ABSTRACT
BACKGROUND: The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood. METHODS: In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples. FINDINGS: Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43 months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90 months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-ß, and ß-catenin signaling. CONCLUSIONS: Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS ≥10 may benefit more from this regimen, and future studies should investigate this potential biomarker. FUNDING: This investigator-initiated trial was funded by Merck.
ABSTRACT
We evaluated the association of disease outcome with T cell immune-related characteristics and T cell receptor (TCR) repertoire in malignant ascites from patients with high-grade epithelial ovarian cancer. Ascitic fluid samples were collected from 47 high-grade epithelial ovarian cancer patients and analyzed using flow cytometry and TCR sequencing to characterize the complementarity determining region 3 TCR ß-chain. TCR functions were analyzed using the McPAS-TCR and VDJ databases. TCR clustering was implemented using Grouping of Lymphocyte Interactions by Paratope Hotspots software. Patients with poor prognosis had ascites characterized by an increased ratio of CD8+ T cells to regulatory T cells, which correlated with an increased productive frequency of the top 100 clones and decreased productive entropy. TCRs enriched in patients with an excellent or good prognosis were more likely to recognize cancer antigens and contained more TCR reads predicted to recognize epithelial ovarian cancer antigens. In addition, a TCR motif that is predicted to bind the TP53 neoantigen was identified, and this motif was enriched in patients with an excellent or good prognosis. Ascitic fluid in high-grade epithelial ovarian cancer patients with an excellent or good prognosis is enriched with TCRs that may recognize ovarian cancer-specific neoantigens, including mutated TP53 and TEAD1. These results suggest that an effective antigen-specific immune response in ascites is vital for a good outcome in high-grade epithelial ovarian cancer.
Subject(s)
Ascites , Ovarian Neoplasms , Humans , Female , Carcinoma, Ovarian Epithelial/metabolism , Ascites/metabolism , Receptors, Antigen, T-Cell , Ovarian Neoplasms/metabolism , CD8-Positive T-Lymphocytes , ImmunityABSTRACT
OBJECTIVE: To determine the clinical characteristics of patients who attained pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) and to identify specific predictive or prognostic factors associated with pCR. METHODS: Two distinct populations of patients who underwent NACT followed by interval tumor reductive surgery (TRS) were used in this retrospective study. The first contained 472 patients from a single institution. The second contained only pCR patients (67); those identified from population one, plus 44 obtained through collaborative institutions. Cox analysis and log-rank tests were performed to assess associations between clinical characteristics and pCR outcome, recurrence-free survival (RFS), and overall survival (OS). RESULTS: The median RFS and OS in our pCR-only population was 24.2 and 80.8 months, respectively, with a median follow-up time of 32.4 months. In our single institution population, 23 patients attained pCR (4.9%) and had longer RFS compared to non-pCR patients with viable microscopic, optimal, or suboptimal residual disease (24.3 vs. 12.1 vs. 11.6 vs. 9.6 months, p = 0.025, 0.012, 0.008, respectively), and longer OS compared to those with optimal or suboptimal residual disease (54.5 vs. 29.4 vs. 25.7 months, p = 0.027, 0.007, respectively). Patients were more than three-fold likely to attain pCR if their CA125 value was normal at the time of surgery (OR 3.54, 95% CI: 1.14-11.05, p = 0.029). CONCLUSIONS: Women with pCR after NACT have significantly longer RFS compared to those with residual viable tumor at the time of interval tumor-reductive surgery, and CA125 is plausible biomarker for identifying these extreme responders preoperatively.
Subject(s)
Neoadjuvant Therapy , Ovarian Neoplasms , Carcinoma, Ovarian Epithelial/drug therapy , Chemotherapy, Adjuvant , Female , Humans , Neoplasm Staging , Neoplasm, Residual/pathology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/surgery , Retrospective StudiesABSTRACT
Anti-angiogenic therapies, such as anti-VEGF antibodies (AVAs), have shown promise in clinical settings. However, adaptive resistance to such therapies occurs frequently. We use orthotopic ovarian cancer models with AVA-adaptive resistance to investigate the underlying mechanisms. Genomic profiling of AVA-resistant tumors guides us to endothelial p130cas. We find that bevacizumab induces cleavage of VEGFR2 in endothelial cells by caspase-10 and that VEGFR2 fragments internalize into the nucleus and autophagosomes. Nuclear VEGFR2 and p130cas fragments, together with TNKS1BP1 (tankyrase-1-binding protein), initiate endothelial cell death. Blockade of autophagy in AVA-resistant endothelial cells retains VEGFR2 at the membrane with bevacizumab treatment. Targeting host p130cas with RGD (Arg-Gly-Asp)-tagged nanoparticles or genomic ablation of vascular p130cas in p130casflox/floxTie2Cre mice significantly extends the survival of mice with AVA-resistant ovarian tumors. Higher vascular p130cas is associated with shorter survival of individuals with ovarian cancer. Our findings identify opportunities for new strategies to overcome adaptive resistance to AVA therapy.
