Neoadjuvant chemotherapy with bevacizumab for locally advanced vulvar cancer.

OBJECTIVES: External beam radiation with sensitizing platinum is the recommended therapy for locally advanced vulvar cancers not amenable to curative surgery and is associated with considerable acute and chronic side effects. Radical vulvectomy post-radiation for persistent disease is often compromised with poor wound healing. We describe clinical outcomes for patients who received neoadjuvant chemotherapy plus bevacizumab followed by radical vulvectomy for locally advanced vulvar cancer. METHODS: We performed retrospective analyses of all patients at our institution who underwent radical vulvectomy from January 2015 to November 2023. Of 113 patients, 13 patients underwent neoadjuvant chemotherapy. Demographics and clinicopathologic data were extracted, and descriptive statistical analyses were performed. Cases with neoadjuvant chemotherapy plus bevacizumab were further evaluated for response, adverse effects, and survival. RESULTS: Neoadjuvant chemotherapy was administered to 13 patients with stage II-IV disease that involved the urethra, vagina, or anus. Lesion sizes ranged from 4 to 20 cm (median 7 cm). Patients received 2-6 cycles of carboplatin or cisplatin, paclitaxel, and bevacizumab. Nine (69.2%) patients had partial pathologic responses, and four patients had complete responses. All patients had negative surgical margins. Ten (76.9%) patients had radiographic evidence of inguinal lymph node metastasis prior to neoadjuvant chemotherapy, and four had residual nodal disease. Only one patient developed a superficial groin seroma. Three patients developed recurrence, two locally and one distant, and there was one death. The median follow-up was 23 months (range 6-84 months). CONCLUSIONS: Neoadjuvant chemotherapy using combination platinum/paclitaxel/bevacizumab was efficacious for locally advanced vulvar cancer, resulting in complete resections, negative margins, and excellent wound healing. A multi-institutional phase II trial is warranted to validate these findings.

Malignant peritoneal cytologic contamination with robotic hysterectomy for endometrial cancer.

BACKGROUND: Malignant peritoneal cytology in endometrial cancer (EC) is not considered an independent adverse prognostic factor for uterine-confined disease and is not a determinant factor in the International Federation of Gynecology and Obstetrics (FIGO) staging system. NCCN Guidelines still recommend obtaining cytologies. The aim of this study was to determine the prevalence of peritoneal cytologic contamination following robotic hysterectomy for EC. METHODS: Peritoneal cytology from the pelvis and diaphragm were obtained at the initiation of surgery, and from the pelvis only at the completion of robotic hysterectomy with sentinel lymph node mapping (SLNM). Cytology specimens were evaluated for the presence of malignant cells. Pre- and post-hysterectomy cytology results were compared, and pelvic contamination was defined as conversion from negative to positive cytology following surgery. RESULTS: 244 patients underwent robotic hysterectomy with SLNM for EC. Pelvic contamination was identified in 32 (13.1%) cases. In multivariate analysis, pelvic contamination was associated with >50% myometrial invasion, tumor size >2 cm, lymphovascular space invasion (LVSI), and lymph node metastasis. There was no association with FIGO stage or histology subtypes. CONCLUSIONS: Malignant peritoneal contamination occurred during robotic surgery for EC. Large lesions (>2 cm), deep invasion (>50%), LVSI, and lymph node metastasis were each independently associated with peritoneal contamination. Whether or not peritoneal contamination increases risk for disease recurrence should be studied in larger series, including an evaluation of patterns of recurrence and the potential impact of adjuvant therapies. Until the clinical impact of peritoneal contamination during hysterectomy for EC is better understood, methods to reduce peritoneal contamination are warranted.

Carcinomatosis in Early-Stage Cervical Cancer Treated with Robotic Radical Hysterectomy: Recurrence Patterns, Risk Factors, and Survival.

