Plasma pharmacokinetics and cerebrospinal fluid concentrations of erlotinib in high-grade gliomas: A novel, phase I, dose escalation study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2054-2054 ◽  
Author(s):  
L. W. Buie ◽  
C. Lindley ◽  
T. Shih ◽  
M. Ewend ◽  
J. K. Smith ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Partial Response ◽  
Disease Progression ◽  
Dose Escalation ◽  
Stable Disease ◽  
Peak Plasma ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Plasma Concentrations ◽  
High Grade

2054 Background: Erlotinib (ERL) is an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. EGFR is overexpressed in glioblastoma multiforme (GBM). The primary objectives of this study were to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and to evaluate plasma and cerebrospinal fluid (CSF) ERL concentrations using a novel every 72 hour ERL dosing schedule. Methods: Patients = 18 years of age with GBM or high grade glioma with evidence of disease progression following first line therapy (surgery/XRT/chemotherapy) and Karnofsky performance status = 60 % were included. Patients were stratified based on use of enzyme-inducing antiepileptic drugs (EIAED). Patients not on EIAED were initiated on ERL 450 mg PO every 72h, while those on EIAED were initiated on 900 mg PO every 72 h. Results: Six patients have been enrolled and assessed for safety, 5 for plasma PK and 3 for CSF concentrations. For ERL, the area under the plasma concentration versus time curve (AUC) was greater and the half-life longer in patients not receiving EIAED. However, the AUC of OSI-420, the major metabolite of ERL, was lower in patients not receiving EIAED. The OSI-420 AUC: ERL AUC ratio was increased 3 fold among patients receiving EIAED, indicative of increased hepatic metabolism and increased clearance. CSF concentrations were detectable and ranged from 1 to 3% of peak plasma concentrations. Neither group has experienced a DLT or reached the MTD. The most common side effects (grade 1/2) have been diarrhea (83%), rash (100%) and fatigue (33%). To date, there has been 1 partial response, 1 patient with stable disease and 4 patients with disease progression. The partial response and stable disease have occurred in patients with GBM. Conclusions: ERL is a well tolerated therapy. Patient enrollment and subsequent dose escalation is ongoing and updated results will be presented at the ASCO 2007 meeting. [Table: see text] No significant financial relationships to disclose.

Oblimersen (OBL; Genasense®), a Phosphorothioate (PS) Bcl-2 Antisense Oliogonucleotide (ASO), Can Be Safely Administered by Bolus Subcutaneous (SC) Injection and Brief IV Infusion.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4724-4724
Author(s):  
Anthony Tolcher ◽  
Thomas Julian ◽  
Anila Qureshi
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Complement Activation ◽  
Peak Plasma ◽  
Performance Status ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Lymphocytic Leukemia ◽  
Cytotoxic Drugs ◽  
Dose Proportional