Subject(s)
Crk-Associated Substrate Protein/metabolism , Drug Resistance, Neoplasm/physiology , Endothelial Cells/metabolism , Ovarian Neoplasms/pathology , Angiogenesis Inhibitors/pharmacokinetics , Animals , Bevacizumab/pharmacology , Female , Humans , Mice , Ovarian Neoplasms/metabolism , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/metabolismABSTRACT
Ovarian cancer is associated with a high mortality rate due to diagnosis at advanced stages. Dissemination often occurs intraperitoneally within the ascites fluid. The microenvironment can support dissemination through several mechanisms. One potential ascites factor which may mediate dissemination are EVs or extracellular vesicles that can carry information in the form of miRNAs, proteins, lipids, and act as mediators of cellular communication. We present our observations on EVs isolated from ascitic supernatants from patients diagnosed with high grade serous ovarian carcinoma in augmenting motility, growth, and migration towards omental fat. MicroRNA profiling of EVs from malignant ascitic supernatant demonstrates high expression of miR 200c-3p, miR18a-5p, miR1246, and miR1290 and low expression of miR 100- 5p as compared to EVs isolated from benign ascitic supernatant. The migration of ovarian cancer spheroids towards omental fat is enhanced in the presence of malignant ascitic EVs. Gene expression of these cells showed increased expression of ZBED2, ZBTB20, ABCC3, UHMK1, and low expression of Transgelin and MARCKS. We present evidence that ovarian ascitic EVs increase the growth of ovarian cancer spheroids through miRNAs.
Subject(s)
Ascitic Fluid/metabolism , Extracellular Vesicles/metabolism , Ovarian Neoplasms/pathology , Aged , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Down-Regulation/drug effects , Female , Humans , MicroRNAs/metabolism , MicroRNAs/pharmacology , Microfilament Proteins/genetics , Microfilament Proteins/metabolism , Middle Aged , Multidrug Resistance-Associated Proteins/genetics , Multidrug Resistance-Associated Proteins/metabolism , Muscle Proteins/genetics , Muscle Proteins/metabolism , Ovarian Neoplasms/metabolism , Spheroids, Cellular/cytology , Spheroids, Cellular/metabolism , Tumor Microenvironment , Up-Regulation/drug effectsABSTRACT
PURPOSE: To evaluate the effect of dasatinib therapy on EphA2 signaling in cancers of women with measurable (biopsy amenable) advanced-stage, chemo-naïve primary or recurrent endometrial cancer. Preliminary efficacy was also assessed. PATIENTS AND METHODS: We performed a pilot study of single-agent dasatinib lead-in, followed by triplet dasatinib, paclitaxel, and carboplatin. We measured the downstream effectors of EphA2 signaling in pre- and post-dasatinib treatment biopsy tissue samples; we also determined the severity of adverse events and patients' progression-free survival and overall survival durations. RESULTS: Eighteen patients were recruited and given dasatinib (150 mg orally daily for 14 days), followed by paclitaxel, carboplatin and dasatinib (daily) for six cycles (21-day cycles). Seventeen patients were evaluable for toxicity and 11 patients for response. A reverse phase protein array and proximity ligation assay revealed that CRAF/BRAF dimerization, caveolin-1 level, and Notch pathway signaling were predictive of response and resistance to dasatinib. Overall, the objective response rate was 45% (95% CI: 17%-77%), with median progression-free survival duration of 10.5 months and median overall survival duration of 30.4 months. The most common grade 3 or 4 adverse events were neutropenia (76%), thrombocytopenia (53%), anemia (53%), and fatigue (12%). CONCLUSIONS: Caveolin-1 expression, in combination with CRAF/BRAF heterodimerization, is associated with resistance to EphA2 targeting by dasatinib. The triplet combination showed interesting clinical activity in endometrial cancer with acceptable toxicity. Pretreatment with dasatinib may accentuate combination therapy toxicity.