Platinum Taxane Research Articles

Response and outcomes in elderly patients with stages IIIC–IV ovarian cancer receiving platinum–taxane chemotherapy

Objective. Recent reports have suggested that only half of women age ≥ 65 with advanced ovarian cancer are treated with platinum-based chemotherapy. The objective of this study was to compare the response to platinum–taxane chemotherapy and subsequent outcomes between patients older and younger than 65 years of age with stages IIIC–IV epithelial ovarian cancer (EOC). Patients and methods. A cohort study was performed of all patients with stages IIIC–IV EOC who had their primary surgery at our institution from 1998 to 2004 and subsequently began platinum–taxane chemotherapy. Main outcomes were response to primary chemotherapy, platinum resistance and progression-free (PFS) and overall survival (OS). Results. A total of 292 patients began primary platinum–taxane therapy after surgery and comprised our study group. Of these, 108 (37%) were ≥ 65 years old and 184 (63%) were < 65. Stage of disease, optimal cytoreduction rate, number of chemotherapy cycles and chemotherapy regimen alterations were similar between groups. Patients ≥ 65 achieved a clinical complete response with a similar frequency to those < 65 (70% vs. 79%) and had similar rates of platinum sensitivity at 6 months (61% vs. 65%). Patients ≥ 65 had equivalent PFS ( P = 0.99) and OS ( P = 0.36) to those < 65. Age ≥ 65 years was not independently associated with impaired survival. Conclusions. Patients ≥ 65 years of age demonstrated similar rates of initial response, platinum resistance, PFS and OS to younger patients. Elderly women who can tolerate primary cytoreductive surgery should receive combination platinum–taxane chemotherapy.

The impact of induction chemotherapy on the outcome of second-line therapy with pemetrexed or docetaxel in patients with advanced non-small-cell lung cancer

Using data from a large phase III study of previously treated advanced non-small-cell lung cancer (NSCLC) that showed similar efficacy for pemetrexed and docetaxel, this retrospective analysis evaluates the impact of first-line chemotherapy on the outcome of second-line chemotherapy. In all, 571 patients with advanced NSCLC were randomly assigned to receive pemetrexed 500 mg/m(2) or docetaxel 75 mg/m(2) on day 1 of a 21-day cycle. Comparisons were made based on type of first-line therapy [gemcitabine + platinum (GP), taxane + platinum (TP), or other therapies (OT)], response to initial therapy, time since initial therapy, and clinical characteristics. The two second-line treatment groups were pooled for this analysis due to similar efficacy and were assumed to have no interaction with the first-line therapies. Baseline characteristics were generally balanced. By multivariate analysis, gender, stage at diagnosis, performance status (PS), and best response to first-line therapy significantly influenced overall survival (OS). Additional factors by univariate analysis, histology, and time elapsed from first- to second-line therapy significantly influenced OS. Future trials in the second-line setting should stratify patients by gender, stage at diagnosis, PS, and best response to first-line therapy.

Current management of ovarian carcinosarcoma

Ovarian carcinosarcomas (OCS), also known as malignant mixed müllerian tumors, are uncommon malignancies that carry a poor prognosis. The presentation of OCS is usually indistinguishable from that of epithelial ovarian cancer. Due to its low frequency, prospective trials have been difficult to perform, but there is evidence that OCS are sensitive to platinum-based chemotherapy. Recent studies have shown encouraging results with platinum-ifosfamide and platinum-taxane schedules, which are usually considered the treatment of choice. However, poor performance status at presentation is also a common problem, so that many patients may be unsuitable for combination chemotherapy but may still benefit from single-agent platinum or ifosfamide or, occasionally, from nonplatinum schedules such as ifosfamide plus paclitaxel. Aggressive cytoreductive surgery appears to have a positive impact on outcome and should probably be offered to most patients. However, this procedure has been associated with higher rates of complication in OCS and should only be attempted by experienced (gynecological) surgeons in centers with expertise in the management of gynecological malignancies.

