Standard chemotherapy for advanced epithelial ovarian cancer is a combination of platinum-paclitaxel. One strategy to improve the outcome for patients is to add other agents to standard therapy. Doxil is active in relapsed disease and has a response rate of 25% in platinum-resistant relapsed disease. A dose finding study of doxil-carboplatin-paclitaxel was therefore undertaken in women receiving first-line therapy. Thirty-one women with epithelial ovarian cancer or mixed Mullerian tumours of the ovary were enrolled. The doses of carboplatin, paclitaxel and doxil were as follows: carboplatin AUC 5 and 6; paclitaxel, 135 and 175 mg m−2; doxil 20, 30, 40 and 50 mg m−2. Schedules examined included treatment cycles of 21 and 28 days, and an alternating schedule of carboplatin-paclitaxel (q 21) with doxil being administered every other course (q 42). The dose-limiting toxicities were found to be neutropenia, stomatitis and palmar plantar syndrome and the maximum tolerated dose was defined as; carboplatin AUC 5, paclitaxel 175 mg m−2 and doxil 30 mg m−2 q 21. Reducing the paclitaxel dose to 135 mg m−2 did not allow the doxil dose to be increased. Delivering doxil on alternate cycles at doses of 40 and 50 mg m−2 also resulted in dose-limiting toxicities. The recommended doses for phase II/III trials are carboplatin AUC 6, paclitaxel 175 mg m−2, doxil 30 mg m−2 q 28 or carboplatin AUC 5, paclitaxel 175 mg m−2, doxil 20 mg m−2 q 21. Grade 3/4 haematologic toxicity was common at the recommended phase II doses but was short lived and not clinically important and non-haematologic toxicities were generally mild and consisted of nausea, paraesthesiae, stomatitis and palmar plantar syndrome.
British Journal of Cancer (2002) 86, 1379–1384. DOI: 10.1038/sj/bjc/6600250 www.bjcancer.com
© 2002 Cancer Research UK
ovarian cancer; liposomal doxorubicin; carboplatin; paclitaxel
Current protocols for the treatment of ovarian cancer include combination chemotherapy with a platinating agent and a taxane. However, many patients experience relapse of their cancer and the development of drug resistance is not uncommon, making successful second line therapy difficult to achieve. The objective of this study was to develop and characterize a cell line resistant to both carboplatin and docetaxel (dual drug resistant ovarian cell line) and to compare this cell line to cells resistant to either carboplatin or docetaxel.
The A2780 epithelial endometrioid ovarian cancer cell line was used to select for isogenic carboplatin, docetaxel and dual drug resistant cell lines. A selection method of gradually increasing drug doses was implemented to avoid clonal selection. Resistance was confirmed using a clonogenic assay. Changes in gene expression associated with the development of drug resistance were determined by microarray analysis. Changes in the expression of selected genes were validated by Quantitative Real-Time Polymerase Chain Reaction (QPCR) and immunoblotting.
Three isogenic cell lines were developed and resistance to each drug or the combination of drugs was confirmed. Development of resistance was accompanied by a reduced growth rate. The microarray and QPCR analyses showed that unique changes in gene expression occurred in the dual drug resistant cell line and that genes known to be involved in resistance could be identified in all cell lines.
Ovarian tumor cells can acquire resistance to both carboplatin and docetaxel when selected in the presence of both agents. Distinct changes in gene expression occur in the dual resistant cell line indicating that dual resistance is not a simple combination of the changes observed in cell lines exhibiting single agent resistance.
Ovarian cancer; Multidrug resistance; Carboplatin; Docetaxel; Microarray analysis; A2780 cell line
Few reports delineate the pharmacokinetics of combination chemotherapy with paclitaxel and carboplatin in hemodialysis (HD) patients with epithelial ovarian cancer. However, the optimal carboplatin dose and the timing of HD have yet to be elucidated. We presented a case of an advanced-stage epithelial ovarian cancer patient with chronic renal failure requiring HD. After 4 courses of combination chemotherapy consisting of paclitaxel and carboplatin, a partial response was obtained; therefore, she underwent interval debulking surgery. Paclitaxel was administered for 3 h at a dose of 150 mg/m2, and carboplatin was administered for 1 h at a dose of 4–7 area under the concentration/time curve (AUC), which was calculated by the Calvert formula. HD was initiated 24 h after the start of administration of carboplatin and performed for a period of 3 h. Pharmacokinetic studies showed that the AUCs of free platinum and paclitaxel were 3.48–5.55 mg·min/ml and 13.5 μg·h/ml, respectively. Combination chemotherapy consisting of paclitaxel and carboplatin is a feasible approach to improving the treatment outcome of epithelial ovarian cancer patients with chronic renal failure requiring HD. The measurement of free platinum is useful in determining the optimal dose of carboplatin in order to obtain an adequate AUC. Determining the dose of carboplatin according to the Calvert formula and initiating HD after 24 h would ensure a favorable therapeutic effect with limited side effects.
