Neoadjuvant Chemoradiation Therapy Followed by Extrafascial Hysterectomy in Locally Advanced Type II Endometrial Cancer Clinically Extending to Cervix.

PURPOSE: The role of neoadjuvant chemoradiation therapy in locally advanced type II endometrial cancer is controversial. We thus aimed to present our experience with the hypothesis that neoadjuvant chemoradiation therapy is associated with similarly high rates of downstaging and locoregional control for type II endometrial cancer and type I endometrial cancer. METHODS AND MATERIALS: Thirty-four patients with type II endometrial cancer with clinical evidence of cervical ± parametrium involvement treated with neoadjuvant external beam radiation therapy (45-50.4 Gy in 25-28 fractions) and high-dose-rate brachytherapy with a median total dose of 20 Gy (range, 15-27.5) in 4 fractions (range, 3-5) and concurrent platinum chemotherapy ± adjuvant chemotherapy from 2008 to 2018 were retrospectively reviewed. Patients with type I pathologic diagnoses and those treated with definitive (rather than preoperative) intent were excluded. RESULTS: Pathologic characteristics were as follows: 38% were carcinosarcoma, 18% serous, and 24% clear cell. Ninety-four percent of patients were downstaged to an extrafascial hysterectomy, and 94% had negative surgical margins. The 2-year local control, regional control, distant control, disease-free survival, and overall survival were 87.8%, 81.3%, 76.3%, 52.5%, and 63.7%, respectively. There was 1 subacute grade 3 and 1 late grade 3 small bowel obstruction, directly attributable to radiation therapy. CONCLUSIONS: Neoadjuvant chemoradiation therapy effectively downstages the majority of locally advanced type II endometrial cancers, thereby increasing the likelihood of achieving complete resection with negative margins.

Single-Institution Experience in 3D MRI-Based Brachytherapy for Cervical Cancer for 239 Women: Can Dose Overcome Poor Response?

PURPOSE: Recent Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology guidelines recommend that the dose to 90% (D90) of the high-risk clinical target volume (HRCTV) in cervical cancer be at least 85 Gy, with higher doses for poor response to radiation therapy. METHODS AND MATERIALS: A retrospective review of brachytherapy delivered at a single institution was evaluated for dosimetry and outcomes. Significance of tumor parameters on local control was evaluated with Kaplan-Meier and univariable and multivariable Cox regression analysis. Correlations were determined with a linear regression model. RESULTS: A total of 239 women underwent high-dose-rate brachytherapy for cervical cancer between 2007 and 2018 with evaluable dosimetry. Median follow-up was 28.6 months. The median prescribed dose was 27.5 Gy in 5 fractions, with a median HRCTV D90 of 83.9 Gy (range, 81.9-85.7 Gy), HRCTV volume of 31 cm3 (range, 14.9-121.9 cm3), and treatment time of 51 days (range, 36-83 days). Local control for the entire cohort at 5 years was 90.8%. Local control was worse with adenocarcinomas, HRCTV >40 cm3 at brachytherapy, requirement for a higher brachytherapy dose, and treatment >51 days. On multivariable analysis, local control was worse with adenocarcinoma (hazard ratio, 4.141; 95% confidence interval, 1.498-11.444; P = .006) and HRCTV >40 cm3 (hazard ratio, 3.640; 95% confidence interval, 1.316-10.069; P = .013). HRCTV EQD2 D90 > 85 Gy did not statistically improve outcomes for any subset. The 2-year progression-free survival for HRCTV >40 cm3 was 66.2% versus 84.1% if ≤40 cm3 (P < .001). Overall survival was predicted by HRCTV and overall treatment time in multivariable analysis. For women with HRCTV ≤40 cm3, overall survival at 2 years was 90.4% versus 68.5% if >40 cm3 (P < .001). CONCLUSION: Local control was excellent with magnetic resonance imaging-based planning in the entire cohort of patients. A poor response to external beam radiation (larger HRCTV) and adenocarcinoma histology predicted for worse local control despite association with higher brachytherapy prescription. Women with these risk factors face higher rates of extrapelvic progression and poorer overall survival.