Abstract Background: Oblimersen (OBL) is an 18-mer PS-ASO that down-regulates Bcl-2 and amplifies the activity of cytotoxic drugs in patients (pts) with chronic lymphocytic leukemia (CLL), non-Hodgkin’s lymphoma (NHL), and melanoma. PS-ASOs like OBL are commonly administered by continuous intravenous infusion (CIV) in order to avoid high peak plasma concentrations that have been associated with cardiovascular collapse, complement activation, and death in primates. However, we consistently observed no such reactions in patients who received inadvertent overdoses of OBL. Furthermore, preclinical studies in xenograft tumors in mice indicated that intratumoral uptake and retention of OBL was enhanced with short IV infusion. Given the inconvenience of CIV and based on recent preclinical data, we evaluated the safety and pharmacokinetics (PK) of OBL administered as weekly subcutaneous (SC) injection, a brief 2-hr IV infusion for 5 days, and a weekly 2-hr infusion. Methods: Eligible pts had: advanced solid tumors; no available standard therapy; adequate organ function; and ECOG performance status of 0 to 2. In the SC study, single doses of 75, 150, and 225 mg were given to 8 pts, followed by a multiple dose study at 150 mg, 225 mg, and 300 mg. Pts received OBL by 2-hr IV infusion once weekly for 3 weeks (Days 1, 8, 15) starting at a dose of 300 mg and increasing in increments of 100 mg to the maximum tolerated dose (MTD). Blood samples were obtained for complement, Bcl-2, and PK analyses. Dose escalation utilized an accelerated dose escalation schedule. Results: Single pt cohorts were treated at each 2-hr dose level ranging from 300 to 800 mg. Syncope occurred in 1 pt treated with 900 mg, but treatment of 2 additional pts at this dose was uneventful. At the 1000 mg dose level, all pts experienced fever, chills, and moderate decreases in blood pressure, generally limited to the first infusion, which were not felt to be dose-limiting. The PK were dose-proportional over the 300 to 900 mg dose range. AUC and Cmax levels nearly were dose-proportional, and dose-normalized AUC and Cmax values were constant. Cmax values at 900 mg were > 50 μg/mL, and exceeded by >10-fold the Css of CIV schedules in solid tumor pts. There was no change in metabolism or plasma clearance with increasing doses. Large inter-patient variability was observed; however, intra-patient variability was low, as indicated by a coefficient of variation of < 20% for Cmax values obtained on Days 1, 8, and 15. No consistent pattern in complement activation was observed. One patient with metastatic NSCLC remains on study at 14 weeks with a 10% reduction in tumor size. OBL given by SC injection was associated with a Grade 1 erythematous rash at the injection site in all pts, which resolved within 7 days. AUC0–24 exposure at the 225-mg SC dose was similar to previously established 24-h steady-state AUCs after 3 mg/kg by CIV infusion. Conclusions: OBL AUC exposure from a single SC injection is similar to that observed using the 3mg/kg daily dose level administered by CIV to pts with CLL. OBL can also be administered safely by 2-hr IV infusion at weekly doses up to 1,000 mg. Corticosteroids are being tested to evaluate whether constitutional reactions can be ameliorated, and then a twice-per-week schedule will be designed to examine OBL-induced down-regulation of Bcl-2 alone and in combination with cytotoxic drugs in specific diseases.

A Dose Escalation Study of RP6530, a Novel Dual PI3K Delta/Gamma Inhibitor, in Patients with Relapsed/Refractory Hematologic Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1495-1495 ◽  
Author(s):  
Carmelo Carlo-Stella ◽  
Richard Delarue ◽  
Prajak J Barde ◽  
Lydia Scarfo ◽  
Thamila Saheb ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Escalation ◽  
Research Funding ◽  
Performance Status ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Hematologic Malignancies ◽  
Prognostic Scores ◽  
Dose Escalation Study ◽  
Human Dose

