Acute colonic pseudo-obstruction (ACPO), also known as Ogilvie's syndrome, is defined by poor peristaltic activity of the colon that mimics mechanical obstruction in the absence of any mechanical ...occlusive gut lesion. This case report is the first to be published on ACPO occurring after robotic-assisted radical hysterectomy. Given that robotic-assisted laparoscopic surgery has become the next major stage of advancement for a range of operations, especially in gynecologic oncology surgery, this report emphasizes the importance of recognizing precipitating factors associated with this syndrome, including minimally invasive surgery.
Purpose
Given the evidence that coordinate inhibition of AKT induces autophagy, we studied the combination of the AKT inhibitor, MK-2206 with hydroxychloroquine (HCQ) in patients with advanced solid ...tumors.
Methods
Patients were treated with weekly MK-2206 (135 mg or 200 mg) plus HCQ (200 mg, 400 mg or 600 mg BID).
Results
Thirty-five patients were enrolled across 5 dose levels. Two DLTs of grade 3 maculo-papular rash were observed at dose level 2 (MK-2206 200 mg weekly plus HCQ at 400 mg BID) and 1 DLT of grade 3 fatigue at dose level 2B (MK-2206 135 mg weekly plus HCQ 600 mg BID). The maximum tolerated dose (MTD) was declared as dose level 2B. The most common adverse events attributed to MK-2206 were hyperglycemia (
N
= 18; 51%), fatigue (
N
= 17; 49%), maculo-papular rash (
N
= 16; 46%), diarrhea (
N
= 12; 34%), anorexia (
N
= 11; 31%), and nausea (
N
= 11; 31%). Patients experiencing adverse events attributed to HCQ were small in number (
N
= 13) and primarily included fatigue (
N
= 5; 14%) and maculo-papular rashes (
N
= 3; 9%). Statistically significant effects on the pharmacokinetic properties of MK-2206 were observed in combination with HCQ. In addition, the plasma concentrations of HCQ in the combination with MK-2206 were significantly higher than the plasma levels of HCQ as monotherapy in prior studies. The best overall response of stable disease was observed in 5/34 (15%) patients.
Conclusion
The combination of MK-2206 and hydroxychloroquine was tolerable, but with substantial number of drug-related AEs and minimal evidence of antitumor activity.
Summary
Background
AT-101 is a BH3 mimetic that inhibits the heterodimerization of Bcl-2, Bcl-xL, Bcl-W, and Mcl-1 with pro-apoptotic proteins, thereby lowering the threshold for apoptosis. This ...phase I trial investigated the MTD of AT-101 in combination with paclitaxel and carboplatin in patients with advanced solid tumors.
Methods
Patients were treated with AT-101 (40 mg) every 12 h on days 1, 2 and 3 of each cycle combined with varying dose levels (DL) of paclitaxel and carboplatin DL1: paclitaxel (150 mg/m
2
) and carboplatin (AUC 5) on day 1 of each cycle; DL2: paclitaxel (175 mg/m
2
) and carboplatin (AUC 6) on day 1 of each cycle. Secondary objectives included characterizing toxicity, efficacy, pharmacokinetics, and pharmacodynamics of the combination.
Results
Twenty-four patients were treated across two DLs with a planned expansion cohort. The most common tumor type was prostate (
N
= 11). Two patients experienced DLTs: grade 3 abdominal pain at DL1 and grade 3 ALT increase at DL2; however, the MTD was not determined. Moderate hematologic toxicity was observed. One CR was seen in a patient with esophageal cancer and 4 patients achieved PRs (1 NSCLC, 3 prostate). PD studies did not yield statistically significant decreases in Bcl-2 and caspase 3 protein levels, or increased apoptotic activity induced by AT-101.
Conclusion
The combination of AT-101 at 40 mg every 12 h on days 1, 2 and 3 combined with paclitaxel and carboplatin was safe and tolerable. Based on the modest clinical efficacy seen in this trial, this combination will not be further investigated. Clinical Trial Registration: NCT00891072, CTEP#: 8016.