Gefitinib in combination with tamoxifen in patients with ovarian cancer refractory or resistant to platinum–taxane based therapy—A phase II trial of the AGO Ovarian Cancer Study Group (AGO-OVAR 2.6)☆

Tamoxifen and gefitinib (IRESSA) combination therapy was studied in patients with ovarian cancer refractory or resistant to platinum- and taxane-based therapy. In this phase II study, 56 patients with epithelial ovarian carcinoma or cancer of the fallopian tube or peritoneum received oral tamoxifen 40 mg/day and gefitinib 500 mg/day until progression or unacceptable toxicity. Seventeen patients (mean age: 59.6 years) had previously received first-line platinum/taxane treatment only, while 39 had received 2-8 (median 2) prior chemotherapy regimens. Gefitinib dose reduction to 250 mg/day was performed in 10 patients (14.9%), predominantly due to diarrhea (6 patients [10.7%]). Trial medication was discontinued in 6 patients (10.7%) due to adverse events (AEs). The most frequent drug-related AEs were diarrhea and acne-like skin rash. There were no tumor responses, but 16 patients had stable disease. Median time-to-progression was 58 days (95% CI, 55-71 days) and median survival was 253 days (95% CI, 137-355 days). Gefitinib plus tamoxifen did not appear to be efficacious in the treatment of patients with refractory/resistant ovarian cancer. The addition of tamoxifen did not worsen the known side effects of gefitinib, or induce additional side effects.

Efficacy and Antivascular Effects of EphA2 Reduction With an Agonistic Antibody in Ovarian Cancer

EphA2 is an oncoprotein and tyrosine kinase receptor that is overexpressed in ovarian and many other cancers. We investigated the effects of reduced EphA2 levels on tumor growth and the tumor microenvironment in an orthotopic ovarian cancer model. The effect of the EphA2-agonistic monoclonal antibody EA5, alone or in combination with paclitaxel, on the growth of ovarian cancer cells (SKOV3ip1, HeyA8, and HeyA8MDR [taxane-platinum resistant]) was determined in vitro and in vivo by immunoblotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and immunohistochemical analysis. Expression of EphA2 and markers of angiogenesis (CD31, vascular endothelial growth factor [VEGF], and basic fibroblast growth factor), proliferation (proliferating cell nuclear antigen), and endothelial cell apoptosis (CD31-terminal deoxynucleotidyl transferase biotin-deoxyuridine triphosphate nick-end labeling colocalization) and phosphorylation of Src were analyzed by immunoblotting, immunohistochemistry, immunofluorescence, and in situ hybridization in tumors from treated mice. Statistical tests were two-sided. EA5 antibody treatment led to a more than 90% reduction in EphA2 expression in HeyA8 tumors in vivo. In mice bearing orthotopic SKOV3ip1 or HeyA8 tumors, 4 weeks of EA5 treatment resulted in tumors that weighed 31% and 45% less, respectively, than those in control (IgG-treated) mice (95% confidence interval [CI] = -0.09% to 71% and 20% to 70%, P = .27 and .01, respectively). Combination therapy with EA5 and paclitaxel reduced tumor weight by 77% and 80% (95% CI = 63% to 91% and 68% to 91%), respectively, compared with paclitaxel alone and by 92% and 88% (95% CI = 87% to 97% and 80% to 94%), respectively, compared with IgG alone. Combination therapy also reduced the weight of HeyA8MDR tumors by 47% (95% CI = 24% to 72%) compared with paclitaxel. Mice bearing SKOV3ip1 or HeyA8 tumors that were treated with combination therapy survived longer than those treated with paclitaxel alone (median survival = 144 versus 69 days and 46 versus 37 days, respectively). EA5-treated tumors had reduced microvascular density, proliferation, and VEGF protein and mRNA levels, with increased endothelial cell apoptosis. EphA2 was associated with Src, which was rapidly dephosphorylated after EA5 treatment. EA5 in combination with paclitaxel decreased tumor growth in an orthotopic ovarian cancer mouse model through antiangiogenic mechanisms associated with reduced levels of VEGF and phosphorylated Src. Humanized antibody constructs against EphA2 are worthy of future study.