The Prognostic Significance of p16 Status in Patients With Vulvar Cancer Treated With Vulvectomy and Adjuvant Radiation.

PURPOSE: Vulvar squamous cell carcinoma (VSCC) is a relatively rare malignancy. Human papillomavirus has been implicated as a causative factor for a subset of these patients. The purpose of this study was to evaluate whether p16-positivity (a human papillomavirus surrogate) predicts for better response rates in women who undergo surgery followed by adjuvant radiation therapy (RT). METHODS AND MATERIALS: We retrospectively analyzed data from women with VSCC who were treated with adjuvant RT. p16-Positivity was defined as diffuse strong immunoreactivity within the tumor. Time to event outcomes was performed with Kaplan-Meier and cumulative incidence methodologies. RESULTS: Thirty-nine women were identified. Ten had positive results for p16 (p16+), and 29 had negative results (p16-). The median follow-up was 25.7 months. The median age at diagnosis was 59 years for women with p16+ tumors and 74 years for women with p16- tumors (P = .022). The distribution of stage did not differ by p16 status. The indications for adjuvant RT were close/positive margins in 19 women, positive nodes in 9 women, and both in 11 women. There were 21 recurrences: 15 vulvar, 3 isolated nodal, 2 synchronous vulvar/nodal, and 1 distant metastasis. In-field relapse rates at 3 years were lower in p16+ patients (32.5%) than in p16- patients (59.1%, P = .072). This trend was also observed in progression-free survival (P = .062). A p16+ status and a lower International Federation of Gynecology and Obstetrics stage were associated with fewer in-field relapses and improved progression-free survival in multivariable analyses. The p16 status was not a predictor of overall survival. CONCLUSIONS: p16-Positivity appears to be a prognostic factor for in-field relapse rates in patients with VSCC appropriately treated with adjuvant RT.

Inflammatory biomarker in adipose stem cells of women with endometrial cancer.

AIM: To explore inflammatory biomarkers secreted by adipose stem cells (ASCs) in omental, retroperitoneal and subcutaneous adipose tissues of women with endometrial cancer. PATIENTS & METHODS: ASCs were collected from 22 women, aged 35-83 years, undergoing hysterectomy for endometrial cancer. Angiopoietin-2, EGF, IL-8, leptin, VEGFA, VEGFC and VEFGD levels in the ASC-conditioned media were analyzed by Luminex. RESULTS: We found a significant difference between the three depots for IL-8 (p < 0.0001), with the highest levels of IL-8 in the omental depot. VEGFA levels were highest in the retroperitoneal depot. CONCLUSION: This is one of the first studies to explore biomarker expression in ASC-conditioned media in adipose tissue. ASC characteristics may be important to evaluate in relation to cancer risk.

Image-based multichannel vaginal cylinder brachytherapy for the definitive treatment of gynecologic malignancies in the vagina.

PURPOSE: Brachytherapy is integral to vaginal cancer treatment and is typically delivered using an intracavitary single-channel vaginal cylinder (SCVC) or an interstitial brachytherapy (ISBT) applicator. Multi-channel vaginal cylinder (MCVC) applicators allow for improved organ-at-risk (OAR) sparing compared to SCVC while maintaining target coverage. We present clinical outcomes of patients treated with image-based high dose-rate (HDR) brachytherapy using a MCVC. METHODS AND MATERIALS: Sixty patients with vaginal cancer (27% primary vaginal and 73% recurrence from other primaries) were treated with combination external beam radiotherapy (EBRT) and image-based HDR brachytherapy utilizing a MCVC if residual disease thickness was 7 mm or less after EBRT. All pts received 3D image-based BT to a total equivalent dose of 70-80 Gy. RESULTS: The median high-risk clinical target volume was 24.4 cm3 (interquartile range [IQR], 14.1), with a median dose to 90% of 77.2 Gy (IQR, 2.8). After a median follow-up of 45 months (range, 11-78), the 4-year local-regional control, distant control, DFS, and OS rates were 92.6%, 76.1%, 64.0%, and 67.2%, respectively. The 4-year LRC rates were similar between the primary vaginal (92%) and recurrent (93%) groups (p = 0.290). Pts with lymph node positive disease had a lower rate of distant control at 4 years (22.7% vs. 89.0%, p < 0.001). There were no Grade 3 or higher acute complications. The 4-year rate of late Grade 3 or higher toxicity was 2.7%. CONCLUSIONS: Clinical outcomes of pts with primary and recurrent vaginal cancer treated definitively in a systematic manner with combination EBRT with image-guided HDR BT utilizing a MCVC applicator demonstrate high rates of local control and low rates of severe morbidity. The MCVC technique allows interstitial implantation to be avoided in select pts with ≤7 mm residual disease thickness following EBRT while maintaining excellent clinical outcomes with extended 4-year follow-up in this rare malignancy.

