Hypersensitivity to platinum salts according to BRCA status in ovarian cancer: Retrospective analysis of clinical outcomes.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6053-6053
Author(s):  
Gaia Giannone ◽  
Giulia Scotto ◽  
Ugo De Giorgi ◽  
Alberto Farolfi ◽  
Dionyssios Katsaros ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cumulative Incidence ◽  
Drug Exposure ◽  
Total Duration ◽  
Brca Mutations ◽  
First Line Therapy ◽  
Platinum Salts ◽  
Grade 3 ◽  
Line Of Therapy ◽  
Few Data

6053 Background: Hypersensitivity reactions (HSRs) to platinum salts are an important issue in the treatment of ovarian cancer (OC) patients (pts). Few data suggest that, along with number of previous cycles, germline BRCA mutations could be a risk factor. We aimed at evaluating the incidence and severity of HSRs to platinum salts in a large group of OC pts with known BRCA status and correlated them with drug exposure time. Methods: Between March 2003 and September 2019, 432 pts with a diagnosis of OC and a known BRCA status, were recorded in our 5 Institutions and retrospectively analyzed. The following data were collected: histology, BRCA status, type of surgery and first line therapy, number of total lines and cycles received, line and cycle of HSR onset, symptoms, history of other allergies and if desensitization was attempted. We graded the severity of HSRs according to CTCAE v5.0. We calculated the total duration of exposure to platinum salts, summing up the duration of all platinum lines received by the pts. Results: Four hundred nine of 432 (94.7%) pts were treated with at least one platinum-based line of therapy and were eligible for the analysis. Among them, 314 pts were BRCA wild type (BRCAwt) (76.8%) and 95 were BRCA mutated (BRCAmut) (23.2%). There was no statistical difference in number of prior lines of therapy [median 1 (2-6) for BRCA wt and 2 (1-6) for BRCAmut pts (p = 0.194)] and duration of exposure to platinum [median 126 (42 – 893) and 197 (42 – 896) days for BRCAwt and BRCAmut pts, respectively (p = 0.145)]. Incidence of any grade HSRs was 29 / 314 (9.2%) among BRCAwt pts vs. 17/ 95 (17.9%) among BRCAmut pts (Odds ratio [OR] 0.47, 95% CI 0.24 – 0.89, p= 0.019). All recorded HSRs to platinum salts were related to carboplatin. We observed a numerically higher incidence of Grade 3-4 HSRs in BRCAmut pts (5.1% in BRCAwt vs. 10.5% in BRCAmut cohort, OR 0.46, 95% CI 0.20 – 1.04, p = 0.057). The risk to develop HSRs increases with duration of exposure to platinum, particularly in BRCAmut pts. The cumulative incidence of any grade HSRs was 20.6% vs. 23.3% after 12 months and 38.4% vs. 59.7% after 18 months in BRCAwt and BRCAmut pts, respectively (Hazard Ratio [HR] 1.72, 95% CI 0.94 – 3.12, p = 0.073). The cumulative incidence of severe HSRs was 10.9% vs. 15.7% after 12 months and 26.5% vs. 41.0% after 18 months in BRCAwt and BRCAmut pts, respectively (HR 1.88, 95% CI 0.85 – 4.16, p = 0.11). Conclusions: In BRCAmut OC pts, there is a significantly higher incidence of HSRs to carboplatin, that seems not justified by longer drug exposure only.

Topotecan, paclitaxel, and carboplatin in advanced ovarian cancer: A phase II trial of the Minnie Pearl Cancer Research Network

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 15015-15015 ◽  
Author(s):  
J. D. Zubkus ◽  
J. D. Hainsworth ◽  
D. R. Spigel ◽  
J. F. Patton ◽  
D. L. Shipley ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Standard Dose ◽  
Advanced Ovarian Cancer ◽  
Response Rates ◽  
Research Network ◽  
Stage Iii ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Grade 3