Abstract Introduction: Phosphoinositide-3-kinases (PI3Ks) are pivotal in cell proliferation and survival, cell differentiation, intracellular trafficking and immunity. The delta (δ) and gamma (γ) isoforms of PI3K are often dysregulated in various hematologic malignancies and therefore key targets for the treatment of lymphomas/ leukemia. RP6530 is a novel, highly specific dual PI3K δ/γ inhibitor with nanomolar inhibitory potency that effectively inhibits AKT phosphorylation and induces apoptosis in lymphoma/leukemic cell lines. We herein present results from an ongoing Phase I, first-in-human, dose escalation study of RP6530 (NCT02017613). Methods: The dose escalation will determine the maximum tolerated dose (MTD) of RP6530 using a standard 3+3 design. Patients (pts) with a confirmed diagnosis of hematological malignancy and at least one prior therapy are eligible. Additional eligibility criteria include an ECOG performance status ≤ 2, measurable/evaluable disease, and life expectancy of at least 12 weeks. Primary endpoints are safety and pharmacokinetic (PK) and are supported by secondary endpoints such as pharmacodynamic and efficacy parameters (overall and complete response rates) and correlative biomarkers. RP6530 is given orally twice daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal from study. The study is designed to enroll up to 120 pts in the dose-escalation and expansion phase. Adverse events (AE) are assessed using the CTCAE v4.0/IWCLL guidelines as applicable. Efficacy evaluations are conducted every 8 wks. Results: Twenty six pts were enrolled to date across various dose levels: BID 25mg, 50mg, 100mg, 200mg, 400mg, 600mg and 800mg. Sixteen were males; ECOG score was 0/1/2 in 20/3/3 pts, respectively, with a mean age of 59 yrs (range 20-83). Pts had a median of 5 (range: 1-11) prior treatment regimens, and 19 were refractory to prior treatments. Malignancy categories included HL (9), TCL (4), DLBCL (4), MCL (3), CLL/SLL (2), FL (1), MZL (1), WM (1), and MM (1). Majority of them were considered as "high tumor burden patients" as per different prognostic scores. Sixteen patients were discontinued mainly due to disease progression. RP6530 was well tolerated with no DLT reported to date. Majority of AEs were mild and resolved with/without concomitant medication. None of Grade III/IV AEs or SAEs were deemed related to RP6530. No drug related increase in ALT/AST, colitis, pneumonia, or neutropenia was observed to date. Dose escalation is currently ongoing at 800 mg BID. Single agent activity, manifested by a reduction in tumor size by CT or PET scan, was noticed at ≥ 200 mg BID. The efficacy observations are mostly in indications, that are difficult-to-treat or with minimal therapeutic options. The ORR is 20 % [CR 2 (10 %) + PR 2 (10%)] with disease control rate of 65%. The responders are HL (2), PTCL (1) and DLBCL (1). The CLL/SLL patients, known to be the best responders to selective PI3K inhibitors, were not included in dose-cohorts ≥ 200 mg BID. Clinical response was associated with a significant reduction in pAKT expression. Dose-proportional increase in plasma concentrations were observed upon oral administration of RP6530. Conclusions: To date, RP6530 has been well tolerated in pts with heavily pre-treated relapsed/refractory hematologic malignancies. Reported toxicities were manageable with no DLTs. Single agent activity was evident in difficult-to-treat patients at ≥ 200 mg BID. Enrolment continues at higher dose cohorts. Updated safety, efficacy, PK, and PD data will be presented at the annual meeting. Disclosures Barde: Rhizen Pharmaceuticals SA: Employment. Kumar:Rhizen Pharmaceuticals SA: Employment. Viswanadha:Incozen: Employment. Vakkalanka:Rhizen Pharmaceuticals SA: Employment, Equity Ownership. Ghia:Adaptive: Consultancy; GSK: Research Funding; Acerta Pharma BV: Research Funding; Roche: Consultancy, Research Funding; Pharmacyclics: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau.

NCOG-18. RELATIONSHIP BETWEEN RANO-PRO WORKING GROUP STANDARDIZED PRIORITY CONSTRUCTS AND DISEASE PROGRESSION AMONG MALIGNANT GLIOMA PATIENTS AS MEASURED THROUGH CLINICAL OUTCOMES ASSESSMENTS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi155-vi156
Author(s):  
Elizabeth Vera ◽  
Tito Mendoza ◽  
Alvina Acquaye ◽  
Nicole Briceno ◽  
Anna Choi ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Disease Progression ◽  
Clinical Outcomes ◽  
Stable Disease ◽  
Working Group ◽  
Karnofsky Performance Status ◽  
Clinical Care ◽  
Self Care ◽  
Work Activity ◽  
Core Symptoms

