scholarly journals How to sequence treatment in relapsed ovarian cancer

2020 ◽  
Author(s):  
Sandro Pignata ◽  
Sabrina Chiara Cecere
Keyword(s):  
Ovarian Cancer ◽  
Recurrent Disease ◽  
Recurrent Ovarian Cancer ◽  
Platinum Resistance ◽  
Front Line ◽  
Related Factors ◽  
Drug Classes ◽  
Stage Disease ◽  
Platinum Based Chemotherapy ◽  
Line Setting

Numerous disease- and patient-related factors must be considered when selecting systemic therapy for recurrent ovarian cancer. Anti-angiogenics (bevacizumab) and poly(ADP-ribose) polymerase inhibitors (olaparib, niraparib, rucaparib) have an important role as maintenance of platinum-based chemotherapy for recurrent disease and their use in the first-line setting of advanced-stage disease is becoming established. As previous exposure to none, one or both of these drug classes is integral to selecting next therapy, front-line use impacts on options available to treat recurrent disease. A key strategy to delay platinum resistance and improve prognosis of recurrent disease is to alternate treatments with different mechanisms of action. The multiple mechanisms of trabectedin and its complementarity with platinum allow intercalation between platinum regimens in potentially platinum-responsive patients with recurrent disease.

Olaparib in the treatment of ovarian cancer

2019 ◽  
Vol 15 (30) ◽  
pp. 3435-3449 ◽  
Author(s):  
Christina R Washington ◽  
Debra L Richardson ◽  
Kathleen N Moore
Keyword(s):  
Ovarian Cancer ◽  
Disease Free Survival ◽  
Front Line ◽  
Platinum Sensitive ◽  
Formidable Challenge ◽  
Platinum Based Chemotherapy ◽  
Measurable Disease ◽  
Treatment Naïve ◽  
Line Setting ◽  
Disease Free

The poly ADP ribose polymerase olaparib is currently approved in front line BRCA-associated epithelial ovarian cancer (EOC), platinum-sensitive recurrence agnostic to BRCA status and for gBRCA as treatment in the fourth line and beyond. Women who are diagnosed with advanced stage EOC face a formidable challenge in overcoming their disease and achieving long-term, disease-free survival. The qualifier here is disease free. EOC is largely exquisitely chemosensitive, especially in the treatment naive (first line) setting and the expectation is that the vast majority of women will complete front line platinum-based chemotherapy with a response. When unselected (not selected by BRCA) women are enrolled on clinical trials, the response rate among those who have measurable disease at the time of chemotherapy initiation is 48% for carboplatin/paclitaxel and 67% for carboplatin/paclitaxel plus bevacizumab. When one considers the addition of women who start chemotherapy without measurable disease, they will likely also end chemotherapy without measurable disease and the overall rate of no evidence of disease at conclusion of chemotherapy approaches 80%. Despite this, the majority of women will suffer relapse of their disease, typically within the first 3 years following completion of therapy. Once recurrent, the disease is highly treatable for many years but no longer considered curable. This review will cover indications for olaparib in ovarian cancer as well as ongoing combination trials and rationale for these combinations.

scholarly journals Cisplatin Resistance in Ovarian Cancer: Classical Outlook and Newer Perspectives

2021 ◽  
Vol 14 (4) ◽  
pp. 1993-2005
Author(s):  
Prachitee Borkar ◽  
Prasan Bhandari ◽  
Shraddha Yadav ◽  
Ashwini Prabhu
Keyword(s):  
Ovarian Cancer ◽  
Molecular Mechanisms ◽  
Cisplatin Resistance ◽  
Tumor Biology ◽  
Platinum Resistance ◽  
Related Factors ◽  
Platinum Based Chemotherapy ◽  
Analog Resistance ◽  
Advanced Stages ◽  
Novel Strategy

