Feasibility of intraoperative injection of radioactive tracer and blue dye for sentinel lymph node biopsy in vulvar cancer.

OBJECTIVE: The objective of this study was to examine the feasibility and success rate of intraoperative injection of radiotracer and blue dye performed by the surgeon without the use of preoperative lymphoscintigraphy for the detection of sentinel lymph nodes in clinically early stage vulvar cancer. METHODS: All patients with clinically early stage vulvar cancer who underwent attempted sentinel lymph node biopsy using intraoperative injection of Technetium-99 m (99mTc) tracer and blue dye performed by the surgeon after induction of anesthesia at single academic institution from 12/2009 to 5/2022 were identified. Demographic and clinicopathologic variables were collected. Data were compared using descriptive statistics. RESULTS: One hundred sixty-four patients (median age 66.4 years) underwent intraoperative injection of radioactive tracer and dye for sentinel lymph node biopsy. Most patients (n = 156, 95.1%) were white. Squamous cell carcinoma accounted for 138 cases (84.1%), melanoma for 10 (6.1%), extra-mammary invasive Paget's disease for 11 (6.7%), and other histologies for 5 (3%). A majority of cases were stage I disease on final pathology (n = 119, 72.6%). Most patients (n = 117, 71%) had tumors located within 2 cm of the midline and underwent planned bilateral groin assessment, while 47 (29%) had well lateralized lesions and underwent unilateral groin assessment. For the patients undergoing unilateral groin assessment, 44 of 47 (93.6%) had successful unilateral mapping. Of the patients who underwent bilateral groin assessment, 87 of 117 (74.4%) had successful bilateral mapping, and 26 of 117 (22.2%) had successful unilateral mapping. Of the 26 patients who underwent bilateral assessment but only had unilateral mapping, 19 had unilateral mapping to ipsilateral groin but failed contralateral mapping, six had midline lesions with successful mapping to one groin but failed mapping to the other groin, and one had unilateral mapping to the contralateral groin but not ipsilateral groin. The total successful sentinel lymph node mapping rate in this cohort was 86.5% (243/281 total sentinel lymph node attempts). CONCLUSION: In this cohort, the overall success rate of sentinel lymph node mapping and biopsy was 86.5%. The high rate of successful sentinel lymph node mapping supports the use of intraoperative radiotracer and blue dye injection by trained providers.

Is Substantial Lymphovascular Space Invasion Prognostic in Patients With Pathologically Lymph Node-Negative Endometrial Cancer?

PURPOSE: Lymphovascular space invasion (LVSI) predicts for higher rates of recurrence and increased mortality in endometrial cancer. Using 3-tier LVSI scoring, a PORTEC-1 and -2 trials analysis demonstrated that substantial LVSI was associated with worse locoregional (LR-DFS) and distant metastasis disease-free survival (DM-DFS), and these patients possibly benefited from external beam radiation therapy (EBRT). Furthermore, LVSI is a predictor for lymph node (LN) involvement, but the significance of substantial LVSI is unknown in patients with a pathologically negative LN assessment. We aimed to evaluate clinical outcomes of these patients in relation to the 3-tier LVSI scoring system. METHODS AND MATERIALS: We performed a single-institutional retrospective review of patients with stage I endometrioid-type endometrial cancer who underwent surgical staging with pathologically negative LN evaluation from 2017 to 2019 with 3-tier LVSI scoring (none, focal, or substantial). Clinical outcomes (LR-DFS, DM-DFS, and overall survival) were analyzed using the Kaplan-Meier method. RESULTS: A total of 335 patients with pathologically LN-negative stage I endometrioid-type endometrial carcinoma were identified. Substantial LVSI was present in 17.6% of patients; 39.7% of patients received adjuvant vaginal brachytherapy and 6.9% of patients received EBRT. Adjuvant radiation treatment varied by LVSI status. In patients with focal LVSI, 81.0% received vaginal brachytherapy. Among patients with substantial LVSI, 57.9% received vaginal brachytherapy alone, and 31.6% of patients received EBRT. The 2-year LR-DFS rates were 92.5%, 98.0%, and 91.4% for no LVSI, focal LVSI, and substantial LVSI, respectively. The 2-year DM-DFS rates were 95.5%, 93.3%, and 93.8% for no LVSI, focal LVSI, and substantial LVSI, respectively. CONCLUSIONS: In our institutional study, patients with pathologically LN-negative stage I endometrial cancer with substantial LVSI had similar rates of LR-DFS and DM-DFS compared with patients with none or focal LVSI. These findings highlight the need for multi-institutional studies to validate the prognostic value of substantial LVSI in this patient population.