15015 Background: Topotecan (T) is standard therapy for patients (pts) with relapsed platinum refractory ovarian cancer (OC). The addition of T to paclitaxel/carboplatin (PC) may improve the first-line therapy for pts with stage III/IV OC. Methods: The primary endpoints were to assess the toxicity and response rate of TPC in previously untreated pts with advanced OC. Pts with previously untreated stage III/IV OC with performance (PS) 0 or 1, normal hematologic and organ function were eligible. Topotecan 1mg/m2 per day IV days 1, 2, and 3; paclitaxel 175mg/m2 IV on day 3 and carboplatin (AUC=5) IV on day 3 were administered at 21-day intervals for 6 cycles with standard dose modifications for toxicities. Responses were assessed clinically after 2 cycles and at completion of therapy. Second look laporatory (SLL) was required for pts without evaluable tumor. Results: 50 pts were enrolled: age range 27–79 (median 63); performance status 0=16, 1=34; suboptimal debulking surgery (tumor > 1 cm) 32; 70% high grade tumors. Intent to treat response rates: complete response (CR) 20 pts (40%); partial response (PR) 12 pts (24%); stable (S) 13 pts (26%); progression 2 pts (4%); not evaluable 3 pts (6%). 13 pts had SLL with 5 CR, 5 PR and 3 S. Toxicities included: grade 3/4 neutropenia/thrombocytopenia 84%/44%; grade 3/4 fatigue/infection 10%/10%; no treatment-related deaths. Median progression-free survival (PFS) for all pts was 13.6 months and 1-, 2-, 3-year PFS 60%, 42%, 36%. Median survival 33.9 months for all pts with 1-, 2-, 3-year survivals 90%, 65%, 49%. Conclusions: The combination of TPC is active and relatively well tolerated with PC given on day 3. The response rates, PFS, and survivals appear similar to standard regimens. Randomized prospective trials will be required to determine the value of T added to PC for first-line therapy of advanced OC. [Table: see text]

Multicenter phase II study of FOLFOX or biweekly XELOX and cetuximab as first-line treatment in patients with wild-type KRAS/BRAF metastatic colorectal cancer (mCRC) (FLEET study).

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 463-463
Author(s):  
Ho Min Kim ◽  
Hitoshi Soda ◽  
Shoichi Hazama ◽  
Takao Takahashi ◽  
Naoki Nagata ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Predictive Biomarker ◽  
Wild Type ◽  
First Line ◽  
First Line Therapy ◽  
Multicenter Phase ◽  
Grade 3 ◽  
Few Data

463 Background: Cetuximab and chemotherapy as first-line therapy for patients with KRAS wild type prolong survival. However, COIN trial has not demonstrated the survival benefit of FOLFOX or XELOX and cetuximab therapy. Few data are available on its benefit for patients with KRAS and BRAF wild-type. Methods: The aim of this study was to assess the efficacy of first-line FOLFOX or bi-weekly XELOX and bi-weekly cetuximab in KRAS/BRAF wt mCRC. Chemonaive patients received FOLFOX or biweekly XELOX (oxaliplatin 85 mg/ m2/day 1 plus capecitabine 2000/m2/days 1-7) and biweekly cetuximab 500mg m2/ day 1 every 2 weeks. Primary endpoint was response rate(RR), other secondary endpoints were PFS, OS, DCR, safety, DI and resection rate. KRAS test (codon12,13) and BRAF test (V600E) by direct sequence were performed in Yamaguchi University. Patients with KRAS/BRAF wt were enrolled in this study. The regimen of FOLFOX or XELOX were selected by investigator’s preference, not randomized. Results: From April 2010 to May 2011, 139 pts were preregistered. KRAS and BRAF were examined from paraffin-embedded sample. 70 (50.3%) pts were KRAS/BRAF wt, and 62 pts were enrolled: The main characteristics of the entered pts were: sex (M/F) 34/28, median age 66 yrs (range 34-83 yrs). Grade 3/4 adverse events were leucopenia 4.8%, neutropenia 25.8%, skin toxity (paronychia/fissure) 9.7%, and acne 9.7%. Two CR (3.2%) and 40 PR (64.5%), 15 SD (24.2%) and 3 PD (4.8%) 2NE were observed, with an overall response rate of 67.7% and a disease control rate (CR+PR+SD) of 91.9%. The RR of FOLFOX or XELOX were 64.9% (24/37) and 72.0% (18/25), DCR were 89.2% and 96% respectively. Conclusions: FLEET was the first multicenter phase II study with prospective KRAS/BRAF analysis as a predictive biomarker for cetuximab in first-line mCRC in Japan. Results of this study indicate that both biweekly combination regimens are feasible, tolerable, and clinically active. Biweekly XELOX+cetuximab study (FLEET2) is ongoing. Clinical trial information: UMIN000003253.

Impact of cyclophosphamide on relationships between carboplatin exposure and response or toxicity when used in the treatment of advanced ovarian cancer.

