Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment (ICON8): overall survival results from an open-label, randomised, controlled, phase 3 trial.
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ABSTRACT:
SUBMITTER: Clamp AR
PROVIDER: S-EPMC9630160 | biostudies-literature | 2022 Jul
REPOSITORIES: biostudies-literature
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Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment (ICON8): overall survival results from an open-label, randomised, controlled, phase 3 trial.
Clamp Andrew R AR James Elizabeth C EC McNeish Iain A IA Dean Andrew A Kim Jae-Won JW O'Donnell Dearbhaile M DM Gallardo-Rincon Dolores D Blagden Sarah S Brenton James J Perren Tim J TJ Sundar Sudha S Lord Rosemary R Dark Graham G Hall Marcia M Banerjee Susana S Glasspool Rosalind M RM Hanna C Louise CL Williams Sarah S Scatchard Kate M KM Nam Helena H Essapen Sharadah S Parkinson Christine C McAvan Lucy L Swart Ann Marie AM Popoola Babasola B Schiavone Francesca F Badrock Jonathan J Fananapazir Fuad F Cook Adrian D AD Parmar Mahesh M Kaplan Richard R Ledermann Jonathan A JA
The Lancet. Oncology 20220609 7
<h4>Background</h4>Standard-of-care first-line chemotherapy for epithelial ovarian cancer is carboplatin and paclitaxel administered once every 3 weeks. The JGOG 3016 trial reported significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly (ie, once every 3 weeks) carboplatin. However, this benefit was not observed in the previously reported progression-free survival results of ICON8. Here, we present the final coprimary outcomes of overall s ...[more]
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Project description:BackgroundCarboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer.MethodsIn this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC-IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0·75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3).FindingsBetween June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24·4 months [97·5% CI 23·0-26·0] in group 1, 24·9 months [24·0-25·9] in group 2, 25·3 months [23·9-26·9] in group 3; median progression-free survival 17·7 months [IQR 10·6-not reached] in group 1, 20·8 months [11·9-59·0] in group 2, 21·0 months [12·0-54·0] in group 3; log-rank p=0·35 for group 2 vs group 1; group 3 vs 1 p=0·51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups.InterpretationWeekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations.FundingCancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia.
| S-EPMC6902268 | biostudies-literature
Project description:A combination of cytoreductive surgery, either primary (PCS) or interval (ICS), and chemotherapy with a platinum-paclitaxel regimen is the well-accepted treatment for advanced-stage epithelial ovarian cancer (EOC), fallopian tube cancer (FTC), and primary peritoneal serous carcinoma (PPSC), but it is still uncertain whether a combination of dose-dense weekly paclitaxel and low-dose triweekly cisplatin is useful in the management of these patients. Therefore, we retrospectively evaluated the outcomes of women with advanced-stage EOC, FTC, and PPSC treated with PCS and subsequent dose-dense weekly paclitaxel (80 mg/m2) and low-dose triweekly cisplatin (20 mg/m2). Between January 2011 and December 2017, 32 women with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV EOC, FTC, or PPSC were enrolled. Optimal PCS was achieved in 63.5% of patients. The mean and median progression-free survival was 36.5 and 27.0 months, respectively (95% confidence interval (CI): 26.8-46.2 and 11.3-42.7 months, respectively). The mean overall survival was 56.0 months (95% CI: 43.9-68.1 months), and the median overall survival could not be obtained. The most common all-grade adverse events (AEs) were anemia (96.9%), neutropenia (50%), peripheral neuropathy (28.1%), nausea and vomiting (34.4%), and thrombocytopenia (15.6%). These AEs were predominantly grade 1/2, and only a few patients were complicated by grade 3/4 neutropenia (21.9%) and anemia (6.3%). A multivariate analysis indicated that only suboptimal PCS was significantly correlated with a worse prognosis, resulting in an 11.6-fold increase in the odds of disease progression. In conclusion, our data suggest that dose-dense weekly paclitaxel (80 mg/m2) combined with low-dose triweekly cisplatin (20 mg/m2) is a potentially effective and highly tolerable front-line treatment in advanced EOC, FTC, and PPSC. Randomized trials comparing the outcome of this regimen to other standard therapies for FIGO stage IIIC-IV EOC, FTC, and PPSC are warranted.
