First-line Therapy For Ovarian Cancer Research Articles

The Immune Subtype Contributes to Distinct Overall Survival for Ovarian Cancer Patients With Platinum-Based Adjuvant Therapy.

ObjectiveNowadays, platinum-based therapy has been widely used as the first-line therapy of ovarian cancer. However, the effect of the tumor microenvironment on platinum-based therapy remains unclear. In this study, we aim to investigate the relationship between immune microenvironment subtypes and the prognosis of platinum-based therapy in ovarian cancer.MethodsWe integrated 565 ovarian cancer samples from two datasets and obtained the immune subtypes (ISs) by consistent clustering of 1190 immune-related gene expressions. The proportional hazards regression model was used to assess the relationship between ISs and the prognosis of platinum-based adjuvant therapy including progression-free survival (PFS) and overall survival (OS). The prognostic contribution of ISs was validated in three additional cohorts. Non-parametric tests were used to assess genomic characteristics, the proportion of immune cells, and immune-related signature differences among ISs.ResultsWe identified and validated five ISs associated with different clinical outcomes of the platinum-based adjuvant therapy in ovarian cancer patients. These differences were only found in OS rather than PFS. An immune subtype had the worst OS. Those patients mainly derived from the mesenchymal subtype had the lowest tumor purity with a high leukocyte fraction as well as stromal fraction and had the highest TGF-β response signaling. By contrast, an immune subtype characterized by immunoreactive status with the highest CD8+T cell infiltration and elevated IFN-γ response signaling had the best prognosis. Other subtypes with more diverse immunologic features such as lowest macrophage regulation signaling showed intermediate prognoses. Notably, the contribution of ISs to OS was independent of the clinical response to platinum-based drugs.ConclusionOur analysis revealed the association between different immune characteristics and platinum-based adjuvant therapy, indicating the combination of ISs and chemotherapy could optimize the treatment strategy of OC patients.

Inflammation and immunity in ovarian cancer

The standard first-line therapy for ovarian cancer is a combination of surgery and carboplatin/paclitaxel-based chemotherapy. Patients with longer survival and improved response to chemotherapy usually present T-cell inflamed tumours. The presence of tumour-infiltrating T cells (TILs) notably varies among the different subtypes of ovarian tumours, being highest in high-grade serous ovarian carcinoma, intermediate in endometrioid tumours, and lowest in low-grade serous, mucinous and clear cell tumours. Interestingly, the presence of TILs is often accompanied by a strong immunosuppressive tumour environment. A better understanding of the immune response against ovarian cancer and the tumour immune evasion mechanisms will enable improved prognostication, response prediction and immunotherapy of this disease. This article provides an overview of some ovarian cancer cell features relevant for antitumour response, such as tumour-associated antigens, including neoantigens, expression of inhibitory molecules, and other mechanisms of immune evasion. Moreover, we describe relevant immune cell types found in epithelial ovarian tumours, including T and B lymphocytes, regulatory T cells, natural killer cells, tumour-associated macrophages, myeloid-derived suppressor cells and neutrophils. We focus on how these components influence the burden of the tumour and the clinical outcome.

PARP Inhibitors in First-Line Therapy of Ovarian Cancer: Are There Any Doubts?

The standard of care for newly diagnosed advanced ovarian cancer (NADOC) is represented by surgical debulking followed by systemic platinum–taxanes combination chemotherapy. At the last European Society for Medical Oncology (ESMO) Congress, results from three trials testing three different poly-adenosine-diphosphate-ribose-polymerase (PARP) inhibitors (olaparib, niraparib, veliparib) in first-line therapy of OC have been presented. For the first time, these studies evaluated the efficacy of PARP inhibitors in this setting and the relative predictive biomarkers for patients' selection. The use of a PARP inhibitor is related with prolonged progression free survival (PFS) in the whole population of NADOC, although the magnitude of benefit varies widely among subgroups, highlighting the need to identify specific biological subtypes into clinical practice. In this minireview, we discuss the updated data available from clinical studies in this scenario.