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Endometrial Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carboplatin/adverse effects , Caveolin 1/metabolism , Dasatinib/administration & dosage , Dasatinib/adverse effects , Drug Administration Schedule , Endometrial Neoplasms/blood , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Female , Humans , Middle Aged , Molecular Targeted Therapy , Neoplasm Recurrence, Local/blood , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Neoplastic Cells, Circulating/metabolism , Neoplastic Cells, Circulating/pathology , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Pilot Projects , Receptor, EphA2/metabolism , Signal Transduction/drug effects , Survival RateABSTRACT
BACKGROUND: The incidence of complex atypical hyperplasia and early-stage endometrioid endometrial cancer is increasing, in part owing to the epidemic of obesity, which is a risk factor tightly linked to the development of endometrial hyperplasia and cancer. The standard upfront treatment for complex atypical hyperplasia and early-stage endometrial cancer is hysterectomy. However, nonsurgical treatment of early-stage endometrial neoplasia may be necessary owing to medical comorbidities precluding surgery or desired future fertility. OBJECTIVE: This study aimed to evaluate the efficacy of the levonorgestrel intrauterine device to treat complex atypical hyperplasia and grade 1 endometrioid endometrial carcinoma. STUDY DESIGN: A single-institution, single-arm, phase II study of the levonorgestrel intrauterine device (52 mg levonorgestrel, Mirena) was conducted in patients with complex atypical hyperplasia or grade 1 endometrioid endometrial cancer. The primary endpoint was pathologic response rate at 12 months, including complete or partial response. Quality of life and toxicity were assessed. Molecular analyses for proliferation markers, hormone-regulated genes, and wingless-related integration site pathway activation were performed at baseline and 3 months. RESULTS: A total of 57 patients were treated (21 endometrial cancer, 36 complex atypical hyperplasia). The median age was 48.0 years, and the median body mass index was 45.5 kg/m2. Of the 47 evaluable patients, 12-month response rate was 83% (90% credible interval, 72.7-90.3)-37 were complete responders (8 endometrial cancer; 29 complex atypical hyperplasia), 2 were partial responders (2 endometrial cancer), 3 had stable disease (2 endometrial cancer; 1 complex atypical hyperplasia), and 5 had progressive disease (3 endometrial cancer; 2 complex atypical hyperplasia). After stratification for histology, the response rate was 90.6% for complex atypical hyperplasia and 66.7% for grade 1 endometrioid endometrial cancer. Notably, 4 patients (9.5%) experienced relapse after the initial response. Adverse events were mild, primarily irregular bleeding and cramping. Quality of life was not negatively affected. At 3 months, exogenous progesterone effect was present in 96.9% of responders (31 of 32) vs 25% of nonresponders (2 of 8) (P=.001). Nonresponders had higher baseline proliferation (Ki67) and lower dickkopf homolog 3 gene expression than responders (P=.023 and P=.030). Nonresponders had significantly different changes in secreted frizzled-related protein 1, frizzled class receptor 8, and retinaldehyde dehydrogenase 2 compared with responders. CONCLUSION: The levonorgestrel intrauterine device has a substantial activity in complex atypical hyperplasia and grade 1 endometrioid endometrial cancer, with a modest proportion demonstrating upfront progesterone resistance. Potential biomarkers were identified that may correlate with resistance to therapy; further exploration is warranted.