Super-Utilization of Health Care Resources Among Gynecologic Oncology Patients.

Super-utilizers account for many emergency department visits (EDV) and hospitalizations. Among Medicare/Medicaid patients, 5% to 10% account for >50% of spending. Little is known about super-utilization in gynecologic oncology. Charts of 64 gynecologic oncology patients with ≥3 EDV and/or admissions over 12 months were reviewed retrospectively. Cancer type distribution was 47% ovarian, 23% cervical, 23% endometrial, and 6% vulvar. Treatment at index visit was 61% chemotherapy, 16% no treatment, 8% recent surgery, and 6% radiation. Mean visits was 5.7 (SD 3.9, range 3-28). Most common presenting complaints were gastrointestinal and pain. Patients near end of life were more likely to be admitted. EDV frequently occurred outside standard work hours (63%). EDV/admissions resulted in total variable expenses of $1 462 581 ($982 933 direct expense, $479 648 service expense). Interventions to decrease super-utilization could target symptom management, off-hour support, patients on chemotherapy, and end of life. Approaches could include multidisciplinary resources, palliative care teams, extending office hours, and earlier initiation of hospice.

Single-institutional outcomes of adjuvant brachytherapy for Stage I endometrial cancer-Are outcomes consistent with randomized studies?

PURPOSE: Vaginal brachytherapy (VBT) alone has been shown to be a viable adjuvant treatment strategy for most patients with Stage I endometrioid endometrial cancer. We sought to examine our institutional data following practice pattern changes resulting from the publications of GOG-99 and PORTEC-2. METHODS AND MATERIALS: We retrospectively analyzed women who underwent adjuvant VBT after surgical staging for Stage 1 endometrioid endometrial cancer at our institution from 2007 to 2014. RESULTS: We identified 297 women. Median time to last followup or death was 52.3 months (interquartile range: 32.3-72.3 months). By International Federation of Gynecology and Obstetrics 2009 staging, 162 patients (54.5%) had Stage IA and 128 (43.1%) had Stage IB disease. Ninety-nine (33.3%) patients had Grade 1, 153 (51.5%) had Grade 2, and 45 (15.2%) had Grade 3 disease. According to GOG-249 and PORTEC-2 criteria, 167 (56.2%) and 127 (42.7%) patients were with high-intermediate-risk disease. Two women had Stage IB Grade 3 disease. The most common high-dose-rate-VBT regimen was 2100 cGy/three fractions to a depth of 5 mm. Four (two acute and two late) (1.3%) Grade 3 genitourinary toxicities were reported: three episodes of vaginal dehiscence (after second course of VBT, 2 months after completion of VBT, and 1 year after completion of VBT) and one episode of radiation necrosis. Twenty-one (7%) women recurred: three recurred in the vagina, two recurred in the pelvic lymph nodes, and 16 recurred distantly. CONCLUSIONS: Outcomes appear consistent with published randomized data in women with high-intermediate-risk endometrial cancer who are treated with brachytherapy alone. Recurrence and complication rates were minimal.

Racial and Socioeconomic Disparities in Hysterectomy Route for Benign Conditions.