Abstract Recognizing the importance of clinical outcomes assessments (COA), the RANO-PRO Working Group recommends inclusion of core symptoms/functions in clinical care/research for malignant glioma patients. This study evaluated the association between the recommended symptoms (pain, perceived cognition, seizures, aphasia, treatment-specific symptoms) and functions (physical: weakness, walking; and role/social: work, usual activities) and disease progression in these patients. MDASI-Brain Tumor and EQ-5D-3L scores, Karnofsky Performance Status (KPS), and Neurologic Function Score (NFS) were evaluated in relation to disease progression by chi-square tests, independent- and paired-samples t-tests, adjusted for multiple comparisons. Our sample included 336 patients with malignant glioma; 82% white, 64% male, median age=52 (21-79). Imaging study revealed disease progression for 46% of patients. All symptoms except seizures and difficulty concentrating were worse in the group whose imaging showed disease progression versus stable disease, as well as the functions of walking, work, activity, and self-care (0.8 &lt; difference &lt; 1.8). Patients with disease progression were 4 times more likely to have a poor KPS (≤ 80) and worse NFS. Among patients with disease progression (n=112), all symptoms, except seizures, worsened from first assessment to time of progression. Up to 22% of patients reported worsening mobility, self-care, and usual activity; 46% and 35% had worsened KPS and NFS, respectively. Seven symptoms and functions were each individually reported by at least 10% of patients as having worsened the most. Worsening of symptoms and functions was not observed among patients with stable disease, except in difficulty understanding. Identified core symptoms/functions worsen at the time of progression demonstrating the relationship between priority constructs and a traditional tumor response measure while highlighting the importance of longitudinal collection of COA. The pattern of worsening was observed via both patient- and clinician-reported outcomes, emphasizing the utility of COA in clinical care and clinical trials.

Anlotinib alone or in combination with temozolomide in recurrent high-grade glioma: A retrospective study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14019-e14019
Author(s):  
Qun-ying Yang ◽  
Cheng-Cheng Guo ◽  
Zhenqiang He ◽  
Fuhua Lin ◽  
Ji Zhang ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Initial Dose ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Objective Response ◽  
High Grade Glioma ◽  
Combination Regimen ◽  
High Grade ◽  
Multikinase Inhibitor ◽  
Rano Criteria

e14019 Background: High-grade glioma (HGG) is the most common malignant brain tumor and lacks effective treatment regimen. Anlotinib is a multikinase inhibitor blocking angiogenesis and tumor cell proliferation simultaneously. This study was performed to evaluate the efficacy and safety of anlotinib alone or in combination with temozolomide (TMZ) in the treatment of recurrent HGG. Methods: This is a single-center, retrospective study. Eligible patients (pts) were diagnosed with pathologically confirmed high grades (WHO III/IV) glioma and had recurrent or progressive disease on or after prior treatment. Other key eligibility criteria included Karnofsky Performance Status (KPS) ≥ 40, aged 16 ̃75 years and having at least one measurable lesion (RANO criteria). Pts were administrated with anlotinib once daily for 14 days every 3 weeks till disease progression, intolerable toxicities or death. The initial dose was 12mg for younger pts ( < 40 years old) with KPS ≥ 60 and 10 mg for others. Combination treatment was allowed if previous TMZ was effective and tolerable. TMZ was administered on dose-dense schedule (150mg/m2, QD, d1-d7 and d15-d21 every 28 days) or metronomic schedule (25-50mg/m2 QD). The primary endpoint was progression-free survival at 6 months (PFS6m) accessed according to RANO criteria. The second endpoints included overall survival (OS), objective response rate (ORR) and disease control rate (DCR). Results: Between August 2019 and June 2020, 23 pts with HGG (15 grade IV; 8 grade III; 12 males, 11 females) were enrolled. The median age and median KPS was 42 years and 60. 16 pts have multifocal or disseminated disease. 18 pts received ≥2 lines previous treatment. At the data cutoff date on September 2020, the median duration of treatment was 9 weeks (range: 3-33). The PFS6m was 39.1% and the median PFS was 4.2 months (95% CI: 2.8, 5.6). The median OS was not reached (95% CI: NE, NE) and the OS at 12 months (OS12m) was 54.8%. 8 pts observed tumor response and 9 pts had stable disease. The ORR and DCR were 34.8% and 73.9% respectively. The results of survival analysis for subgroups were summarized in table below. Grade 1 or 2 treatment-related adverse events (TRAEs) occurred in 65.2% pts. No ≥ grade 3 TRAE was found. All hematological TRAEs occurred in patients received combination regimen. No TRAE-induced treatment termination occurred. The lower incidence of TRAE may partly attributed to that most pts (18/23) received lower initial dose (10mg) of anlotinib and the relatively shorter treatment duration. Conclusions: This study showed treatment with anlotinib alone or in combination with TMZ had promising efficacy and favorable tolerability in patients with recurrent HGG.[Table: see text]