Subject(s)
Carcinoma, Endometrioid/drug therapy , Contraceptive Agents, Hormonal/administration & dosage , Endometrial Hyperplasia/drug therapy , Endometrial Neoplasms/drug therapy , Intrauterine Devices, Medicated , Levonorgestrel/administration & dosage , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adult , Aged , Aged, 80 and over , Aldehyde Dehydrogenase 1 Family/genetics , Aldehyde Dehydrogenase 1 Family/metabolism , Biomarkers/metabolism , Biomarkers, Tumor/metabolism , Body Mass Index , Carcinoma, Endometrioid/metabolism , Carcinoma, Endometrioid/pathology , Endometrial Hyperplasia/metabolism , Endometrial Hyperplasia/pathology , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Female , Gene Expression , Humans , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Ki-67 Antigen/genetics , Ki-67 Antigen/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Middle Aged , Neoplasm Grading , Neoplasm Staging , Quality of Life , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Retinal Dehydrogenase/genetics , Retinal Dehydrogenase/metabolism , Treatment Outcome , Wnt Signaling Pathway/genetics , Young AdultABSTRACT
OBJECTIVE: This randomized open-label phase II study evaluated the safety and clinical activity of EP-100 plus weekly paclitaxel in patients with recurrent ovarian cancer expressing positive LHRH receptor. METHODS: In a limited "run-in" dose escalation phase for EP-100, six patients were treated with ascending dose levels (13 mg/m2, 20 mg/m2, 30 mg/m2). In the randomized phase, patients received weekly paclitaxel (80 mg/m2 intravenously) plus twice weekly EP-100 (30 mg/m2 intravenously; combination arm) or weekly paclitaxel alone (80 mg/m2 intravenously; paclitaxel arm). The primary study endpoint was overall response rate (ORR). RESULTS: Forty-four patients were then randomized to either the experimental combination arm (n = 23) or the standard of care paclitaxel monotherapy arm (n = 21). The ORR was 35% (95%CI 16%-57%) for the combination arm and 33% (95% CI 15%-57%) for the paclitaxel arm. An interesting observation from an unplanned analysis was that a subset of patients with target liver lesions showed a greater overall response rate to the combination (69%) compared to paclitaxel alone (16%). The frequency of treatment-related grade 3-4 adverse events was similar between treatment arms: 48% vs 43% for the combination and paclitaxel arms, respectively. CONCLUSIONS: ORR in the EP-100 combination arm was similar to that in the group treated with paclitaxel alone; however, a subset of patients with liver metastases appeared to benefit from the combination. The addition of EP-100 did not appear to augment the adverse event profile of paclitaxel and was well tolerated.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Liver Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/drug therapy , Paclitaxel/administration & dosage , Peptide Fragments/administration & dosage , Recombinant Fusion Proteins/administration & dosage , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cell Membrane/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Female , Follow-Up Studies , Humans , Infusions, Intravenous , Ligands , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Middle Aged , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Paclitaxel/adverse effects , Peptide Fragments/adverse effects , Progression-Free Survival , Receptors, LHRH/metabolism , Recombinant Fusion Proteins/adverse effectsABSTRACT
INTRODUCTION: The surgical approach for interval debulking surgery after neoadjuvant chemotherapy has been extrapolated from primary tumor reductive surgery for high-grade ovarian cancer. The study objective was to compare pathologic distribution of malignancy at interval debulking surgery versus primary tumor reductive surgery. METHODS: Patients with a diagnosis of high-grade serous or mixed, non-mucinous, epithelial ovarian, fallopian tube or primary peritoneal cancer who underwent neoadjuvant chemotherapy or primary tumor reductive surgery and had at least 6 months of follow-up were identified through tumor registry at a single institution from January 1995 to April 2016. Pathologic involvement of organs was categorized as macroscopic, microscopic, or no tumor. Statistical analyses included Mann-Whitney and Fisher's exact tests. RESULTS: Of 918 patients identified, 366 (39.9%) patients underwent interval debulking surgery and 552 (60.1%) patients underwent primary tumor reductive surgery. Median age was 62.3 years (range 25.3-92.5). The majority of patients in the interval debulking surgery group were unstaged (261, 71.5%). In the patients who had a primary tumor reductive surgery, 406 (74.6%) had stage III disease. In both groups, the majority of patients had serous histology: 325 (90%) and 435 (78.8%) in the interval debulking and primary tumor reductive surgery groups, respectively. There was a statistically significant difference between disease distribution on the uterus between the groups; 31.4% of the patients undergoing interval debulking surgery had no evidence of uterine disease compared with 22.1% of primary tumor reductive surgery specimens (p<0.001). In the adnexa, there was macroscopic disease present in 253 (69.2%) and 482 (87.4%) of cases in the interval vs primary surgery groups, respectively (p<0.001). Within the omentum, no tumor was present in the omentum in 52 (14.2%) in the interval surgery group versus 91 (16.5%) in the primary surgery group (p<0.001). In the interval surgery group, there was no tumor involving the small and large bowel in 49 (13.4%) and 28 (7.7%) pathologic specimens, respectively. This was statistically significantly different from the small and large bowel in the primary surgery group, of which there was no tumor in 20 (3.6%, p<0.001) and 16 (2.9%, p<0.001) of cases, respectively. CONCLUSION: In patients undergoing interval debulking surgery, there was less macroscopic involvement of tumor in the uterus, adnexa and bowel compared with patients undergoing primary cytoreductive surgery.
