Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates.

BACKGROUND: Anti-programmed death 1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies have shown modest activity as monotherapy in recurrent ovarian cancer. Platinum chemotherapies induce T-cell proliferation and enhance tumor recognition. We assessed activity and safety of pembrolizumab with carboplatin in recurrent platinum-resistant ovarian cancer. PATIENTS AND METHODS: This phase I/II, single-arm clinical trial studied concurrent carboplatin and pembrolizumab in recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer. Primary platinum refractory patients were excluded. Patients were treated after progression on subsequent non-platinum systemic therapy after becoming platinum resistant or refractory. Pembrolizumab 200 mg was given on day 1 and carboplatin area under the curve 2 on days 8 and 15 of a 3-week cycle until progression. Imaging was assessed by blinded independent review. PD-L1 expression was assessed by immunohistochemistry. Flow cytometry on peripheral blood mononuclear cells was performed for CD3, CD4, CD8, PD1, CTLA4 and Ki67. RESULTS: The most common treatment-related adverse events were lymphopenia (18%) and anemia (9%) with most being grade 1 or 2 (93%). Of 29 patients treated, 23 patients were evaluable for best objective response: 10.3% (95% CI 2.2 to 27.4) had partial response (PR), 51.7% (95% CI 32.5 to 70.6) had stable disease (SD). 56.5% of patients had decreases in target lesions from baseline. All PD-L1-positive patients achieved PR (3/7, 42.8%) or SD (4/7, 57.2%). Median progression-free survival was 4.63 months (95% CI 4.3 to 4.96). Median OS was 11.3 months (95% CI 6.094 to 16.506). Peripheral CD8+PD1+Ki67+ T cells expanded after 3 (p=0.0015) and 5 (p=0.0023) cycles. CTLA4+PD1+CD8+ T cells decreased through the course of treatment up to the 12th cycle (p=0.004). When stratified by ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden at baseline, patients with a ratio ≥0.0375 who had a significantly longer median OS of 18.37 months compared with those with a ratio <0.0375 who had a median OS of 8.72 months (p=0.0099). No survival advantage was seen with stratification by tumor burden alone (p=0.24) or by CD8+PD1+Ki67+ T cells alone (p=0.53). CONCLUSIONS: Pembrolizumab with carboplatin was well-tolerated and active in recurrent platinum-resistant ovarian cancer. A ratio of peripheral T-cell exhaustion to radiographic tumor burden may identify patients more likely to benefit from this chemoimmunotherapy. TRIAL REGISTRATION NUMBER: NCT03029598.

Robotic-Assisted Gynecologic Surgery and Perioperative Morbidity in Elderly Women.

STUDY OBJECTIVE: To assess perioperative complications, conversions, and operative times in patients age ≥75 years undergoing robotic-assisted gynecologic surgery. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: High-volume, 2-physician gynecologic oncology practice. PATIENTS: A total of 705 women who underwent any robot-assisted gynecologic procedure for benign (n = 380) or malignant (n = 325) conditions between July 2008 and May 2014. Fifty patients age ≥75 years (elderly group) were compared with 655 patients age <75 years (younger group). INTERVENTIONS: Operative data were gathered prospectively for all robotic-assisted procedures. Demographic and perioperative outcomes were analyzed retrospectively for this study. MEASUREMENTS AND MAIN RESULTS: The mean age was 81.3 ± 4.2 years (range, 75.0-90.5 years) in the elderly group and 52.8 ± 11.5 years (range, 22.9-74.6 years) in the younger group. The elderly group had higher rates of surgery for malignancy (90.0% vs 43.2%; p < .01) and lymphadenectomy (44.0% vs 23.4%; p < .01), and was more likely to have cardiovascular disease (88.0% vs 37.6%; p < .01). There were no between-group differences in body mass index or history of chronic obstructive pulmonary disease, diabetes mellitus, or more than 1 previous abdominal surgical procedure. The elderly group was more likely to have a length of stay greater than postoperative day one (30.0% vs 14.8%; p = .01) and had a higher incidence of postoperative cardiac arrhythmia (8.0% vs 1.2%; p < .01). The elderly group also had a smaller median uterine size (83.0 ± 49.1 g vs 126.0 ± 189.5 g; p < .01), but total operative time, rate of conversion (6.0% vs 1.8%) and rate of blood transfusion (2.0% vs 1.5%) were not significantly different between the 2 groups. Rates of bowel and genitourinary injury were <1% in both groups, and there was no between-group difference in postoperative infectious morbidity, vaginal cuff complications, or reoperation. CONCLUSION: The perioperative complication rates of robotic-assisted surgery are comparable in elderly women and younger women, despite a longer hospital length of stay and greater likelihood of postoperative arrhythmia in elderly women.

