508 patients with nonmetastatic, intact cervical cancer treated from 1999 to 2011, who were <65 years of age and received >10 fractions of radiation. Treatments received were identified using procedure codes and compared with 3 quality benchmarks: receipt of brachytherapy, receipt of chemotherapy, and radiation treatment duration not exceeding 63 days. The Cochran-Armitage test was used to evaluate temporal trends. Results: Seventy-eight percent of patients (n=1182) received brachytherapy, with brachytherapy receipt stable over time (Cochran-Armitage P{sub trend}=.15). Among patients who received brachytherapy, 66% had high–dose rate and 34% had low–dose rate treatment, although use of high–dose rate brachytherapy steadily increased to 75% by 2011 (P{sub trend}<.001). Eighteen percent of patients (n=278) received intensity modulated radiation therapy (IMRT), and IMRT receipt increased to 37% by 2011 (P{sub trend}<.001). Only 2.5% of patients (n=38) received IMRT in the setting of brachytherapy omission. Overall, 79% of patients (n=1185) received chemotherapy, and chemotherapy receipt increased to 84% by 2011 (P{sub trend}<.001). Median radiation treatment duration was 56 days (interquartile range, 47-65 days); however, duration exceeded 63 days in 36% of patients (n=543). Although 98% of patients received at least 1 benchmark treatment, only 44% received treatment that met all 3 benchmarks. With more stringent indicators (brachytherapy, ≥4 chemotherapy cycles, and duration not exceeding 56 days), only 25% of patients received treatment that met all benchmarks. Conclusion: In this cohort, most cervical cancer patients received treatment that did not comply with all 3 benchmarks for quality treatment. In contrast to increasing receipt of newer radiation technologies, there was little improvement in receipt of essential treatment benchmarks.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2015

Propensity-Weighted Comparison of Long-Term Risk of Urinary Adverse Events in Elderly Women Treated For Cervical Cancer

Purpose: Cervical cancer treatment is associated with a risk of urinary adverse events (UAEs) such as ureteral stricture and vesicovaginal fistula. We sought to measure the long-term UAE risk after surgery and radiation therapy (RT), with confounding controlled through propensity-weighted models. Methods and Materials: From the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we identified women ≥66 years old with nonmetastatic cervical cancer treated with simple surgery (SS), radical hysterectomy (RH), external beam RT plus brachytherapy (EBRT+BT), or RT+surgery. We matched them to noncancer controls 1:3. Differences in demographic and cancer characteristics were balanced by propensity weighting. Grade 3 to 4 UAEs were identified by diagnosis codes plus treatment codes. Cumulative incidence was measured using Kaplan-Meier methods. The hazard associated with different cancer treatments was compared using Cox models. Results: UAEs occurred in 272 of 1808 cases (17%) and 222 of 5424 (4%) controls; most (62%) were ureteral strictures. The raw cumulative incidence of UAEs was highest in advanced cancers. UAEs occurred in 31% of patients after EBRT+BT, 25% of patients after RT+surgery, and 15% of patients after RH; however, after propensity weighting, the incidence was similar. In adjusted Cox models (reference = controls), the UAE risk was highest after RT+surgery (hazard ratio [HR], 5.07; 95% confidence interval [CI], 2.32-11.07), followed by EBRT+BT (HR, 3.33; 95% CI, 1.45-7.65), RH (HR, 3.65; 95% CI, 1.41-9.46) and SS (HR, 0.99; 95% CI, 0.32-3.01). The higher risk after RT+surgery versus EBRT+BT was statistically significant, whereas, EBRT+BT and RH were not significantly different from each other. Conclusions: UAEs are common after cervical cancer treatment, particularly in patients with advanced cancers. UAEs are more common after RT, but these women tend to have the advanced cancers. After propensity weighting, the risk after RT was similar to that after surgery.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2015

Inverse Planned High-Dose-Rate Brachytherapy for Locoregionally Advanced Cervical Cancer: 4-Year Outcomes