PURPOSE: Minimally invasive radical hysterectomy has been associated with increased recurrence of disease and worse survival compared with open radical hysterectomy for early-stage cervical cancer. We evaluated patterns of recurrence and histopathologic risk factors in patients who underwent robotic radical hysterectomy (RRH). METHODS: Patients who underwent RRH (4/2007-12/2018) were evaluated for specific locations of recurrent disease, disease-free survival, overall survival (OS), and histopathologic risk factors for recurrence. Inclusion criteria were follow-up ≥ 1 year, histology with adenocarcinoma, adenosquamous, or squamous carcinoma and clinical stage IA2 to IB ≤ 4-cm tumor size cervical cancers (FIGO-2018). RESULTS: A total of 140 patients underwent RRH and 112 met criteria. Median tumor size was 2.1 cm [interquartile range (IQR): 1.1-3.3]. Median follow-up was 61 months (IQR: 36-102). Fifty (45%) patients underwent adjuvant radiation ± cisplatin with either Sedlis' or Peters' risk factors. There were 11 (9.8%) recurrences with median disease-free survival of 12 (IQR 8.5) months. All patients with recurrence had measured tumor size ≥ 2 cm (median tumor size 3-cm (IQR: 2.6-4.0). Tumor size > 2 cm was associated with Sedlis' intermediate-risk factors (p < 0.05) and Peters' high-risk factors (p < 0.05). Forty patients underwent preoperative conization, and two (5%) with deep positive margins in lesions > 2 cm recurred. Five (4.5%) of patients had carcinomatosis representing 45% of all recurrences. Carcinomatosis was associated with reduced OS compared with other recurrence patterns (22 months vs. 7.8 years, p < 0.05). CONCLUSIONS: Carcinomatosis was observed in early-stage cervical cancers treated with RRH and was associated with reduced OS. All recurrences were associated with lesions ≥ 2 cm, and no recurrences were identified with negative conization margins.

A phase 1b study of intraperitoneal oncolytic viral immunotherapy in platinum-resistant or refractory ovarian cancer.

OBJECTIVE: Our objective was to assess safety and adverse events associated with intraperitoneal Olvi-Vec virotherapy in patients with platinum-resistant or refractory ovarian cancer (PRROC). Secondary objectives included objective response rate (ORR) per RECIST 1.1 and progression-free survival (PFS). METHODS: Olvi-Vec is a modified vaccinia virus that causes oncolysis and immune activation. An open-label phase 1b trial using a 3 + 3 dose escalation was conducted. Intraperitoneal Olvi-Vec was given as monotherapy in two consecutive daily doses. Translational analyses included anti-virus antibody levels, viral shedding, circulating tumor cells (CTCs) and T cells. RESULTS: Twelve patients (median age: 69 years, range: 45-77) with median 5 prior therapies (range: 2-10) and 2 prior platinum lines (range: 1-5) were enrolled. There were three dose level cohorts: 3 × 109 (n = 6), 1 × 1010 (n = 5), and 2.5 × 1010 (n = 1) plaque forming units (PFU)/day on two consecutive days. Treatment-related adverse events (TRAEs) included G1/G2 nausea (n = 6), fever (n = 6), abdominal distention (n = 5), and abdominal pain (n = 4). There were no Grade 4 TRAEs, no dose relationship to TRAEs, and no deaths attributed to Olvi-Vec. The ORR was 9% (1/11). Stable disease (SD) was 64% (7/11), and SD ≥15 weeks was 46% (5/11). Median PFS was 15.7 weeks (95%CI: 5.7-34.5), including extended PFS in four patients (23.2, 34.5, 59.4+ and 70.8 weeks). Three patients had extended overall survival (deceased 33.6 months, and alive with disease at 54 and 59 months). CTCs diminished in 6/8 (75%) baseline-positive patients. Immune activation was demonstrated from virus-enhanced tumor infiltration of CD8+ T-cells and activation of tumor-specific T-cells in peripheral blood. CONCLUSIONS: Oncolytic viral therapy with intraperitoneal Olvi-Vec showed promising safety, clinical activities, and immune activation in patients with PRROC, warranting further clinical investigation.

Robotic sentinel lymph node (SLN) mapping in endometrial cancer: SLN symmetry and implications of mapping failure.

PURPOSE: To establish the bilateral pelvic concordance rate of the sentinel lymph node (SLN) and determine the likelihood of lymph node metastasis in cases of mapping failure. METHODS: A database analysis was performed on 414 patients with clinical stage I endometrial cancer who underwent SLN mapping followed by robotic hysterectomy and completion pelvic (n=414, 100%) and aortic (n=186, 44.9%) lymphadenectomy from March 2011 to August 2016. Stage, histology, SLN sites, and surgico-pathologic findings were analyzed. The bilateral concordance rate of SLN location, successful unilateral and bilateral mapping rates, false negative rate, and non-SLN metastasis associated with mapping failure were calculated. RESULTS: Histologies included 354 (85.5%) endometrioid, 39 (9.4%) serous, 16 (3.9%) carcinosarcoma, 4 (1.0%) clear cell, and 1 (0.2%) undifferentiated. Final stages included 262 (63.3%) IA, 36 (8.7%) IB, 15 (3.6%) II, 6 (1.4%) IIIA, 68 (16.4%) IIIC1, and 27 (6.5%) IIIC2. Bilateral SLN mapping was successful in 355 (85.7%) patients, and 266 (74.9%) demonstrated mapping to the symmetrical lymphatic group contralaterally. The mapping failure rate was 13.5% (56/414) unilaterally and 0.7% (3/414) bilaterally. SLN locations were external iliac (69.1%), obturator (25.1%), internal iliac (2.2%), common iliac (1.9%), pre-sacral (0.9%), aortic (0.4%), parametrial (0.3%), and para-rectal (0.1%). Lymph node metastases were identified in 95 (22.9%) pelvic and 27 (6.5%) aortic nodes. 10 (16.9%) cases with mapping failure had lymph node metastasis on completion lymphadenectomy, similar to the proportion of SLNs with metastases (p=0.35). However, macro-metastases were more common in mapping failure completion lymphadenectomies than in the positive SLNs (80% vs 22.3%, p<0.001). CONCLUSION: The contralateral SLN location concordance rate was 75%. Most SLNs were along the medial external iliac or obturator locations. The rate of positive lymph nodes associated with SLN mapping failure was 16.9%, similar to the overall node-positive rate. The detection of pelvic node metastasis with SLN mapping failure was largely populated with macro-metastases and confirms the necessity of completion lymphadenectomy with mapping failure.