Phase I and Pharmacokinetic Study of Farnesyl Protein Transferase Inhibitor R115777 in Advanced Cancer

2000 ◽  
Vol 18 (4) ◽  
pp. 927-927 ◽  
Author(s):  
J. Zujewski ◽  
I.D. Horak ◽  
C.J. Bol ◽  
R. Woestenborghs ◽  
C. Bowden ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Performance Status ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Oral Drug ◽  
Total Daily Dose ◽  
Pharmacokinetic Data ◽  
Metastatic Colon Cancer ◽  
Phase Ii Trials ◽  
Farnesyl Protein Transferase

PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of the farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks. PATIENTS AND METHODS: Twenty-seven patients with a median age of 58 years received 85 cycles of R115777 using an intrapatient and interpatient dose escalation schema. Drug was administered orally at escalating doses as a solution (25 to 850 mg bid) or as pellet capsules (500 to 1300 mg bid). Pharmacokinetics were assessed after the first dose and the last dose administered during cycle 1. RESULTS: Dose-limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 fatigue (decrease in two performance status levels) was seen in four of six patients treated with 1,300 mg bid. The most frequent clinical grade 2 or 3 adverse events in any cycle included nausea, vomiting, headache, fatigue, anemia, and hypotension. Myelosuppression was mild and infrequent. Peak plasma concentrations of R115777 were achieved within 0.5 to 4 hours after oral drug administration. The elimination of R115777 from plasma was biphasic, with sequential half-lives of about 5 hours and 16 hours. There was little drug accumulation after bid dosing, and steady-state concentrations were achieved within 2 to 3 days. The pharmacokinetics were dose proportional in the 25 to 325 mg/dose range for the oral solution. Urinary excretion of unchanged R115777 was less than 0.1% of the oral dose. One patient with metastatic colon cancer treated at the 500-mg bid dose had a 46% decrease in carcinoembryonic antigen levels, improvement in cough, and radiographically stable disease for 5 months. CONCLUSION: R115777 is bioavailable after oral administration and has an acceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1,000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous dosing and studies of R115777 in combination with chemotherapy are ongoing.

Phase I evaluation of a water-soluble etoposide prodrug, etoposide phosphate, given as a 5-minute infusion on days 1, 3, and 5 in patients with solid tumors.

1994 ◽  
Vol 12 (9) ◽  
pp. 1902-1909 ◽  
Author(s):  
D R Budman ◽  
L N Igwemezie ◽  
S Kaul ◽  
J Behr ◽  
S Lichtman ◽  
...  
Keyword(s):  
High Performance ◽  
Peak Plasma ◽  
Performance Status ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Water Soluble ◽  
High Dose ◽  
Maximum Plasma ◽  
Rapid Infusion ◽  
Etoposide Phosphate