Purpose: Evaluate the efficacy and toxicity of image guided brachytherapy using inverse planning simulated annealing (IPSA) high-dose-rate brachytherapy (HDRB) boost for locoregionally advanced cervical cancer. Methods and Materials: From December 2003 through September 2009, 111 patients with primary cervical cancer were treated definitively with IPSA-planned HDRB boost (28 Gy in 4 fractions) after external radiation at our institution. We performed a retrospective review of our experience using image guided brachytherapy. Of the patients, 70% had a tumor size >4 cm, 38% had regional nodal disease, and 15% had clinically evident distant metastasis, including nonregional nodal disease, at the time of diagnosis. Surgical staging involving pelvic lymph node dissection was performed in 15% of patients, and 93% received concurrent cisplatin-based chemotherapy. Toxicities are reported according to the Common Terminology Criteria for Adverse Events version 4.0 guidelines. Results: With a median follow-up time of 42 months (range, 3-84 months), no acute or late toxicities of grade 4 or higher were observed, and grade 3 toxicities (both acute and late) developed in 8 patients (1 constitutional, 1 hematologic, 2 genitourinary, 4 gastrointestinal). The 4-year Kaplan-Meier estimate of late grade 3 toxicity was 8%. Local recurrence developed in 5 patients (4 to 9 months after HDRB), regional recurrence in 3 (6, 16, and 72 months after HDRB), and locoregional recurrence in 1 (4 months after HDR boost). The 4-year estimates of local, locoregional, and distant control of disease were 94.0%, 91.9%, and 69.1%, respectively. The overall and disease-free survival rates at 4 years were 64.3% (95% confidence interval [CI] of 54%-73%) and 61.0% (95% CI, 51%-70%), respectively. Conclusions: Definitive radiation by use of inverse planned HDRB boost for locoregionally advanced cervical cancer is well tolerated and achieves excellent local control of disease. However, overall survival continues to be limited by the high rates of distant metastasis.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2015

Clinical Outcomes of Computed Tomography–Based Volumetric Brachytherapy Planning for Cervical Cancer

Purpose/Objectives: A report of clinical outcomes of a computed tomography (CT)-based image guided brachytherapy (IGBT) technique for treatment of cervical cancer. Methods and Materials: Seventy-six women with International Federation of Gynecology and Obstetrics stage IB to IVA cervical carcinoma diagnosed between 2007 and 2014 were treated with definitive external beam radiation therapy (EBRT) with or without concurrent chemotherapy followed by high-dose-rate (HDR) IGBT. All patients underwent planning CT simulation at each implantation. A high-risk clinical target volume (HRCTV) encompassing any visible tumor and the entire cervix was contoured on the simulation CT. When available, magnetic resonance imaging (MRI) was performed at implantation to assist with tumor delineation. The prescription dose was prescribed to the HRCTV. Results: The median follow-up time was 17 months. Thirteen patients (17%) had an MRI done before brachytherapy, and 16 patients (21%) were treated without MRI guidance. The mean EBRT/IGBT sum 2-Gy equivalent dose (EQD2) delivered to the 90% volume of the HRCTV was 86.3 Gy. The mean maximum EQD2s delivered to 2 cm{sup 3} of the rectum, sigmoid, and bladder were 67.5 Gy, 66.2 Gy, and 75.3 Gy, respectively. The 2-year cumulative incidences of local, locoregional, and distant failure were 5.8% (95% confidence interval [CI]: 1.4%-14.8%), 15.1% (95% CI: 5.4%-29.4%), and 24.3% (95% CI: 12.1%-38.9%), respectively. The 2-year overall and disease-free survival rates were 75% (95% CI, 61%-91%) and 73% (95% CI, 60%-90%), respectively. Twenty-nine patients (38%) experienced grade ≥2 acute toxicity, with 5 cases of acute grade 3 toxicity and no grade ≥4 toxicities. One patient experienced grade 3 gastrointestinal toxicity. No other late grade ≥3 events were observed. Conclusions: This is the largest report to date of CT/MRI-based IGBT for the treatment of cervical cancer. The results are promising, with excellent local control and acceptable toxicity. Further investigation is needed to assess the long-term safety and efficacy of this treatment.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2015

Assessment of Parametrial Response by Growth Pattern in Patients With International Federation of Gynecology and Obstetrics Stage IIB and IIIB Cervical Cancer: Analysis of Patients From a Prospective, Multicenter Trial (EMBRACE)

