A phase I study of Mirvetuximab Soravtansine and gemcitabine in patients with FRα-positive recurrent ovarian, primary peritoneal, fallopian tube, or endometrial cancer, or triple negative breast cancer.

OBJECTIVE: Platinum-resistant epithelial ovarian cancer (EOC), recurrent endometrial cancer (EC), and triple negative breast cancer (TNBC) are difficult to treat after failing standard therapies. This phase I study evaluated mirvetuximab soravtansine (MIRV) and gemcitabine in patients with recurrent FRα-positive EOC, EC, or TNBC to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) (primary endpoint). METHODS: FRα-positive patients with platinum-resistant EOC, EC, or TNBC with ≤4 prior chemotherapy regimens (2 for EC) were enrolled. FRα expression requirement varied among eligible tumors and changed during the study. RESULTS: Twenty patients were enrolled; 17 were evaluable for DLT. Half the patients received ≥3 prior chemotherapy lines. Most EOC and EC patients (78%) were medium (50-74%) or high(75-100%) FRα expressors. TNBC patients were low (25-49%) FRα expressors. The MTD/RP2D was MIRV 6 mg/kg AIBW D1 and gemcitabine 800 mg/m2 IV, D1 and D8, every 21 days (Dose Level [DL] 3), where 5/7 patients demonstrated a partial response (PR) as their best response, including 2 confirmed ovarian responses whose time-to-progression and duration of response were 7.9/5.4 and 8.0/5.7 months respectively. Most common treatment-related adverse events at MTD were anemia and neutropenia (3/7 each, 43%), diarrhea, hypophosphatemia, thrombocytopenia, and leukopenia (2/7 each, 29%). DLTs were thrombocytopenia (DL1), oral mucositis (DL4) and diarrhea (DL4). Nine of 20 patients (45%; 95% CI: 21.1-68.9%) achieved PR as their best response, with 3/20 patients or 15% (95%CI, 0-32.1%) confirmed PR. CONCLUSION: MIRV and gemcitabine demonstrate promising activity in platinum resistant EOC at RP2D, but frequent hematologic toxicities.

Safety and Efficacy of Oxaliplatin Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC) in Colorectal and Appendiceal Cancer with Peritoneal Metastases: Results of a Multicenter Phase I Trial in the USA.

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a laparoscopic locoregional treatment for peritoneal metastases (PM) from colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery (CRS). While PIPAC has been studied in Europe and Asia, it has not been investigated in the USA. PATIENTS AND METHODS: We evaluated PIPAC with 90 mg/m2 oxaliplatin alone (cycle 1) and preceded by systemic chemotherapy with fluorouracil (5-FU) and leucovorin (LV) (cycle 2-3) as a multicenter prospective phase I clinical trial (NCT04329494). The primary endpoint was treatment-related adverse events (AEs). Secondary endpoints included survival and laparoscopic, histologic, and radiographic response. RESULTS: 12 patients were included: 8 with CRC and 4 with AC. Median prior chemotherapy cycles was 2 (interquartile range (IQR) 2-3). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median peritoneal carcinomatosis index (PCI) was 28 (IQR 19-32). Six (50%) of twelve patients completed three PIPAC cycles. No surgical complications or dose-limiting toxicities were observed. Two patients developed grade 3 treatment-related toxicities (one abdominal pain and one anemia). Median overall survival (OS) was 12.0 months, and median progression-free survival (PFS) was 2.9 months. OS was correlated with stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria but not with laparoscopic response by PCI or histologic response by peritoneal regression grading system (PRGS). CONCLUSIONS: This phase I trial in the USA demonstrated safety, feasibility, and early efficacy signal of PIPAC with oxaliplatin and chemotherapy in patients with PM from AC or CRC who are refractory to standard lines of systemic chemotherapy.

Impact of Sodium Thiosulfate on Prevention of Nephrotoxicities in HIPEC: An Ancillary Evaluation of Cisplatin-Induced Toxicities in Ovarian Cancer.

PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin confers a survival benefit in epithelial ovarian cancer (EOC) but is associated with renal toxicity. Sodium thiosulfate (ST) is used for nephroprotection for HIPEC with cisplatin, but standard HIPEC practices vary. METHODS: A prospective, nonrandomized, clinical trial evaluated safety outcomes of HIPEC with cisplatin 75 mg/m2 during cytoreductive surgery (CRS) in patients with EOC (n = 34) and endometrial cancer (n = 6). Twenty-one patients received no ST (nST), and 19 received ST. Adverse events (AEs) were reported according to CTCAE v.5.0. Serum creatinine (Cr) was collected preoperatively and postoperatively (Days 5-8). Progression-free survival (PFS) was followed. Normal peritoneum was biopsied before and after HIPEC for whole transcriptomic sequencing to identify RNAseq signatures correlating with AEs. RESULTS: Forty patients had HIPEC at the time of interval or secondary CRS. Renal toxicities in the nST group were 33% any grade AE and 9% grade 3 AEs. The ST group demonstrated no renal AEs. Median postoperative Cr in the nST group was 1.1 mg/dL and 0.5 mg/dL in the ST group (p = 0.0001). Median change in Cr from preoperative to postoperative levels were + 53% (nST) compared with - 9.6% (ST) (p = 0.003). PFS did not differ between the ST and nST groups in primary or recurrent EOC patients. Renal AEs were associated with downregulation of metabolic pathways and upregulation of immune pathways. CONCLUSIONS: ST significantly reduces acute renal toxicity associated with HIPEC with cisplatin in ovarian cancer patients. As nephrotoxicity is high in HIPEC with cisplatin, nephroprotective agents should be considered.

Integrative review of remote patient monitoring in gynecologic and urologic surgical oncology.

Patients with cancer facing complex and invasive urologic and gynecologic cancer surgery often experience symptoms and rapid declines in functional capacity postoperatively. Remote patient monitoring that leverages patient-generated health data is a potential approach to assess and promote postoperative recovery. This integrative review aims to provide an overview of the current literature and research on remote patient monitoring in gynecologic and urologic surgical oncology.

Feasibility of combining pelvic reconstruction with gynecologic oncology-related surgery.

INTRODUCTION AND HYPOTHESIS: At our institution, every patient seen by the gynecologic oncology service is screened for pelvic floor dysfunction. This study was aimed at determining if a combined surgical approach by gynecologic oncology and urogynecology services at our institution was feasible and safe for this patient population. METHODS: We performed a retrospective review of patients undergoing combined surgery by gynecologic oncology and urogynecology services at our institution from 2013 to 2021. Perioperative variables, postoperative adverse events, and long-term outcomes were assessed, and descriptive statistics were performed. RESULTS: From 20 December 2013 to 29 January 2021, a total of 102 patients underwent concurrent surgical repair of pelvic organ prolapse and/or stress urinary incontinence. Seventy-three patients (71.6%) had normal/benign pathologic conditions, and 29 (28.4%) had premalignant/malignant pathologic conditions. Ten patients (9.8%) had a postoperative complication, including reoperation for exposed midurethral sling (4.9%), urinary retention requiring midurethral sling release (2.9%), reoperation for hemoperitoneum (1.0%), and anemia requiring blood transfusion (1.0%). Nine complications occurred in patients with benign/normal pathologic conditions (12.3%), and one complication occurred in patients with pre-malignant/malignant pathologic conditions (3.4%). CONCLUSIONS: In our single-institution experience, concurrent gynecologic oncology and pelvic floor reconstructive surgery were safe and feasible in combination with no reported major morbidity events.

Specific targeting of ovarian tumor-associated macrophages by large, anionic nanoparticles.

Immunotherapy is emerging as one of the most effective methods for treating many cancers. However, immunotherapy can still introduce significant off-target toxicity, and methods are sought to enable targeted immunotherapy at tumor sites. Here, we show that relatively large (>100-nm) anionic nanoparticles administered intraperitoneally (i.p.) selectively accumulate in tumor-associated macrophages (TAMs). In a mouse model of metastatic ovarian cancer, fluorescently labeled silica, poly(lactic-co-glycolic acid), and polystyrene nanoparticles administered i.p. were all found to selectively accumulate in TAMs. Quantifying silica particle uptake indicated that >80% of the injected dose was in TAMs. Particles that were smaller than 100 nm or cationic or administered intravenously (i.v.) showed no TAM targeting. Moreover, this phenomenon is likely to occur in humans because when freshly excised human surgical samples were treated with the fluorescent silica nanoparticles no interaction with healthy tissue was seen but selective uptake by TAMs was seen in 13 different patient samples. Ovarian cancer is a deadly disease that afflicts ∼22,000 women per year in the United States, and the presence of immunosuppressive TAMs at tumors is correlated with decreased survival. The ability to selectively target TAMs opens the door to targeted immunotherapy for ovarian cancer.

PIPAC for the Treatment of Gynecologic and Gastrointestinal Peritoneal Metastases: Technical and Logistic Considerations of a Phase 1 Trial.