Current First-line Therapy for Ovarian Cancer: A Comprehensive Review

Ovarian, fallopian tube, and primary peritoneal cancers constitute the deadliest gynecologic malignancies. After primary cytoreductive surgery, there are several standard first-line cytotoxic treatments for providers to consider. Newer molecular targeted therapies are becoming more common and may have a role as first-line therapy in the future. This article provides an evidence-based review of all approved standard therapies for first-line treatment of advanced-stage, high-grade serous ovarian cancer. Treatment schedules, dose modifications, and drug substitutions are reviewed. Ongoing trials and pending approvals for newer molecular therapies are discussed. A comprehensive primary literature review was performed using MEDLINE, the Cochrane Collaborative Database, and PubMed. Guidelines from the National Comprehensive Cancer Network and the Society for Gynecologic Oncology were also reviewed. Seven different approved first-line regimens for high-grade serous ovarian cancer are available based on literature review. These vary in route of administration, dose intensity, drug combinations, and treatment schedules. Molecular targeted therapies, including antiangiogenic drugs and poly(ADP-ribose) polymerase inhibitors, have also been studied in multiple randomized controlled trials in the first-line setting. Cytotoxic regimens remain the foundation of first-line treatment for high-grade serous ovarian cancer. Choosing which regimen is best for a patient depends on both patient and disease factors. Molecular therapies in first-line treatment are a promising and exciting possibility, with regulatory approval pending.

Audit of CA125 Follow-Up After First-Line Therapy for Ovarian Cancer.

The Medical Research Council OVO5/EORTC 55955 trial showed that patients in remission after first-line therapy for ovarian cancer did not benefit from routine measurement of CA125 during follow-up. Since the presentation of these results, we have counseled patients about the options for follow-up and provided them with an information leaflet about the trial results and the symptoms that should prompt an early appointment and CA125 measurement. We present an audit of practice after the presentation of those results. The medical records of 143 consecutive patients completing first-line therapy for epithelial ovarian, fallopian tube, or primary peritoneal cancer in our unit between July 2009 and December 2013 were analyzed. An agreed plan of CA125 follow-up was recorded in 69 (79%) of 87 eligible patients on completion of first-line therapy. No routine CA125 follow-up was selected by 55 (80%) patients, and routine CA125 follow-up was selected by 14 (20%), of whom 3 wished not to be informed of the results. CA125 levels were checked in 28 (51%) patients in the no routine CA125 follow-up group, in 26 cases because of the development of symptoms. Relapse was confirmed in 22. Median follow-up was 360 days (range, 100-836). CA125 levels were checked in all 14 patients who had requested routine CA125 follow-up. Relapse has been confirmed in 2 patients. Median follow-up was 560 days (range, 500-620). If patients are given sufficient information about the role of routine CA125 measurements during follow-up, the majority decide against CA125 monitoring and hence, avoid these blood tests.

Independent review of AGO-OVAR 12, a GCIG/ENGOT-Intergroup phase III trial of nintedanib (N) in first-line therapy for ovarian cancer (OC).

5556^ Background: N is an oral inhibitor of VEGFR, PDGFR, and FGFR. As reported earlier, in the AGO-OVAR12 trial, N compared to placebo (Pl), added to standard chemotherapy, significantly prolonged...

Paclitaxel-exposed ovarian cancer cells induce cancer-specific CD4+ T cells after doxorubicin exposure through regulation of MyD88 expression

Ovarian cancer has the highest mortality rate among gynecological malignancies due to high chemoresistance to the combination of platinum with taxane. Immunotherapy against ovarian cancer is a promising strategy to develop from animal-based cancer research. We investigated changes in the immunogenicity of paclitaxel-exposed ovarian cancer cells following exposure to other chemotherapeutic drugs. Murine ovarian surface epithelial cells (MOSECs) showed some resistance to paclitaxel, a first-line therapy for ovarian cancer. However, MOSECs pre-exposed to paclitaxel died through apoptosis after incubation with doxorubicin or cisplatin for 2 h. Injected into mice, the paclitaxel-exposed MOSECs post-treated with doxorubicin induced more MOSEC-specific CD4(+) T cells and extended survival for a greater time than MOSECs treated with paclitaxel alone; and bone marrow-derived dendritic cells (BMDCs) expressed higher levels of co-stimulatory molecules and produced IL-12 after co-culture with paclitaxel-exposed MOSECs treated with doxorubicin. We also observed that in paclitaxel-exposed MOSECs treated with doxorubicin, but not cisplatin, the expression of MyD88 and related target proteins decreased compared to paclitaxel-exposed MOSECs only, while in BMDCs co-cultured with these MOSECs the expression of myeloid differentiation primary response gene 88 (MyD88) increased. These findings suggest that paclitaxel pre-exposed cancer cells treated with doxorubicin can induce significant apoptosis and a therapeutic antitumor immune response in advanced ovarian cancer.