PURPOSE To determine the toxicities, maximum-tolerated dose (MTD), and pharmacology of etoposide phosphate, a water-soluble etoposide derivative, administered as a 5-minute intravenous infusion on a schedule of days 1, 3, and 5 repeated every 21 days. PATIENTS AND METHODS Thirty-six solid tumor patients with a mean age of 63 years, performance status of 0 to 1, WBC count > or = 4,000/microL, and platelet count > or = 100,000/microL, with normal hepatic and renal function were studied. Doses evaluated in etoposide equivalents were 50, 75, 100, 125, 150, 175, and 200 mg/m2/d. Etoposide in plasma and urine and etoposide phosphate in plasma were measured by high-performance liquid chromatography (HPLC). Eleven of 36 patients were treated with concentrated etoposide phosphate at 150 mg/m2/d. RESULTS Grade I/II nausea, vomiting, alopecia, and fatigue were common. Leukopenia (mainly neutropenia) occurred at doses greater than 75 mg/m2, with the nadir occurring between days 15 and 19 posttreatment. All effects were reversible. Hypotension, bronchospasm, and allergic reactions were not observed in the first 25 patients. The MTD due to leukopenia was determined to be between 175 and 200 mg/m2/d. In 11 patients treated with concentrated etoposide phosphate, no local phlebitis was noted, but two patients did develop allergic phenomena. The conversion of etoposide phosphate to etoposide was not saturated in the dosages studied. Etoposide phosphate had peak plasma concentrations at 5 minutes, with a terminal half-life (t1/2) of 7 minutes. Etoposide reached peak concentrations at 7 to 8 minutes, with a t1/2 of 6 to 9 hours. Both etoposide phosphate and etoposide demonstrated dose-related linear increases in maximum plasma concentration (Cmax) and area under the curve (AUC). CONCLUSION Etoposide phosphate displays excellent patient tolerance in conventional dosages when administered as a 5-minute intravenous bolus. The suggested phase II dose is 150 mg/m2 on days 1, 3, and 5. The ability to administer etoposide phosphate as a concentrated, rapid infusion may prove of value both in the outpatient clinic and in high-dose regimens.

Gemcitabine as a Single Agent in the Treatment of Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma

1999 ◽  
Vol 17 (12) ◽  
pp. 3786-3792 ◽  
Author(s):  
A. Fosså ◽  
A. Santoro ◽  
W. Hiddemann ◽  
L. Truemper ◽  
N. Niederle ◽  
...  
Keyword(s):  
Partial Response ◽  
Confidence Interval ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Single Agent ◽  
World Health ◽  
Hematologic Toxicity ◽  
Grade 3 ◽  
Health Organization ◽  
Hodgkin's Lymphomas

PURPOSE: A multicenter phase II trial was conducted to evaluate the efficacy and toxicity of gemcitabine in patients with relapsed or refractory aggressive non-Hodgkin's lymphomas (NHL). PATIENTS AND METHODS: Thirty-one patients with B-cell intermediate or high-grade NHL (Working Formulation) were enrolled onto the study. The median age was 61 years, with a Karnofsky performance status of ≤ 80% in 65% of patients. Forty-eight percent had stage III or IV (Ann Arbor Classification) at study entry. Pretreatment consisted of one, two, or three chemotherapeutic regimens in nine, 11, and 11 patients, respectively. Gemcitabine 1,250 mg/m2 was administered intravenously over 30 minutes on days 1, 8, and 15 of a 28-day schedule. RESULTS: Thirty patients were assessable for efficacy, and 31 were assessable for toxicity. No complete responses were observed, but six patients showed a partial response, 11 stable disease, and 13 progressive disease. The overall response rate was 20% (95% confidence interval, 8% to 39%) for assessable patients and 19% (95% confidence interval, 8% to 34%) for the intent-to-treat analysis. The median duration of partial response was 6 months (range, 3.7 to 15+ months). Nonhematologic World Health Organization grade 3 toxicity included hepatic toxicity in four patients and infection in two. Hematologic toxicity was observed as grade 3 anemia in three patients, grade 3 leukopenia in two patients, grade 3/4 neutropenia in two patients, and grade 3/4 thrombocytopenia in six patients. CONCLUSION: The present schedule of gemcitabine displays modest efficacy and mild toxicity in pretreated aggressive NHL.

scholarly journals Navigated Intraoperative 2-Dimensional Ultrasound in High-Grade Glioma Surgery: Impact on Extent of Resection and Patient Outcome

2019 ◽  
Author(s):  
Alessandro Moiraghi ◽  
Francesco Prada ◽  
Alberto Delaidelli ◽  
Ramona Guatta ◽  
Adrien May ◽  
...  
Keyword(s):  
Real Time ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Intraoperative Ultrasound ◽  
High Grade Glioma ◽  
Extent Of Resection ◽  
High Grade ◽  
Glioma Surgery ◽  
Supratentorial Gliomas ◽  
The Impact