BACKGROUND: Peritoneal metastases (PM) from ovarian, gastric, appendiceal, or colorectal origin can be treated via cytoreductive surgery with or without the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) for selected patients. Unfortunately, not all patients are candidates for aggressive surgical debulking. For these patients, pressurized intraperitoneal aerosolized chemotherapy (PIPAC) has emerged as an alternative method for intraperitoneal (IP) chemotherapy administration. This report presents the design and implementation of the first phase 1 trial to evaluate the safety and efficacy of PIPAC in the United States. METHODS: This is an ongoing prospective phase 1 clinical trial of PIPAC for patients who have histologically confirmed ovarian, uterine, gastric, appendiceal, or colorectal cancer with PM and have progressed to at least one evidence-based chemotherapeutic regimen. The trial has two clinical arms. The patients in arm 1 have gynecologic and gastric malignancies treated with IP cisplatin and doxorubicin, and the arm 2 patients have colorectal and appendiceal malignancies treated with intravenous fluorouracil and leucovorin followed by IP oxaliplatin. All the patients are monitored for dose-limiting toxicities and adverse events. RESULTS: Practical and technical considerations for the phase 1 PIPAC trial are presented. These considerations include patient selection, operating room setup, and technical details for successful aerosolized chemotherapy delivery. The phase 1 study results will be reported separately at completion of the trial. CONCLUSIONS: The PIPAC treatment is a feasible, minimally invasive approach that permits IP delivery of chemotherapy. Once completed, the ongoing phase 1 trial will help to provide safety and initial efficacy data.

Characterizing impact of positive lymph node number in endometrial cancer using machine-learning: A better prognostic indicator than FIGO staging?

BACKGROUND: Number of involved lymph nodes (LNs) is a crucial stratification factor in staging of numerous disease sites, but has not been incorporated for endometrial cancer. We evaluated whether number of involved LNs provide improved prognostic value. PATIENTS AND METHODS: Patients diagnosed with node-positive endometrial adenocarcinoma without distant metastasis were identified in the National Cancer Database. We trained a machine-learning based model of overall survival. Shapley additive explanation values (SHAP) based on the model were used to identify cutoffs of number of LNs involved. Results were validated using a Cox proportional hazards regression model. RESULTS: We identified 11,381 patients with endometrial cancer meeting the inclusion criteria. Using the SHAP values, we selected the following thresholds: 1-3 LNs, 4-5 LNs, and 6+ LNs. The 3-year OS was 82.0% for 1-3 LNs, 74.3% for 4-5 LNs (hazard ratio [HR] 1.38; p < 0.001), and 59.9% for 6+ LNs (HR 2.23; p < 0.001). On univariate Cox regression, PA nodal involvement was a significant predictor of OS (HR 1.20; p < 0.001) but was not significant on multivariate analysis when number of LNs was included (HR 1.05; p = 0.273). Additionally, we identified an interaction between adjuvant therapy and number of involved LNs. Patients with 1-3 involved LNs had 3-year OS of 85.2%, 78.7% and 74.2% with chemoradiation (CRT), chemotherapy, and radiation, respectively. Patients with 6+ involved LNs had 3-yr OS of 67.8%, 49.6%, and 48.9% with CRT, chemotherapy, and radiation, respectively (p < 0.001). CONCLUSION: Number of involved LNs is a stronger prognostic and predictive factor compared to PA node involvement.

Who is hurting? A prospective study of surgeon ergonomics.

BACKGROUND: There is a paucity of prospective data related to surgeon ergonomics, which affects career longevity. Robotic surgical systems may mitigate pain and workload. We hypothesized that ergonomic outcomes would vary based on surgeon height and gender, and the relative benefit of robotic surgery would vary based on these demographics. METHODS: Surgeons received questionnaires to fill out immediately before and after surgery to enable calculation of pain scores and task load. Surgeons who were ≤ 66 inches tall were considered "short". Univariable and multivariable regression analyses were performed where appropriate using Stata-MP version 14.2 (StataCorp LLC, College Station, TX). RESULTS: There were 124 questionnaires given to 20 surgeons; 97 (78%) were returned, and 12 (12%) laparoscopic operations were excluded, leaving 85 (69%) questionnaires for further analysis: 33 (38%) from short surgeons, and 24 (28%) from women, for 30 (35%) robotic and 55 (65%) open operations. There were 44/85 (52%) surgeons who reported worse pain after surgery. Overall pain scores (1.1 ± 2.6 vs 1.5 ± 2.6, p = 0.70) were similar for robotic and open operations. In multivariable analysis, greater surgeon pain scores were significantly associated with short surgeons (p < 0.001), male surgeons (p < 0.001), and long operative times (p = 0.03). Physical demand was lower for robot vs open operations (median 10 vs 13, p = 0.03). When short surgeons (p = 0.04) and male surgeons (p = 0.03) were examined as sub-groups, lower physical demand during robotic operations persisted, but was lost when only examining tall surgeons (p = 0.07) and female surgeons (p = 0.13). CONCLUSIONS: Short surgeons and male surgeons reported significantly more pain after both open and robotic operations but had less physical demand when using the robotic system. Future work should focus on mitigation of surgeon height-related factors and seek to understand ergonomic gender differences beyond height.