Abstract A53: Biomarkers of chemotherapy resistance in serous epithelial ovarian cancer identified by integrative genomic and transcriptomic analysis

Abstract Resistance to platinum-based chemotherapy remains a major impediment in the treatment of serous epithelial ovarian cancer. The objective of this study was to use gene expression and copy number profiling to delineate major deregulated pathways and biomarker networks associated with the development of intrinsic chemotherapy resistance with exposure to standard first-line therapy for ovarian cancer. The study cohort comprised 28 high grade serous ovarian cancer patients divided into two groups based on their varying sensitivity to first-line chemotherapy using progression free survival (PFS) as a surrogate of response. Twelve patient tumors demonstrating relative resistance to platinum based chemotherapy corresponding to shorter PFS (less than 6 months) were compared to 16 tumors from platinum-sensitive patients (PFS more than 18months). Molecular profiling was performed using Affymetrix high-resolution microarray platforms to permit global comparisons of gene expression levels and copy number profiles between tumors from the resistant group with the sensitive group. Microarray data analysis using statistical methods revealed a set of 204 discriminating genes of which expression levels may be influencing differential chemotherapy response between the two groups. Pathway analysis of the differentiating genes showed IGF1 network to be significantly altered between the two groups in addition to PI3K, NFkB, distinguishing the chemotherapy resistant with the sensitive group. Copy number analysis showed differences in the chromosomal regions, 4q31.22, 5q13.2, 9p24.3, 2p23.2, 16q21, 6q14.1, 7p22.3, 12p13 and Xq. Integrative copy number and gene expression profiling will delineate the drivers of chemotherapy resistance in patients undergoing standard platinum-based treatment of ovarian cancer. Future studies to validate these markers are necessary to apply this knowledge to biomarker-based clinical trials. Citation Format: Madhuri Koti, Robert J. Gooding, Paulo Nuin, Alexandria Haslehurst, Colleen Crane, Johanne Weberpals, Timothy Chids, Peter Bryson, Moyez Dharsee, Kenneth R. Evans, Harriet E. Feilotter, Paul C. Park, Jeremy A. Squire. Biomarkers of chemotherapy resistance in serous epithelial ovarian cancer identified by integrative genomic and transcriptomic analysis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A53.

Platelet-Derived Growth Factor Receptor Beta Serum Concentrations during First-Line Therapy in Ovarian Cancer

Objectives: Angiogenesis plays an important role in ovarian cancer. The interaction of platelet-derived growth factor receptor-beta (PDGFR-β) with vascular endothelial growth factor (VEGF) in the process of angiogenesis may represent an essential feature in the progression of the disease. Methods: Patients with epithelial ovarian cancer, who underwent primary surgery and platinum-based first-line chemotherapy, were included. A total of 133 serum samples from 39 patients were analyzed. Samples were prospectively collected at 4 time points: (1) before surgery, (2) after surgery and before chemotherapy, (3) during chemotherapy and (4) after chemotherapy. Serum PDGFR-β was quantified by ELISA. We analyzed the correlation of serum levels to chemotherapy response, progression-free and overall survival (PFS and OS) and the serum markers CA-125 and VEGF-165. Results: Serum concentration of PDGFR-β ranged between 4 and 72 ng/ml and increased significantly during first-line chemotherapy (p = 0.019). PDGFR-β serum concentrations showed an inverse correlation with CA-125 and VEGF-165 after chemotherapy (r = -0.495, p = 0.003 and r = -0.345, p = 0.04, respectively). Increased PDGFR-β serum levels after chemotherapy were significantly correlated with better PFS (p = 0.026) and OS (p = 0.013) in a univariate analysis. Conclusion: PDGFR-β might be a useful biomarker in terms of prognosis and could be important as antiangiogenic agents become a component of standard treatment in ovarian cancer.