A phase II evaluation of nintedanib (BIBF-1120) in the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study.

INTRODUCTION: Patients presenting with advanced, recurrent, or metastatic endometrial cancer have limited treatment options. On behalf of the Gynecologic Oncology Group, we conducted this phase II trial of nintedanib (BIBF 1120), a potent small molecule triple receptor tyrosine kinase inhibitor of PDGFR α and ß, FGFR 1/3, and VEGFR 1-3, in this population. OBJECTIVES: The primary objectives were to estimate event-free survival (EFS) at 6 months and the proportion of patients who have an objective tumor response. In addition, we sought to determine the nature and degree of toxicity. Secondary objectives were to estimate progression-free and overall survival. METHODS: This was a two-stage, single-arm phase II study. Eligible patients were treated with single-agent nintedanib at a dose of 200mg twice daily. RESULTS: Of 37 patients enrolled, 32 were eligible. There were zero complete and three partial responses for an overall response rate of 9.4% (90% 2-sided CI=2.6-22.5%). Seven patients (21.9%; 90% 2-sided CI=10.7-37.2%) were EFS at 6 months, with one patient continuing on study at the time of this writing. Serious toxicity included the following grade 3 events: gastrointestinal toxicity (5), neutropenia (1), edema (1), hypertension (1), and liver function abnormalities (5). CONCLUSIONS: Nintedanib lacked sufficient activity as a single agent to warrant enrollment to second stage. However, preclinical data indicate it may be synergistic with paclitaxel in a population of patients enriched for specific p53 mutations that result in loss of function. Subsequent studies may evaluate this agent in combination with paclitaxel.

Combined weekly topotecan and biweekly bevacizumab in women with platinum-resistant ovarian, peritoneal, or fallopian tube cancer: results of a phase 2 study.

BACKGROUND: A phase 2 trial was conducted to determine the toxicity and efficacy of combined weekly topotecan and biweekly bevacizumab in patients with primary or secondary platinum-resistant ovarian, peritoneal, or fallopian tube cancer (OC). METHODS: Patients were treated with bevacizumab 10 mg/kg on days 1 and 15 and topotecan 4 mg/m(2) on days 1, 8, and 15 of a 28-day cycle until progressive disease (PD) or excessive toxicity. The primary endpoint was progression-free survival (PFS); secondary objectives included overall survival (OS), objective response, and toxicity. RESULTS: Patients (N = 40) received a median of 8 treatment cycles. Toxicity was generally mild or moderate, with neutropenia (18%), hypertension (20%), gastrointestinal toxicity (18%), pain (13%), metabolic toxicity (15%), bowel obstruction (10%), and cardiotoxicity (8%) being the most common grade 3 and 4 adverse events. No bowel perforations, febrile neutropenia, or treatment-related deaths occurred. Median PFS and OS were 7.8 (95% confidence interval [CI], 3.0-9.4) and 16.6 months (95% CI, 12.8-22.9), with 22 (55%) patients progression-free for ≥6 months. Ten (25%) patients had partial response (PR), 14 (35%) had stable disease (SD), and 16 (40%) had PD. Patients treated with 2 prior regimens received greater benefit than patients treated with 1: PR/SD, 78.9% versus 42.9% (P = .03); median PFS, 10.9 versus 2.8 months (P = .08); median OS, 22.9 versus 12.8 months (P = .02). CONCLUSIONS: A weekly topotecan and biweekly bevacizumab combination demonstrates acceptable toxicity and encouraging efficacy in patients with platinum-resistant OC; further study is warranted.