Subject(s)
Carcinoma, Ovarian Epithelial/surgery , Cytoreduction Surgical Procedures/methods , Ovarian Neoplasms/surgery , Peritoneal Neoplasms/surgery , Adolescent , Adult , Carcinoma, Ovarian Epithelial/pathology , Female , Humans , Middle Aged , Neoadjuvant Therapy/methods , Ovarian Neoplasms/pathology , Peritoneal Neoplasms/pathology , Time Factors , Young AdultABSTRACT
OBJECTIVE: Low-grade serous carcinoma of the ovary/peritoneum (LGSC) is relatively chemoresistant in the adjuvant, neoadjuvant, and recurrent settings. We sought to expand our prior work and evaluate response rates of women with LGSC to neoadjuvant chemotherapy (NACT) compared to women with high-grade serous carcinoma of the ovary/peritoneum (HGSC). METHODS: Thirty-six patients with LGSC who received NACT were matched to patients with HGSC. A single radiologist re-reviewed pre- and post-NACT imaging for response using RECIST 1.1. Pre- and post-NACT CA-125 values were compared using paired t-tests. Kaplan-Meier estimates of progression free survival (PFS) and overall survival (OS) were performed. RESULTS: All patients received neoadjuvant platinum-based regimens. LGSC patients received a median of 5 cycles (range 3-9), HGSC patients received a median of 4 cycles (range 3-9). Interval cytoreductive surgery was performed in 29/36 (81%) of LGSC and 32/36 (89%) HGSC patients. Complete cytoreduction was reported and achieved in 11/29 (38%) of LGSC patients and 24/32 (75%) of HGSC patients (p = 0.002). Median pre- and post-treatment CA-125 levels for LGSC patients were 295.5 U/mL and 144 U/mL (52% decrease) (p < 0.001). The median pre- and post-treatment CA-125 levels for HGSC patients were 767.5 and 35.6 (96% decrease) (p < 0.001). For LGSC patients, 4/36 (11%) had partial response (PR), 30/36 (83%) had stable disease (SD), and 2/36 (6%) had progressive disease (PD). In HGSC patients, 27/36 (75%) had PR, and 9/36 (25%) SD. Median PFS for LGSC patients was 18.5 months and median OS was 47.4 months. CONCLUSIONS: This study provides further evidence of relative chemoresistance of LGSC in patients treated with NACT.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cystadenocarcinoma, Serous/drug therapy , Ovarian Neoplasms/drug therapy , Peritoneal Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Bridged-Ring Compounds/administration & dosage , CA-125 Antigen/metabolism , Cystadenocarcinoma, Serous/metabolism , Cystadenocarcinoma, Serous/pathology , Cystadenocarcinoma, Serous/surgery , Drug Resistance, Neoplasm , Female , Humans , Ki-67 Antigen/metabolism , Membrane Proteins/metabolism , Middle Aged , Neoadjuvant Therapy , Organoplatinum Compounds/administration & dosage , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Ovarian Neoplasms/surgery , Peritoneal Neoplasms/metabolism , Peritoneal Neoplasms/pathology , Peritoneal Neoplasms/surgery , Progression-Free Survival , Response Evaluation Criteria in Solid Tumors , Taxoids/administration & dosage , Young AdultABSTRACT
Although 70-80% of newly diagnosed ovarian cancer patients respond to first-line therapy, almost all relapse and five-year survival remains below 50%. One strategy to increase five-year survival is prolonging time to relapse by improving first-line therapy response. However, no biomarker today can accurately predict individual response to therapy. In this study, we present analytical and prospective clinical validation of a new test that utilizes primary patient tissue in 3D cell culture to make patient-specific response predictions prior to initiation of treatment in the clinic. Test results were generated within seven days of tissue receipt from newly diagnosed ovarian cancer patients obtained at standard surgical debulking or laparoscopic biopsy. Patients were followed for clinical response to chemotherapy. In a study population of 44, the 32 test-predicted Responders had a clinical response rate of 100% across both adjuvant and neoadjuvant treated populations with an overall prediction accuracy of 89% (39 of 44, p < 0.0001). The test also functioned as a prognostic readout with test-predicted Responders having a significantly increased progression-free survival compared to test-predicted Non-Responders, p = 0.01. This correlative accuracy establishes the test's potential to benefit ovarian cancer patients through accurate prediction of patient-specific response before treatment.