BACKGROUND: The aim of this paper was to explore disparities associated with the route of hysterectomy in the University of Pittsburgh Medical Center (UPMC) health system and to evaluate whether the hysterectomy clinical pathway implementation impacted disparities in the utilization of minimally invasive hysterectomy (MIH). METHODS: We performed a retrospective medical record review of all the patients who have undergone hysterectomy for benign indications at UPMC-affiliated hospitals between fiscal years (FY) 2012 and 2014. RESULTS: A total number of 6373 hysterectomy patient cases were included in this study: 88.7% (5653) were European American (EA), 11.02% (702) were African American (AA), and the remaining 0.28% (18) were of other ethnicities. We found that non-EA, women aged 45-60, traditional Medicaid, and traditional Medicare enrollees were more likely to have a total abdominal hysterectomy (TAH). Residence in higher median income zip code (> $61,000) was associated with 60% lower odds of undergoing TAH. Both FY 2013 and 2014 were associated with significantly lower odds of TAH. Logistic regression results from the model for non-EA patients for FY 2012 and FY 2014 demonstrated that FY and zip code income group were not significant predictors of surgery type in this subgroup. Pathway implementation did not reduce racial disparity in MIH utilization. CONCLUSION: This study demonstrated that there is a significant disparity in MIH utilization, where non-EA and Medicaid/Medicare recipients had higher odds of undergoing TAH. Further research is needed to investigate how care standardization may alleviate healthcare disparities.

Outcomes of stage II endometrial cancer: The UPMC Hillman Cancer Center experience.

PURPOSE: Previous studies of stage II endometrial cancer have included cancers with cervical glandular involvement, a factor no longer associated with risk of recurrence. In order to better assess relapse patterns and the impact of adjuvant therapy, a retrospective analysis was conducted for patients with modern stage II endometrial cancer, defined as cervical stromal invasion. MATERIALS AND METHODS: Patients diagnosed with surgically staged FIGO stage II endometrial cancer at the UPMC Hillman Cancer Center from 1990-2013 were reviewed. Factors associated with rates of locoregional control (LRC), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS) were analyzed using the log rank test. RESULTS: 110 patients with FIGO stage II disease were identified. Most (84.5%) received EBRT±BT, with 13.6% receiving BT alone. With a median follow-up of 64.6months, the 5-year actuarial rates of LRC, DM, DFS, and OS were 94.9%, 85.1%, 67.9%, and 75.0%, respectively. With 5 locoregional failures, the only factor predictive of LRC was pelvic lymph node dissection. Characteristics associated with DM included age, LVSI, depth of myometrial invasion, and receipt of chemotherapy. Factors predictive of both DFS and OS were age, grade, adverse histology, LVSI, depth of myometrial invasion, and receipt of chemotherapy. CONCLUSIONS: This represents the largest single-institution study for modern stage II endometrial cancer, confirming high rates of pelvic disease control after surgery and adjuvant therapy. With most patients receiving adjuvant radiotherapy, the predominant mode of failure, albeit low in absolute number, remains distant metastases.

Implementation of Hysterectomy Pathway: Impact on Complications.

OBJECTIVE: Hysterectomy is one of the most common surgical procedures in the United States. For women who need hysterectomy, it is important to ensure that minimally invasive hysterectomy procedures are used appropriately to reduce surgical complications and improve value of care. Although we previously demonstrated a reduction in total abdominal hysterectomy rates after the implementation of hysterectomy pathway treatment algorithm in 2012, this study focuses on exploring the effect of pathways implementation on surgical outcomes. METHODS: All retrospective medical records for hysterectomy surgeries performed for benign indications at University of Pittsburgh Medical Center hospitals between the fiscal years (FY) 2012 and 2014 were identified. We analyzed the health care outcomes by route of surgery and year using Χ2 test for categorical data, and non-parametric approaches for non-normal continuous variables. RESULTS: A total of 6,569 hysterectomies for benign indications were performed between FY 2012 and 2014. In FY 2012, 1,154 patients (59.15%) had a length of stay of 1 day or less, whereas in FY 2014 this number increased to 1,791 (74.53%; p < .0001). Within 3 years of implementing the pathway, surgical site infections had a reduction of 47%, with a considerable trend toward significance (p = .067). CONCLUSIONS: Implementation of hysterectomy pathway has been associated with reduction of surgical complications in benign hysterectomy settings. Implementation of clinical pathways offers an opportunity for improving patient outcomes that should be investigated in various health care settings and across procedures.