Leukocytosis after robotic hysterectomy: commonly observed but clinically insignificant.

Laboratory studies are commonly performed after surgery, but with little evidence of clinical utility. We evaluated our experience with measuring a complete blood count (CBC) to determine peripheral blood leukocyte count (WBC) postoperatively following consecutive robotic hysterectomies. From January 2008 through November 2009, two surgeons (KM, HM) performed 204 robotic hysterectomies. Patient age, weight, height, indication for surgery, surgical procedure, operative time, estimated blood loss, hospital length of stay, postoperative fever, and complications were prospectively recorded and correlated with WBC measured on the day after surgery. The postoperative WBC was elevated (>11,000/µl) in 59/204 (29%) patients. Eight (4%) patients had marked leukocytosis (WBC >15,000/µl; maximum 16,600/µl). There was no correlation between postoperative leukocytosis and operative time, BMI, performance of lymphadenectomy, or length of hospitalization. The only factor significantly associated with elevated postoperative WBC was elevated preoperative WBC (P < .001). Also, there was no correlation between postoperative leukocytosis with fever or infectious complications. The mean T max was 37.1ºC and T max over 38ºC was seen in nine patients. Of the five women who developed infectious complications, only one (diagnosed with pneumonia) had a minimally elevated postoperative WBC (11,600/µl); the other four (pneumonia and pelvic abscess, two each) had normal postoperative WBC. Routine measurement of WBC after robotic hysterectomy is not useful. In about 25% of cases there will be a slight leukocytosis, and rarely (about 4%) will the WBC exceed 15,000/µl. In no case was measurement of postoperative WBC clinically relevant.

Robot-assisted total laparoscopic hysterectomy in obese and morbidly obese women.

Total laparoscopic hysterectomy (TLH) in obese patients is challenging. We sought to evaluate whether total laparoscopic hysterectomies using the da Vinci robotic system in obese patients, in comparison with non-obese patients, is a reasonable surgical approach. One-hundred consecutive robot-assisted TLHs were performed over a 17-month period. Obesity was not a contraindication to robotic surgery, assuming adequate respiratory function to tolerate Trendelenburg position and, for cancer cases, a small enough uterus to allow vaginal extraction without morcellation. Data were prospectively collected on patient characteristics, total operative time, hysterectomy time, estimated blood loss, length of stay, and complications. Outcomes with non-obese and obese women were compared. The median age, weight, and BMI of the 100 patients who underwent robot-assisted TLH was 57.6 years (30.0-90.6), 82.1 kg (51.9-159.6), and 30.2 kg/m(2) (19.3-60.2), respectively. Fifty (50%) patients were obese (BMI ≥ 30); 22 patients were morbidly obese (BMI ≥ 40). There was no increase in complications (p = 0.56) or blood loss (p = 0.44) with increasing BMI. While increased BMI was associated with longer operative times (p = 0.05), median time increased by only 36 min when comparing non-obese and morbidly obese patients. Median length of stay was one day for all weight categories (p = 0.42). Robot-assisted TLH is feasible and can be safely performed in obese patients. More data are needed to compare robot-assisted TLH with other hysterectomy techniques in obese patients. Nonetheless, our results are encouraging. Robot-assisted total laparoscopic hysterectomy may be the preferred technique for appropriately selected obese patients.

Phase 2 study of intraperitoneal topotecan as consolidation chemotherapy in ovarian and primary peritoneal carcinoma.