Sentinel lymph nodes (SLN) in endometrial cancer: The relationship between primary tumor histology, SLN metastasis size, and non-sentinel node metastasis.

OBJECTIVES: To examine sentinel lymph node pathology and describe relationships to uterine pathology, non-sentinel pelvic lymph nodes, and para-aortic lymph nodes. METHODS: Patients with apparent uterine-confined endometrial cancer underwent robotic hysterectomy, SLN mapping, completion pelvic lymphadenectomy (LND), and para-aortic (PaLND) directed by frozen section. Patients were risk stratified by histology: low-risk (LR) endometrioid <50% depth-of-invasion (DOI), intermediate-risk (IR) endometrioid ≥50% DOI, and high-risk (HR) type II histology for comparison to other pelvic/aortic metastases. RESULTS: 414 patients were stratified: 275 LR, 80 IR, and 59 HR cases. PaLND was performed in 84.2% of IR/HR patients and 25.1% LR patients. Pelvic node metastasis was detected in 11.6% LR, 50.0% IR, and 39.0% HR patients. PaLN metastasis was detected in 2.9% LR, 11.3% IR, and 16.9% HR patients. Proportionally, isolated tumor cells (ITC) SLNs were more common in LR or IR vs. HR group (51.6% and 44.7% vs. 15.0%, p < 0.05). The SLN false negative rates (FNR) were 0% LR, 2.5% IR, and 5.1% HR. Non-sentinel pelvic node metastases were present in 28(31.5%) of all SLN+ cases, but only 3(8.3%) of SLN with ITC. PaLN metastasis was found in 18.8% LR, 11.8% IR, and 33.3% HR cases with ITC SLNs. After controlling for DOI, LVSI, and grade, ITC-positive SLNs had a significant association with non-sentinel pelvic and aortic metastasis (p = 0.03 and p = 0.008, respectively). CONCLUSIONS: Patients with HR histology have more micro/macro-metastases in both SLNs and non-SLN metastases compared to LR/IR patients. SLN ITCs were associated with a clinically significant incidence of PaLN metastasis across all histology risk groups. There were no cases of isolated aortic node metastasis in this study. SLN mapping had an increased, although clinically acceptable FNR in the HR cohort compared to LR patients.

A prospective randomized trial of intravenous ketorolac vs. acetaminophen administered with opioid patient-controlled analgesia in gynecologic surgery.

OBJECTIVE: To determine which non-narcotic analgesic, acetaminophen (Ofirmev®) or ketorolac (Toradol®), provides better post-operative pain control when combined with an opioid patient-controlled analgesia (PCA) pump. Secondary objectives include comparisons of the rates of ileus, post-operative bleeding, transfusions, and length-of-hospitalization (LOH). METHODS: A prospective, randomized trial of acetaminophen (A) 1-g intravenous (IV) every 6-h or ketorolac (K) 15-mg IV every 6-h from post-operative day 1-3 in addition to an opioid PCA for patients undergoing benign or malignant gynecologic laparotomy procedures was performed. Abstracted data included pain levels via visual analogue pain scales (VAS), amount of narcotic used, hepatic enzyme levels, hemoglobin, urine output, blood transfusions, time to return of flatus and LOH. RESULTS: One-hundred patients were accrued and underwent 55 benign gynecologic laparotomies and 45 cancer-related laparotomies. VAS pain levels (3.3 K, 3.5 A) and morphine PCA use (79.1 oral morphine equivalents [OME] K vs. 84.5 A) were not different, however dilaudid PCA usage was less by K patients (84.4 OME K and 136.8 OME A, p < 0.001). There was a significant hemoglobin change between the two groups (2.6 g K vs. 2 g A, p = 0.015), however blood transfusions were equal (28% K, 22% A, p > 0.05). Return of flatus was 2.7-days for K vs. 3.4-days for A (p = 0.011) and LOH was not different (4.4-days K vs. 5.1-days A, p = 0.094). CONCLUSIONS: Both intravenous ketorolac and acetaminophen provide similar post-operative analgesia through VAS pain scales and total usage of morphine via PCA pumps. Use of ketorolac with dilaudid PCA was associated with less dependence on dilaudid and a quicker return of bowel function than acetaminophen, however length of stay and transfusion rates were not different.