Ovarian cancer is one of the most common gynecological cancers. Recently, there is increase in incidence of ovarian cancer not only India but also worldwide. Ovarian cancer patients exhibit nonspecific symptoms during early course of disease. As a consequence, 70% of these patients are diagnosed in advanced stages. Ovarian cancer treatment includes cytoreductive surgery followed by platinum-based chemotherapy. However, these patients develop fatal recurrence due to development of platinum resistance. Cisplatin, (platinum analog) resistance is multifactorial and complex. Earlier, resistance was mainly attributed to conventional molecular mechanisms like decreased intracellular accumulation of cisplatin, enhanced DNA repair and increased cisplatin detoxification. Nevertheless, emergence of knowledge of tumor biology have lead to discovery of other contributing mechanisms. These tumor microenvironment related factors include physical blockade, hypoxia, cancer stem cells, cancer associated fibroblasts and many others. Understanding these mechanisms of cisplatin resistance is crucial for development of novel strategy to combat the same. Hence, this review summarizes all the mechanisms of resistance of cisplatin in ovarian cancer.

Retrospective Analysis of Carboplatin and Paclitaxel as Initial Second-Line Therapy for Recurrent Epithelial Ovarian Carcinoma: Application Toward a Dynamic Disease State Model of Ovarian Cancer

2002 ◽  
Vol 20 (5) ◽  
pp. 1238-1247 ◽  
Author(s):  
Don S. Dizon ◽  
Martee L. Hensley ◽  
Elizabeth A. Poynor ◽  
Paul Sabbatini ◽  
Carol Aghajanian ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Recurrent Disease ◽  
Second Line ◽  
Front Line ◽  
New Paradigm ◽  
Second Line Therapy ◽  
Platinum Sensitive ◽  
Line Therapy ◽  
Platinum Based Chemotherapy ◽  
Line Chemotherapy

PURPOSE: The majority of patients with epithelial ovarian cancer (EOC) who achieve a complete remission with front-line chemotherapy develop recurrent disease. Carboplatin and paclitaxel are used for patients with platinum-sensitive recurrent disease, although there is little information regarding the response and survival in unselected patients treated with this strategy. We sought to determine the outcomes for patients with EOC treated with carboplatin and paclitaxel at the time of first recurrence. In addition, we sought to define a new paradigm for disease transition in patients with EOC. PATIENTS AND METHODS: Eighty-nine patients were identified who had a complete response to front-line platinum-based chemotherapy for EOC, relapsed 6 months after completion of front-line chemotherapy, and were treated with carboplatin and paclitaxel as second-line therapy. RESULTS: Eighty-four cases were available for analysis of survival end points, and 66 were assessable for response. The median follow-up was 27 months. The overall response rate was 70%. The median progression-free interval for the cohort was 13 months (95% confidence interval [CI], 10.7 to 13.8 months). The 3-year survival rate was 72% (95% CI, 59.4 to 86.1%). Toxicity was limited, and no deaths from treatment were observed. Using this data, it is possible to construct a disease states model of EOC, which provides risk estimates for transitions between clinically distinct categories. CONCLUSION: Re-treatment with carboplatin and paclitaxel is effective as initial therapy in recurrent EOC. This should form the basis of a randomized trial to determine the best agents for initial treatment of relapse from EOC in potentially platinum-sensitive patients.

Outcomes of ovarian cancer patients treated with platinum or non-platinum based chemotherapy after PARP inhibitor maintenance.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5563-5563
Author(s):  
Ralynn Brann ◽  
Kevin Michael Kremer ◽  
Matthew Carlson ◽  
Salvatore LoCoco ◽  
Jayanthi Sivasothy Lea ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Treatment Time ◽  
Statistical Tests ◽  
Parp Inhibitor ◽  
Tertiary Care ◽  
Platinum Resistance ◽  
Time To Progression ◽  
Front Line ◽  
Platinum Based Chemotherapy