Rare presentation of metastatic cervical cancer to the right upper extremity skeletal muscle and gluteal adipose tissue.

Metastatic patterns of squamous cell cervical cancer are well described in the literature. Advancements in radiologic imaging have improved the ability to detect unusual sites of metastatic disease. We describe a unique case of isolated distant metastases to the skeletal muscle and adipose tissue detected by PET-CT. A patient with a new diagnosis of squamous cell cervical cancer was incidentally found to have FDG-avid lesions in the right upper extremity skeletal muscle and right gluteal adipose tissue without other evidence of metastatic disease. Initial cytology of the right upper extremity lesion revealed no evidence of malignancy. After the patient developed worsening pain and swelling in the right arm and gluteal region, repeat cytology confirmed metastatic squamous cell cervical cancer. With increasing sensitivity of radiologic imaging studies, the frequency of incidentally noted lesions is likely to rise and may be challenging to interpret in a patient with a history of malignancy. Continued assessment and reporting of these lesions is imperative for improved understanding of the natural history of disease.

Do air gaps with image-guided vaginal cuff brachytherapy impact failure rates in patients with high-intermediate risk FIGO Stage I endometrial cancer?

PURPOSE: The aim of this study was to assess the impact of air gaps at the cylinder surface on the rate of vaginal cuff failure (VCF) after image-guided adjuvant vaginal cuff brachytherapy (VCBT) in the treatment of high-intermediate risk (HIR) FIGO (Fédération Internationale de Gynécologie et d'Obstétrique (International Federation of Gynecology and Obstetrics)) Stage I endometrial cancer. METHODS AND MATERIALS: A retrospective review of patients treated with image-guided VCBT from 2009 to 2016 for HIR FIGO Stage I endometrial cancer was performed. Air gaps present at the applicator surface on the first postinsertion CT were contoured. Vaginal cuff failure-free survival (VCFFS) was measured from the first fraction of VCBT to VCF. RESULTS: A total of 234 patients were identified. Air gaps were present on the first postinsertion CT scan in 82% of patients. The median number of air gaps was 2 (interquartile range [IQR] 1-3), median depth of the largest air gap was 2.7 mm (IQR 2.1-3.4 mm), and the median cumulative volume of air gaps was less than 0.1 cm3 (range < 0.1-0.7 cm3). At a median followup of 56 months (IQR 41-69), 12 patients (5%) experienced VCF, of which 4 had isolated VCF and 8 had synchronous pelvic or distant failure. Five-year VCFFS and isolated VCFFS were 96% (95% confidence interval 93-98%) and 98% (95% confidence interval 96-100%), respectively. On univariate analysis, no factors, including the presence, number, maximum depth, or cumulative volume of air gaps, were predictive for VCFFS. CONCLUSIONS: In this population, VCFFS remained high despite most patients having air gaps present on postinsertion CT scan.

Dose-escalated intensity modulated radiation therapy in patients with locally-advanced vulvar cancer - does it increase response rate?