Abstract 810: Integrative genomic and transcriptomic analysis in idenfitication of biomarkers of chemoresistance in serous epithelial ovarian cancer.

Abstract Resistance to platinum-based chemotherapy remains a major impediment in the treatment of serous epithelial ovarian cancer. The objective of this study was to use gene expression and copy number profiling to delineate major deregulated pathways and biomarker networks associated with the development of intrinsic chemotherapy resistance with exposure to standard first-line therapy for ovarian cancer. The study cohort comprised 28 high grade serous ovarian cancer patients divided into two groups based on their varying sensitivity to first-line chemotherapy using progression free survival (PFS) as a surrogate of response. Twelve patient tumors demonstrating relative resistance to platinum based chemotherapy corresponding to shorter PFS (less than 6 months) were compared to 16 tumors from platinum-sensitive patients (PFS more than 18months). Molecular profiling was performed using Affymetrix high-resolution microarray platforms to permit global comparisons of gene expression levels and copy number profiles between tumors from the resistant group with the sensitive group. Microarray data analysis revealed a set of 227 discriminating genes of which expression levels may be influencing differential chemotherapy response between the two groups. Pathway analysis of these genes showed the,PI3K,NFkB and IGF1 networks as some of the significant networks distinguishing the chemotherapy resistant with the sensitive group. Copy number analysis performed using Nexus copy number version 6.1 revealed differences in the chromosomal regions, 4q31.22, 5q13.2, 9p24.3, 2p23.2, 16q21, 6q14.1, 7p22.3, 12p13 and Xq. Integrative copy number and gene expression profiling will delineate the drivers of chemotherapy resistance in patients undergoing standard platinum-based treatment of ovarian cancer. Future studies to validate these markers are necessary to apply this knowledge to biomarker-based clinical trials. Citation Format: Madhuri Koti, Robert J. Gooding, Paulo Nuin, Alexandria Haslehurst, Colleen Crane, Johanne Weberpals, Timothy Childs, Peter Bryson, Moyez Dharsee, Kenneth Evans, Harriet E. Feilotter, Paul C. Park, Jeremy A. Squire. Integrative genomic and transcriptomic analysis in idenfitication of biomarkers of chemoresistance in serous epithelial ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 810. doi:10.1158/1538-7445.AM2013-810

Cost-utility assessment of amifostine as first-line therapy for ovarian cancer

Bennett CL, Golub R, Calhoun E, Weinstein J; Fishman D, Lurain J, Roland P, Medio F, Bukowski RM. Cost-utility assessment of amifostine as first-line therapy for ovarian cancer. Int J Gynecol Cancer 1998; 8: 64-72. Nearly 27,000 female patients were diagnosed with ovarian cancer in the United States in 1997. While chemotherapeutic agents are effective in prolonging the time to progression of disease, concerns exist over treatment- related toxicities. In addition to considerations related to effectiveness, the decision to prescribe new cytoprotective agents requires consideration of costs and cost-effectiveness. The objective of this study was to describe cost-utility estimates of a new supportive care agent, amifostine, and to illustrate these issues for patients with ovarian cancer. The phase III Food and Drug Administration (FDA) licensing trial found that pretreatment with amifostine prior to each cycle of chemotherapy resulted in reduction of cumulative toxicities with cyclophosphamide and cisplatinum. While amifostine use is approximately $3,146 more per patient, after adjustment for direct medical costs and potential health status changes from reductions in hematologic toxicity, neurotoxicity, and nephrotoxicity, its use was estimated to cost $36,161 in direct medical costs per quality-adjusted life year saved. Sensitivity analyses indicated that cost-effectiveness estimates of amifostine therapy ranged front $25,474 to $78,574. Based on the phase III FDA licensing trial, amifostine use is associated with a favorable cost-utility profile that is in the range associated with widely used cancer therapeutic and supportive care agents. The decision to use (or not use) amifostine in conjunction with cisplatin and cyclophosphamide for women with ovarian cancer should be based on clinical, not economic, considerations.