5563 Background: PARP inhibitors (PARPi) are approved for maintenance treatment of platinum sensitive ovarian cancers either after front-line therapy or after treatment for recurrence. Current recommendations include retreatment with platinum-based chemotherapy (PC) after progression on maintenance PARPi. There exists a theoretical concern that progression of disease (POD) on PARPi is indicative of the development of platinum resistance due to similar DNA targets of platinum chemotherapy and PARPi. Our objective was to evaluate the response to subsequent chemotherapy in patients who progressed on PARPi maintenance. Methods: All patients with ovarian, fallopian tube, or primary peritoneal cancer treated with PARPi treatment from 2017 to 2021 at two academic tertiary care centers were retrospectively identified. Patients were assessed for treatment time on PARPi, time to POD on PARPi (PFS), type of chemotherapy regimen following PARPi maintenance, and time to disease progression on subsequent therapy following PARPi (PFS2). Comparative statistical analyses were performed with appropriate two-sided statistical tests. Time to progression on chemotherapy after PARPi was calculated using the Kaplan-Meier method. Results: A total of 83 ovarian cancer patients treated with PARPi were identified, and of these, 61 (73.5%) were treated with PARPi in the maintenance setting. Among the patients treated with PARPi maintenance, 22 (36.1%) remain on treatment. 19 (31.1%) patients were started on PARPi maintenance after front-line chemotherapy. While on PARPi maintenance, 63.9% discontinued PARPi, the majority due to POD, and 26.2% due to patient intolerance of side effects. Following POD, 21/29 (72.4%) received subsequent PC and 8/29 (27.6%) received non-platinum based chemotherapy (NPC). Treatment time, PFS, and PFS2 are listed in Table. Of the patients who received PC, 14/21 (66.7%) had a PFS2 of over six months and 5/21 (23.8%) had a PFS2 of over 12 months. Of the patients who received NPC, 7/8 (87.5%) had a PFS2 of over six months and 2/8 (25.0%) had a PFS2 of over 12 months. Conclusions: Following POD on PARPi, patients responded to both PC and NPC. Time to progression on subsequent chemotherapy after treatment with PARPi does not differ significantly between PC and NPC regimens. Many patients continue to see benefit from PC after PARPi maintenance. Retreatment with PC following POD on PARPi maintenance should still be considered.[Table: see text]

Carboplatin hypersensitivity induced by low-dose paclitaxel/carboplatin in multiple platinum-treated patients with recurrent ovarian cancer

2005 ◽  
Vol 15 (2) ◽  
pp. 224-227 ◽  
Author(s):  
Y. Watanabe ◽  
H. Nakai ◽  
H. Ueda ◽  
K. Nozaki ◽  
H. Hoshiai
Keyword(s):  
Ovarian Cancer ◽  
Low Dose ◽  
Recurrent Disease ◽  
Recurrent Ovarian Cancer ◽  
Concentration Curve ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy ◽  
Carboplatin Hypersensitivity ◽  
Third Line ◽  
Platinum Agents

We report five cases of carboplatin (CBDCA) hypersensitivity after weekly low-dose paclitaxel (60 mg/m2)/CBDCA (area under the concentration curve = 2) therapy in patients with recurrent ovarian cancer receiving multiple platinum-based chemotherapy. Paclitaxel and CBDCA therapy was indicated as second-line chemotherapy in one patient and as third line in four patients with recurrent disease. The range of previously administered total CBDCA was 2582–9589 mg, and the CBDCA area under the concentration curve of the first treatment exhibited appropriate intensity (mean, 1.92 ± 0.10; range, 1.76–2.10) in all patients. However, one patient exhibited severe hypersensitivity reactions including cardiac arrest and apnea, and another four patients developed eruptions, hypotension, and tachycardia soon after administration of CBDCA. Our report suggested that CBDCA hypersensitivity was correlated with the total dose of previously administered platinum agents and that CBDCA should be excluded in patients who have received multiple platinum-based chemotherapy, even in platinum-sensitive cases, because CBDCA hypersensitivity can occur even with low-dose CBDCA administration.

scholarly journals Novel epigenetic-metabolic inhibitor combination treatment blocks platinum-induced ovarian cancer stem cell enrichment