Surgical Outcomes of Patients Undergoing Extrafascial Hysterectomy After Neoadjuvant Radiotherapy With or Without Chemotherapy for Locally Advanced Endometrial Cancer Clinically Extending to the Cervix or Parametria.

OBJECTIVES: Recent data have shown high rates of clinical and pathologic responses to neoadjuvant radiation therapy for locally advanced endometrial cancer. There are limited data on the surgical outcomes of these patients in the era of modern radiation and surgical techniques. We sought to characterize surgical outcomes after extrafascial hysterectomy in this population. METHODS: Patients with endometrial cancer of all histologies clinically involving the cervix or parametria treated with neoadjuvant brachytherapy followed by extrafascial hysterectomy from 1999 to 2014 were identified. Patient charts were reviewed for data regarding treatment characteristics and postoperative outcomes. Pearson χ and logistic regression analyses were used to assess correlations between surgical complications and treatment-related variables. RESULTS: Twenty-nine patients met inclusion criteria. Mean operating time for the cohort was 115 minutes. Mean estimated blood loss was 100 mL. No visceral injuries occurred. Mean length of hospital stay was 1 and 4 days for the minimally invasive and laparotomy groups, respectively. Rates of postoperative ileus, blood transfusion, wound infection, and readmission were 3%, 3%, 6%, and 3%, respectively. No case of prolonged urodynamic dysfunction was noted. The rate of vaginal complications was significantly higher in the group of patients who underwent minimally invasive surgery as compared with laparotomy (33% vs 5%, P < 0.041). CONCLUSIONS: These data support adjuvant extrafascial hysterectomy after neoadjuvant radiotherapy for endometrial cancer with cervical or parametrial involvement as a safe and viable procedure, with low rates of postoperative complications. Extra care should be taken when closing the vaginal cuff to reduce the risk of vaginal cuff complications.

Changes in Hysterectomy Trends After the Implementation of a Clinical Pathway.

OBJECTIVE: To investigate the effect of hysterectomy pathway implementation on the proportion of total abdominal hysterectomy (TAH) procedures performed between fiscal years 2012 and 2014. METHODS: We conducted a retrospective medical record review. All hysterectomy surgeries performed for benign indications at University of Pittsburgh Medical Center hospitals from fiscal year 2012 to fiscal year 2014 were identified through various systems including Medipac and EpicCare. We analyzed the cases by surgical approach (TAH compared with minimally invasive hysterectomy), age, and indication of surgery. Changes over time were analyzed using Cochran-Armitage test for linear trends. RESULTS: A total number of 6,544 patients were included in this study. The mean age of the participants was 48.6 years (standard deviation 11.69). In fiscal year 2012, of 1,934 hysterectomies performed as a result of noncancerous conditions, 538 were TAH procedures (27.8%). However, this number declined in fiscal year 2013 to 22% (485 TAH procedures of 2,186 hysterectomies) and further declined in fiscal year 2014 to 17% (413 TAH surgeries of 2,424 hysterectomies). Overall, there was a significant reduction in the proportion of TAH procedures, from 27.8% in fiscal year 2012 to 17% in fiscal year 2014 (P for trend <.001). After adjusting for surgery indication, the decreasing trend of TAH procedures still persisted (P for trend <.001). CONCLUSION: Implementation of a hysterectomy pathway has been associated with a decrease in the proportion of TAH hysterectomy procedures.

Evaluation of Silicon Phthalocyanine 4 Photodynamic Therapy Against Human Cervical Cancer Cells In Vitro and in Mice.