BACKGROUND: Intravenous topotecan is approved for the treatment of ovarian cancer (OC). In intraperitoneal (i.p.) topotecan studies, 20 mg/m(2) dosing was tolerable. This study evaluated the feasibility, safety, and preliminary efficacy of i.p. topotecan as consolidation chemotherapy in patients with OC or primary peritoneal cancers (PPCs). METHODS: Patients with stage III/IV ovarian or PPC in clinical complete response after surgical cytoreduction and intravenous carboplatin/paclitaxel chemotherapy who had benign findings or minimal persistent disease (< or = 1 cm diameter) at second-look surgery were eligible. Intraperitoneal topotecan 20 mg/m(2) was infused once every 21 days for 4 to 6 cycles. Kaplan-Meier estimates were used to calculate progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty patients were enrolled (18 [90%] patients had OC). Sixteen patients received 4 cycles, 3 patients received 6 cycles, and 1 patient withdrew after 1 cycle. The mean delivered dose was 18 mg/m(2). Grade 3/4 toxicities included neutropenia and thrombocytopenia (45% for both). Grade 1/2 abdominal distension and nausea were reported in 60% and 40% of patients, respectively. Median PFS was 24 months from second-look surgery (95% confidence intervals [CI]: +/-10 months). Sixteen patients were alive and median OS was not reached at the time of data analysis. OS estimated at either 30 months from second-look surgery, or 3 years from initial diagnosis, was 84% (95% CI, 68%-100%). CONCLUSIONS: Consolidation i.p. topotecan is a feasible option for women withadvanced ovarian and primary peritoneal cancers. Further investigation of i.p. topotecan is warranted in this patient population.

Paint-only is equivalent to scrub-and-paint in preoperative preparation of abdominal surgery sites.

BACKGROUND: Antiseptic preoperative skin site preparation is used to prepare the operative site before making a surgical incision. The goal of this preparation is a reduction in postoperative wound infection. The most straightforward technique necessary to achieve this goal remains controversial. STUDY DESIGN: A prospective randomized trial was designed to prove equivalency for two commonly used techniques of surgical skin site preparation. Two hundred thirty-four patients undergoing nonlaparoscopic abdominal operations were consented for the trial. Exclusion criteria included presence of active infection at the time of operation, neutropenia, history of skin reaction to iodine, or anticipated insertion of prosthetic material at the time of operation. Patients were randomized to receive either a vigorous 5-minute scrub with povidone-iodine soap, followed by absorption with a sterile towel, and a paint with aqueous povidone-iodine or surgical site preparation with a povidone-iodine paint only. The primary end point of the study was wound infection rate at 30 days, defined as presence of clinical signs of infection requiring therapeutic intervention. RESULTS: Patients randomized to the scrub-and-paint arm (n = 115) and the paint-only arm (n = 119) matched at baseline with respect to age, comorbidity, wound classification, mean operative time, placement of drains, prophylactic antibiotic use, and surgical procedure (all p > 0.09). Wound infection occurred in 12 (10%) scrub-and-paint patients, and 12 (10%) paint-only patients. Based on our predefined equivalency parameters, we conclude equivalence of infection rates between the two preparations. CONCLUSIONS: Preoperative preparation of the abdomen with a scrub with povidone-iodine soap followed by a paint with aqueous povidone-iodine can be abandoned in favor of a paint with aqueous povidone-iodine alone. This change will result in reductions in operative times and costs.

Incidence and management of abdominal sacrocolpopexy mesh erosions.

OBJECTIVE: This study was undertaken to evaluate the occurrence and management of mesh erosions in patients undergoing abdominal sacrocolpopexy. STUDY DESIGN: A retrospective chart review of the abdominal sacrocolpopexy procedure (n = 92) between 1997 and 2003 was performed. Patients with mesh erosion were identified. Incidence by graft type and treatment required for erosion resolution was analyzed with chi 2 and Fisher exact test. RESULTS: Erosions occurred in 7.6 % (7/92). Erosions were identified only in patients with Gore-Tex (3/33, 9%) or silicone-coated mesh (4/21, 19%) compared with none of 38 patients with polypropylene mesh (n = 24) or fascia (n = 14) grafts ( P = .068.). Partial excision of exposed graft resolved all 3 Gore-Tex erosions, compared with none of the silicone-coated mesh erosions ( P = .03). Complete graft removal was required to resolve silicone-coated mesh erosions. CONCLUSION: We observed a high rate of erosion with Gore-Tex and silicone-coated mesh. Partial graft excision was adequate for Gore-Tex erosions, but complete graft removal was necessary to resolve erosions associated with silicone-coated mesh.

High complication rate identified in sacrocolpopexy patients attributed to silicone mesh.