epithelial ovarian cancer; carboplatin; paclitaxel; hemodialysis
Nab-paclitaxel is a novel Cremophor®-free nanoparticle of albumin-stabilized paclitaxel, which has favorable efficacy and toxicity characteristics relative to other solvent-based taxanes, such as paclitaxel and docetaxel.
Eligible patients had platinum- and taxane-resistant ovarian cancer, defined by persistent or progressive disease following primary chemotherapy (n=5) or recurrence within six months of treatment completion (n=42). All patients had measurable disease, no prior therapy for recurrent disease and Gynecologic Oncology Group performance status of ≤ 2. Treatment was nab-paclitaxel, 100 mg/m2 days 1,8,15 on a 28-day schedule. The primary endpoint was Response Evaluation Criteria in Solid Tumors v1.0 response rate, evaluated in a 2-stage design (with power of 0.90 for a RR of 25% and with alpha of 0.05 for RR of 10%).
Fifty-one patients were enrolled of which 47 were evaluable; median time from frontline therapy completion to registration was 21 days. Patient demographics include median age: 59 (34–78) years, serous histology: 72%, and high-grade: 81%. Efficacy: One complete and 10 partial responses were confirmed (23%); 17 patients (36%) had stable disease. The median progression-free survival was 4.5 months (95%CI: 2.2–6.7); overall survival was 17.4 months (95%CI: 13.2–20.8). Seventeen patients (36%) had PFS>six months. Toxicity: there were no grade 4 events; grade 3 events were neutropenia (6), anemia (3), GI (2), metabolic (2), pain (2), and leukopenia (1); neurosensory toxicity was observed as grade 2:5, grade 3:1.
Nab-paclitaxel has noteworthy single-agent activity and is tolerable in this cohort of refractory ovarian cancer patients previously treated with paclitaxel.
ovarian cancer; fallopian tube cancer; primary peritoneal cancer; platinum-resistant; taxane-resistant; nab-paclitaxel
Ovarian cancer is the most lethal gynecologic malignancy. It appears that the vast majority of what seem to be primary epithelial ovarian and primary peritoneal carcinomas is, in fact, secondary from the fimbria, the most distal part of the fallopian tube.
Treatment of epithelial ovarian cancer is based on the combination of cytoreductive surgery and combination chemotherapy using taxane and platinum. Although clear cell type is categorized in indolent type, it is known to show relatively strong resistance to carboplatin and paclitaxel regimen and thus poor prognosis compared to serous adenocarcinoma, especially in advanced stages. Irinotecan plus cisplatin therapy may effective for the clear cell adenocarcinoma.
The larger expectation for improved prognosis in ovarian carcinoma is related to the use of the new biological agents. One of the most investigated and promising molecular targeted drugs in ovarian cancer is bevacizumab, a monoclonal antibody directed against VEGF. PARP inhibitor is another one. A few recent studies demonstrated positive results of bevacizumab on progression-free survival in ovarian cancer patients, however, investigation of molecular targeting drugs in patients with ovarian cancer are still underway.
Review; ovarian cancer; conventional treatment; novel treatment; clear cell carcinoma; bevacizumab; PARP inhibitor
Resistance to platinum- and taxane-based chemotherapy is a major cause of treatment failure in ovarian cancer. Thus, it is necessary to develop a predictive marker and molecular target for overcoming drug resistance in ovarian cancer treatment. In a previous report, using an in vitro model, we found that the RET finger protein (RFP) (also known as tripartite motif-containing protein 27, TRIM27) confers cancer cell resistance to anticancer drugs. However, the significance of RFP expression in cancer patients remains elusive. In this study, we showed that RFP was expressed in 62% of ovarian cancer patients and its positivity significantly correlated with drug resistance. Consistent with clinical data, depletion of RFP by RNA interference (RNAi) in ovarian cancer cell lines, SKOV3 and HEY, significantly increased carboplatin- or paclitaxel-induced apoptosis and resulted in reduced anticancer drug resistance. In a nude mouse tumor xenograft model, inoculated RFP-knockdown ovarian cancer cells exhibited lower carboplatin resistance than control cells. These findings suggest that RFP could be a predictive marker for chemoresistance in ovarian cancer patients and also a candidate for a molecular-targeted agent.