A Prospective Cohort Study Comparing Colorimetric and Fluorescent Imaging for Sentinel Lymph Node Mapping in Endometrial Cancer.

BACKGROUND: This prospective cohort study aimed to assess sentinel lymph node (SLN) mapping using isosulfan blue (ISB) compared with ISB plus indocyanine green (ICG) and near-infrared imaging (NIR) for patients with endometrial cancer. METHODS: In this study, 200 patients with endometrial cancer underwent SLN assessments and were randomized to ISB + ICG (n = 180) or ISB alone (n = 20). Blue dye determinations were recorded for all 200 cases followed by NIR imaging of ICG for 180 randomized subjects. All the patients underwent robotically assisted hysterectomy with pelvic ± aortic lymphadenectomy. RESULTS: The mean age of the patients was 64.5 ± 8.4 years, and the mean body mass index (BMI) was 33 ± 7.6 kg/m2. The histologies were endometrioid G1 (43%), G2 (30%), G3 (7%), and type 2 (20%). The mean time from dye injection to initiation of mapping was 13.4 ± 6.2 min, and the time to removal of SLN was 17.4 ± 11.2 min. Detection of SLN for the 20 ISB control cases did not differ from that for the 180 ISB + ICG cases (p > 0.05). The rates of SLN detection for ISB + ICG/NIR (n = 180) versus ISB (n = 200) were as follows: bilateral (83.9 vs. 40%), unilateral (12.2 vs. 36%), and none (3.9 vs. 24%) (p < 0.001). The median SLN per case was 2 (range 0-4). Positive SLNs were found in 21.1% (n = 38) of the ISB + ICG cases compared with 13.5% (n = 27) of the ISB cases (p = 0.056). The false-negative rate for SLN biopsy was 2.5% (95% confidence interval, 0.1-14.7%). In 61% (25/41) of the node-positive cases, SLN was the only positive lymph node (LN). Isolated tumor cells were found in 39.5% (15/38) of the SLN metastasis cases compared with 26.7% (4/15) of the non-SLN metastasis cases (p = 0.528). CONCLUSIONS: In this prospective study, ISB + ICG and NIR detected more SLNs and more LN metastases than ISB alone. Assessment of SLN with ICG + ISB/NIR imaging had excellent sensitivity for detection of metastasis and no safety issues.

A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcoma of the uterus, an NRG Oncology/Gynecologic Oncology Group study.

BACKGROUND: The primary objectives were to determine the objective response rate (ORR) and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS. METHODS: Patients had measurable disease; up to two prior chemotherapeutic regimens were allowed, but must have included a taxane. Women received ixabepilone 40mg/m2 as a 3hour IV infusion on day 1 of a 21daycycle. Treatment was continued until disease progression or unacceptable toxicity occurred. RESULTS: Forty-two women were enrolled, with 34 eligible and evaluable. Median age was 68years. ECOG performance status was 0 in 56% of women, 38% had received radiation, and 15% had received 2 lines of chemotherapy. Overall ORR was 11.8% (4/34, 90% CI 4.2-25.1%); all were partial responses. Stable disease for at least 8weeks was achieved in 8 patients (23.5%). Median PFS and OS were 1.7mo and 7.7mo, respectively, with a median follow-up of 37mo. Six month PFS was 20.6%. Major grade≥3 toxicities were neutropenia (47%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 peripheral neuropathy was reported in 18%. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS. CONCLUSION: In this cohort of women, single agent ixabepilone showed modest but insufficient clinical activity.

Prognostic Significance of the Standardized Uptake Value of Pretherapeutic 18F-Labeled 2-Fluoro-2-Deoxyglucose Positron Emission Tomography/Computed Tomography in Patients With Locally Advanced Cervical Cancer.