OBJECTIVES: To report on our experience using a preconfigured Y-shaped silicone-coated polyester mesh and polypropylene mesh for vaginal vault suspension. A variety of materials have been used for both open and laparoscopic sacrocolpopexy in the management of vaginal vault prolapse. Recently, a preconfigured Y-shaped silicone-coated polyester mesh was introduced to facilitate the vaginal cuff suspension to the sacrum. METHODS: We reviewed the data of 45 consecutive patients who underwent abdominal (n = 28) or laparoscopic (n = 17) sacrocolpopexy. Of the 45 patients, 21 underwent silicone mesh suspension of the vaginal cuff to the anterior sacrum, with a mean follow-up of 23 months (range 16 to 41). A comparative analysis was performed of 24 patients who underwent the same procedure with polypropylene mesh. RESULTS: Of the 21 patients in the silicone group, 5 (23.8%) have had a major complication (four vaginal mesh erosions and one mesh infection) after a median follow-up of 9.5 months (range 4 to 20). The presenting symptoms were persistent or new vaginal discharge and/or nonspecific pelvic pain. One patient underwent successful removal of the mesh transvaginally, but the rest required abdominal exploration. To date, the 24 patients who underwent vaginal cuff suspension with polypropylene mesh have had no vaginal mesh extrusions or infections, with a mean follow-up of 12 months (range 1 to 38). CONCLUSIONS: Silicone-coated polyester mesh has recently been associated with a high rate of vaginal erosion when used as a transvaginal suburethral sling. Our experience specifically with vaginal vault suspension corroborates this. We have abandoned the use of silicone mesh because of the unacceptably high extrusion rate and presently use polypropylene mesh.

Pseudomyxoma peritonei is a disease of MUC2-expressing goblet cells.

Pseudomyxoma peritonei, a syndrome first described by Karl F. Rokitansky in 1842, is an enigmatic, often fatal intra-abdominal disease characterized by dissecting gelatinous ascites and multifocal peritoneal epithelial implants secreting copious globules of extracellular mucin. Although past interest in the syndrome has focused on the questions of the site of origin (appendix versus ovary), mechanisms of peritoneal spread (multicentricity, redistribution phenomenon, or metastasis), and the degree of malignant transformation present (adenoma, borderline tumor, or carcinoma), another important question is the mechanism behind the accumulation of extracellular mucin, the real cause of the disease's morbidity and mortality irrespective of the site of origin, mechanism of peritoneal spread, or transformed status of its epithelium. Taking advantage of the recently cloned human mucin genes, we decided to investigate this question. Our studies revealed that pseudomyxoma peritonei is a disease of MUC2-expressing goblet cells. These cells also express MUC5AC but the latter mucin is not specific for pseudomyxoma peritonei. MUC2 expression accounts for the voluminous deposits of extracellular mucin (mucin:cell ratios exceeding 10:1) and distinguishes pseudomyxoma peritonei secondarily involving the ovary from primary ovarian mucinous tumors with peritoneal implants. Because mucinous tumors of the appendix similarly express MUC2, the MUC2 expression profile also supports an appendiceal rather than ovarian origin for pseudomyxoma peritonei. Increased steady-state mRNA is observed in pooled cases of pseudomyxoma peritonei but does not occur on the basis of gene rearrangement or gene amplification. Primary epithelial cell cultures obtained from pseudomyxoma peritonei express MUC2 whose levels can be epigenetically regulated. These lines up-regulate MUC2 expression in response to both methylation inhibition by 5-azacytidine and exposure to Pseudomonas aeruginosa lipopolysaccharide, both of whose effects can be suppressed by genistein pretreatment. Both immunocytochemical as well as in situ hybridization studies with ancillary digital image analysis reveal that MUC2 expression in cases of pseudomyxoma peritonei is independent of the degrees of malignant transformation that are present and, in fact, reflects the constitutive levels of expression observed in normal goblet cells of the appendix. Extracellular mucin accumulates dramatically in pseudomyxoma peritonei because the number of MUC2-secreting cells dramatically increase and because this MUC2 has no place to drain. These studies suggest that pseudomyxoma peritonei should be regarded as a disease of MUC2-expressing goblet cells whose MUC2 expression might be susceptible to pharmacological targeting.