Purpose: To assess disease response along the parametrial space according to tumor morphology in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIB and IIIB cervical cancer at the time of image-guided adaptive brachytherapy. Methods and Materials: Patients with FIGO stage IIB and IIIB cervical cancer registered as of November 2013 in the EMBRACE study were evaluated. Tumors were stratified according to morphologic subtype on magnetic resonance imaging (expansive and infiltrative), and the characteristics of those subtypes were analyzed. Parametrial involvement at diagnosis and at brachytherapy was evaluated, and the response to chemo-radiotherapy was classified as good, moderate, or poor. The response grade was compared between the 2 groups and analyzed with regard to tumor volumes, and dosimetric parameters. Results: A total of 452 patients were evaluated, of whom 186 had expansive growth type and 266 had infiltrative morphology. Patients with infiltrative tumors had more extensive disease, as indicated by a higher rate of FIGO stage IIIB disease, as well as radiologic evidence of extension into the distal parametrial space and to the pelvic side wall on magnetic resonance imaging. Cervical necrosis was more common in the infiltrative group. Good response was more common in the expansive group (34% vs 24%; P=.02), and poor response was more common in the infiltrative group (11% and 19%; P=.02). Mean gross tumor volume at diagnosis was equal in both groups (51.7 cm{sup 3}). The high-risk clinical target volume was larger in infiltrative tumors (37.9 cm{sup 3} vs 33.3 cm{sup 3}, P=.005). The mean high-risk clinical target volume D{sub 90} was slightly higher in expansive tumors (92.7 Gy and 89.4 Gy, P<.001). Conclusion: Infiltrative tumors are more advanced at presentation and respond less favorably to chemo-radiotherapy when compared with expansive tumors that are more or less equivalent in size. The use of image-guided adaptive brachytherapy allows achieving reasonably high doses in both groups.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2015

Postoperative Chemoradiation Therapy in High-Risk Cervical Cancer: Re-evaluating the Findings of Gynecologic Oncology Group Study 109 in a Large, Population-Based Cohort

Purpose: To review the National Cancer Database (NCDB) to evaluate postoperative high-risk cervical cancer patients for factors associated with a benefit from chemoradiation therapy (CRT) over external beam radiation therapy alone (EBRT). Methods and Materials: The National Cancer Database was queried for women with cervical cancer treated with hysterectomy and adjuvant EBRT from 2002 to 2012. Only patients with pathologic lymph node involvement (LN+), positive surgical margins, and/or parametrial invasion were included in our analysis (on the basis of Peter's criteria). Univariable and multivariable analyses (MVA) were performed, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to investigate for factors associated with of CRT utilization and overall survival (OS). Results: A total of 3053 patients met inclusion criteria, and 2479 received adjuvant CRT (81%), whereas 574 (19%) received EBRT alone. Factors associated with increased CRT utilization on MVA included age <69 years, year of diagnosis ≥2008, non-adenocarcinoma histology, and LN+. Use of CRT improved OS among the entire cohort on MVA (HR 0.76, CI 0.601-0.962; P=.022). On MVA, CRT improved OS in patients with LN+ as their sole Peter's criteria (HR 0.58, CI 0.413-0.814; P=.002). Chemoradiation therapy did not improve OS in patients with only positive margins (P=.73), only parametrial invasion (P=.95), or any combination of these 2 factors without LN+ (P=.63). Conclusions: The use of adjuvant CRT after hysterectomy improves OS in patients with high-risk cervical cancer compared with EBRT alone, but this benefit seems to be restricted to patients with LN+. The benefits of adjuvant CRT over EBRT alone in patients with parametrial invasion and/or positive margins (without nodal involvement) are unknown.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2016

Phase 2 Randomized Controlled Trial of Radiation Therapy Plus Concurrent Interferon-Alpha and Retinoic Acid Versus Cisplatin for Stage III Cervical Carcinoma

Purpose: Because a combination of retinoic acid, interferon-alpha, and radiation therapy demonstrated synergistic action and effectiveness to treat advanced cervical cancers in earlier studies, we designed this randomized phase 2 open-label trial to assess efficacy and safety of interferon alpha-2b (IFN) and 13-cis-retinoic acid (RA) administered concomitantly with radiation therapy (IFN-RA-radiation) to treat stage III cervical cancer. Methods and Materials: Stage III cervical cancer patients were randomized to study and control groups in a 1:1 ratio. All patients were treated with radiation therapy; study arm patients received IFN (3 × 10{sup 6} IU subcutaneously) 3 times a week for 4 weeks and daily RA (40 mg orally) for 30 days starting on day 1 of radiation, whereas control arm patients received weekly cisplatinum (40 mg/m{sup 2}) for 5 weeks during radiation. Patients were followed for 3 years. The primary endpoint was overall survival at 3 years. Results: Patients in the study (n=104) and control (n=105) groups were comparable for clinicopathological characteristics, radiation therapy–related variables and treatment response. Proportions of disease-free patients in the study and control groups were 38.5% and 44.8%, respectively, after median follow-up of 29.2 months. Hazard ratios were 0.67 (95% confidence interval [CI]: 0.44-1.01) and 0.69 (95% CI: 0.44-1.06) for overall and disease-fee survival, respectively, comparing the study group to control, and demonstrated an inferior outcome with RA-IFN-radiation, although differences were statistically nonsignificant. Kaplan-Meier curves of disease-free and overall survival probabilities also showed inferior survival in the study group compared to those in the control. Acute toxicities of chemoradiation were significantly higher with 2 acute toxicity-related deaths. Conclusions: Treatment with RA-IFN-radiation did not demonstrate survival advantage over chemoradiation despite being less toxic. The trends predicted an inferior outcome with the RA-IFN combination.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2016