OBJECTIVES: To determine the prognostic significance of the pretreatment and posttreatment maximum standardized uptake value (SUVmax) of F-labeled 2-fluoro-2-deoxyglucose positron emission tomography (PET)/computed tomography imaging in patients with stage IB2-IVA cervical cancer. METHODS: This was a retrospective review of cervical cancer patients with International Federation of Gynecology and Obstetrics stages IB2-IVA, from March 2008 to April 2014. All patients had pretreatment and posttreatment PET imaging and received primary whole pelvic radiation therapy with concurrent radiosensitizing chemotherapy, followed by intracavitary brachytherapy. Of the 58 patients who met the inclusion criteria, 31 patients (group A) showed no evidence of disease at last follow-up, and 27 patients (group B) presented with recurrence/persistence of disease. RESULTS: The mean pretreatment SUVmax in group A was 17.65 ± 7.82 versus 18.8 ± 7.77 in group B (P = 0.577). The mean posttreatment SUVmax between the groups was 0.85 ± 1.83 versus 6.05 ± 3.01 (P < 0.001), respectively. The mean difference between pretreatment and posttreatment SUVmax was 17.73 ± 7.50 in group A versus 13.29 ± 7.15 in group B (P = 0.045). In group A, 80.7% of patients demonstrated no posttreatment hypermetabolic activity on PET imaging versus 11.1% in group B. Of the patients who experienced treatment failure, the site of failure was pelvic in 25.9%, distant in 44.4%, and both pelvic and distant in 29.6%. CONCLUSIONS: No threshold was identified for the pretreatment SUVmax relative to the risk of recurrence. However, distinct correlations were found between the risk of recurrence, percent reduction in SUVmax, and the observation of residual hypermetabolic activity. This finding may help identify candidates for sequential chemotherapy.

Sentinel lymph node mapping with staging lymphadenectomy for patients with endometrial cancer increases the detection of metastasis.

OBJECTIVES: To compare the performance of sentinel lymph node (SLN) mapping with staging lymphadenectomy versus staging lymphadenectomy alone for the detection of metastasis and the use of adjuvant therapies in patients with endometrial cancer. METHODS: All patients with apparent early-stage endometrial cancer (n=780) who underwent robotic-assisted hysterectomy with pelvic±aortic lymphadenectomy from July-2006 to June-2013 were compared [pelvic±aortic lymphadenectomy (n=661) versus SLN-mapped cases with pelvic±aortic lymphadenectomy (n=119)]. Isosulfan-blue and indocyanine-green with near-infrared imaging were used for SLN mapping. Clinico-pathological data, FIGO stage, GOG risk category, and adjuvant therapies were compared. RESULTS: Non-mapped and mapped cases were comparable with respect to BMI, histology, depth-of-invasion, and lympho-vascular space invasion. The mapped group had more pelvic lymph node (LN) harvested compared to non-mapped group (26.4±10.5 vs. 18.8±8.5, p<0.001). Aortic LN yields were identical for both groups (9.0±5.6 vs. 9.0±6.0). The mapped group had more LN metastasis detected (30.3% vs. 14.7%, p<0.001), more stage IIIC (30.2% vs. 14.5%, p<0.001), more GOG high-risk cases (32.8% vs. 21.8%, p=0.013), and received more chemotherapy+radiation (28.6% vs. 16.3%, p<0.003). The SLN was the only metastasis in 18 (50%) mapped cases with positive nodes. The SLN false negative rate was 1/36 (2.8%). Micrometastases or isolated tumor cells were identified in 22/35 (62.9%) SLN metastases. Multivariate analysis demonstrated that SLN mapping imparted a significant effect on the detection of metastatic disease [adjusted OR=3.29, p<0.001]. CONCLUSIONS: The performance of SLN mapping with staging lymphadenectomy increased the detection of lymph node metastasis and was associated with more use of adjuvant therapies.

Phase II evaluation of dalantercept, a soluble recombinant activin receptor-like kinase 1 (ALK1) receptor fusion protein, for the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study 0229N.

OBJECTIVE: This two-stage phase II study assessed activity of single agent dalantercept in patients with recurrent/persistent endometrial carcinoma (EMC). METHODS: Eligible patients had persistent/recurrent EMC after 1-2 prior cytotoxic regimens, measurable disease (RECIST 1.1), and GOG performance≤2. Dalantercept 1.2mg/kg subcutaneous was administered once every 3weeks until disease progression (PD)/development of prohibitory toxicity. Primary objectives were to estimate the proportion of patients with persistent/recurrent EMC, who survive progression-free without receiving non-protocol therapy (TPFS) for at least 6months and to estimate the proportion having objective tumor response. RESULTS: All 28 enrolled patients were eligible and evaluable. Median age: 62years. Most common histologies: 32% Grade 1/2 endometrioid and 54% serous tumors. Prior treatment: 1 or 2 regimens in 82% and 18% of patients, respectively. Eighteen patients received prior radiation therapy. Patients received 1-12 cycles of dalantercept, and 46% of patients received ≤2cycles. The most common adverse events (AE) were fatigue, anemia, constipation and peripheral edema. Grade 3/4 AEs occurred in 39% and 4% of patients. One grade 5 gastric hemorrhage in a patient with a history of radiation fibrosis/small bowel obstruction was deemed possibly dalantercept-related. All patients are off study: 86% for PD. No ORs were observed; 57% had stable disease and 11% had TPFS>6 mos. Median progression-free and overall survival: 2.1months (90% CI: 1.4-3.2) and 14.5months (90% CI: 7.0-17.5), respectively. CONCLUSIONS: Dalantercept has insufficient single agent activity in recurrent EMC to warrant further investigation at this dose level and schedule.

Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study.

OBJECTIVE: This two-stage phase II study was designed to assess the activity of the combination of temsirolimus and bevacizumab in patients with recurrent or persistent endometrial carcinoma (EMC). METHODS: Eligible patients had persistent or recurrent EMC after receiving 1-2 prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status ≤ 2. Treatment consisted of bevacizumab 10 mg/kg every other week and temsirolimus 25 mg IV weekly until disease progression or prohibitory toxicity. Primary end points were progression-free survival (PFS) at six months and overall response rate using RECIST criteria. RESULTS: Fifty-three patients were enrolled. Forty-nine patients were eligible and evaluable. Median age was 63 years, and prior treatment consisted of one or two regimens in 40 (82%) and 9 (18%), respectively. Twenty (41%) received prior radiation. Adverse events were consistent with those expected with bevacizumab and temsirolimus treatment. Two gastrointestinal-vaginal fistulas, one grade 3 epistaxis, two intestinal perforations and 1 grade 4 thrombosis/embolism were seen. Three patient deaths were possibly treatment related. Twelve patients (24.5%) experienced clinical responses (one complete and 11 partial responses), and 23 patients (46.9%) survived progression free for at least six months. Median progression-free survival (PFS) and overall survival (OS) were 5.6 and 16.9 months, respectively. CONCLUSION: Combination of temsirolimus and bevacizumab is deemed active based on both objective tumor response and PFS at six months in recurrent or persistent EMC. However, this treatment regimen was associated with significant toxicity in this pretreated group. Future study will be guided by strategies to decrease toxicity and increase response rates.

Clinical Activity of Olvimulogene Nanivacirepvec-Primed Immunochemotherapy in Heavily Pretreated Patients With Platinum-Resistant or Platinum-Refractory Ovarian Cancer: The Nonrandomized Phase 2 VIRO-15 Clinical Trial.

Importance: Patients with platinum-resistant or platinum-refractory ovarian cancer (PRROC) have limited therapeutic options, representing a considerable unmet medical need. Objective: To assess antitumor activity and safety of intraperitoneal (IP) olvimulogene nanivacirepvec (Olvi-Vec) virotherapy and platinum-based chemotherapy with or without bevacizumab in patients with PRROC. Design, Setting, and Participants: This open-label, nonrandomized multisite phase 2 VIRO-15 clinical trial enrolled patients with PRROC with disease progression following their last prior line of therapy from September 2016 to September 2019. Data cutoff was on March 31, 2022, and data were analyzed between April 2022 and September 2022. Interventions: Olvi-Vec was administered via a temporary IP dialysis catheter as 2 consecutive daily doses (3 × 109 pfu/d) followed by platinum-doublet chemotherapy with or without bevacizumab. Main Outcomes and Measures: Primary outcomes were objective response rate (ORR) via Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) and cancer antigen 125 (CA-125) assay, and progression-free survival (PFS). Secondary outcomes included duration of response (DOR), disease control rate (DCR), safety, and overall survival (OS). Results: Twenty-seven heavily pretreated patients with platinum-resistant (n = 14) or platinum-refractory (n = 13) ovarian cancer were enrolled. The median (range) age was 62 (35-78) years. The median (range) prior lines of therapy were 4 (2-9). All patients completed both Olvi-Vec infusions and chemotherapy. Median follow-up duration was 47.0 months (95% CI, 35.9 months to NA). Overall, ORR by RECIST 1.1 was 54% (95% CI, 33%-74%), with a DOR of 7.6 months (95% CI, 3.7-9.6 months). The DCR was 88% (21/24). The ORR by CA-125 was 85% (95% CI, 65%-96%). Median PFS by RECIST 1.1 was 11.0 months (95% CI, 6.7-13.0 months), and the PFS 6-month rate was 77%. Median PFS was 10.0 months (95% CI, 6.4-NA months) in the platinum-resistant group and 11.4 months (95% CI, 4.3-13.2 months) in the platinum-refractory group. The median OS was 15.7 months (95% CI, 12.3-23.8 months) in all patients, with a median OS of 18.5 months (95% CI, 11.3-23.8 months) in the platinum-resistant group and 14.7 months (95% CI, 10.8-33.6 months) in the platinum-refractory group. Most frequent treatment-related adverse events (TRAEs) (any grade, grade 3) were pyrexia (63.0%, 3.7%, respectively) and abdominal pain (51.9%, 7.4%, respectively). There were no grade 4 TRAEs, and no treatment-related discontinuations or deaths. Conclusions and Relevance: In this phase 2 nonrandomized clinical trial, Olvi-Vec followed by platinum-based chemotherapy with or without bevacizumab as immunochemotherapy demonstrated promising ORR and PFS with a manageable safety profile in patients with PRROC. These hypothesis-generating results warrant further evaluation in a confirmatory phase 3 trial. Trial Registration: ClinicalTrials.gov Identifier: NCT02759588.