Carboplatin; chemoresistance; epithelial ovarian cancer; paclitaxel; RET finger protein
In vitro testing of the activity of chemotherapeutic agents has been suggested as 1 method to optimally select drugs for patients with ovarian cancer. There are limited prospectively obtained data examining the clinical utility of this approach. We sought to obtain a preliminary assessment of this strategy in a trial that examined the administration of neoadjuvant chemotherapy followed by surgical cytoreduction and intraperitoneal chemotherapy in women with advanced ovarian cancer.
Women with stage III/IV epithelial ovarian carcinoma that presented with large-volume disease were treated with neoadjuvant intravenous paclitaxel and carboplatin for three 21-day cycles followed by cytoreductive surgery. If optimally debulked, patients received intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel for six 28-day cycles. Tumor cloning assay results (Oncotech) were correlated with progression-free survival.
Sixty-two patients (58 eligible) were registered from March 2001 to February 2006. Thirty-six eligible patients had interval debulking and 26 received postcytoreduction chemotherapy. Twenty-two patients had tumor cloning assay results available. The clinical features of this population were similar to those of the larger group of women who entered this study. There was no difference in progression-free survival between patients whose cancers were defined as ‘resistant’ or ‘nonresistant’ to either platinum or paclitaxel.
While the small patient numbers in this trial do not permit definitive conclusions, these data fail to provide support for the argument that prospectively obtained in vitro data regarding platinum or paclitaxel resistance will be highly predictive of clinical outcome in advanced ovarian cancer.
Paclitaxel; Carboplatin; Ovarian cancer; Cytoreduction; Neoadjuvant chemotherapy
In most patients with ovarian cancer, diagnosis occurs after the tumour has disseminated beyond the ovaries. In these cases, post-surgical taxane/platinum combination chemotherapy is the "gold standard". However, most of the patients experience disease relapse and eventually die due to the emergence of chemotherapy resistance. Histone deacetylase inhibitors are novel anticancer agents that hold promise to improve patient outcome.
We compared a prototypic histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), and paclitaxel for their treatment efficacy in ovarian cancer cell lines and in primary patient-derived ovarian cancer cells. The primary cancer cells were isolated from malignant ascites collected from five patients with stage III ovarian carcinomas. Cytotoxic activities were evaluated by Alamar Blue assay and by caspase-3 activation. The ability of SAHA to kill drug-resistant 2780AD cells was also assessed.
By employing the cell lines OVCAR-3, SK-OV-3, and A2780, we established SAHA at concentrations of 1 to 20 μM to be as efficient in inducing cell death as paclitaxel at concentrations of 3 to 300 nM. Consequently, we treated the patient-derived cancer cells with these doses of the drugs. All five isolates were sensitive to SAHA, with cell killing ranging from 21% to 63% after a 72-h exposure to 20 μM SAHA, while four of them were resistant to paclitaxel (i.e., <10% cell death at 300 nM paclitaxel for 72 hours). Likewise, treatment with SAHA led to an increase in caspase-3 activity in all five isolates, whereas treatment with paclitaxel had no effect on caspase-3 activity in three of them. 2780AD cells were responsive to SAHA but resistant to paclitaxel.
These ex vivo findings raise the possibility that SAHA may prove effective in the treatment of paclitaxel-resistant ovarian cancer in vivo.
On the basis of reversal of taxane resistance with AKT inhibition, we initiated a phase I trial of the AKT inhibitor perifosine with docetaxel in taxane and platinum-resistant or refractory epithelial ovarian cancer.
Patients with pathologically confirmed high-grade epithelial ovarian cancer (taxane resistant, n = 10; taxane refractory, n = 11) were enrolled. Peripheral blood samples and tumor biopsies were obtained and 18F-FDG-PET and DCE-MRI scans were performed for pharmacodynamic and imaging studies.
Patients received a total of 42 treatment cycles. No dose-limiting toxicity was observed. The median progression-free survival and overall survival were 1.9 months and 4.5 months, respectively. One patient with a PTEN mutation achieved a partial remission (PR) for 7.5 months, and another patient with PIK3CA mutation had stable disease (SD) for 4 months. Two other patients without apparent PI3K pathway aberrations achieved SD. Two patients with RAS mutations demonstrated rapid progression. Decreased phosphorylated S6 correlated with 18F-FDG-PET responses.