Computed Tomography–Planned High-Dose-Rate Brachytherapy for Treating Uterine Cervical Cancer

Purpose: To evaluate the long-term results of computed tomography (CT)–planned high-dose-rate (HDR) brachytherapy (BT) for treating cervical cancer patients. Methods and Materials: CT-planned HDR BT was performed according to the adapted Group European de Curietherapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) recommendations in 216 consecutive patients with locally advanced cervical cancer, International Federation of Gynecology and Obstetrics (FIGO) stage IB to IVA, who were treated with conformal external beam radiation therapy and concomitant chemotherapy. We analyzed outcomes and late side effects evaluated according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer and Subjective, Objective, Management, Analysis evaluation scoring system and compared them with the results from a historical group. Results: The median age was 56 years (range, 32-83 years). The median follow-up time for living patients was 52 months (range 37-63 months). The 5-year cumulative incidence function for the local recurrence rate for patients with FIGO II and III was 5.5% and 20%, respectively (P=.001). The 5-year rates of overall survival (OS) and disease-free survival (DFS) were 66.4% and 58.5%, respectively. The relative risk of failure for OS and DFS for FIGO III in relation to FIGO II was 2.24 (P=.003) and 2.6 (P=.000) and for lymph node enlargement was 2.3 (P=.002) and 2 (P=.006), respectively. In 2 patients, rectovaginal fistula occurred, and in 1 patient, vesicovaginal fistula occurred without local progression. Comparison of late adverse effects in patients treated according to the GEC-ESTRO recommendations and in the historical group revealed a reduction in fistula formation of 59% and also a reduction in rectal grade 3 to 4 late toxicity of >59%. Conclusions: This is the largest report with mature data of CT-planned BT HDR for the treatment of cervical cancer with good local control and acceptable toxicity. In comparison with the historical series, there is a substantial benefit in terms of severe late effects. FIGO III and enlarged lymph nodes in positron emission tomography–CT/CT are negative prognostic factors, both with a relative risk of failure of approximately 2.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2016

Prospective Validation of a High Dimensional Shape Model for Organ Motion in Intact Cervical Cancer

Purpose: Validated models are needed to justify strategies to define planning target volumes (PTVs) for intact cervical cancer used in clinical practice. Our objective was to independently validate a previously published shape model, using data collected prospectively from clinical trials. Methods and Materials: We analyzed 42 patients with intact cervical cancer treated with daily fractionated pelvic intensity modulated radiation therapy and concurrent chemotherapy in one of 2 prospective clinical trials. We collected online cone beam computed tomography (CBCT) scans before each fraction. Clinical target volume (CTV) structures from the planning computed tomography scan were cast onto each CBCT scan after rigid registration and manually redrawn to account for organ motion and deformation. We applied the 95% isodose cloud from the planning computed tomography scan to each CBCT scan and computed any CTV outside the 95% isodose cloud. The primary aim was to determine the proportion of CTVs that were encompassed within the 95% isodose volume. A 1-sample t test was used to test the hypothesis that the probability of complete coverage was different from 95%. We used mixed-effects logistic regression to assess effects of time and patient variability. Results: The 95% isodose line completely encompassed 92.3% of all CTVs (95% confidence interval, 88.3%-96.4%), not significantly different from the 95% probability anticipated a priori (P=.19). The overall proportion of missed CTVs was small: the grand mean of covered CTVs was 99.9%, and 95.2% of misses were located in the anterior body of the uterus. Time did not affect coverage probability (P=.71). Conclusions: With the clinical implementation of a previously proposed PTV definition strategy based on a shape model for intact cervical cancer, the probability of CTV coverage was high and the volume of CTV missed was low. This PTV expansion strategy is acceptable for clinical trials and practice; however, we recommend daily image guidance to avoid systematic large misses in select patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