2021 ◽  
Author(s):  
Riddhi Sood ◽  
Sikai Xiao ◽  
Shruthi Sriramkumar ◽  
Christiane Hassel ◽  
Kenneth P. Nephew ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Recurrent Ovarian Cancer ◽  
Dna Methyltransferases ◽  
Metabolic Inhibitor ◽  
Platinum Resistance ◽  
Dna Hypermethylation ◽  
Ovarian Cancer Stem Cells ◽  
Promoter Dna ◽  
Rate Limiting ◽  
Platinum Agents

AbstractHigh grade serous ovarian cancer (HGSOC) is the most common and aggressive type of ovarian cancer. Platinum resistance is a common occurrence in HGSOC and a main cause of tumor relapse resulting in high patient mortality rates. Recurrent ovarian cancer is enriched in aldehyde dehydrogenase (ALDH)+ ovarian cancer stem cells (OCSCs), which are resistant to platinum agents. We demonstrated that acute platinum treatment induced a DNA damage-dependent decrease in BRCA1 levels throughBRCA1promoter DNA hypermethylation. In a parallel pathway associated with G2/M arrest, platinum treatment also induced an increase in expression ofNAMPT, the rate limiting regulator of NAD+production from the salvage pathway, and NAD+levels, the cofactor required for ALDH activity. Both decreased BRCA1 and increased NAD+levels were required for the platinum-induced enrichment of OCSCs, and inhibition of both DNA methyltransferases (DNMT) and NAMPT synergistically abrogated the platinum-induced increase in OCSCs. We conclude that these two separate pathways lead to platinum-induced OCSC enrichment, providing preclinical evidence that in the neoadjuvant setting, combining DNMT and NAMPT inhibitors with platinum has the potential to reduce OC reoccurrence.

scholarly journals Development of a Genomic Signatures-Based Predictor of Initial Platinum-Resistance in Advanced High-Grade Serous Ovarian Cancer Patients

2021 ◽  
Vol 10 ◽  
Author(s):  
Yuan Li ◽  
Xiaolan Zhang ◽  
Yan Gao ◽  
Chunliang Shang ◽  
Bo Yu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Predictive Accuracy ◽  
Predictive Performance ◽  
Platinum Resistance ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Single Nucleotide Variants ◽  
Tissue Samples ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy

BackgroundHigh grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. Although platinum-based chemotherapy has been the cornerstone for HGSOC treatment, nearly 25% of patients would have less than 6 months of interval since the last platinum chemotherapy, referred to as platinum-resistance. Currently, no precise tools to predict platinum resistance have been developed yet.MethodsNinety-nine HGSOC patients, who have finished cytoreductive surgery and platinum-based chemotherapy in Peking University Third Hospital from 2018 to 2019, were enrolled. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were performed on the collected tumor tissue samples to establish a platinum-resistance predictor in a discovery cohort of 57 patients, and further validated in another 42 HGSOC patients.ResultsA high prevalence of alterations in DNA damage repair (DDR) pathway, including BRCA1/2, was identified both in the platinum-sensitive and resistant HGSOC patients. Compared with the resistant subgroup, there was a trend of higher prevalence of homologous recombination deficiency (HRD) in the platinum-sensitive subgroup (78.95% vs. 47.37%, p=0.0646). Based on the HRD score, microhomology insertions and deletions (MHID), copy number changes load, duplication load of 1–100 kb, single nucleotide variants load, and eight other mutational signatures, a combined predictor of platinum-resistance, named as DRDscore, was established. DRDscore outperformed in predicting the platinum-sensitivity than the previously reported biomarkers with a predictive accuracy of 0.860 at a threshold of 0.7584. The predictive performance of DRDscore was validated in an independent cohort of 42 HGSOC patients with a sensitivity of 90.9%.ConclusionsA multi-genomic signature-based analysis enabled the prediction of initial platinum resistance in advanced HGSOC patients, which may serve as a novel assessment of platinum resistance, provide therapeutic guidance, and merit further validation.