1993 ◽  
Vol 11 (6) ◽  
pp. 1156-1164 ◽  
Author(s):  
L M Reyno ◽  
M J Egorin ◽  
R M Canetta ◽  
D I Jodrell ◽  
K D Swenerton ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Drug Exposure ◽  
Single Agent ◽  
Advanced Ovarian Cancer ◽  
Dose Intensity ◽  
Time Curve ◽  
University Of Maryland ◽  
Grade 3 ◽  
The Impact ◽  
Carboplatin Auc

PURPOSE To determine (1) the impact of cyclophosphamide 600 mg/m2 on previously defined relationships between carboplatin area under the plasma concentration versus time curve (AUC) and indices of toxicity and response in women with advanced ovarian cancer; and (2) the relationships between indices of cumulative drug exposure and clinical outcomes. METHODS Carboplatin AUC = dose/(creatinine clearance [CCr] + 25) and was calculated in 224 women who received carboplatin 300 mg/m2 and cyclophosphamide 600 mg/m2. The likelihood of grade 3 or greater myelotoxicity at any carboplatin AUC was compared with the likelihood of myelotoxicity at the same single-agent carboplatin AUC. The nadir count predicted using the University of Maryland single-agent carboplatin dosing formula was compared with the nadir count observed. Received and relative-received dose-intensity were calculated. Carboplatin exposure-intensity was defined by substituting cumulative carboplatin exposure for total dose. Relationships were sought between these indices and therapeutic outcomes. RESULTS The incidence of leukopenia and thrombocytopenia at any carboplatin AUC was greater for the two-drug combination than for single-agent carboplatin. The platelet nadir in 83% of patients was less than or equal to the nadir predicted for the same single-agent carboplatin AUC. Despite a narrow range of received dose-intensities, carboplatin exposure-intensity was distributed over a twofold range. There were no relationships between received and relative-received dose-intensity or carboplatin exposure-intensity and time to progression or survival. CONCLUSION Any carboplatin AUC when administered with cyclophosphamide 600 mg/m2 produces greater myelotoxicity than the same AUC of single-agent carboplatin. Received carboplatin dose-intensity underestimates the range of plasma drug exposure resulting from a fixed carboplatin dosing regimen. Whether higher carboplatin exposures can improve outcome requires prospective validation.

CTNI-33. METRONOMIC TEMOZOLOMIDE THERAPY IN HEAVILY PRETREATED PATIENTS WITH RECURRENT GLIOBLASTOMA: A LARGE MONO-INSTITUTIONAL RETROSPECTIVE STUDY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi66-vi67
Author(s):  
Alberto Bosio ◽  
Giulia Cerretti ◽  
Marta Padovan ◽  
Mario Caccese ◽  
Valentina Guarneri ◽  
...  
Keyword(s):  
Univariate Analysis ◽  
Recurrent Glioblastoma ◽  
First Line ◽  
First Line Therapy ◽  
Common Grade ◽  
Heavily Pretreated ◽  
Third Line ◽  
Grade 3 ◽  
Line Of Therapy ◽  
Ecog Ps

Abstract BACKGROUND Despite advances in surgical and first-line treatment, all glioblastoma pts relapse. The aim of this study is to evaluate the benefit of metronomic temozolomide (mTMZ) for recurrent glioblastoma. METHODS 120 pts treated at Veneto Institute of Oncology from September 2013 to March 2021 were retrospectively reviewed. Major inclusion criteria were: first-line therapy with Stupp protocol, relapse after first or subsequent line of therapy, treatment with mTMZ schedule (50mg/m2 continuously), hystologically confirmed diagnosis. RESULTS mFollow-up was 15.6ms, mAge 59ys (range 18-81), ECOG PS 0-2 in 107pts (89%) and 3 in 11 (9%). MGMT was methylated in 66 of 105 (62%) evaluable pts, IDH mutated in 9 of 106 (8%). mNumber of prior lines of treatment was 2 (range 1-7); 41% of pts received mTMZ beyond the third line. mTime between last standard TMZ (sTMZ) cycle and mTMZ administration was 6ms (range 1-50); 40% of pts started mTMZ after 3ms from sTMZ. All pts were evaluable for response: 3 (2%) and 48 (40%) showed PR and SD. mOS from the start of mTMZ was 5.4ms (95% CI 4.3-6.4), mPFS 2.6ms (95% CI 2.3-2.8). On univariate analysis, MGMTmet and MGMTunmet pts had a mOS of 5.6 and 4.4ms (p= 0.03); mOS for pts with ECOG PS > or ≤ 2 was 2.3 and 6.0ms (p< 0.001). On multivariate analysis, MGMTmet status (HR= 2.3, 95% CI, p= 0.004) and ECOG PS (HR= 0.5, 95% CI, p= 0.017) remained significant for PFS; ECOG PS (HR= 0.4, 95% CI, p= 0.001) was the only factor significantly associated with OS. The most common grade 3-4 hematologic toxicities were lymphopenia (10%) and thrombocytopenia (3%). Grade 3-4 nonhematologic toxicities were uncommon. CONCLUSIONS Rechallenge with mTMZ can be a well tolerated treatment option for recurrent glioblastoma, even in heavily pretreated pts. Pts with MGMTmet and good ECOG PS might report the major benefit.