PURPOSE: GOG 205 safely increased clinical (cCR) and pathologic complete response (pCR) in locally-advanced vulvar cancer through dose escalation using three-dimensional radiotherapy (RT). The aim of this study is to assess the response of dose-escalated intensity modulated radiotherapy (IMRT) in locally-advanced vulvar cancer. METHODS: A retrospective review of patients treated with dose-escalated (≥ 55Gy) IMRT from 2012 to 2018 for locally-advanced vulvar cancer was performed. Patients treated with preoperative or definitive intent were included. Rates of cCR and pCR were assessed, and predictors of disease-free survival (DFS) were analyzed using the Kaplan Meier method with log rank test between groups and a parsimonious multivariate Cox model. RESULTS: Median dose to the vulva was 66.0 Gy (Interquartile Range [IQR]: 66.0-68.0) for definitive and 59.4 Gy (IQR: 58.0-59.4) for preoperative IMRT. The overall rates of cCR and pCR were 76% and 70%, respectively. DFS at two years was 65% (95% Confidence Interval [CI] 50-80%) for all patients, 81% (95% CI 63% - 98%) for definitive IMRT, and 55% (95% CI 35% - 76%) for preoperative IMRT. On multivariate analysis, cCR predicted for disease-free survival (HR 0.21; 95% CI 0.06-0.76; p = 0.02), and pCR predicted for OS (HR 0.12; 95% CI 0.02-0.60; p = 0.01). Grade 3 acute and late RT toxicity was seen in 14 (29%) and 3 (6%) of patients, respectively. CONCLUSION: Dose-escalated IMRT for locally-advanced vulvar cancer is well tolerated, with rates of cCR and pCR that compare favorably with published data.

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.

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.

Primary gynecologic melanoma: A report of two unusual cases.

BACKGROUND: Primary ovarian and cervical melanomas are extremely rare tumors with a poor prognosis. Diagnosis requires a high index of suspicion as presentation can mimic benign conditions clinically and other neoplasms histologically. CASES: A 41 year-old with an adnexal mass underwent surgical staging for a stage IA ovarian melanoma. Imaging revealed a brain metastasis treated with radiation. Subsequent nodal recurrence was treated with immune and targeted therapies. She is alive with disease at 61 months follow-up. A 54 year-old presented after endocervical melanoma was diagnosed with polypectomy. She underwent radical hysterectomy, lymphadenectomy, and adjuvant brachytherapy. Immediate post-treatment imaging revealed widespread liver and pulmonary metastasis, currently being treated with ipilimumab. CONCLUSION: Immunohistochemistry can facilitate the diagnosis of gynecologic melanoma, and multidisciplinary treatment is recommended.

Outcomes analysis of an alternative formulation of PEGylated liposomal doxorubicin in recurrent epithelial ovarian carcinoma during the drug shortage era.

BACKGROUND: In response to the critical shortage of Doxil(®), the US Food and Drug Administration (FDA) allowed temporary importation of non-FDA-approved second-generation liposomal doxorubicin, Lipo-Dox(®). Lipo-Dox utilizes a different liposomal particle than Doxil and demonstrates different pharmacokinetic properties. Its use has never been evaluated in a North American population. The objective of this study was to evaluate the efficacy and tolerability of Lipo-Dox at Magee-Womens Hospital, University of Pittsburgh Medical Center, for patients with recurrent epithelial ovarian cancer who were treated during the Doxil shortage. METHODS: Patients treated with Lipo-Dox from January 2012 to December 2012 were identified retrospectively. Disease response was defined radiographically by RECIST (Response Evaluation Criteria in Solid Tumors) or biochemically by CA-125 level if measurable disease was not present. Survival was defined from the start date of Lipo-Dox until the date of progression or death. Toxicity was assessed by the Gynecologic Oncology Group common toxicity criteria. RESULTS: Eighteen patients with recurrent epithelial ovarian cancer who received Lipo-Dox were identified. These patients had a median of three prior treatment regimens. The median number of Lipo-Dox cycles given was 3.5 (range 1-8). No patients had a complete or partial response. Two patients had stable disease over a mean follow-up of 144.5 days. Fourteen patients had progressive disease, with a median time to progression of 82 days. Progression was based on CA-125 in four patients and RECIST in the remainder. Nine patients died from the disease. CONCLUSION: Although this represents a small, pretreated population, there were no clinical responses to Lipo-Dox, raising the question as to whether it is an equivalent substitute for Doxil. Further evaluation is needed, but if confirmed, these findings raise concerns regarding the use of current stocks of Lipo-Dox, as well as the prudence of managing future drug shortages with pharmacologically similar, but clinically untested drugs.