Abstract
PURPOSE: The effectiveness of standard-of-care platinum-taxane chemotherapy in the treatment of patients with advanced gynecologic cancers is limited by the development of chemotherapy ...resistance in nearly all patients. Based on our preclinical findings that selenium, an essential trace element, inhibits the development of carboplatin drug resistance in an ovarian cancer mouse model, a phase I trial of a combination of selenious acid/carboplatin/paclitaxel was designed to determine the maximum tolerated dose (MTD) and safety of selenium administered with chemotherapy in chemo-naïve women with gynecologic cancers. In addition, the effects of selenium on carboplatin pharmacokinetics were evaluated in this group of patients, and correlative studies were performed to identify potential gene targets of selenium.
METHODS: Patients with gynecologic malignancy not previously treated with chemotherapy received 50-5000 µg elemental selenium IV in the form of selenious acid on day 1 followed by carboplatin (cycle 1, AUC 5; subsequent cycles, AUC 6) IV and paclitaxel 175mg/m2 IV on day 3. A standard 3+3 trial design was used in the selenium dose escalation phase. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed. RNA expression in tumor specimens and breast and ovarian cancer cell lines were compared before and after treatment with selenium plus chemotherapy using the Human Exon 1.0 ST exon microarray platform. In addition, Western immunoblotting was performed to evaluate protein expression of RAD51AP1, a protein involved in DNA repair, in untreated MCF-7/Adr cells and MCF-7/Adr cells treated with selenium, carboplatin, and the combination of selenium and chemotherapy.
RESULTS: Forty-five patients were enrolled and a total of 291 treatment cycles were administered. Grade 3/4 toxicities included neutropenia (66.6%), febrile neutropenia (2.2%), as well as pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The MTD of elemental selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. In the subset of patients with stage III/IV ovarian cancer/fallopian tube/peritoneal cancer, median progression-free survival was 15 months; in those patients within this subset with measurable disease, 30%, 35%, and 23% experienced complete response, partial response, and stable disease, respectively. Correlative studies showed downregulation of RAD51AP1 by selenium plus chemotherapy in cancer cell lines as well as in tumors of patients treated within this clinical trial.
CONCLUSION: Selenium in combination with carboplatin and paclitaxel is safe and does not affect carboplatin pharmacokinetics. It is possible that selenium-mediated downregulation of RAD51AP1 plays a role in circumventing the development of resistance to carboplatin/paclitaxel chemotherapy. A phase II study to further investigate these findings is underway.
Citation Format: Mihae Song, Muthu N. Kumaran, Murugesan Gounder, Darlene Gibbon, Wilberto Nieves-Neira, Ami Vaidya, Mira Hellman, Michael P. Kane, Brian Buckley, Lorna Rodriguez-Rust. Phase I trial of selenium plus chemotherapy in gynecologic cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT025.
Gynecologic oncology patients represent a distinct patient population with a variety of surgical risks. The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) ...database provides an opportunity to analyze large cohorts of patients over extended periods with high accuracy. Our goal was to develop a postoperative risk assessment calculator capable of providing a standardized, objective means of preoperatively identifying high-risk patients in the gynecologic oncology population.
We queried the ACS NSQIP database for gynecologic oncology patients from 2005 to 2013. Multivariate logistic regression was performed to generate predictive models specific for 30-day postoperative mortality and major morbidity.
There were 12,831 patients with a primary gynecologic malignancy identified: 7847 uterine, 3366 adnexal, 1051 cervical, and 567 perineum cancers. In this cohort, 125 (0.97%) patients died, and 784 (6.11%) major morbidity events were recorded within 30 days of their surgery. For 30-day mortality, the mean calculated predictive probability was 0.128 (SD, 0.219) compared with 0.009 (SD, 0.027) in patients alive 30 days postoperatively (P < 0.0001). The mean predictive probability of major morbidity was 0.097 (SD, 0.095) compared with 0.059 (SD, 0.043) in patients who did not experience major morbidity 30 days postoperatively (P < 0.0001).