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Project description:Ovarian cancer is the most lethal gynecological malignancy, primarily because its origin and initiation factors are unknown. A secretory murine oviductal epithelial (MOE) model was generated to address the hypothesis that the fallopian tube is an origin for high-grade serous cancer. MOE cells were stably altered to express mutation in p53, silence PTEN, activate AKT, and amplify KRAS alone and in combination, to define if this cell type gives rise to tumors and what genetic alterations are required to drive malignancy. Cell lines were characterized in vitro and allografted into mice. Silencing PTEN formed high-grade carcinoma with wide spread tumor explants including metastasis into the ovary. Addition of p53 mutation to PTEN silencing did not enhance this phenotype, whereas addition of KRAS mutation reduced survival. Interestingly, PTEN silencing and KRAS mutation originating from ovarian surface epithelium generated endometrioid carcinoma, suggesting that different cellular origins with identical genetic manipulations can give rise to distinct cancer histotypes. Defining the roles of specific signaling modifications in tumorigenesis from the fallopian tube/oviduct is essential for early detection and development of targeted therapeutics. Further, syngeneic MOE allografts provide an ideal model for pre-clinical testing in an in vivo environment with an intact immune system.
| S-EPMC4653021 | biostudies-literature
Project description:BackgroundThis multi-center RP2 study assessed activity/safety of ixabepilone + bevacizumab compared to ixabepilone in platinum-resistant/refractory ovarian/fallopian tube/primary peritoneal cancer. Additional objectives were to examine the role of prior bevacizumab and taxanes, and explore class III-ß-tubulin (TUBB3) as a predictive biomarker.MethodsParticipants were randomised to receive ixabepilone 20 mg/m2 days 1, 8, 15 with (IXA + BEV) or without (IXA) bevacizumab 10 mg/kg days 1, 15 every 28 days. Patients were stratified by prior BEV. The primary endpoint was PFS. OS, safety, and ORR served as secondary endpoints.ResultsAmong 76 evaluable patients who received IXA + BEV (n = 39) compared to IXA (n = 37), the ORR was 33% (n = 13) versus 8% (n = 3)(P = 0.004), durable at 6 months in 37% (n = 14) and 3% (n = 1) (P < 0.001). BEV significantly improved PFS (median:5.5 vs 2.2 months, HR = 0.33, 95%CI 0.19-0.55, P < 0.001) and OS (median:10.0 vs 6.0 months, HR = 0.52, 95%CI 0.31-0.87, P = 0.006). Both regimens were well-tolerated. TUBB3 expression did not predict response. Subgroup analyses revealed minimal effect of prior BEV or taxane resistant/refractory status on response to IXA + BEV.ConclusionsIXA + BEV is a well-tolerated, effective combination for platinum/taxane-resistant ovarian cancer that extends PFS and likely OS relative to IXA monotherapy. Prior receipt of BEV should not preclude the use of IXA + BEV. TUBB3 is not a predictive biomarker.Clinical trial registrationNCT3093155.
| S-EPMC8853032 | biostudies-literature
Project description: Not available
| S-EPMC10113072 | biostudies-literature
Project description:BackgroundRecurrent, platin-resistant ovarian cancer (rPROC) has a poor survival. Even with the AURELIA trial, which is the best available treatment today, progression-free survival (PFS) is still only 6.7 months from the start of the second-line chemotherapy. Innovative, effective therapies are urgently needed. Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is a novel drug delivery system for administering drugs into the abdomen. PIPAC with cisplatin and doxorubicin (PIPAC C/D) may be safely used at an intraperitoneal dose of 10.5 mg/m2 and 2.1 mg/m2, respectively. Systemic toxicity of this therapy is low. In a phase II trial with 53 women, 62 % patients had an objective tumor response. Tumor regression on histology was observed in 76 % patients who underwent all three PIPACs. Randomized phase III studies are now required to evaluate the effect of PIPAC C/D compared to other standard treatments (sequential or simultaneous applications with systemic chemotherapy).MethodsThe present phase III study is a prospective, open, randomized, multicentric pivotal trial. A total of 244 patients will be randomly assigned (1:1) to the control (A) or to the experimental (B) group. Group A: Systemic palliative chemotherapy, physician's best choice (monotherapy consisting of pegylated liposomal doxorubicin or topotecan or gemcitabine or paclitaxel weekly. Bevacizumab can be used in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin). Group B: Intraperitoneal chemotherapy, 3×PIPAC C/D, performed every 6 weeks. Combination with systemic therapy is not allowed. Treatment is continued until disease progression, death, or patient refusal. In case of progression, no recommendation for further therapy is given by protocol. Patients are allowed to receive PIPAC C/D or systemic chemotherapy after study termination. The primary endpoint is PFS (according to RECIST v1.1) or death from any cause. The co-primary endpoint is the health-related quality of life (HRQoL) measured as the global health status (GHS, QLQ-30 of EORTC). Secondary outcomes comprise overall survival, safety (CTCAE 5.0), and tumor response according to peritoneal regression grading score (PRGS).DiscussionWe expect PIPAC C/D to control peritoneal disease and preserve the QoL on this subset of patients.Trial registrationThe EudraCT number 2018-003664-31.