scholarly journals The Prognostic and Predictive Role of Somatic BRCA Mutations in Ovarian Cancer: Results from a Multicenter Cohort Study

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 565
Author(s):  
Angela Toss ◽  
Claudia Piombino ◽  
Elena Tenedini ◽  
Alessandra Bologna ◽  
Elisa Gasparini ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Positive Impact ◽  
Progression Free Survival ◽  
Molecular Testing ◽  
Wild Type ◽  
Brca Mutations ◽  
Multicenter Cohort Study ◽  
Advanced Stages ◽  
Predictive Role

Previous research involving epithelial ovarian cancer patients showed that, compared to germline BRCA (gBRCA) mutations, somatic BRCA (sBRCA) mutations present a similar positive impact with regard to overall survival (OS) and platinum and PARP (poly (ADP-ribose) polymerase) inhibitor sensitivity. Nevertheless, molecular testing in these studies did not include copy number variation (CNV) analyses of BRCA genes. The aim of this study was to explore the prognostic and predictive role of sBRCA mutations as compared to gBRCA mutations in patients who were also tested for CNVs. Among the 158 patients included in the study, 17.09% of patients carried a pathogenic or likely pathogenic gBRCA variant and 15.19% of patients presented pathogenetic or likely pathogenic sBRCA variants and/or CNVs. Overall, 81.6% of the patients included in this study were diagnosed with a serous histotype, and 77.2% were in advanced stages. Among women diagnosed in advanced stages, gBRCA patients showed better progression-free survival and OS as compared to sBRCA and wild-type patients, whereas sBRCA patients did not show any advantage in outcome as compared to wild-type patients. In this study, the introduction of CNV analyses increased the detection rate of sBRCA mutations, and the resulting classification among gBRCA, sBRCA and wild-type patients was able to properly stratify the prognosis of OC patients. Particularly, sBRCA mutation patients failed to show any outcome advantage as compared to wild-type patients.

scholarly journals Tumour Versus Germline BRCA Testing in Ovarian Cancer: A Single-Site Institution Experience in the United Kingdom

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 547
Author(s):  
Iolia Akaev ◽  
Siavash Rahimi ◽  
Olubukola Onifade ◽  
Francis John Edward Gardner ◽  
David Castells-Rufas ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Unknown Origin ◽  
Parp Inhibitors ◽  
Serous Carcinoma ◽  
High Grade ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Epithelial Cancers ◽  
Pathogenic Variants ◽  
Pathogenic Mutations

The aim of this audit was to evaluate the usefulness and serviceability of testing for pathogenic mutations in BRCA1 or BRCA2 (BRCA1/2) genes in ovarian cancer (OC) patients. One hundred and thirty-five patients with more common histological sub-types of OC were retrospectively identified between 2011 and 2019. The fail rate of the molecular analysis was 7.4% (10/135). One hundred and twenty-five records were evaluated: 99 (79.2%) patients had wild-type BRCA (both somatic and germline); tumour BRCA1/2 (tBRCA1/2) pathogenic mutations were found in 20 (16%) patients with distribution between BRCA1 and BRCA2 being 40% and 60%, respectively; 13 (10.4%) patients with pathogenic variants had germline mutations; and tBRCA1/2 with variant of unknown significance (VUS), in the absence of pathogenic BRCA1 or BRCA2 variants, was detected in 6 (4.8%) patients. Our data show that expanding the molecular service to the routine first-tumour testing for patients with OC will potentially increase the detection rate of BRCA mutations, thereby providing early benefits of PARP inhibitors therapy. The tumour testing service should continue to be offered to newly diagnosed patients with high-grade epithelial cancers, including high-grade serous carcinoma, but also with carcinosarcomas and poorly-differentiated metastatic adenocarcinomas of unknown origin.