Abstract BACKGROUND Maximizing extent of resection (EOR) and reducing residual tumor volume (RTV) while preserving neurological functions is the main goal in the surgical treatment of gliomas. Navigated intraoperative ultrasound (N-ioUS) combining the advantages of ultrasound and conventional neuronavigation (NN) allows for overcoming the limitations of the latter. OBJECTIVE To evaluate the impact of real-time NN combining ioUS and preoperative magnetic resonance imaging (MRI) on maximizing EOR in glioma surgery compared to standard NN. METHODS We retrospectively reviewed a series of 60 cases operated on for supratentorial gliomas: 31 operated under the guidance of N-ioUS and 29 resected with standard NN. Age, location of the tumor, pre- and postoperative Karnofsky Performance Status (KPS), EOR, RTV, and, if any, postoperative complications were evaluated. RESULTS The rate of gross total resection (GTR) in NN group was 44.8% vs 61.2% in N-ioUS group. The rate of RTV > 1 cm3 for glioblastomas was significantly lower for the N-ioUS group (P < .01). In 13/31 (42%), RTV was detected at the end of surgery with N-ioUS. In 8 of 13 cases, (25.8% of the cohort) surgeons continued with the operation until complete resection. Specificity was greater in N-ioUS (42% vs 31%) and negative predictive value (73% vs 54%). At discharge, the difference between pre- and postoperative KPS was significantly higher for the N-ioUS (P < .01). CONCLUSION The use of an N-ioUS-based real-time has been beneficial for resection in noneloquent high-grade glioma in terms of both EOR and neurological outcome, compared to standard NN. N-ioUS has proven usefulness in detecting RTV > 1 cm3.

Measuring response to neoadjuvant chemotherapy in high-grade serous tubo-ovarian carcinoma: an analysis of the correlation between CT imaging and chemotherapy response score

2019 ◽  
Vol 29 (5) ◽  
pp. 929-934 ◽  
Author(s):  
Meabh McNulty ◽  
Adarsh Das ◽  
Paul A Cohen ◽  
Andrew Dean
Keyword(s):  
Overall Survival ◽  
Neoadjuvant Chemotherapy ◽  
Partial Response ◽  
Stable Disease ◽  
Progression Free Survival ◽  
Chemotherapy Response ◽  
High Grade ◽  
Free Survival ◽  
Radiological Response ◽  
Response Score

IntroductionResponse to neoadjuvant chemotherapy is measured by CT and the decision to proceed with interval surgery is made on the radiological response after two or three cycles of therapy. The Chemotherapy Response Score grades histological tumor regression in omental metastases resected at interval surgery and is associated with progression-free survival and overall survival. It is uncertain whether radiological response is associated with prognosis and whether radiological response predicts Chemotherapy Response Score.To assess if radiological response is associated with progression-free survival and overall survival. Additionally, to investigate whether radiological response predicts the Chemotherapy Response Score.MethodsRetrospective cohort study of patients with high-grade serous ovarian cancer treated with neoadjuvant chemotherapy. Radiological response was assessed by comparing CT imaging at baseline and after neoadjuvant chemotherapy using RECIST (Response Evaluation Criteria In Solid Tumors) and classified as stable disease, partial response, complete response, or progressive disease. Survival analysis was performed using Cox proportional-hazard models and the log-rank test.ResultsA total of 71 patients met the inclusion criteria. Of these, 51 had pre- and post-neoadjuvant chemotherapy CT scans available for analysis. Radiological response was not associated with progression-free survival or overall survival on univariate analysis (stable disease vs partial response; HR for progression-free survival 1.15; 95% CI 0.57 to 2.32; p = 0.690; HR for overall survival 1.19; 95% CI 0.57 to 2.46; p = 0.645). In a multivariate model, radiological response was not associated with either progression-free survival (stable disease vs partial response; HR=1.19; 95% CI 0.498 to 2.85; p = 0.694) or overall survival (stable disease vs partial response; HR=0.954; 95% CI 0.38 to 2.40; p = 0.920). There was a significant association between the Chemotherapy Response Score and radiological response (p = 0.005).DiscussionA partial response and stable disease on radiological assessment after neoadjuvant chemotherapy in women with advanced high-grade serous ovarian cancer were not associated with survival, despite having a correlation with the Chemotherapy Response Score.