BACKGROUND: Cervical cancer is the second most common cancer in women worldwide [1]. Photodynamic therapy has been used for cervical intraepithelial neoplasia with good responses, but few studies have used newer phototherapeutics. We evaluated the effectiveness of photodynamic therapy using Pc 4 in vitro and in vivo against human cervical cancer cells. METHODS: CaSki and ME-180 cancer cells were grown as monolayers and spheroids. Cell growth and cytotoxicity were measured using a methylthiazol tetrazolium assay. Pc 4 cellular uptake and intracellular distrubtion were determined. For in vitro Pc 4 photodynamic therapy cells were irradiated at 667nm at a fluence of 2.5 J/cm2 at 48 h. SCID mice were implanted with CaSki and ME-180 cells both subcutaneously and intracervically. Forty-eight h after Pc 4 photodynamic therapy was administered at 75 and 150 J/cm2. RESULTS: The IC50s for Pc 4 and Pc 4 photodynamic therapy for CaSki and ME-180 cells as monolayers were, 7.6µM and 0.016µM and >10µM and 0.026µM; as spheroids, IC50s of Pc 4 photodynamic therapy were, 0.26µM and 0.01µM. Pc 4 was taken up within cells and widely distributed in tumors and tissues. Intracervical photodynamic therapy resulted in tumor death, however mice died due to gastrointestinal toxicity. Photodynamic therapy resulted in subcutaneous tumor death and growth delay. CONCLUSIONS: Pc 4 photodynamic therapy caused death within cervical cancer cells and xenografts, supporting development of Pc 4 photodynamic therapy for treatment of cervical cancer. Support: P30-CA47904, CTSI BaCCoR Pilot Program.

The Role of High-Risk Human Papilloma Virus Testing in the Surveillance of Cervical Cancer After Treatment.

CONTEXT: Cervical cancer affects 12 000 women in the United States annually. However, despite its prevalence, there remains no good methodology to detect its recurrence. OBJECTIVE: To identify the role of cervicovaginal high-risk human papilloma virus (hr-HPV) testing in predicting cervical cancer recurrence. DESIGN: This is a retrospective study of patients who underwent hr-HPV testing as part of their routine surveillance for cervical cancer. Standard statistical analyses, including χ² test and multivariable logistic regression, were performed with IBM SPSS 19.0. RESULTS: A total of 133 patients were identified, of whom 107 (80%) had squamous cell carcinoma. Ninety patients (68%) had bulky disease and were treated primarily with chemoradiation and brachytherapy. Of patients whose disease recurred, 5 patients (42%) had tested positive for hr-HPV during their surveillance period, compared to 13 patients (11%) for whom disease did not recur (relative risk: 3.88, P = .002). On multivariate logistic regression, hr-HPV status remained significantly predictive of disease recurrence (odds ratio: 12.3, P = .02, 95% confidence interval: 1.5-99.6). Using 2 × 2 table analysis, we found that while cervicovaginal cytology has limited specificity (5.7%) in predicting recurrence, the combination of cytology with hr-HPV testing increases the specificity of testing to 89.3%. CONCLUSIONS: Persistence of hr-HPV is a risk factor for disease recurrence. High-risk-HPV testing is not routinely used during surveillance for cervical cancer, but this study suggests that large, prospective trials investigating the role of hr-HPV testing in cervical cancer surveillance are needed.

MRI-guided high-dose-rate intracavitary brachytherapy for treatment of cervical cancer: the University of Pittsburgh experience.