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Project description:ObjectivesChanges in cognitive function have been identified in and reported by many cancer survivors. These changes have the potential to impact patient quality of life and functional ability. This prospective longitudinal study was designed to quantify the incidence of change in cognitive function in newly diagnosed ovarian cancer patients throughout and following primary chemotherapy.MethodsEligible patients had newly diagnosed, untreated ovarian cancer and had planned to receive chemotherapy. Web-based and patient reported cognitive assessments and quality of life questionnaires were conducted prior to chemotherapy, prior to cycle four, after cycle six, and six months after completion of primary therapy.ResultsTwo-hundred-thirty-one evaluable patients entered this study between May 2010 and October 2011. At the cycle 4 time point, 25.2% (55/218) of patients exhibited cognitive impairment in at least one domain. At the post-cycle 6 and 6-month follow up time points, 21.1% (44/208) and 17.8% (30/169) of patients, respectively, demonstrated impairment in at least one domain of cognitive function. There were statistically significant, but clinically small, improvements in processing speed (p<0.001) and attention (p<0.001) but not in motor response time (p=0.066), from baseline through the six-month follow up time period.ConclusionsThis was a large, prospective study designed to measure cognitive function in ovarian cancer. A subset of patients had evidence of cognitive decline from baseline during chemotherapy treatment in this study as measured by the web-based assessment; however, changes were generally limited to no more than one domain.
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Project description:PurposeA simple measure to predict chemotherapy tolerance in elderly patients would be useful. We prospectively tested the association of baseline Instrumental Activities of Daily Living (IADL) score with ability to complete 4 cycles of first line chemotherapy without dose reductions or >7days delay in elderly ovarian cancer patients.Patients and methodsPatients' age ≥70 along with their physicians chose between two regimens: CP (Carboplatin AUC 5, Paclitaxel 135mg/m2) or C (Carboplatin AUC 5), both given every 3weeks either after primary surgery or as neoadjuvant chemotherapy (NACT) with IADL and quality of life assessments performed at baseline, pre-cycle 3, and post-cycle 4.ResultsTwo-hundred-twelve women were enrolled, 152 selecting CP and 60 selecting C. Those who selected CP had higher baseline IADL scores (p<0.001). After adjusting for age and PS, baseline IADL was independently associated with the choice of regimen (p=0.035). The baseline IADL score was not found to be associated with completion of 4 cycles of chemotherapy without dose reduction or delays (p=0.21), but was associated with completion of 4 cycles of chemotherapy regardless of dose reduction and delay (p=0.008) and toxicity, with the odds ratio (OR) of grade 3+ toxicity decreasing 17% (OR: 0.83; 95%CI: 0.72-0.96; p=0.013) for each additional activity in which the patient was independent. After adjustment for chemotherapy regimen, IADL was also associated with overall survival (p=0.019) for patients receiving CP.ConclusionPatients with a higher baseline IADL score (more independent) were more likely to complete 4 cycles of chemotherapy and less likely to experience grade 3 or higher toxicity.
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Project description:PURPOSE:Presence of circulating tumor cells (CTCs) is associated with impaired clinical outcome in several solid cancers. Limited data are available on the significance of CTCs in gynaecological malignancies. The aims of the present study were to evaluate the dynamics of CTCs in patients with ovarian, fallopian tube and peritoneal cancer during chemotherapy and to assess their clinical relevance. METHODS:43 patients with ovarian, fallopian tube and peritoneal cancer were included into this prospective study. Patients received chemotherapy according to national guidelines. CTC analysis was performed using the CellSearch system prior to chemotherapy, after three and six cycles. RESULTS:In 26% of the patients,???1CTC per 7.5 ml of blood was detected at baseline (17% of patients with de novo disease, compared to 35% in recurrent patients). Presence of CTCs did not correlate with other factors. After three cycles of therapy, CTC positivity rate declined to 4.8%. After six cycles, no patient showed persistent CTCs. Patients with???1 CTC at baseline had significantly shorter overall survival and progression-free survival compared to CTC-negative patients (OS: median 3.1 months vs. not reached, p?=?0.006, PFS: median 3.1 vs. 23.1 months, p?=?0.005). When only the subgroup with newly diagnosed cancer was considered, the association between CTC status and survival was not significant (OS: mean 17.4 vs. 29.0 months, p?=?0.192, PFS: 14.3 vs. 26.9 months, p?=?0.085). Presence of???1 CTC after three cycles predicted shorter OS in the entire patient cohort (p?<?0.001). CONCLUSIONS:Hematogenous tumor cell dissemination is a common phenomenon in ovarian, fallopian tube and peritoneal cancer. CTC status before start of systemic therapy correlates with clinical outcome. Chemotherapy leads to a rapid decline in CTC counts; further research is needed to evaluate the clinical value of CTC monitoring after therapy.
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