Analysis of third-line and fourth-line chemotherapy for recurrent ovarian cancer treated with first-line platinum/taxane regimens

15045 Background: Limited information is available regarding to the usefulness of third-line chemotherapy (TLC) and forth-line chemotherapy (FLC) for recurrent ovarian cancer treated with first-line platinum/taxane (PT) regimens. Methods: We retrospectively reviewed the medical records of patients (pts) with ovarian cancer treated with PT regimens at the National Cancer Center Hospital from 1998 to 2004. The aim of this study is to investigate the important clinical factor such as response rate (RR), time to treatment progression (TTP), overall survival (OS) and predictor of response to TLC and FLC. Kaplan-Meier method was used for estimating TTP and OS. Wilcoxon test was performed for survival times and p-values &lt; 0.05 were considered to be statistically significant. Results: There were 183 pts received first-line PT regimens in study period, 77 of 183 pts received second-line chemotherapy (SLC), 61 of 77 progressed after SLC and 55 of 61 pts received TLC. The RR to TLC was 34.5%. The median TTP was 5 months (mo) (range; 1–19 mo) and the median OS was 12 mo (range; 2–38 mo). The TLC regimen was consisted of P and/or T regimens of 36 pts and the other regimens of 19 pts. The RR according to the duration of response of previous chemotherapy (DRPC) (&lt; 6 mo and ≥ 6 mo) were 31.4% and 37.3%, respectively. The median OS of DRPC (&lt; 6 mo and ≥ 6 mo) were 8 mo (range; 2–33 mo) and 12 mo (range; 2–38 mo), respectively (p = 0.002). After TLC 47 pts progressed and 29 pts received FLC. The RR to FLC was 27.5%. The median TTP was 3 mo (range; 0–11 mo). The median OS of 18 pts who didn’t receive FLC and 29 pts received FLC were 2 mo (range; 2–16 mo) and 7 mo (range; 2–25 mo), respectively (p = 0.01). The RR according to DRPC (&lt; 4 mo and ≥ 4mo) were 22.2% and 30%, respectively. The median OS of DRPC (&lt; 4 mo and ≥ 4 mo) were 3 mo (range; 2–23 mo) and 6 mo (range; 2–25 mo), respectively (p = 0.4). Conclusions: The DRPC is considered to be predictor of response to TLC but not to FLC. Giving TLC and FLC if the pts have tolerable may improve OS, however this analysis is prone to several well-established potential biases and limitations. Further prospective study is warranted. [Table: see text]

Combined PEG liposomal doxorubicin and gemcitabine are active and have acceptable toxicity in patients with platinum-refractory and -resistant ovarian cancer after previous platinum–taxane therapy: A phase II Austrian AGO study

Objectives. Platinum resistance is a significant problem in patients with ovarian cancer. The aim of this phase II study was to define the response rates, the progression-free survival and the toxicity profile of the combination of PEG liposomal doxorubicin (L-DXR) and gemcitabine (GEM). Material and methods. Thirty one patients with histologically confirmed platinum-refractory or -resistant epithelial ovarian cancer were scheduled to receive 6 cycles of L-DXR 30 mg/m 2 on day 1 as well as GEM 650 mg/m 2 on days 1 and 8 every 28 days. Results. The median number of chemotherapy cycles given was 4. The mean dose intensity for L-DXR and GEM on day 1 was 96% and 97%, respectively. The mean dose intensity for GEM on day 8 was 93%. The overall response rate was 33% (10 of 30 evaluable patients; 20% complete responses). The median progression-free survival was 3.8 months, and the median overall survival was 15.8 months, respectively. Toxicity was acceptable. One quarter of patients developed grade 3 or 4 neutropenia, but none developed febrile neutropenia. Palmoplantar erythrodysesthesia (PPE) grades 2 and 3 occurred in 13% and 3% only, respectively, and no grade 4 PPE was observed. Grades 1 to 3 stomatitis was found in 58% of patients (10% grade 3). Conclusion. The combination of L-DXR and GEM is an active and acceptably tolerated option in the treatment of patients with platinum-resistant and -refractory ovarian cancer. Dose reductions seem advisable in the case of ≥grade 2 stomatitis and/or PPE ≥grade 2.