Subject(s)
Ovarian Neoplasms/diagnosis , Precision Medicine/methods , Prognosis , Spheroids, Cellular , Female , Humans , Middle Aged , Models, Biological , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Progression-Free Survival , Treatment Outcome , Tumor Cells, CulturedABSTRACT
OBJECTIVE: To determine the feasibility of pharmacologic beta-adrenergic blockade in women with newly diagnosed stage II-IV epithelial ovarian cancer (EOC) throughout primary treatment. METHODS: Patients initiated propranolol prior to beginning chemotherapy or surgery. Feasibility was assessed as proportion able to complete 6 chemotherapy cycles while on adrenergic suppression. Descriptive statistics summarized surveys, and paired changes were analyzed using signed rank tests. Random-intercept Tobit models examined immune response. RESULTS: Median age was 59.9; 88.5% were stage IIIC/IV; and 38.5% underwent primary debulking. Thirty-two patients were enrolled; 3 excluded because they never took propranolol; an additional 3 didn't meet inclusion criteria, leaving 26 evaluable. Eighteen of 26 (69%), 90% credible interval (CI) of 53-81%, completed 6 chemotherapy cycles plus propranolol (an 82% posterior probability that the true proportion of success is ≥60%). Among the 23 patients with baseline and six month follow up data, overall QOL, anxiety, and depression improved (Pâ¯<â¯0.05) and leukocyte expression of pro-inflammatory genes declined (Pâ¯=â¯0.03) after completion of therapy. Decrease from baseline of serum IL-6 and IL-8 preceded response to chemotherapy (Pâ¯<â¯0.0014). Change from baseline IL-10 preceded complete response. CONCLUSION: Use of propranolol during primary treatment of EOC is feasible and treatment resulted in decrease in markers of adrenergic stress response. In combination with chemotherapy, propranolol potentially results in improved QOL over baseline.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Ovarian Epithelial/drug therapy , Ovarian Neoplasms/drug therapy , Propranolol/administration & dosage , Adrenergic beta-Antagonists/administration & dosage , Aged , Carboplatin/administration & dosage , Carcinoma, Ovarian Epithelial/genetics , Carcinoma, Ovarian Epithelial/immunology , Carcinoma, Ovarian Epithelial/surgery , Chemotherapy, Adjuvant , Cytokines/blood , Cytokines/genetics , Cytokines/immunology , Feasibility Studies , Female , Gene Expression/drug effects , Gene Expression/immunology , Humans , Leukocytes/drug effects , Leukocytes/immunology , Longitudinal Studies , Middle Aged , Neoadjuvant Therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/immunology , Ovarian Neoplasms/surgery , Paclitaxel/administration & dosage , Pilot Projects , Prospective Studies , Quality of LifeABSTRACT
OBJECTIVE: To compare symptom burden and functional recovery in women undergoing primary cytoreductive surgery (PCS) or neoadjuvant chemotherapy (NACT) and interval cytoreductive surgery (ICS) within an enhanced recovery after surgery program (ERAS). METHODS: Symptom burden was measured using the MD Anderson Symptom Inventory-Ovarian Cancer, a 27-item validated tool that was administered preoperatively, daily while hospitalized, and weekly for 8â¯weeks after hospital discharge. Mixed-effect modeling was performed. RESULTS: 196 patients (71 PCS, 125 ICS) participated. Patients in the PCS group were younger, median age of 59 vs. 63 in ICS group. Median length of stay was 4â¯days for PCS and 3â¯days for ICS group. PCS pts had a significantly higher median surgical complexity score (4 vs. 2, pâ¯=â¯0.002), and longer median surgical time (257â¯min vs. 220â¯min, pâ¯=â¯0.03). While patients undergoing PCS had significantly different symptom burden profiles prior to surgery compared to those undergoing ICS, there were no significant differences in symptoms in the immediate in-hospital and extended post-hospital discharge period. Irrespective of the timing of surgery in relation to chemotherapy, patients undergoing intermediate or high complexity surgery had more nausea, fatigue, and higher total interference scores compared to patients undergoing low complexity surgery. CONCLUSION: Within a center with a standardized, systematic method for patient selection for PCS and a standardized ERAS care pathway, there were not significant differences in surgery-related symptoms related to recovery between patients undergoing PCS or ICS. However, patient-reported symptom burden and symptom interference did meaningfully differentiate based on surgical complexity score.