Safety and Efficacy of Bortezomib (VELCADE™) in 104 Patients with Relapsed and/or Refractory Multiple Myeloma Who Have Received at Least Two Previous Lines of Therapy: Impact of Cytogenetics on Response from a Canadian Cohort.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5118-5118
Author(s):  
Joseph R. Mikhael ◽  
Donna E. Reece ◽  
Andrew Belch ◽  
Nizar J. Bahlis ◽  
Deepa Sharma
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Poor Prognosis ◽  
Progressive Disease ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
M Protein ◽  
Cytogenetic Abnormalities ◽  
Refractory Multiple Myeloma ◽  
The Impact

Abstract Background: Bortezomib (VELCADE™) is a reversible proteasome inhibitor that has been shown to be safe and efficacious in patients (pts) with relapsed and/or refractory multiple myeloma (MM) using a dose of 1.3 mg/m2 on days 1, 4, 8 & 11 of a 21-day cycle. Certain cytogenetic abnormalities are associated with poor prognosis in MM, including deletion 13, t(4;14) and the p53 deletion.(Stewart et al, JCO2005; 23(26):6339–44). Bortezomib has demonstrated the ability to overcome the poor prognosis associated with deletion 13 (Jagannath, JCO2005; 23(16S) 6501). The impact of bortezomib on a broader range of cytogenetic abnormalities, such as t(4;14) has yet to be determined. Methods: In this multicentre, open-label, non-randomized, phase 3b study, pts with MM across 13 centres in Canada, who had received at least 2 previous lines of therapy and who were refractory to or had relapsed after their last therapy were enrolled. Pts received up to eight 3-week cycles of bortezomib on days 1, 4, 8 & 11. Dexamethasone 20 mg PO was administered on each day of and day after bortezomib administration if the pts either experienced progressive disease after receiving at least 2 treatment cycles of bortezomib or had no change in disease status from baseline after receiving at least 4 treatment cycles of bortezomib. Results: 104 pts were enrolled; the mean age in this cohort was 60.7 years, and 65 (62.5%) were male. Approximately 30% of pts had a Karnofsky performance status of 70 or less at baseline. 71 pts (68.3%) had received prior thalidomide therapy, 32 (30.8%) had received a prior autotransplant and 4 (3.8%) had received prior bortezomib treatment. 74 (71.2%) received 3 or more lines of prior MM therapy. During the study, mean number of bortezomib cycles completed was 4.6 (range, 0–11 cycles), and the number of pts that completed 8 cycles of therapy was 36 (34.6%). 15.2% of pts received dexamethasone at cycle 3 and 19.2% at cycle 5. Cytogenetic analysis was performed on approximately half of the pts. Response data for cycle 5 is currently available for 69/99 (69.7%) of evaluable pts (see Table 1). Overall, 76.9% of the pts experienced Grade 3 & 4 adverse events. Safety profile observed is similar to past trial results with bortezomib. Conclusion: In this large Canadian cohort of extensively pre-treated patients with mulitple myeloma, bortezomib demonstrated good response, consistent with previous studies. Analysis correlating cytogenetic profile and response rate is ongoing and will be available at the time of conference. In addition, a detailed safety analysis and impact of prior treatment on response will be analyzed and made available at the time of conference. Table 1. Response to Bortezomib Category of Response* No. of Patients (%) *Modified SWOG: CR 100% M-protein reduction; R 75–99%; PR 50–74%; MR 25–49%; SD<25%, PD increasing M-protein Any Response (CR + VGPR + PR + MR) 47 (68.1) ---Complete Response (CR) + Very Good Partial Response (VGPR) ---22 (31.9) ---Partial Response (PR) + Minimal Response (MR) ---25 (36.2) Stable Disease 10 (14.5) Progressive Disease 12 (17.4)

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