Novel, dose intensive, single-agent cisplatin in the first-line management of advanced stage ovarian cancer

Cisplatin-based combination chemotherapy is the current standard chemotherapy for the management of advanced stage, epithelial ovarian cancer. However, correlation has been demonstrated previously between dose intensity and response for cisplatin, but not for the other cytotoxic drugs commonly used. We treated 46 consecutive, newly diagnosed patients following standard debulking laparotomy with cisplatin 60 mg m⁻² every 2 weeks for a total of 8 cycles. Survival and toxicity were compared with those of a similar cohort of 24 consecutive, newly diagnosed patients treated with cisplatin 75 mg m⁻² plus cyclophosphamide 600 mg m⁻² every 4 weeks for 6 cycles, at the same institution immediately prior to the current cohort. The single-agent cisplatin cohort received a mean relative cisplatin-equivalent dose intensity of 1.43 compared with a received mean relative cisplatin-equivalent dose intensity of 0.88 in the combination chemotherapy cohort, a 62.5% increase in the cisplatin dose intensity. At 2 years, 69% of the patients receiving single-agent cisplatin were alive, compared with 38% of the group receiving the combination chemotherapy ( P = 0.014). Alopecia ( P < 0.00001) and myelosuppression ( P < 0.0000001) were markedly less in the patient group receiving single-agent cisplatin. There was no significant difference in the incidence of neurotoxicity ( P = 0.28) or nephrotoxicity ( P = 0.38) between the two patient groups. In summary, relatively dose intensive, single-agent cisplatin given in a biweekly schedule for the first-line management of advanced stage, ovarian cancer produced a survival advantage compared with the previous combination cyclophosphamide/platinum combination chemotherapy. This novel therapy takes one-third less time to complete and causes fewer side effects than the current standard of combination cyclophosphamide and cisplatin.     

Twelve-year follow-up of a randomized trial comparing cisplatin and cyclophosphamide with cisplatin, doxorubicin and cyclophosphamide in patients with advanced epithelial ovarian cancer

From 1982 to 1984, 131 patients with FIGO stage Ic-IV epithelial ovarian cancer were included in a randomized clinical trial comparing cisplatin 50 mg m⁻² plus cyclophosphamide 600 mg m⁻² (PC regimen) with PC plus doxorubicin 45 mg m⁻² (PAC regimen). Chemotherapy was repeated every 4 weeks for six cycles. The criteria for entry, the characteristics of the elegible patients, the response rates and the toxicities have been previously reported. The study was updated in August 1994 with a median follow-up of 10.5 years (range 10–12 years). In the whole series, the median time to progression is 13 months and the 12-year progression-free survival (PFS) is 18%, whereas the median time to survival is 21 months and the 12-year survival is 21%. By log-rank test survival is significantly related to residual disease after first surgery ( P <0.0001), ECOG performance status (PS) ( P <0.0001), FIGO stage ( P =0.0001) and histologic grade ( P =0.04), but not to type of chemotherapy and age. By Cox proportional hazard model residual disease ( P =0.0004), histologic grade ( P =0.01) and ECOG performance status ( P =0.049), but not FIGO stage, treatment arm and age, are independent prognostic variables for survival. The survival curves are superimposable in the two treatment arms among patients with residual disease <2 cm, whereas there is a trend in favor of the PAC regimen among patients with larger residual disease. By log-rank test PFS is not significantly related to chemotherapy arm. However, it is worth noting that among patients with residual disease >2 cm 12-year PFS is 12.5% for PAC arm, while all patients of PC arm progressed by the sixth year. Conversely, the PFS curves are superimposable in the two treatment arms among patients with residual disease <2 cm.     

A meta-analysis of the efficacy of intraperitoneal cisplatin for the front-line treatment of ovarian cancer

Ovarian cancer is the fourth leading cause of cancer death among women in the United States. First-line chemotherapy offered to patients with ovarian cancer generally consists of an intravenous (IV) platinum plus taxane regimen and has remained virtually unchanged for the past 10 years. A number of recently completed phase III randomized trials in the United States have reported improved progression-free survival (PFS) and/or overall survival (OS) with the intraperitoneal (IP) administration of cisplatin. The purpose of this study was to pool the published data to perform a meta-analysis of randomized trials of IP cisplatin in the initial chemotherapy treatment of ovarian cancer patients. This study was initiated to obtain a more valid estimate of the therapeutic impact of IP treatment for these patients. A search strategy was initiated that searched published findings of randomized trials of IP cisplatin therapy from multiple sources from January 1990 through January 2006. Six randomized trials of 1716 ovarian cancer patients were identified and included in this analysis. The pooled hazard ratio (HR) for PFS of IP cisplatin as compared to IV treatment regimens is 0.792 (95% CI: 0.688-0.912, P= 0.001), and the pooled HR for OS is 0.799 (95% CI: 0.702-0.910, P= 0.0007). These findings strongly support the incorporation of an IP cisplatin regimen to improve survival in the front-line treatment of stage III, optimally debulked ovarian cancer.     