Impact of a weekly multidisciplinary tumor board conference on the management of women with gynecologic malignancies.

BACKGROUND: The objective of this study was to evaluate the impact of a weekly tumor board conference on the management of patients with gynecologic malignancies. METHODS: The medical records of consecutive patients referred to a multidisciplinary gynecologic oncology tumor board were reviewed. Patient demographics were abstracted from medical records and tumor board minutes. An evaluation was made whether the pathological or radiological findings were changed by the tumor board consultants. If a discrepancy existed, it was determined whether the change impacted clinical management. RESULTS: From January 2004 to December 2006, 741 patients presented at the tumor board were evaluable. Seventy-one percent of the patients were presented for pathology review and 29% for radiology review. The most common diagnoses were ovarian cancer (29%), endometrial cancer (26%), and cervical cancer (12%). Of the 526 pathology reviews, 27% had a change in diagnosis; this discrepancy altered clinical management 74% of the time (20% of all reviews). Of the 215 radiology presentations, 89% were reviewed to confirm recurrent or persistent disease; malignant disease was confirmed 74% of the time. Review of imaging studies resulted in a new diagnosis or upstaging 10% of the time. CONCLUSIONS: A multidisciplinary tumor board allows a wide range of gynecologic diagnoses and clinical scenarios to be discussed. Careful review of pathology results in a change in the clinical management of 20% of patients presented at the tumor board. The majority of radiology reviews are presented to confirm persistent or recurrent cancer before recommending further therapy.

The risk of gastrointestinal perforation and/or fistula in patients with recurrent ovarian cancer receiving bevacizumab compared to standard chemotherapy: a retrospective cohort study.

OBJECTIVE: To determine the rate of gastrointestinal perforation and/or fistula in patients with recurrent ovarian cancer treated with and without bevacizumab. METHODS: A retrospective chart review from January 2004 to August 2007 identified two cohorts of patients with recurrent ovarian cancer: 1) patients who were receiving bevacizumab either alone or in combination with standard chemotherapy; 2) patients who were receiving standard chemotherapy alone. Gastrointestinal toxicity (perforation and fistula) was assessed using NCI Common Toxicity Criteria. Relative risk and 95% confidence intervals were calculated. Chi square test and student's t test were used for statistical analysis. RESULTS: Sixty-eight patients receiving bevacizumab for recurrent ovarian cancer were identified. 67% of these patients received chemotherapy in combination with bevacizumab. For comparison, 195 patients receiving standard chemotherapy alone for recurrent ovarian cancer were identified. A history of previous gastrointestinal resection (40% vs. 37%; p=0.79) and gastrointestinal obstruction (30% vs. 27%; p=0.74) was similar in both cohorts. Five patients (7.2%) developed a gastrointestinal perforation and/or fistula in the bevacizumab cohort compared to 13 patients (6.5%) in the chemotherapy alone cohort. The relative risk for developing a perforation and/or fistula is 1.09 (95% CI, 0.40 to 2.96). CONCLUSIONS: Although a substantial number of patients with recurrent ovarian cancer experience gastrointestinal obstruction, the rate of gastrointestinal perforation and/or fistula is relatively low. Treatment with bevacizumab does not significantly increase gastrointestinal toxicity compared to standard salvage chemotherapy.

The safety and efficacy of day 1 versus day 2 administration of pegfilgrastim in patients receiving myelosuppressive chemotherapy for gynecologic malignancies.