PURPOSE: Image-based brachytherapy is increasingly used for gynecologic malignancies. We report early outcomes of magnetic resonance imaging (MRI)-guided brachytherapy. METHODS AND MATERIALS: Consecutive patient cases with FIGO stage IB1 to IVA cervical cancer treated at a single institution were retrospectively reviewed. All patients received concurrent cisplatin with external beam radiation therapy along with interdigitated high-dose-rate intracavitary brachytherapy. Computed tomography or MRI was completed after each application, the latter acquired for at least 1 fraction. High-risk clinical target volume (HRCTV) and organs at risk were identified by Groupe Européen de Curiethérapie and European SocieTy for Radiotherapy and Oncology guidelines. Doses were converted to equivalent 2-Gy doses (EQD2) with planned HRCTV doses of 75 to 85 Gy. RESULTS: From 2007 to 2013, 128 patients, median 52 years of age, were treated. Predominant characteristics included stage IIB disease (58.6%) with a median tumor size of 5 cm, squamous histology (82.8%), and no radiographic nodal involvement (53.1%). Most patients (67.2%) received intensity modulated radiation therapy (IMRT) at a median dose of 45 Gy, followed by a median brachytherapy dose of 27.5 Gy (range, 25-30 Gy) in 5 fractions. At a median follow up of 24.4 months (range, 2.1-77.2 months), estimated 2-year local control, disease-free survival, and cancer-specific survival rates were 91.6%, 81.8%, and 87.6%, respectively. Predictors of local failure included adenocarcinoma histology (P<.01) and clinical response at 3 months (P<.01). Among the adenocarcinoma subset, receiving HRCTV D90 EQD2 ≥84 Gy was associated with improved local control (2-year local control rate 100% vs 54.5%, P=.03). Grade 3 or greater gastrointestinal or genitourinary late toxicity occurred at a 2-year actuarial rate of 0.9%. CONCLUSIONS: This study constitutes one of the largest reported series of MRI-guided brachytherapy in North America, demonstrating excellent local control with acceptable morbidity. Dose escalation may be warranted when feasible for adenocarcinomas to offset the risk of local failure.

Complete Pathologic Response Following Neoadjuvant Chemoradiotherapy and High-Dose-Rate Brachytherapy for Locally Advanced Endometrial Carcinoma.

The majority of uterine cancers present at an early stage because of abnormal post-menopausal bleeding. Locally advanced endometrial carcinoma with extension to the parametria represents a rare subset of patients with treatment options involving neoadjuvant therapy followed by extrafascial hysterectomy or definitive non-operative management. Neoadjuvant therapy enables R0 resection in the majority of patients but with relatively low rates of complete pathologic response. Herein, we detail the case of a patient with bulky FIGO Stage IIIB endometrial carcinoma with pelvic and para-aortic lymphadenopathy who achieved a complete response with neoadjuvant chemoradiotherapy and high-dose-rate brachytherapy prior to extrafascial hysterectomy.

Image-based multichannel vaginal cylinder brachytherapy for vaginal cancer.

PURPOSE: To investigate the clinical feasibility and treatment outcomes of image-based high-dose-rate (HDR) brachytherapy using an intracavitary multichannel vaginal cylinder for the definitive treatment of vaginal cancers. METHODS AND MATERIALS: A total of 41 patients with vaginal cancer (24% primary vaginal and 76% recurrence from other gynecologic primaries) treated with definitive radiotherapy ± chemotherapy including image-based HDR brachytherapy with a multichannel vaginal cylinder were included in the study. Image-based brachytherapy was completed using either CT- (41%) or MR-based planning (59%) with each fraction. The high-risk clinical target volume was defined based on the pre- and postexternal beam radiotherapy gross tumor volume. Doses were converted to equivalent dose of 2Gy per fraction. Endpoints examined were dose-volume parameters and early clinical outcomes. RESULTS: The median high-risk clinical target volume was 24.2 cc (interquartile range [IQR], 12.6), with a median dose to 90% (D90) of 77.1 Gy (IQR, 3.4). The median dose to 2 cc (D(2 cc)) for the bladder, rectum, and sigmoid were 59.4 Gy (IQR, 5.6), 58.2 Gy (IQR, 4.1), and 52.3 Gy (IQR, 5.5), respectively. After a median followup of 16 months (range, 3-35), complete clinical response was documented in 98% of the patients. The 2-year local, regional, and distant control; and disease-free and overall survival were 93%, 100%, 81%, 78%, and 88%, respectively. The 2-year actuarial rate of late Grade 3 or higher toxicity was 4% overall with 0%, 0%, 0%, and 4% for vaginal, bladder, urethral, and gastrointestinal, respectively. CONCLUSIONS: Image-based HDR brachytherapy using an intracavitary multichannel cylinder seems feasible in definitive vaginal cancer treatment. The described clinical implementation shows promising early clinical outcomes with high rates of local control and little toxicity, which should be validated with extended followup.