Patients tolerated perifosine 150 mg PO daily plus docetaxel at 75 mg/m2 every 4 weeks. Further clinical evaluation of effects of perifosine with docetaxel on biological markers and efficacy in patients with ovarian cancer with defined PI3K pathway mutational status is warranted.
Paclitaxel is a front-line agent for ovarian cancer chemotherapy, along with the platinum agents. Derived from the Pacific yew tree, Taxus brevifolia, paclitaxel has covered significant ground from the initial discovery of its antineoplastic properties to clinical applications in many forms of human cancers, including ovarian cancer. Although much has been published about the unique mechanism of action of this agent, several issues remain to be resolved. Finding the appropriate dosage schedule for paclitaxel in chemo-naïve and recurrent ovarian cancer, defining the role of paclitaxel in maintenance chemotherapy, and elucidating the mechanisms of taxane resistance are areas of intense research. Newer forms of taxanes are being manufactured to avoid troublesome adverse effects and to improve clinical efficacy. These issues are reviewed in detail in this paper with an emphasis on clinically relevant evidence-based information.
paclitaxel; clinical trials; ovarian cancer; treatment
Mitotic spindle-disrupting agents target and alter microtubule dynamics. These agents include clinically important chemotherapies, such as taxanes (paclitaxel [Taxol], docetaxel [Taxotere]) and vinca alkaloids (vincristine [Oncovin], vinblastine). Taxanes are a standard component of treatment for many malignancies, often in conjunction with other cytotoxic agents. However, the optimal sequencing of these treatments and whether efficacy may be influenced by in vitro cellular growth conditions remain incompletely investigated. Yet such preclinical investigations may guide clinical decision making. We therefore studied the effect of cell density on rapid killing by paclitaxel and vincristine. Breast, ovarian and prostate cancer cells were sensitive to rapid killing by either agent when grown at low density, but were markedly resistant when grown at high density, i.e., nearly confluent. The resistance of densely growing cells to rapid killing by these drugs translated to increased clonogenic survival. Pretreatment of densely growing cancer cells with cisplatin followed by paclitaxel, partially reversed the treatment resistance. Gene ontology associations from microarray analyses of cells grown at low and high density, suggested roles for membrane signal transduction and adhesion, but potentially also DNA damage repair and metabolism. Taken together, the treatment resistance at higher cell density may be associated with a lower proportion of active cycling in cells growing at high density as well as transduction of survival signals induced by increased cell-cell adhesion. Collectively these findings suggest mechanisms by which growth conditions may contribute to resistance to rapid killing by microtubule-disrupting drugs.
cellular density; paclitaxel; microtubule-targeting agents; microarray; cell cycle
Recently, an inverse
relationship between resistance to
platinum-based chemotherapeutic agents and
taxanes has been implicated in breast and
ovarian cancers, and a possible pivotal role for
BRCA1 has also been suggested. Because
(CDDP) and taxanes are the most active antitumor
agents against head and neck squamous cell
carcinoma (HNSCC), we analyzed the sensitivity
of nine HNSCC cell lines and their previously
established derived CDDP-resistant cell lines to
two representative taxanes: docetaxel and
paclitaxel. None of the nine original cell lines
showed any cross resistance between CDDP and
taxanes, but one of the CDDP-resistant cell
lines, RPMI2650CR, demonstrated hypersensitivity
to both taxanes when compared to the parental
cell line, RPMI2650. Furthermore, RPMI2650CR
exhibited increased expression of BRCA1. These
data suggest that (i) taxanes are a good
candidate for a second-line therapeutic drug for
HNSCC patients with acquired CDDP resistance
and (ii) BRCA1 can be a candidate marker for
predicting an inverse CDDP/taxane sensitivity
phenotype in HNSCC.
Background: Docetaxel is associated with prolonged survival in castration-resistant prostate cancer (CRPC). Platinum compounds have modest but distinct single-agent activity. Carboplatin may have greatest potential for benefit when combined with taxanes. We investigated whether there is a subset of patients with CRPC for whom the efficacy of combination taxane–estramustine–carboplatin (TEC) chemotherapy may be greatest.
Patients and methods: Individual patient data (n = 310) were obtained from seven trials using TEC chemotherapy. Prostate-specific antigen (PSA) response was defined as ≥50% post-therapy decline from baseline. Overall survival was defined from baseline to death from any cause. Logistic and Cox regression were used to investigate heterogeneity in outcome to TEC by patient and disease characteristics. Predicted survival probabilities were calculated from the Halabi Cancer and Leukemia Group B (CALGB) nomogram.