scholarly journals Maintenance with Trabectedin in the Treatment of Platinum-Sensitive Recurrent Ovarian Cancer

2019 ◽  
Vol 12 (2) ◽  
pp. 447-455 ◽  
Author(s):  
Eva María Guerra Alía ◽  
Cayetano Sempere Ortega ◽  
Alfonso Cortés Salgado ◽  
Concepción Sanchez Martínez ◽  
Julio Galindo Álvarez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Pegylated Liposomal Doxorubicin ◽  
Abdominal Distension ◽  
Recurrent Ovarian Cancer ◽  
Response To Treatment ◽  
Case Presentation ◽  
Good Tolerance ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy ◽  
Selection Of

Ovarian cancer is the seventh most common type of cancer and the fifth leading cause of cancer death among women worldwide. The current usual therapeutic approach in this disease includes optimal cytoreductive therapy followed by platinum-based adjuvant chemotherapy, along with neoadjuvant chemotherapy prior to surgery in selected cases. The platinum-free interval (PFI) continues to be the most useful tool to assist in the selection of the subsequent therapy and to predict response to treatment. The combination of trabectedin and pegylated liposomal doxorubicin (PLD) is useful in patients with partially platinum-sensitive recurrent ovarian cancer, in patients who have previously received two or more platinum-based chemotherapy regimens, in patients who have already experienced a platinum-induced hypersensitivity reaction and in patients who have previously failed to respond to a platinum-based treatment. Case Presentation: A 64-years-old postmenopausal woman with pain, abdominal distension, and an altered intestinal transit and with partially platinum-sensitive recurrent ovarian cancer, was successfully treated with a second line of trabectedin chemotherapy in combination with PLD, followed by trabectedin in monotherapy. This case proves the effectiveness of the combination of trabectedin and PLD and demonstrates how the administration of trabectedin, even in monotherapy, allows to maintain an adequate clinical response with good tolerance to the treatment during more than two years of drug administration.

Responses to second-line cisplatin-based intraperitoneal therapy in ovarian cancer: influence of a prior response to intravenous cisplatin.

1991 ◽  
Vol 9 (10) ◽  
pp. 1801-1805 ◽  
Author(s):  
M Markman ◽  
B Reichman ◽  
T Hakes ◽  
W Jones ◽  
J L Lewis ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase Ii ◽  
Small Volume ◽  
Recurrent Ovarian Cancer ◽  
Second Line ◽  
Front Line ◽  
Phase Ii Trials ◽  
Two Phase ◽  
Overall Response ◽  
Intraperitoneal Therapy

Phase II trials of second-line intraperitoneal (IP) cisplatin-based therapy in patients with ovarian cancer have demonstrated the ability of this approach to produce objective antitumor responses, including surgically defined complete responses (CRs), in individuals with persistent small-volume disease after front-line cisplatin-based intravenous (IV) treatment. To examine the influence of a prior response to systemic cisplatin on the activity of second-line IP cisplatin, we retrospectively analyzed two phase II trials of cisplatin-based IP therapy in persistent/recurrent ovarian cancer conducted at our institution. Of the 89 assessable patients on the two trials, 52 (58%) had previously responded to IV cisplatin. The overall response and CR rates to second-line IP cisplatin-based therapy in this previously responding population were 56% and 33%, respectively, compared with overall response and CR rates in the 37 nonresponders to IV cisplatin of 11% and 3%, respectively (P less than .001; chi 2, 1 df). In the 36 patients responding to systemic cisplatin and whose largest tumor mass measured less than 1 cm at IP cisplatin initiation, a 42% CR rate was observed, compared with a 7% CR rate in the 14 patients with the same bulk of disease who had previously failed to respond to systemic cisplatin (P less than .025). We conclude that a prior response to systemic cisplatin strongly influences the antineoplastic activity of second-line IP cisplatin in ovarian cancer.

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