Using NSQIP data, these predictive models will help to determine patients at risk for 30-day mortality and major morbidity. Further clinical validation of these models is required.
Abstract Objective To determine the feasibility and clinical utility of using comprehensive genomic profiling (CGP) in the course of clinical care to identify clinically relevant tumor genomic ...alterations for patients with either rare or refractory gynecologic cancers to facilitate point-of-care management. Use of an expert, multidisciplinary, institutional molecular tumor board (MTB) assessment is discussed regarding input on putative targeted options for individualized therapy. Methods A prospective clinical trial is ongoing. We report on the initial 69 patients with gynecologic cancers that were either rare or refractory to standard therapy. CGP was performed by Foundation Medicine, Inc. Genomic alterations were reviewed by members of an MTB. Consensus recommendations on genomically targeted, FDA-approved, on- and off-label therapies and clinical trials were sent to the treating physician, and decisions and outcomes were assessed. Results Study outcomes were available for 64 patients. The mean number of genes altered per tumor was 4.97 (median = 4; range, 1–26), and the average turnaround time from testing laboratory report to generation of formal recommendations was approximately three weeks. Evaluation of genomic and clinical data by the MTB led to generation of targeted treatment options in all 64 patients, and the percentage of patients for whom one or more of these recommendations were implemented by the treating physician was 39%. Sixty-four percent of the patients receiving targeted therapy based on a CGP result experienced radiologic response or showed evidence of clinical benefit or stable disease. Conclusion These data suggest that an institutional MTB is a feasible venue for reviewing tumor genomic profiling results and generating clinical recommendations. These data also support the need for further studies and guidelines on clinical decision making with greater availability of broad genomically based diagnostics.
Abstract
INTRODUCTION: Gynecologic cancers were estimated to occur in 98,280 women in 2015 in the United States and result in 30,440 deaths (Siegel 2015). The most common forms of gynecologic cancers ...occur in the ovary and uterine corpus (Siegel, 2015). Various reasons for poor outcome in these cancers include the late stage of the disease at the time of diagnosis and therapy resistance. We sought to elucidate alternate treatment avenues based on the genomic profiles of recalcitrant or rare gynecologic tumors. In the process, we aim to determine both the clinical utility and the feasibility of using comprehensive genomic profiling (CGP) during clinical care to identify clinically relevant tumor genomic alterations for these patients while enabling point-of-care management.
METHODS: As part of our ongoing prospective clinical trial, we report on the initial 69 patients with gynecologic cancers that were refractory to standard therapy. CGP was performed by Foundation Medicine, Inc. Genomic mutations and alterations were reviewed by members of an expert, multidisciplinary institutional molecular tumor board (MTB). Consensus recommendations by the MTB were provided to the treating physician on genomically targeted, clinically relevant, FDA-approved, on- and off-label therapies and clinical trials. The outcomes were assessed.
RESULTS: Study outcomes were available for 64 patients. On average, patients had 4.97 genomic alterations per tumor (range 1-46), while the time from the testing laboratory report to the formulation of recommendations by the MTB was approximately 3-4 weeks. Targeted
treatment options were recommended by the MTB for 93% of patients; 39% of these patients had the MTB-based recommendations implemented by the treating physician. A response or clinical benefit was seen in 56% of the patients receiving MTB-based targeted therapy.
CONCLUSION: These data suggest that alternatives to standard therapies for recalcitrant gynecologic cancers can be found though CGP and subsequent analysis from members of an expert, multidisciplinary institutional MTB. The formulation of clinical recommendations by an MTB based on tumor genomic profiling results is a feasible option. Further research is needed to understand how this approach shapes clinical decision making.