Prolapse repair after anterior exenteration.

This report presents our experience in performing prolapse repair after anterior exenteration. The patient had a history of invasive bladder cancer and underwent a robotically assisted laparoscopic anterior exenteration with extended bilateral pelvic lymph node dissection and creation of an Indiana pouch continent diversion. Her pelvic organ prolapse progressed over time despite multiple pessary fittings. She eventually decided to proceed with pelvic reconstructive surgery 6 years after her cancer surgery. She underwent a successful vaginal native tissue reconstruction with uterosacral ligament suspension, posterior repair and reconstruction of the anterior compartment. The patient has been followed for 16 months without recurrent prolapse. Vaginal native tissue pelvic reconstruction is feasible in a patient with a history of pelvic exenteration.

Silica Coated Paclitaxel Nanocrystals Enable Neural Stem Cell Loading For Treatment of Ovarian Cancer.

Ovarian cancer is commonly diagnosed only after it has metastasized to the abdominal cavity (stage III). While the current standard of care of intraperitoneal (IP) administration of cisplatin and paclitaxel (PTX) combination chemotherapy has benefit, patient 5-year survival rates are low and have not significantly improved in the past decade. The ability to target chemotherapy selectively to ovarian tumors while sparing normal tissue would improve efficacy and decrease toxicities. We have previously shown that cisplatin-loaded nanoparticles (NPs) loaded within neural stem cells (NSCs) are selectively delivered to ovarian tumors in the abdominal cavity following IP injection, with no evidence of localization to normal tissue. Here we extended the capabilities of this system to also include PTX delivery. NPs that will be loaded into NSCs must contain a high amount of drug by weight but constrain the release of the drug such that the NSCs are viable after loading and can successfully migrate to tumors. We developed silica coated PTX nanocrystals (Si[PTX-NC]) meeting these requirements. Si[PTX-NC] were more effective than uncoated PTX-NC or Abraxane for loading NSCs with PTX. NSCs loaded with Si[PTX-NC] maintained their migratory ability and, for low dose PTX, were more effective than free PTX-NC or Si[PTX-NC] at killing ovarian tumors in vivo. This work demonstrates that NSC/NP delivery is a platform technology amenable to delivering different therapeutics and enables the pursuit of NSC/NP targeted delivery of the entire preferred chemotherapy regimen for ovarian cancer. It also describes efficient silica coating chemistry for PTX nanocrystals that may have applications beyond our focus on NSC transport.

The Comprehensive Complication Index: a New Measure of the Burden of Complications After Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) are complex surgeries with multiple comorbidities. The Clavien-Dindo classification (CDC) is the most commonly used method to report surgical morbidity, but limits it to the highest-grade complication. The Comprehensive Complication Index (CCI) is a score ranging from 0 to 100, calculated using all 30-day complications and their treatment after abdominal surgery. The aim of this study is to assess the CCI's validity in the HIPEC patient population. METHODS: A review of our institutional cytoreduction database from 2009 to 2015 was undertaken. Patient demographics, pathology, Peritoneal Carcinomatosis Index (PCI), complications and their treatments, and length of stay (LOS) were reviewed. The CCI was calculated for each patient. Linear regression was used to assess whether the CCI and CDC were predictors of LOS. RESULTS: Of 157 patients reviewed, 110 (70.1%) underwent HIPEC. The majority were female (77, 66.9%), and the mean age was 53.7 years. Mean PCI was 13.2 [interquartile range (IQR) 7-18]. Median CDC was grade 2 (IQR 0-2), and only 9.8% had CDC of grade 4 or higher. Mean CCI was 21.4, while the median was 20.9 (IQR 0-30.8). Mean LOS was 16.2 days, while the median was 11 days (IQR 8-15 days). The CCI strongly correlated with LOS with coefficient of 0.46 [95% confidence interval (CI) 0.38-0.54, p = 0.000]. CONCLUSIONS: The CCI is an adequate tool to capture all complications and their overall burden in patients having undergone HIPEC. This study shows that the CCI can predict LOS and could be used to quantify and compare the burden of multiple complications.