Two for good measure: Six versus eight cycles of carboplatin and paclitaxel as adjuvant treatment for epithelial ovarian cancer

Introduction. Although the standard of care for advanced epithelial ovarian cancer (EOC) is six cycles (6C) of platinum-taxane (PT), there have been no studies on the optimal duration of treatment in the era of adjuvant taxanes. At our center, some women receive eight cycles (8C) of PT, based on physician judgment. We were interested in evaluating the outcomes of women treated with 8C of PT for EOC as compared to a cohort who received 6C. Methods. We retrospectively identified women with Stage III or IV EOC between 1998 and 2003 who received 6C or 8C of PT. The endpoints were disease-free (DFS) and overall survival (OS). CA-125 response was defined as a decrease in CA-125 of 50% in four serial samples or of 75% over three samples. Results. One hundred and twenty-two women met criteria for inclusion; 84 received 6C, and 38 received 8C. Comparing the cohorts receiving 6C versus 8C, 71% versus 26% were optimally debulked ( P < 0.01). 79 patients were evaluable by CA-125 (52 6C/27 8C), and all responded. 88% receiving 6C and 81% receiving 8C normalized their CA-125 at end of treatment ( P = 0.20). The proportion with a normal CA-125 at Cycle 2 was 29% versus 12%, respectively ( P = 0.15) and, at Cycle 4, was 88% versus 36%, respectively ( P < 0.01). DFS was 13 months with 6C and 8 months with 8C ( P = 0.01). OS was 31 versus 23.5 months ( P = 0.02), respectively. When the survival analysis is restricted to suboptimal debulked patients only, the DFS is 12.5 versus 8 months ( P = 0.02), and OS is 32 versus 26.5 months ( P = 0.15), respectively. Conclusions. Two further cycles of PT did not improve DFS or OS for patients with advanced EOC. Patients who do not achieve remission after 6C are unlikely to benefit from additional chemotherapy using the same agents and should be considered for clinical trials involving novel agents with different mechanisms of action.

Optimizing First-Line Treatment Options for Patients with Advanced NSCLC

The median survival time for advanced non-small cell lung cancer (NSCLC) remains poor, despite years of research into new chemotherapy combinations. Platinum-based chemotherapy has long been the standard of care for the initial treatment of advanced NSCLC. While no one particular platinum-based chemotherapy regimen is definitely superior to the others (as demonstrated in the Eastern Cooperative Oncology Group's E1594 trial), three randomized phase III trials (the Southwest Oncology Group 9509, Italian Lung Cancer Project, and TAX326 trials) have recently demonstrated that taxane-platinum doublets are better tolerated than a combination of vinorelbine and cisplatin (VC). Moreover, a combination of docetaxel and cisplatin produced superior survival and quality of life than VC in the TAX326 study. Nonplatinum combinations, such as a taxane-gemcitabine doublet, appear promising and better tolerated than their platinum-based comparators in other studies. Efforts to evaluate chemotherapy specifically in elderly patients and in those with poor performance status (PS) have increased. Single-agent chemotherapy has been safely administered to these populations, but platinum-based doublet therapy may also be feasible in both elderly patients and patients with PS scores of 2. The addition of the monoclonal antibody against vascular endothelial growth factor, bevacizumab, to standard chemotherapy for patients with non-squamous cell advanced NSCLC significantly extended median survival in the E4599 randomized trial. Each incremental advance demonstrates that progress can be made in first-line treatment of advanced NSCLC.