Citation Format: Lorna Rodriguez-Rodriguez, Kim M. Hirshfield, Veronica Rojas, Siraj Ali, Robert S. DiPaola, Darlene Gibbon, Sara Isani, Aliza Leiser, Gregory M. Riedlinger, Shridar Ganesan. Delivery of point-of-care management to patients with gynecologic malignancies using comprehensive genomic profiling. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3183.
Abstract
Objective: The development of drug resistance is a major cause of gynecologic cancer deaths. Selenium (Se) inhibits the development of carboplatin (C) drug resistance in a mouse ovarian ...cancer xenograft model. Based on this data, a Phase I trial of a combination of Se, (C) and paclitaxel (P) was designed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, and effects of Se in (C) pharmacokinetics (PK) in the treatment of chemo-naive women with gynecologic cancers. Correlative studies identified Se gene targets responsible for reversal of drug resistance.
Methods: Se (50-5000 mcg) IV was given on day 1, and (C) (AUC 5 in cycle 1, AUC 6 in subsequent cycles) IV and (P) 175mg/m2 IV on day 3. A standard 3 + 3 design was used in the selenium dose escalation phase. (C) and Se concentrations in plasma and ultrafiltrate were analyzed.
Results: 45 patients were enrolled. Worst grade toxicities from 291 cycles included neutropenia (Gr 3, n=24; Gr 4, n=19), febrile neutropenia (Gr 3, n=2), anemia (Gr 3, n=1), constitutional (Gr 3, n=3), gastrointestinal (Gr 3, n=5), neurolgic (Gr 3, n=6), pain (Gr 3, n=12), and pulmonary (Gr 3, n= 5). DLT was not reached but IV site pain was recorded at selenium doses higher than 2000 mcg. GFR did not change with Se treatment. Se also had no effect on (C) pharmacokinetics. The average observed AUC was the same as target AUC in each cycle. Between cycle 1 and cycle 2, the estimated PK parameters, clearance (138 vs 133 ml/min) and half-life (312 vs 305 min), were not significantly different. Plasma Se AUC showed dose proportionate increase at higher doses. Of 38 patients with ovarian cancer, there were 9 complete response, 8 partial response, 6 stable disease and 12 disease progression. The median progression-free survival from these 38 patients was 35 months. 33/45 pts had elevated serum CA125 at initiation of therapy. 21/33 had normalization of CA125 after cycle 2 (n=14), and after cycle 6 (n= 7). RNA expression of the tumors as well as cell lines was measured and compared before and after selenium treatment. The samples were run on the Human Exon 1.0 ST exon microarray platform. The results of this analysis pointed to Rad51-AP1 as a gene that is downregulated by selenium. Validation experiments done in vitro confirmed that treatment with Se decreased Rad51-AP1 protein levels, and the cells become more sensitive to (C). Also, cells treated with increasing amounts of (C) showed increased levels of Rad51-AP1.
Conclusion: Se in combination with (C) and (P) is safe, well tolerated and does not affect (C) pharmacokinetics. Although selenium DLT was not reached, at the dose of 5000 mcg, the patients needed central lines for selenium infusion, secondarily to IV site pain. Responses and protracted stable disease are noted in patients with gynecologic cancers. Downregulation of Rad51-AP1, a protein involved in DNA repair, may counteract the development of platinum based drug resistance by selenium.
Citation Format: Lorna Rodriguez-Rodriguez, Mihae Song, Neelakandan Muthukumaran, Murugesan Gounder, Darlene Gibbon, Wilberto Nieves-Neira, Ami Vaidya, Mira Hellmann, Susan Goodin, Brian Buckley. Selenium counteracts carboplatin drug resistance through Rad51-AP1 induction: A phase I trial in women with gynecologic cancers. abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT219. doi:10.1158/1538-7445.AM2014-CT219
PDF