Impact of facility volume on therapy and survival for locally advanced cervical cancer.

OBJECTIVE: Chemosensitizing radiation with brachytherapy is standard of care for treatment of locally advanced cervical cancer, an increasingly rare disease. Treatment facility volume has been correlated with outcome in many diseases. Treatment outcome and likelihood of receiving standard therapy in locally advanced cervical cancer based on facility volume were examined using a large national cancer database. METHODS: The National Cancer Data Base was queried for patients with stage IIB - IIIB cervical cancer from 1/1998 through 12/2010. Facility volumes were tallied. Overall survival was estimated using Kaplan-Meier method. Univariate and multivariable analyses were performed to determine variables affecting survival, receiving standard therapy, and total duration of radiotherapy. RESULTS: We identified a total of 27,660 patients who were treated at 1361 facilities. Thirty of the facilities (2.2%) treated the highest quartile volume of patients (>9.4 patients annually) while 1072 facilities (78.8%) treated <2.4 patients annually. The median age of patients was 53, the majority were Caucasian, treated in a metropolitan area, and of squamous cell histology. Median survival of patients treated at lowest- and highest-volume centers were 42.3 months (95% CI 39.8-44.8) and 53.8 months (50.1-57.5), respectively (p < 0.001). The proportions of patients receiving brachytherapy and chemotherapy were 54.8% and 79.9%, respectively. On multivariable analysis, higher facility volume independently predicted improved survival (p = 0.022), increased likelihood of receiving brachytherapy (p < 0.0005) and chemotherapy (p = 0.013), and shorter time to radiotherapy completion (p < 0.0005). CONCLUSIONS: Patients with locally advanced cervical cancer treated at high volume centers are more likely to receive standard therapy, complete therapy sooner, and experience better survival.

Surgical management of cervical carcinoma.

Surgical management for cervical carcinoma uses a wide variety of procedures for all stages of disease, ranging from the most conservative excisional biopsy to aggressive extirpative surgery with sophisticated reconstruction. Innovative surgical procedures have given fertility-sparing treatment options to women of reproductive age, and refinement and use of minimally invasive surgical approaches have minimized operative morbidity without sacrificing outcomes. Conservative staging procedures are being evaluated to improve survival in locally advanced disease. There have been many breakthroughs in the treatment of cervical carcinoma over recent years, which have improved not only survival but also the quality of ensuing life for women afflicted by this disease.

Modified vertical rectus abdominis myocutaneous flap vaginal reconstruction: an analysis of surgical outcomes.

OBJECTIVE: To examine the early and late flap related morbidity and associated risk factors in patients with modified vertical rectus abdominis myocutaneous (VRAM) flap neovaginal reconstruction at the time of pelvic exenteration for gynecologic malignancy. METHODS: From January 1993 to January 2011, all patients were identified who underwent anterior, posterior, or total pelvic exenteration with VRAM flap neovaginal reconstruction. Patient records were systematically reviewed and demographic, clinicopathologic, operative details, flap related complications, and risk factors for wound healing were recorded and statistical analysis performed. RESULTS: 46 patients were identified who underwent exenteration with VRAM flap vaginal reconstruction. A risk factor for poor healing including obesity, diabetes, smoking, prior radiation, previous abdominal surgery, or poor nutritional status was present in 38 (82.6%) patients, and 24 (52.2%) had two or more risk factors. Flap complications occurred in 9 (19.6%) patients, one with complete flap necrosis that required re-operation, two with superficial flap necrosis, and three with superficial flap separation. Three patients (6.5%) suffered from vaginal stenosis, one of which was complete. Anterior abdominal wound separation occurred in 22 (47.8%) patients and pelvic abscess occurred in 14 (30.4%) patients. No individual risk factor was significantly associated with VRAM flap related morbidity; however obesity, prior radiation, and prior abdominal incision were present in nearly all the patients with flap complications. CONCLUSIONS: This series confirms that modified VRAM flaps can be used successfully at the time of exenteration, even in an increasingly high risk patient population with an acceptable risk for flap complications.