Profiling of proteins associated with cisplatin resistance in ovarian cancer cells

Resistance to cisplatin is a major impediment to the successful treatment of ovarian cancer, but the precise nature of the resistance is still unclear. In the current study, we aimed to investigate and compare the protein expression profiles in cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines. We employed the recent development of surface-enhanced laser desorption/ionization ProteinChip technology to measure protein expression in three human ovarian cancer cell lines (KF-1, MN-1, and A2780) and their sublines (KF-r, MN-r, and A2780cp) resistant to cisplatin. The ProteinChip Arrays were analyzed using the ProteinChip Reader. We did not find any regularity in protein expressions in secretions of cisplatin-sensitive and cisplatin-resistant cells. But on the IMAC3 array, we captured 12 identical expressions which represent a subset of proteins whose expression levels are different between parent ovarian cancer cells and their cisplatin-resistant cells. In particular, at the molecular weight of 7829 d, three kinds of parent cell lines exhibited an elevated expression and their cisplatin-resistant sublines revealed a lowered expression. At the molecular weight of 6881 d, for KF and MN cell lines, opposite protein expressions were seen in the parent cell line and its cisplatin-resistant subline. We think the interesting protein expressions perhaps suggest some mechanisms involved in cisplatin resistance.     

Weekly cisplatin ± glutathione in relapsed ovarian carcinoma

On the basis of experimental data showing the efficacy of glutathione (GSH) as a protective agent on cisplatin-induced neurotoxicity and the clinical evidence of the low incidence of neurotoxicity in high-dose cisplatin + GSH treated patients we evaluated the neuroprotective effect of GSH in a randomized phase II study. Thirty-three patients with relapsed ovarian cancer after a disease-free interval of at least 1 year and a cumulative dose of prior cisplatin ranging 450–650 mg m⁻² were randomized to receive cisplatin 50 mg m⁻² weekly ± 2.5 g GSH for 9 consecutive weeks. Clinical and instrumental neurologic and otologic evaluations were made at the baseline and at the end of the study. Overall response rate in 31 evaluable patients was: 9/15 in group A and 12/16 in group B, including 4/15 vs 7/16 complete responses. The administered dose intensity of cisplatin was higher in the GSH treated patients (100% dose intensity was received by 56% vs 27%). A trend in terms of neuroprotection was detected in the GSH treated group, and no major difference was observed in the other toxicities between the two groups. It is concluded that possible benefit can be expected from the concomitant administration of GSH and cisplatin in patients at high risk of developing neurotoxicity, without decreasing the anti-tumor activity.     

A pharmacokinetic and clinical evaluation of thio-TEPA in combination with cisplatin as first-line chemotherapy for advanced epithelial ovarian carcinoma

The purpose of the study was to explore the combination of thio-TEPA with cisplatin in first-line chemotherapy of epithelial ovarian cancer with special reference to pharmacokinetic and pharmacodynamic relationships. Ten women with advanced disease were included. Pharmacokinetics of thio-TEPA were similar to those in previous studies of single drug therapy with rapid first order elimination of the parent drug and substantial intra- and interindividual variation of the area under the concentration–time curve (AUC). No effects of the drug sequence or repeated treatments were seen on the pharmacokinetics of thio-TEPA, indicating no significant influence from the coadministration of cisplatin on the distribution, metabolism or excretion of thio-TEPA. Pharmacokinetic--pharmacodynamic relationships were less pronounced compared to previous studies, probably due to the influence from cisplatin. Prolongation of treatment intervals, dosage reduction, and withholding of thio-TEPA were required due to myelosuppression, which was the dominating toxicity. Non-hematological toxicity was moderate and easily manageable, cisplatin-related toxicity did not seem to be aggravated. Response rate based on CA 125 fluctuations was 80%, overall median survival was 18 months. In conclusion, the pharmacokinetics of thio-TEPA does not seem to be significantly influenced by concomitant administration of cisplatin in female patients. Manageable toxicity, largely restricted to myelosuppression, and high response rate justify further evaluation of the current regimen.     