Results: The pooled PSA response proportion was 69% [95% confidence interval (CI) 56% to 80%]. There was no evidence of differential PSA response by disease characteristics. Established prognostic factors were associated with survival. The pooled 12-month survival estimate of 79% (95% CI 71% to 84%) was higher than the median 59% 12-month nomogram-predicted survival.
Conclusions: TEC chemotherapy has significant clinical activity in CRPC. A randomized, controlled trial evaluating the addition of carboplatin to taxane-based chemotherapy is needed to elucidate the value of carboplatin in CRPC.
carboplatin; estramustine; prostate cancer; taxanes
The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy.
Dose-dense regimens have been shown to improve outcome when given as adjuvant therapy to patients with breast cancer compared with their three weekly counterparts. We investigated the feasibility of a dose-dense regimen with carboplatin/paclitaxel followed by pegfilgrastim in patients with advanced ovarian cancer. We also investigated the toxicities including the percentage of patients with grade 2 or greater peripheral neurotoxicity and the clinical response of this regimen.
Patients and Methods
Women with untreated Stage III or IV epithelial ovarian, (fallopian) tubal, or primary peritoneal cancer were treated with carboplatin area under the curve (AUC) 5 and paclitaxel 175 mg/m2 day one, and pegfilgrastim 6 mg day two every two weeks for six cycles.
Between 9/06 and 9/08, 43 patients enrolled. Thirty one patients completed six or more cycles of therapy. The dose limiting toxicities resulting in treatment discontinuation included: grade 3 and 4 neuropathy, grade 4 thrombocytopenia, grade 4 thrombocytopenia/grade 3 febrile neutropenia, and grade 4 supraventricular tachycardia. Twelve patients (30%) had ≥ grade 2 neuropathy from this regimen. The overall response rate in patients with measurable disease was 58% (11 out of 19).
Dose dense carboplatin/paclitaxel appears to be effective. However, based on dose limiting toxicities occurring when administering 6 cycles of treatment, it is not feasible. Given the neuropathy and thrombocytopenia, we do not recommend 6 cycles of this regimen without modification.
chemotherapy; dose dense; ovarian cancer
To evaluate the role of lysophosphatidic acid (LPA) as a tumor marker in diagnosis and follow-up of patients with epithelial ovarian cancer.
Eighty-seven epithelial ovarian cancer patients, 74 benign ovarian tumor patients, and 50 healthy women were enrolled in the study. Twenty-nine of 87 epithelial ovarian cancer patients were followed up for 6 cycles of paclitaxel-carboplatin chemotherapy. CA-125 and total plasma LPA levels were measured preoperatively and before each chemotherapy cycle.
Preoperative total plasma LPA and serum CA-125 levels were significantly higher in patients with epithelial ovarian cancer compared to patients with benign ovarian tumors and healthy women. Cut-off value for LPA was determined as 1.3 µmol/L and sensitivity, specificity, positive predictive value and negative predictive value were 95%, 92%, 95% and 92%, respectively. Mean total plasma LPA level of 29 patients who received chemotherapy was 7.21±6.63 µmol/L preoperatively and 6.84±6.34 µmol/L, 6.34±5.92 µmol/L, 6.14±5.79 µmol/L, 5.86±5.68 µmol/L, 5.23±5.11 µmol/L and 5.21±5.32 µmol/L in measurements held just before the 1st, 2nd, 3rd, 4th, 5th and 6th chemotherapy cycles, respectively (ANOVA, p=0.832). Total plasma LPA levels decreased slightly with chemotherapy administration and there was a weak negative correlation (Spearman, rs=-0.151, p=0.034), compared to a significant negative correlation in CA-125 (Spearman, rs=-0.596, p<0.001).
LPA is a better biomarker for diagnosis of epithelial ovarian cancer compared to CA-125. However, measurement of total plasma LPA levels during chemotherapy administration have no superiority to the serum CA-125 levels.
Lysophosphatidic acid; CA-125; Epithelial ovarian cancer; Follow-up; Chemotherapy; Tumor marker
Carboplatin/paclitaxel is the chemotherapy of choice for advanced ovarian cancer, both in first line and in platinum-sensitive recurrence. Although a significant proportion of patients have some neurotoxicity during treatment, the long-term outcome of chemotherapy-induced neuropathy has been scantly studied. We retrospectively assessed the prevalence of residual neuropathy in a cohort of patients in clinical remission after first-line carboplatin/paclitaxel for advanced ovarian cancer.