scholarly journals A phase I study of combined trabectedin and pegylated liposomal doxorubicin therapy for advanced relapsed ovarian cancer

2021 ◽  
Author(s):  
Shunji Takahashi ◽  
Munetaka Takekuma ◽  
Kenji Tamura ◽  
Kazuhiro Takehara ◽  
Hiroyuki Nomura ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Liposomal Doxorubicin ◽  
Advanced Ovarian Cancer ◽  
Pegylated Liposomal Doxorubicin ◽  
Japanese Patients ◽  
Pharmacokinetic Analysis ◽  
Dependent Manner ◽  
Drug Concentrations ◽  
Grade 3

Abstract Background Advanced relapsed ovarian cancer has a poor prognosis, and treatment options are limited. Methods This phase I trial investigated the dosage, safety, pharmacokinetics and efficacy of trabectedin plus pegylated liposomal doxorubicin (PLD) in Japanese patients with advanced relapsed ovarian, fallopian tube, or primary peritoneal cancer. Patients received trabectedin 0.9 or 1.1 mg/m2 immediately after PLD 30 mg/m2; both drugs were given by intravenous infusion. Treatment was repeated every 21 days until disease progression or unacceptable toxicity. The maximum tolerated dose (MTD) was determined in an initial dose escalation phase, and this was used in a subsequent safety assessment phase. Safety and tumor response were monitored throughout the trial, and drug concentrations for pharmacokinetic analysis were measured during cycle 1. Results Eighteen patients were included. The MTD of trabectedin was determined as 1.1 mg/m2. Gastrointestinal adverse events were experienced by all patients, but were mostly grade 1 or 2 in intensity. Most patients had grade ≥ 3 elevations in transaminase levels or grade ≥ 3 reductions in neutrophil count, but these events were generally manageable through dose reduction and/or supportive therapies, as appropriate. There were no deaths during the trial. Trabectedin exposure increased in a dose-dependent manner. The overall response rate was 27.8%. Conclusions Trabectedin, in combination with PLD, may have clinical benefits in Japanese patients with relapsed advanced ovarian cancer. The recommended dosage of trabectedin for further study in this population is 1.1 mg/m2 once every 21 days. Clinical trial registration number: JapicCTI-163164

scholarly journals FAS and Subsequent Therapies in Pancreatic Neuroendocrine Tumors

2021 ◽  
Author(s):  
Jane E. Rogers ◽  
Michael Lam ◽  
Daniel M. Halperin ◽  
Cecile G. Dagohoy ◽  
James C. Yao ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Pancreatic Neuroendocrine Tumors ◽  
Free Survival ◽  
Prior Therapy ◽  
Well Differentiated ◽  
Grade 3 ◽  
Line Of Therapy

We evaluated outcomes of treatment with 5-fluorouracil (5-FU), doxorubicin, and streptozocin (FAS) in well-differentiated pancreatic neuroendocrine tumors (PanNETs) and its impact on subsequent therapy (everolimus or temozolomide). Advanced PanNET patients treated at our center from 1992 to 2013 were retrospectively reviewed. Patients received bolus 5-FU (400 mg/m2), streptozocin (400 mg/m2) (both IV, days 1-5) and doxorubicin (40 mg/m2 IV, day 1) every 28 days. Overall response rate (ORR) was assessed using RECIST version 1.1. Of 243 eligible patients, 220 were evaluable for ORR, progression-free survival (PFS), and toxicity. Most (90%) had metastatic, nonfunctional PanNETs; 14% had prior therapy. ORR to FAS was 41% (95% confidence interval [CI]: 36-48%). Median follow-up was 61 months. Median PFS was 20 (95% CI: 15-23) months; median overall survival (OS) was 63 (95% CI: 60-71) months. Cox regression analyses suggested improvement with first-line vs subsequent lines of FAS therapy. Main adverse events ≥ grade 3 were neutropenia (10%) and nausea/vomiting (5.5%). Dose reductions were required in 32% of patients. Post-FAS everolimus (n=108; 68% second line) had a median PFS of 10 (95% CI: 8-14) months. Post-FAS temozolomide (n=60; 53% > fourth line) had an ORR of 13% and median PFS of 5.2 (95% CI: 4-12) months. In this largest reported cohort of PanNETs treated with chemotherapy, FAS demonstrated activity without significant safety concerns. FAS did not appear to affect subsequent PFS with everolimus; this sequence is being evaluated prospectively. Responses were noted with subsequent temozolomide-based regimens although PFS was possibly limited by line of therapy.

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