Cisplatinum rechallenge in relapsed ovarian cancer patients with platinum reinduction therapy and carboplatin hypersensitivity

Hypersensitivity reactions have been reported as limiting side effect in patients re-exposed to carboplatin for relapsed gynecologic malignancy. This study analyzed the incidence, clinical features, management, and outcome of carboplatin-associated hypersensitivity reactions. We performed a retrospective study and analyzed medical records of all gynecological cancer patients treated with carboplatin in our institution from 2000 to 2003. No hypersensitivity reactions were observed in 171 patients during the first carboplatin-containing chemotherapy. All six carboplatin-associated hypersensitivity reactions occurred in 69 patients who were re-exposed to carboplatin (9%). The median number of carboplatin cycles prior to hypersensitivity reaction was nine (range, 8-13). Cisplatin rechallenge was performed in five patients, and no hypersensitivity occurred. An increase in neurotoxicity (National Cancer Institute Common Toxicity Criteria grade 2) was documented in two patients who had residual neurotoxicity grade 1 due to prior taxane treatment. Cisplatinum rechallenge is a feasible strategy to overcome carboplatin hypersensitivity. However, close monitoring of neurotoxicity is necessary, particularly in patients with residual neurotoxicity due to prior platinum- and taxane-containing chemotherapy.     

Expression of glutathione S-transferase π and cisplatin resistance in human ovarian cancer

Glutathione S-transferase π (GSTπ) expression in tumor cells is thought to relate to cisplatin resistance. We attempted to clarify immunohistochemically the correlation between GSTπ expression and clinical response in ovarian cancer. Fifty-nine patients with ovarian cancer underwent initial debulking surgery and received from three to five courses of cisplatin-based chemotherapy after surgery. Immunostaining for GSTπ was performed on formalin fixed sections of the patients' tumor by the streptoavidin-biotin-peroxidase complex method. Positive staining of GSTπ was observed diffusely in nuclei and cytoplasm of cancer cells. Of 59 tumors, 38 (64.4%) were GSTπ positive. Twenty-three of 25 patients (92.0%) who showed no response to chemotherapy had GSTπ positive tumor cells. The predictive value of positive GSTπ staining for drug resistance was 79.3% (23/29). The 5-year survival rate of patients with GSTπ positive tumors was significantly lower than that of those with GSTπ negative tumors by the Kaplan-Meier method ( P < 0.01). The results suggest that overexpression of GSTπ is related to resistance to cisplatin and to prognosis in patients with ovarian cancer.     

Carboplatin with cyclophosphamide in patients with advanced ovarian cancer: an efficacy and quality-adjusted survival analysis

The efficacy and toxicity of a combination of carboplatin and cyclophosphamide (CC) were studied in a group of 76 patients with advanced ovarian cancer. Progression-free (PFS) and overall survival were compared with a historical group of 65 patients treated with CAP-5 (cyclophosphamide, adriamycin, cisplatin). Subjective toxicity was compared by the measurement of TWiST, the Time Without Symptoms of Disease or Treatment. Of 75 evaluable patients treated with CC, 18 (24%) had a pathologically complete remission (pCR), and 31 (41%) a partial remission (PR). CC led to leukopenia grade III in 38% and grade IV in 3% of 421 treatment cycles. Thrombocytopenia grade III was seen after 7% and grade IV after 2% of cycles. Treatment delay occurred in 11.5% and dose reduction in 21% of cycles. Nephro- or neurotoxicity did not occur. After a median follow-up of 18 months, the median PFS was 24 months and the overall survival was 25 months. Median duration of TWiST was 22 versus 10 months after CAP-5 ( P < 0.01). Compared with historical controls, treatment with CC is equivalent to CAP-5. It is free of nephro- and neurotoxicity, but is more myelosuppressive. Quality of life, measured by TWiST, is significantly better during CC. As a consequence of its equivalent efficacy, but lower subjective toxicity, carboplatin should replace cisplatin in treating patients with advanced ovarian cancer.     

Tamoxifen in patients with advanced epithelial ovarian cancer

Tamoxifen was administered to 30 patients with persistent or recurrent epithelial ovarian cancer following initial plantinum-based chemotherapy. Two complete remissions (lasting 41 months and 12 months, respectively) were documented (6.6%), while 10 patients (33.3%) had stabilization of disease for a mean duration of 11.5 months. Tamoxifen was not associated with any significant toxicity and is a reasonable therapeutic option for patients with persistent or recurrent ovarian cancer, although it is only associated with modest activity. This paper reviews our experience with tamoxifen and summarizes the world literature.     