Abstract 3645: Integrative molecular profiling in serous epithelial ovarian cancer for identification of biomarkers of chemoresistance

Abstract Ovarian cancer is the fifth leading cause of death due to gynecological cancers in women in the western world. Development of primary resistance to carboplatin and paclitaxel poses a major challenge in the management of serous epithelial ovarian cancer. To identify the molecular mechanisms underlying the development of instrinsic resistance upon exposure to standard first-line therapy for ovarian cancer, we used microarrays to profile the 1) copy number alteration and SNP, 2) mRNA, 3) miRNA and 4) methylation signatures in a cohort comprising 11 chemoresistant and 14 chemosensitive tumour samples. Copy number analysis showed significant copy number alterations in the chemoresistant group (gains on chromosomal regions, 4q, 6q, 8p, 8q, 19q, 7q and 22q; losses on 8p and 10q) compared to the sensitive group. Gene expression data analysis using R/bioconductor revealed a set of 248 discriminating genes in the two cohorts. Pathway analysis of these genes using Ingenuity Pathway Analysis revealed enrichment in genes primarily involved in epithelial to mesenchymal transition and PI3 Kinase pathway. Additionally, genes related to the pro-inflammatory cytokine pathways, as well as drug transport demonstrated significant differential expression between the two groups. Ongoing concurrent comparative analyses of miRNA profiles within this cohort have also identified several differentially expressed transcripts including mir-34b, mir-155, mir-214, mir-200c and mir-143. Some of these miRNAs have been earlier reported to be associated with tumour progression. Further integrated analysis will elucidate the synergistic roles that the genetic and epigenetic alterations in the deregulation of these and other pathways involved in primary chemoresistance. Our research findings will yield diagnostic and prognostic biomarkers that will lead to development of specific treatment regimens for the improved control of serous epithelial ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3645. doi:1538-7445.AM2012-3645

Optimal assessment of response in ovarian cancer

Objective tumor response and progression, measured by standard criteria such as RECIST 1.1, are important measures of change in tumor size that are utilized as endpoints in phase II and III clinical trials. In ovarian cancer, RECIST criteria, which are based on anatomical tumor size, have been supplemented by CA125 response and progression criteria developed by the Gynecologic Cancer InterGroup. CA125 progression has been integrated with objective criteria into a composite definition of progression often used in the front-line setting, whereas response criteria are generally intended for use in recurrent disease trials. In terms of the performance of these endpoints in clinical trials, objective response, when used to assess the activity of new drugs in phase II trials in recurrent ovarian cancer, has proven to be helpful in identifying agents that have subsequently been shown to improve overall or progression-free survival in randomized trials. Thus, objective response has utility as an endpoint for new drug screening trials. Progression-free survival is often used as the primary (or co-primary) efficacy endpoint in studies of first-line therapy in ovarian cancer. Data from historical studies of platinum-based chemotherapy regimens indicate that improvements in progression-free survival generally translate into overall survival gains, indicating it may qualify as a surrogate endpoint for overall survival. It is not yet clear if this relationship will hold true in randomized trials of targeted agents, making it important to continue to assess overall survival in such studies. Finally, the routine monitoring of CA125 in patients after completion of front-line treatment as part of the standard of care has come under question with the publication of the results of a large European study; therefore, the use of CA125 progression as an endpoint in clinical trials will also likely be debated in the coming years.

First-line therapy for ovarian cancer with carboplatin followed by paclitaxel–gemcitabine (SCOTROC5): A feasibility study and comparative analysis of the SCOTROC series

Background We have conducted a series of four feasibility studies in stage Ic–IV ovarian cancer exploring six sequential first-line schedules with the same entry criteria in a total of 339 patients. Here we present the results of the sixth study, and an analysis of the overall series. Methods In this trial patients received 4 cycles of carboplatin AUC 7 every 3 weeks, followed by 4 cycles of concurrent paclitaxel 175 mg/m 2 (day 1) and gemcitabine 1000 mg/m 2 (days 1 and 8) every 3 weeks. The primary end-point of the trial was feasibility of administering all cycles of planned chemotherapy to >60% of patients. Results Fifty-four patients were recruited to the trial between June 05 and June 06. A total of 40 (74.1%) patients received all 8 cycles of treatment. Reasons for early discontinuation included toxicity ( n = 8) and disease progression ( n = 4). The overall response rate was 73.7%, and the median progression free survival (PFS) was 14.2 months with a median follow-up of 24 months. A comparative analysis of all six regimens from the SCOTROC series suggests that the sequential schedule in which paclitaxel was given weekly (median PFS 19.5 m) is most effective. 1 Conclusion The sequential schedule explored in this trial is feasible, but comparative efficacy analysis suggests that trials involving weekly paclitaxel should be prioritised for further study.