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.

Definitive salvage for vaginal recurrence of endometrial cancer: the impact of modern intensity-modulated-radiotherapy with image-based HDR brachytherapy and the interplay of the PORTEC 1 risk stratification.

PURPOSE: Data for salvage radiotherapy for recurrent endometrial cancer are limited especially in the era of modern radiotherapy including IMRT and 3-dimensional image-based HDR brachytherapy. Theoretically, modern radiotherapy reduces the dose to critical organs-at-risk and maximizes dose to the target volume, possibly decreasing morbidity and increasing tumor control. MATERIALS AND METHODS: Forty-one patients completing definitive salvage radiotherapy for vaginal recurrence of endometrial cancer from June 2004 to December 2013 were retrospectively reviewed. HDR Brachytherapy was completed using image-based planning with contouring/optimization with each fraction to a median dose of 23.75 Gy in 5 fractions. HDR brachytherapy was preceded by external beam radiotherapy predominately using an IMRT technique (90%) to a median dose of 45 Gy in 25 fractions. Toxicity was reported according to CTCAEv4. RESULTS: At a median follow-up of 18 months (range: 3-78), the clinical complete response rate was 95%. The 3-year local control, distant control, recurrence free survival, and overall survival were 95%, 61%, 68%, and 67%. Significant predictors of both distant failure and overall survival were primary prognostic factors of depth of myometrial invasion, FIGO stage, and FIGO grade. There was no grade 3+ acute toxicity; the 3-year rate of grade 3+ late toxicity was 8%. CONCLUSIONS: Salvage IMRT plus 3-dimensional image-based HDR brachytherapy shows excellent tumor control and minimal morbidity for vaginal recurrence of endometrial cancer. Anticipated salvage rates must be taken in the context of primary risk factors including depth of myometrial invasion, FIGO stage, and FIGO grade.

Neoadjuvant radiotherapy with or without chemotherapy followed by extrafascial hysterectomy for locally advanced endometrial cancer clinically extending to the cervix or parametria.

PURPOSE: For locally-advanced uterine cancer clinically extending to the cervix, two treatment paradigms exist: surgical staging radical hysterectomy with tailored adjuvant therapy or neoadjuvant therapy followed by a less extensive simple hysterectomy. Currently, insufficient data exists to guide consensus guidelines and practical application of preoperative radiotherapy. MATERIALS AND METHODS: Retrospective IRB approved cohort study from 1999 to 2014 of 36 endometrial cancer patients with clinical involvement of cervix±parametria treated with neoadjuvant external beam radiotherapy (45-50.4Gy in 25-28 fractions) and image-based HDR brachytherapy (5-5.5Gy times 3-4 fractions)±chemotherapy followed by extrafascial hysterectomy performed at a median of 6weeks after radiotherapy. RESULTS: All patients had clinical cervical extension, 50% also had parametria extension, and 31% had nodal involvement. At the time of surgery 91% had no clinical cervical involvement, 58% had no pathologic cervical involvement, and all had margin negative resection. The pathologic complete response rate was 24%. Median follow-up from the time of surgery was 20months (range: 0-153). The 3-year local control, regional control, distant control, disease free survival and overall survival rates were 96%, 89%, 84%, 73%, and 100%. The 3-year rate of grade 3 complications was 11%, with no grade 4+ toxicity. CONCLUSIONS: Neoadjuvant radiation therapy±chemotherapy followed by extrafascial hysterectomy appears to be a viable option for patients with endometrial cancer clinically extending to the cervix and parametria. The HDR brachytherapy schema of 5-5.5Gy times 3-4 fractions, for a cumulative EQD2 of 60-70Gy, is well tolerated with high rates of clinical and pathological response.