Chemosensitivity testing of ovarian cancer using the histoculture drug response assay: sensitivity to cisplatin and clinical response

Despite cytoreductive surgery and chemotherapy, the prognosis of advanced ovarian cancer is still poor. Predicting the chemosensitivity of tumors might improve the outcome. Therefore, we investigated the clinical value of the histoculture drug response assay for ovarian cancer. Tumor specimens were cultured for 7 days on collagen gel sponge in medium containing cisplatin, and the 50% inhibitory concentration was determined by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay. Then the in vitro sensitivity to cisplatin was compared with the clinical response and survival. Apoptosis of tumor cells was also investigated. Among 173 ovarian cancer patients, 164 were evaluable by the assay, and 29 patients had measurable lesions for which the clinical response could be determined. The 5-year survival rate was significantly higher in patients with chemosensitive tumors than in those with chemoresistant tumors when the cutoff value was set at a 50% inhibitory concentration of 25 microg/mL and the accuracy of the assay was 82.8% (24/29). As chemosensitivity to cisplatin became greater, the number of apoptotic cells also increased. This chemosensitivity assay may help predict the clinical response to cisplatin-based chemotherapy, thus improving the survival of ovarian cancer patients.     

Phase II trial of combination intraperitoneal cisplatin and 5-fluorouracil in previously treated patients with advanced ovarian cancer: long-term follow-up

OBJECTIVES: This trial was performed to determine the response rate and progression-free and overall survivals of patients with advanced recurrent ovarian cancer who were treated with intraperitoneal cisplatin and 5-fluorouracil. METHODS: Twenty-four patients with ovarian cancer were entered on this trial and treated with intraperitoneal (ip) cisplatin (DDP) and ip 5-fluorouracil, every 3 weeks for eight cycles. Following iv hydration, the cisplatin and 5-fluorouracil were administered through an ip catheter in 2 liters of 0.9% normal saline with a 4-h dwell. RESULTS: All patients were evaluable for progression-free and overall survival and toxicity analysis, and 22 patients for response. The median age was 59 (range, 35-71); initial disease status included 9 patients with residual disease following chemotherapy prior to entry on this study; 5 patients had progressed, and 10 patients had recurrent disease more than 6 months following initial chemotherapy. Of the 9 patients with residual disease, 1 complete response and 3 partial responses were observed; of 10 patients with recurrent disease, 1 complete and 1 partial response were observed for an overall response rate of 27%. No objective responses were seen in the 7 patients who were platinum-refractory on protocol entry. The median progression-free and overall survivals are 7.0 (range, 0.5-137) and 15.5 (range, 3-147) months, respectively. Toxicity included hypomagnesemia, vomiting, abdominal pain, and mild anemia. Only one patient required a dosage adjustment of cisplatin for a serum creatinine elevation >2.0 mg/dl. CONCLUSIONS: We conclude that the combination of ip cisplatin and 5-FU is an effective regimen for patients with residual or relapsed epithelial ovarian cancer with survival durations, response rates, and toxicity profiles that compare favorably with those of other second-line ovarian cancer regimens. Patients who are primarily platinum-refractory are unlikely to benefit from these agents administered into the peritoneal cavity.     

Quantitative pathologic features as predictors of long-term survival in patients with advanced ovarian cancer treated with cisplatin

The prognostic value of morphometric and DNA flow cytometric features were studied and compared with FIGO stage, preoperative tumor load, residual disease status, Karnofsky index and classic pathologic features such as Broders' grade and histologic type in 58 FIGO stage III and IV adequately debulked ovarian patients with long-term follow-up. The mitotic activity index, volume percentage of epithelium, and mean and SD of nuclear area were assessed by interactive morphometry, and tumor material was routinely processed for DNA flow cytometric assessment of DNA ploidy and S-phase fraction. Survival analysis (Kaplan-Meier curves, Mantel-Cox test), revealed FIGO stage ( P = 0.013) and the mean and SD of nuclear area to be significant prognosticators ( P = 0.027 and P = 0.012, respectively). In multivariate survival analysis (Cox model), a multivariate combination of FIGO stage, preoperative tumor load and mean nuclear area was the best prognostic combination of features ( P = 0.0034). These results confirm the findings of previous studies. We conclude that, in accord with previous studies, morphometric features are good predictors of survival after cisplatin treatment in advanced ovarian cancer, especially in combination with FIGO stage and preoperative tumor load.     

上皮性卵巢癌保留生育功能治疗

早期上皮性卵巢癌预后良好。保留生育功能治疗是年轻希望生育患者的选项之一,但要严格掌握适应证,规范治疗,以达到理想的预后和良好的妊娠结局。