Serum carbonic anhydrase IX during first-line therapy of ovarian cancer

Objective Carbonic anhydrase IX (CAIX) is primarily involved in maintaining the extracellular pH. It is overexpressed in a variety of tumors including ovarian cancer. To evaluate the potential prognostic and predictive role of serum CAIX for therapy response in ovarian cancer, we analyzed longitudinal serum samples. Methods One hundred forty-eight serum samples from 37 patients with primary epithelial ovarian cancer were analyzed. Samples were prospectively collected at 4 time points: (1) before radical surgery, (2) after surgery and before platinum/taxane chemotherapy, (3) during chemotherapy, and (4) after chemotherapy. Serum CAIX was quantified by ELISA and expression in tumor tissue was verified by immunohistochemistry. Correlation with response and clinical outcome as well as the tumor marker CA-125 was analyzed. Results Serum concentration of CAIX ranged between 30 and 1687 pg/mL and showed no significant changes during first-line therapy (median level before and after surgery 204 and 198 pg/mL, during and after chemotherapy 175 and 181 pg/mL). There was no association between serum CAIX and progression-free or overall survival. CA-125 decreased significantly after surgery (median serum level before and after surgery 413 and 84 kU/L, p < 0.001) and further during and after first-line chemotherapy (median serum levels 21 and 15 kU/L, p < 0.001). No intermarker correlation was observed. Conclusions CAIX is upregulated in ovarian cancer and serum CAIX could be a marker to stratify patients for therapy response. However, CAIX serum levels did not change significantly during first-line therapy and were not prognostically relevant. Based on the findings of the current study, CAIX cannot be recommended for therapy monitoring in this context.

SCOTROC 2B: feasibility of carboplatin followed by docetaxel or docetaxel–irinotecan as first-line therapy for ovarian cancer

The feasibility of combination irinotecan, carboplatin and docetaxel chemotherapy as first-line treatment for advanced epithelial ovarian carcinoma was assessed. One hundred patients were randomised to receive four 3-weekly cycles of carboplatin (area under the curve (AUC) 7) followed by four 3-weekly cycles of docetaxel 100 mg m−2 (arm A, n=51) or docetaxel 60 mg m−2 with irinotecan 200 mg m−2 (arm B, n=49). Neither arm met the formal feasibility criterion of an eight-cycle treatment completion rate that was statistically greater than 60% (arm A 71% (90% confidence interval (CI) 58–81%; P=0.079; arm B 67% (90% CI 55–78%; P=0.184)). Median-dose intensities were >85% of planned dose for all agents. In arms A and B, 15.6 and 12.2% of patients, respectively, withdrew owing to treatment-related toxicity. Grade 3–4 sensory neurotoxicity was more common in arm A (1.9 vs 0%) and grade 3–4 diarrhoea was more common in arm B (0.6 vs 3.5%). Of patients with radiologically evaluable disease at baseline, 50 and 48% responded to therapy in arms A and B, respectively; at median 17.1 months’ follow-up, median progression-free survival was 17.1 and 15.9 months, respectively. Although both arms just failed to meet the formal statistical feasibility criteria, the observed completion rates of around 70% were reasonable. The addition of irinotecan to first-line carboplatin and docetaxel chemotherapy was generally well tolerated although associated with increased gastrointestinal toxicity. Further exploratory studies of topoisomerase-I inhibitors in this setting may be warranted.