120 patients have been included in this study (101 participating in a multicentre phase III trial evaluating the efficacy of consolidation treatment with topotecan, and 19 treated at the National Cancer Institute of Naples after the end of the trial). All patients received carboplatin (AUC 5) plus paclitaxel (175 mg/m2) every 3 weeks for 6 cycles, completing treatment between 1998 and 2003. Data were collected between May and September 2004. Residual sensory and motor neurotoxicity were coded according to the National Cancer Institute – Common Toxicity Criteria.
55 patients (46%) did not experience any grade of neurological toxicity during chemotherapy and of these none had signs of neuropathy during follow-up. The other 65 patients (54%) had chemotherapy-induced neurotoxicity during treatment and follow-up data are available for 60 of them. Fourteen out of 60 patients (23%) referred residual neuropathy at the most recent follow-up visit, after a median follow up of 18 months (range, 7–58 months): 12 patients had grade 1 and 2 patients grade 2 peripheral sensory neuropathy; 3 patients also had grade 1 motor neuropathy. The remaining 46/60 patients (77%) had no residual neuropathy at the moment of interview: recovery from neurotoxicity had occurred in the first 2 months after the end of chemotherapy in 22 (37%), between 2 and 6 months in 15 (25%), or after more than 6 months in 9 patients (15%). Considering all 120 treated patients, there was a 15% probability of persistent neurological toxicity 6 months after the end of chemotherapy.
A significant proportion of patients with advanced ovarian cancer treated with first-line carboplatin/paclitaxel suffer long-term residual neuropathy. This issue should be carefully taken into account before considering re-treatment with the same agents in sensitive recurrent disease.
The polo-like kinase PLK2 has recently been identified as a potential theranostic marker in the management of chemotherapy sensitive cancers. The methylation status of the PLK2 CpG island varies with sensitivity to paclitaxel and platinum in ovarian cancer cell lines. Importantly, extrapolation of these in vitro data to the clinical setting confirms that the methylation status of the PLK2 CpG island predicts outcomes in patients treated with carboplatin & paclitaxel chemotherapy. A second cell cycle regulator, p57Kip2, is also subject to epigenetic silencing in carboplatin resistance in vitro and in vivo, emphasising that cell cycle regulators are important determinants of sensitivity to chemotherapeutic agents and providing insights into the phenomenon of collateral drug sensitivity in oncology. Understanding the mechanistic basis and identification of robust biomarkers to predict collateral sensitivity may inform optimal use of chemotherapy in patients receiving multiple lines of treatment.
Polo Like Kinases; Chemotherapy resistance; collateral sensitivity
Recently a combination of paclitaxel and carboplatin (TC) (without an anthracycline) has begun to be used as an adjuvant or remission induction therapy, without any critical supportive evidence of its efficacy relative to a combination chemotherapy of taxane, platinum and anthracycline such as TEC (paclitaxel, epirubicin and carboplatin). The aim of our present study was to conduct the required clinical evaluations of the relative effectiveness of TC compared to TEC.
A retrospective comparison between the efficacy of TEC and TC regimens used for endometrial carcinoma at the Osaka University Hospital and the Osaka Medical Center for Cancer and Cardiovascular Diseases in Osaka, Japan, respectively, from 1999 to 2009 was performed. The clinical characteristics of the patients who received either TEC or TC were not significantly different, and TEC and TC therapies were initiated based on similar indications for chemotherapy. TEC regimen was paclitaxel (150 mg/m2), epirubicin (50 mg/m2) and carboplatin (AUC 4). TC regimen consisted of paclitaxel (175 mg/m2) and carboplatin (AUC 5).
TEC was demonstrated to provide significantly better survival than TC as an adjuvant therapy for resected Stage III/IV diseases (p = 0.017 for progression-free survival and p = 0.014 for overall survival, by the log-rank test). However, in recurrent or more advanced cases, TC and TEC demonstrated similar effects on survival (p = 0.55 for progression-free survival and p = 0.63 for overall survival).
TEC should be offered as an adjuvant therapy to Stage III/IV patients. TC may be considered for recurrent or unresectable cases as a remission induction therapy.
Endometrial carcinoma; Platinum; Taxane; Anthracycline; Survival
Eribulin mesylate is a tubulin inhibitor with activity superior to paclitaxel in NIH:OVCAR-3 human epithelial ovarian cancer xenograft models. We sought to assess the efficacy of eribulin in platinum-resistant and platinum-sensitive recurrent ovarian cancer.