Subject(s)
Cytoreduction Surgical Procedures/methods , Gynecologic Surgical Procedures/methods , Ovarian Neoplasms/surgery , Adolescent , Adult , Aged , Aged, 80 and over , Chemotherapy, Adjuvant , Female , Humans , Middle Aged , Neoadjuvant Therapy , Ovarian Neoplasms/drug therapy , Patient Reported Outcome Measures , Perioperative Care/methods , Tumor Burden , Young AdultABSTRACT
OBJECTIVE: To estimate the effects of a laparoscopic scoring algorithm to triage patients with advanced ovarian cancer to immediate or delayed debulking to improve complete gross surgical resection rates and determine the resulting clinical outcomes. METHODS: We prospectively performed laparoscopic assessment on patients with suspected advanced-stage ovarian cancer from April 2013 to December 2016 to determine primary resectability at tumor reductive surgery. Patients with medically inoperable or distant metastatic disease received neoadjuvant chemotherapy. Two-surgeon scoring was performed in a blinded fashion using a validated scoring method. Patients with predictive index value scores less than 8 were offered primary surgery and those with scores 8 or greater received neoadjuvant chemotherapy. Univariate and multivariate analysis was performed for effects on progression-free survival. RESULTS: Six hundred twenty-one patients presenting with presumed advanced ovarian cancer were evaluated during the study period and 488 patients met inclusion criteria. Two hundred fifteen patients underwent laparoscopic scoring, of whom 125 had predictive index value scores less than 8 and 84 had predictive index value scores 8 or greater. Blinded two-surgeon predictive index value scoring resulted in bivariate discordance in only 2% of patients. Tumor cytoreduction led to no gross residual disease (R0 resection) in 88% of patients in the primary surgery group and 74% in the neoadjuvant chemotherapy group. Patients triaged to primary surgery had an improved progression-free survival of 21.4 months versus 12.9 months in those patients undergoing neoadjuvant chemotherapy (P<.001). Median progression-free survival by treatment group and residual disease status was as follows: primary surgery-R0 23.5 months; primary surgery-R1 (any gross residual disease) 17.6 months; neoadjuvant chemotherapy-R0 15.5 months; and neoadjuvant chemotherapy-R1 12.9 months (P<.001). On multivariate analysis for progression-free survival, baseline CA 125 (P=.001) and gross residual disease at tumor reductive surgery (P=.01) were significantly associated with progression-free survival. CONCLUSION: Laparoscopic triage assessment allowed for a personalized approach to the management of patients with advanced ovarian cancer and resulted in high complete surgical resection rates at tumor reductive surgery.
Subject(s)
Cytoreduction Surgical Procedures , Ovarian Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Algorithms , Female , Humans , Laparoscopy , Middle Aged , Prospective StudiesABSTRACT
OBJECTIVE: To investigate the effect of an enhanced recovery after surgery (ERAS) program on perioperative outcomes with an emphasis on opioid consumption and patient-reported outcomes in the immediate and extended postoperative periods. METHODS: We initiated our ERAS program as part of a quality improvement initiative in November 2014. We compared clinical outcomes among a cohort of 607 women undergoing open gynecologic surgery before or after implementation of ERAS. For 293 patients, patient-reported outcomes were compared using the MD Anderson Symptom Inventory-Ovarian Cancer. RESULTS: Median age was 58 years (range 18-85 years). Median length of stay decreased by 25% for patients in the ERAS pathway (P<.001). Overall, patients in the ERAS group had a 72% reduction in median opioid consumption and 16% were opioid-free during admission up to postoperative day 3 (P<.001). There was no difference in pain scores (P=.80). Patients on ERAS reported less fatigue (P=.01), interference with walking (P=.003), and total interference (composite score of physical and affective measures) during hospitalization (P=.008). After discharge, those on the ERAS pathway demonstrated a significantly shorter median time to return to no or mild fatigue (10 vs 30 days, P=.03), mild or no interference with walking (5 vs 13 days, P=.003), and mild to no total interference (3 vs 13 days, P=.02). There were no significant differences in complications, rates of readmission, or reoperation between the pre- and post-ERAS groups. CONCLUSION: Implementation of an ERAS program was associated with significantly decreased opioid use after surgery and improvement in key patient-reported outcomes associated with functional recovery after surgery without compromising pain scores.