Neuroprotection with amifostine in the first-line treatment of advanced ovarian cancer with carboplatin/paclitaxel-based chemotherapy—a double-blind, placebo-controlled, randomized phase II study from the Arbeitsgemeinschaft Gynäkologische Onkologoie (AGO) Ovarian Cancer Study Group

Neurotoxicity is a common side effect of platinum/taxane-based therapy of ovarian cancer. We performed a double-blind randomized placebo-controlled trial to evaluate the influence of the cytoprotectant amifostine on the neurotoxicity of first-line therapy of ovarian cancer with paclitaxel/carboplatin with or without epirubicin. Of 72 patients randomized, 71 were treated with paclitaxel 175 mg/m2 and carboplatin AUC5 with or without epirubicin 60 mg/m2 (q21 x 6) and randomized for i.v. premedication with amifostine 740 mg/m2 or placebo. Assessment included a questionnaire, NCI-CTC, tendon reflex activity (TRA), two-point discrimination (2-PD), measurement of vibration perception threshold (VPT) and vibration disappearance threshold (VDT), and quality of life. The majority of neurotoxicity criteria showed a significant impairment during therapy in both treatment arms. A significant protective effect of amifostine was observed for 2-PD, TRA, VPT and VDT. Amifostine failed to improve the 'global health status quality of life' score significantly. Toxicities according to NCI-CTC showed improved sensory neuropathy (P = 0.0046) but a worsening in terms of nausea (P = 0.0005) and vomiting (P = 0.0083). No significant differences were observed for single sensory and motor symptoms, except for a better skilfulness in the amifostine group (P = 0.0404). Amifostine improved sensory neuropathy according to NCI-CTC and with regard to objective neurological assessment, but there were almost no differences in self-estimated specific sensory or motor symptoms. Disadvantages with regard to non-neurological toxicities and inconsistent results for quality of life demand further evaluation of neuroprotection with amifostine as well as alternative approaches to prevent platinum-taxane induced neurotoxicity.

Primary ovarian cancer chemotherapy: current standards of care.

Chemotherapy has been regarded as standard therapy for the majority of women with advanced epithelial ovarian cancer for several decades, with this role filled largely by the alkylating agents — used as monotherapy — until the mid-1980s. The activity of cisplatin in this disorder was established during the 1970s, and combinations of cisplatin and an alkylating agent were widely used during the late 1980s. However, further research prompted by continuing concerns over poor survival and tolerability led to the adoption of paclitaxel in combination with either cisplatin or carboplatin as first-line therapy in ovarian cancer during the 1990s. Most recent research has focused on further optimisation of these regimens to maximise clinical benefit while minimising toxicity, and investigations into alternative taxanes (e.g. docetaxel), other novel agents and new treatment schedules are ongoing.

Carboplatin: first-line therapy for ovarian cancer?

Carboplatin: first-line therapy for ovarian cancer?

Docetaxel in ovarian cancer: Phase III perspectives and future development

In the mid 1990s, the incorporation of paclitaxel into platinum-based therapy for ovarian cancer marked a significant advance in treatment. Future progress will probably involve reductions in toxicity, which may be achieved by combining the less neurotoxic agent docetaxel with carboplatin. In an international phase III study, 1,077 chemotherapy-naive patients with stage Ic-IV ovarian cancer were randomized to receive carboplatin targeted to an AUC of 5 plus either docetaxel 75 mg/m(2) or paclitaxel 75 mg/m(2) for six cycles. Patients treated with paclitaxel plus carboplatin experienced significantly greater neurotoxicity than those treated with docetaxel plus carboplatin. Docetaxel/carboplatin and paclitaxel/carboplatin produced similar rates of objective response (66% and 62%, respectively), and initial data on progression-free survival indicate that the two treatments appear very similar in efficacy. Thus, docetaxel may prove to be a valid alternative to paclitaxel as part of first-line therapy in ovarian cancer. Nevertheless, there remains considerable scope for improvements in treatment. There is the possibility of using existing drugs more effectively, perhaps by the use of sequential rather than concurrent regimens. This would allow the most active drugs to be used at full dose, increase tolerability, and avoid the possibility of negative drug interaction. The integration of molecularly targeted agents, such as those directed at epidermal growth factor receptors, into existing regimens is highly promising but will need to be explored in randomized trials of first-line therapy. Because the prime obstacle to successful treatment is the acquisition of drug resistance, understanding the underlying mechanisms is an important future priority. One candidate is mismatch repair deficiency; the interest here is that experimental resistance reversal is achievable with hypomethylating agents, raising the possibility of future clinical trials if the clinical relevance of this mechanism can be confirmed.