Patients with recurrent measurable epithelial ovarian cancer, ≤2 prior cytotoxic regimens, and adequate organ function were enrolled into two separate cohorts: 1) Platinum resistant (progression-free interval from last platinum-based therapy <6 months); and 2) Platinum sensitive (progression-free interval from last platinum-based therapy ≥6 months). Treatment: Eribulin 1.4 mg/m2 over 15 minutes by vein on days 1 and 8, every 21 days. Efficacy was determined by objective response by computed tomography.
Platinum-resistant cohort: Thirty-seven patients enrolled. Thirty-six patients were evaluable for response and toxicity. Two patients achieved partial response (PR, 5.5%). Sixteen (44%) had a best response of stable disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.4–2.8 months). Platinum-sensitive cohort: Thirty-seven patients enrolled, and all were evaluable for response. Seven patients achieved partial response (PR, 19%). Median progression-free survival was 4.1 months (95% confidence interval, 2.8–5.8 months). The major toxicity was grade 3 or 4 neutropenia (42% in platinum-resistant patients; 54% in platinum-sensitive patients).
Eribulin achieved objective response in 5.5% of women with platinum-resistant recurrent ovarian cancer and in 19% of women with platinum-sensitive disease. Median progression-free survival was 1.8 months in the platinum-resistant group and 4.1 months in the platinum-sensitive group.
eribulin; ovarian cancer; phase II; recurrence
Despite a high initial response rate to first-line platinum/paclitaxel chemotherapy, most women with epithelial ovarian cancer relapse with recurrent disease that becomes refractory to further cytotoxic treatment. We have previously shown that the E3 ubiquitin ligase, EDD, a regulator of DNA damage responses, is amplified and overexpressed in serous ovarian carcinoma. Given that DNA damage pathways are linked to platinum resistance, the aim of this study was to determine if EDD expression was associated with disease recurrence and platinum sensitivity in serous ovarian cancer. High nuclear EDD expression, as determined by immunohistochemistry in a cohort of 151 women with serous ovarian carcinoma, was associated with an approximately two-fold increased risk of disease recurrence and death in patients who initially responded to first-line chemotherapy, independently of disease stage and suboptimal debulking. Although EDD expression was not directly correlated with relative cisplatin sensitivity of ovarian cancer cell lines, sensitivity to cisplatin was partially restored in platinum-resistant A2780-cp70 ovarian cancer cells following siRNA-mediated knockdown of EDD expression. These results identify EDD as a new independent prognostic marker for outcome in serous ovarian cancer, and suggest that pathways involving EDD, including DNA damage responses, may represent new therapeutic targets for chemoresistant ovarian cancer.
ovarian cancer; serous; EDD; recurrence; chemoresistance; cisplatin
Evaluation of the clinical efficacy and tolerance of metronomic chemotherapy as salvage therapy in a young patient with advanced, platinum resistant, ovarian carcinoma and bad performance status.
We tried palliative chemotherapy with daily low dose oral cyclophosphamide with a patient suffering from stage IIIC ovarian cancer that responded to daily cyclophosphamide (CTX) after no response to chemotherapy with paclitaxel and carboplatin as first line and progression after second line with topotecan.
The progression-free survival time on daily low dose oral cyclophosphamide treatment was 65 months without side effects. She was well during the chemotherapy and lived a normal working and social life.
We think that use of low dose of oral CTX should be investigated further as a strategy against tumour progression after standard chemotherapy in patients who are platinum resistant with poor performance status.
Although most patients with advanced gynaecologic malignancies respond to first-line treatment with platinum-taxane doublets, a significant proportion of patients relapse. Combining targeted agents that have non-overlapping mechanisms of action with chemotherapy may potentially increase the disease-free interval. Accordingly, this study evaluated the feasibility of combining pazopanib, an oral angiogenesis inhibitor, with paclitaxel and carboplatin.
This open-label, phase I/II study planned to evaluate the safety and efficacy of paclitaxel 175 mg m–2 plus carboplatin (AUC5 (Arm A) or AUC6 (Arm B)) once in every 3 weeks for up to six cycles with either 800 or 400 mg per day pazopanib.
Dose-limiting toxicities (DLTs) were observed in two of the first six patients enrolled at pazopanib 800 mg plus paclitaxel 175 mg m–2 plus carboplatin AUC5. Of the six patients enrolled in the next and lowest dosing level planned in the study, pazopanib 400 mg plus paclitaxel 175 mg m–2 plus carboplatin AUC5, two patients also experienced DLTs and the study was terminated. Two of the 4 DLTs observed overall were gastrointestinal perforations. Severe myelotoxicity was reported in 6 of 12 patients.