OBJECTIVE: Pegfilgrastim is indicated to decrease the incidence of febrile neutropenia in patients with gynecologic malignancies who are receiving myelosuppressive chemotherapy. We sought to compare the safety and efficacy of day 1 pegfilgrastim administration to day 2 administration in patients with gynecologic malignancies. METHODS: We retrospectively evaluated patients receiving both chemotherapy and pegfilgrastim from June 1, 2006 to August 31, 2007 for a gynecologic malignancy. Abstracted data included patient demographics, pathology, blood counts, toxicity, and chemotherapy. After administration of chemotherapy, all patients either received 6 mg of pegfilgrastim subcutaneously on day 1 or day 2. RESULTS: 1226 administrations of pegfilgrastim in 230 patients were identified. 490 administrations of pegfilgrastim were given on day 1 compared to 736 on day 2. 70% of patients had ovarian cancer with a median age of 64 years (range 15-88). 79% of patients had stage III, IV, or recurrent disease and 67% were undergoing primary chemotherapy. The most common chemotherapy was docetaxel/carboplatin (53%) followed by paclitaxel/carboplatin (19%). The mean absolute neutrophil count (ANC) nadir was 4810/mm(3) in the day 1 cohort compared to 4212/mm(3) in the day 2 cohort (p=.004). The incidence of Grade 3/4 neutropenia was similar in both groups (4.9% in day 1 vs. 5.7% in day 2; p=.63). Grade 3/4 febrile neutropenia was uncommon in both cohorts (0 episodes vs. 3 episodes; p=.41). Treatment delays were similar in both cohorts (5.9% vs. 7.5%; p=.35). Dose modifications were also similar in both cohorts (2.8% vs. 5.3%; p=.06). CONCLUSION: Day 1 administration of pegfilgrastim is as effective as day 2 administration in the prevention of neutropenia in patients with gynecologic malignancies. Treatment delays and dose modifications were not increased after day 1 administration of pegfilgrastim. Administering pegfilgrastim on day 1 appears to be safe, effective, and convenient in selected patients receiving myelopsuppressive chemotherapy for gynecologic malignancies.

Patterns of failure for conservatively managed surgical stage I uterine carcinosarcoma: implications for adjuvant therapy.

To evaluate patterns of failure and overall survival for patients with surgical stage I uterine carcinosarcoma managed conservatively without adjuvant therapy. A computerized database identified 27 patients whose conditions have been diagnosed with surgical stage I uterine carcinosarcoma from 1993 to 2002. Charts were abstracted for patient demographics, tumor characteristics, recurrence, and survival. Of 27 patients, 23(85%) did not receive adjuvant therapy after undergoing total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and paraaortic lymphadenectomy. Five patients were stage IA, 14 were stage IB, and 4 were stage IC. Fourteen patients had either poorly differentiated endometrioid carcinoma alone or in combination with papillary serous carcinoma (61%) as their epithelial tumor component. The median nodal count was 9 (range, 3-21). Eleven patients are alive without evidence of disease with a median follow-up of 63 months (range, 12-164 months). Eleven patients had recurrence with a median time to recurrence of 13 months (range, 6-39 months), and all are dead of disease. Univariate analysis demonstrated that poorly differentiated epithelial or papillary serous histologic diagnosis was the only predictor variable associated with recurrence and, consequently, death (P = 0.04). Approximately 50% of patients with surgical stage I carcinosarcoma who are observed without adjuvant therapy will experience a recurrence. Because most patients will recur distantly, systemic chemotherapy should be considered for patients with early stage uterine carcinosarcoma.

Effect of TRA-8 anti-death receptor 5 antibody in combination with chemotherapy in an ex vivo human ovarian cancer model.

OBJECTIVES: To investigate the cytotoxicity of TRA-8, an antibody that specifically binds death receptor 5, alone and in combination with chemotherapy, using an ex vivo human ovarian cancer model. MATERIALS AND METHODS: Twenty-six ovarian cancer specimens were obtained during ovarian cancer debulking, and tumor slices were prepared with the Krumdieck tissue slicer. The tumor slices were exposed to varying concentrations of TRA-8, carboplatin/paclitaxel, or the combination of TRA-8 and chemotherapy. Using nonlinear modeling, dose-response curves and IC50 values were generated for specimens treated with TRA-8. The additive and synergistic cytotoxic effects of chemotherapy combination with TRA-8 were evaluated in specimens. In addition to adenosine triphosphate viability assays, the treated and untreated slices were assessed by immunohistochemistry to confirm apoptosis induction. RESULTS: Specimens from 13 patients yielded TRA-8-induced IC50 values. Of these specimens, 15% were found to be sensitive to TRA-8-induced cytotoxicity at IC50 doses less than 500 ng/mL. Specimens from 13 patients underwent combination treatment with TRA-8 and carboplatin/paclitaxel. Of these specimens, 77% exhibited additive cytotoxicity in comparison with those treated with either agent alone, whereas 15% exhibited synergistic cytotoxicity. Immunohistochemical analysis of terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling and cleaved caspase 3 staining demonstrated a dose-dependent increase in apoptosis with the combination treatment. CONCLUSIONS: This study demonstrates the efficacy of the death receptor monoclonal antibody TRA-8 in combination with conventional chemotherapy in an ex vivo human ovarian cancer model. This model can be used to assess cytotoxicity of novel agents in combination with chemotherapy in ovarian cancer.