Treatment of recurrent ovarian cancer: a retrospective analysis of women treated with single-agent carboplatin originally treated with carboplatin and paclitaxel: The Memorial Sloan-Kettering Cancer Center experience

Objective There is no standard treatment for recurrent epithelial ovarian cancer (EOC). As there are no curative options, many oncologists choose to treat women who recur with carboplatin, particularly if they are deemed to have platinum-sensitive disease. However, particularly in the era of platinum–taxane treatment as primary therapy, the utility of this treatment has not been established, nor is it clear whether the results of single-agent treatment are equivalent to that of combination therapy. We sought to determine the outcomes for patients with platinum-sensitive EOC who were treated with carboplatin–taxane therapy and received single-agent carboplatin (C) as second chemotherapy. In addition, we sought to compare these results to the outcomes in women who received carboplatin and paclitaxel (C + T) at first relapse. Patients and methods We identified 24 patients using our electronic institutional database with a histologically confirmed diagnosis of ovarian cancer that had a complete response to platinum–paclitaxel chemotherapy, relapsed greater than 6 months after treatment, and received single-agent carboplatin as second-line chemotherapy. We performed a subsequent comparison between a subgroup of this cohort and one that met the same inclusion criteria but received C + T at relapse between January 1998 and December 2000. Results Eighteen patients were evaluable for response, and all were available for analysis of survival end points. For evaluable patients, the overall response rate was 39% (complete, 11%; partial, 28%). Twenty-two percent had stable disease. Six (25%) patients experienced a hypersensitivity reaction, including 1 who required hospitalization. The median overall survival was 22 months. The 2-year overall survival rate was 49%. Stratification by treatment-free interval (TFI) showed a 25% for a TFI between 6 and 12 months and 43% for a TFI > 12 months. When a subgroup of these women (18/24) was compared to a cohort that received C + T (29), the combination was associated with a higher complete and overall response rate, 7 and 36% for C versus 45 and 71% for C + T ( P = 0.02). The overall survival in women who received C was 26 months versus 42 months in the women who received C + T ( P < 0.02). Conclusions Carboplatin as a single agent is effective therapy for recurrent ovarian cancer in women who recur following treatment with carboplatin and paclitaxel, and the treatment-free interval predicts response to single-agent carboplatin. However, our secondary analysis suggests that carboplatin and paclitaxel may produce a higher response rate and a survival benefit compared to C alone. This supports the conclusions of ICON4, which recently reported both overall and progression-free survival benefits with C + T over C in women with platinum-sensitive recurrent disease.

Sequential single agents as first-line chemotherapy for ovarian cancer: a strategy derived from the results of GOG-132

First-line chemotherapy for ovarian cancer during the past decade has evolved toward the use of carboplatin and paclitaxel combinations. This has been based on randomized trials showing that combinations of these two drugs lead to a outcome similar to that obtained using cisplatin and paclitaxel (that had, in turn, proven superior in progression-free survival and overall survival to cisplatin and cyclophosphamide) but with less toxicity. Surprisingly, taxane–platinum combinations were not superior to control arms in two studies (ICON3 and GOG-132) utilizing carboplatin or cisplatin as the comparators. This has renewed interest in the role of single agents in first-line chemotherapy – a concept also supported by a number of prior clinical trials with single-agent platinum compounds yielding results not inferior to combinations. Early ‘pre-emptive’ crossover (prior to the stipulated clinical progression) to paclitaxel or a paclitaxel-containing regimen, however, occurred in 24% of patients initially treated with cisplatin on GOG-132. This has led to the interpretation of this trial as a combination versus sequential design. Although not subscribing to this interpretation, the results of GOG-132 and ICON3 not only raise doubts over a clear superiority of combinations over single agents but also lead to a consideration of sequential treatment designs for first line. Advantages of such designs are: (a) ability to provide ‘dose-dense’ platinums followed by ‘dose-dense’ paclitaxel and, perhaps, other drugs; and (b) the potential of acquiring biological data linked to the antitumor effects of a specific drug. Mathematical modeling and recent positive results in breast cancer adjuvant therapy support the use of ‘dose-dense’ strategies, and these should be considered in the design of future trials in ovarian cancer.