Combining either 800 or 400 mg per day pazopanib with standard carboplatin/paclitaxel chemotherapy is not a feasible treatment option.
ovarian cancer; pazopanib; phase I study
The taxanes paclitaxel and docetaxel are widely used in the treatment of breast, ovarian, and other cancers. Although their cytotoxicity has been attributed to cell-cycle arrest through stabilization of microtubules, the mechanisms by which tumor cells die remains unclear. Paclitaxel has been shown to induce soluble tumor necrosis factor alpha (sTNF-α) production in macrophages, but the involvement of TNF production in taxane cytotoxicity or resistance in tumor cells has not been established. Our study aimed to correlate alterations in the TNF pathway with taxane cytotoxicity and the acquisition of taxane resistance.
MCF-7 cells or isogenic drug-resistant variants (developed by selection for surviving cells in increasing concentrations of paclitaxel or docetaxel) were assessed for sTNF-α production in the absence or presence of taxanes by enzyme-linked immunosorbent assay (ELISA) and for sensitivity to docetaxel or sTNF-α by using a clonogenic assay (in the absence or presence of TNFR1 or TNFR2 neutralizing antibodies). Nuclear factor (NF)-κB activity was also measured with ELISA, whereas gene-expression changes associated with docetaxel resistance in MCF-7 and A2780 cells were determined with microarray analysis and quantitative reverse transcription polymerase chain reaction (RTqPCR).
MCF-7 and A2780 cells increased production of sTNF-α in the presence of taxanes, whereas docetaxel-resistant variants of MCF-7 produced high levels of sTNF-α, although only within a particular drug-concentration threshold (between 3 and 45 nM). Increased production of sTNF-α was NF-κB dependent and correlated with decreased sensitivity to sTNF-α, decreased levels of TNFR1, and increased survival through TNFR2 and NF-κB activation. The NF-κB inhibitor SN-50 reestablished sensitivity to docetaxel in docetaxel-resistant MCF-7 cells. Gene-expression analysis of wild-type and docetaxel-resistant MCF-7, MDA-MB-231, and A2780 cells identified changes in the expression of TNF-α-related genes consistent with reduced TNF-induced cytotoxicity and activation of NF-κB survival pathways.
We report for the first time that taxanes can promote dose-dependent sTNF-α production in tumor cells at clinically relevant concentrations, which can contribute to their cytotoxicity. Defects in the TNF cytotoxicity pathway or activation of TNF-dependent NF-κB survival genes may, in contrast, contribute to taxane resistance in tumor cells. These findings may be of strong clinical significance.
Intraperitoneal (IP) chemotherapy prolongs survival in optimally reduced ovarian cancer patients. For patients in whom optimal debulking cannot be achieved, one could incorporate IP therapy post-operatively if the cancer was optimally debulked following neoadjuvant chemotherapy. We sought to evaluate overall survival (OS), progression-free survival (PFS), percent of patients optimally debulked and toxicity in patients treated with this strategy.
Women with adenocarcinoma by biopsy or cytology with stage III/IV (pleural effusions only) epithelial ovarian, fallopian tube or primary peritoneal carcinoma that presented with bulky disease were treated with neoadjuvant intravenous (IV) paclitaxel 175 mg/m2 and carboplatin AUC 6 q 21 days x 3 cycles followed by surgery (if ≥ 50% decrease in CA125). If optimally debulked they received IV paclitaxel 175 mg/m2 and IP carboplatin AUC 5 (day 1) and IP paclitaxel 60 mg/m2 (day 8) q 28 days x 6 cycles.
Sixty-two patients were registered. Four were ineligible. Fifty-six were evaluated for neoadjuvant chemotherapy toxicities. One patient died of pneumonia. Five patients had grade 4 toxicity, including neutropenia (3), anemia, leukopenia, anorexia, fatigue, muscle weakness, respiratory infection, and cardiac ischemia. Thirty-six patients had debulking surgery. Two had grade 4 hemorrhage. Twenty-six patients received post-cytoreduction chemotherapy. Four had grade 4 neutropenia. At a median follow-up of 21 months, median PFS is 21 months and median OS is 32 months for all 58 patients. PFS and OS for the 26 patients who received IV/IP chemotherapy is 29 and 34 months respectively.
These results compare favorably with other studies of sub-optimally debulked patients.