Improved survival with adjuvant brachytherapy in stage IA endometrial cancer of unfavorable histology.

PURPOSE: We evaluated the utilization of vaginal brachytherapy (BT) and the resulting impact on survival in stage IA endometrial cancer of clear cell (CC), papillary serous (PS), and carcinosarcoma (CS) histology. METHODS: Patients with uterine cancer diagnosed from 2004 to 2015 were identified from the National Cancer Database. Patients underwent hysterectomy, showing FIGO stage IA disease with CC, PS, or CS histology. Logistic regression was used to evaluate predictors of BT utilization and to generate propensity scores. Survival was compared using log-rank test and Cox proportional hazards modeling, with propensity score adjustment. RESULTS: We identified 5711 patients who underwent hysterectomy showing FIGO pT1a, N0 or NX endometrial cancer with CC, PS, or CS histology, of which 29.5% received BT. Multivariate predictors of increased receipt of BT were identified. With a median follow-up of 3.3 years, 3-year overall survival (OS) was 87% for those receiving BT versus 78% for those without (p < 0.001). A survival benefit to BT was maintained across histologies. Similar results were seen whether tumor was confined to endometrium or had <50% myometrial invasion. On multivariate analysis, receipt of BT was associated with increased survival (hazard ratio [HR] 0.75, 95% confidence interval 0.65-0.87, p < 0.001). The benefit of BT persisted after propensity score adjustment (HR 0.76, p < 0.001). CONCLUSIONS: In this cohort of women with stage IA endometrial cancer of unfavorable histology, the use of BT was associated with improved survival. In this study, 29.5% of patients in our cohort received BT.

Secondary Neoplasms of the Female Lower Genital Tract After Hematopoietic Cell Transplantation.

Hematopoietic cell transplantation (HCT) results in long-term survival (≥10 years) in 85% of patients who survive transplant-related complications within the first 2 years posttransplant. Transplant survivors, however, are at an increased risk of chronic health conditions compared with the general population, including the emergence of secondary malignant neoplasms. In particular, female transplant survivors may face a greater risk of lower genital tract (cervical, vulvar, or vaginal) neoplasms due to chronic immune dysregulation in the peritransplant and posttransplant environment. Persistent immune suppression may facilitate the carcinogenesis of human papillomavirus (HPV), the causative agent of nearly all cervical cancers and most vulvar and vaginal cancers. Nevertheless, the risk of these cancers has not been sufficiently quantified in female transplant survivors. Small clinical studies have shown that the rate of cervical cytological abnormalities increases after allogeneic HCT, but large population-based studies have not consistently demonstrated an increased risk of secondary cervical cancer after transplant compared with the general population; the risk of developing secondary vulvar or vaginal cancer after transplant remains unclear. A better understanding of the natural history of HPV-associated lower genital tract neoplasms and their transplant-related risk factors would help delineate optimal long-term follow-up protocols in this population. In this systematic review, we summarize the current literature on this topic and discuss the implications for cervical cancer screening and vaccination in female transplant recipients.

A collaborative surgical approach to upper and lower abdominal cytoreductive surgery in ovarian cancer.

BACKGROUND AND OBJECTIVES: Cytoreductive surgery with complete macroscopic resection in patients with ovarian cancer is associated with improved survival. Institutional reports of combined upper and lower abdominal cytoreductive surgery for more advanced disease have described multidisciplinary approaches. We sought to investigate outcomes in patients undergoing cytoreductive surgery in patients with upper and lower abdominal disease at our institution. METHODS: Patients who underwent cytoreductive surgery for ovarian malignancies from 2008 to 2015 were retrospectively identified from an institutional database. Upper abdominal cytoreduction was defined anatomically as debulking of disease proximal to the ligament of Treitz. Perioperative outcomes were analyzed. RESULTS: A total of 258 operations were performed, the majority for serous ovarian carcinoma (70%). The gynecologic oncologist was the primary surgeon and often assisted by either a surgical oncology fellow and/or attending. In operations with combined upper and lower abdominal cytoreduction, patients were more likely to have an American society of anesthesiologists physical status classification system (ASA) of 3, peritoneal implants, and liver/spleen metastases. Preoperative chemotherapy and optimal cytoreduction were similar between groups. Perioperative morbidity and mortality were not significantly different between groups. CONCLUSIONS: A collaborative surgical approach to combined upper and lower abdominal cytoreductive surgery in patients with ovarian cancer should be performed, if needed, to achieve an optimal cytoreduction.