The diminishing oocyte toxicity following intraperitoneal infusion of cisplatin (CDDP) combined with subcutaneous injection of sodium thiosulfate (STS) in syngeneic young mice

Small oocytes in 6-week-old C57BL/6 mice were destroyed in a dose-dependent fashion following intraperitoneal infusion of CDDP. ED65, the effective dose of which theoretically produced 65% destruction of small oocytes according to Probit analysis, was determined as 0.2mg/mouse. In this study, the oocyte toxicity induced with intraperitoneal treatment with CDDP (0.2mg) was offset by subcutaneous treatment with STS (40mg, 400 x molar ratio compared to that of CDDP). STS was subcutaneously injected into the back skin of mice at 60, 30, 15 minutes before, at the same time or at 15, 30, 60 minutes after the CDDP injection. STS markedly diminished the oocyte toxicity and reduced oocyte destruction about 45% when it was injected at 30, 15 minutes before or at the same time as CDDP infusion. On the other hand STS failed to reduce oocyte destruction when it was injected 15, 30 or 60 minutes later. STS might neutralize CDDP in the circulating blood to decrease the amount of active CDDP, but STS might not have any effect on CDDP once it is incorporated and conjugated with the DNA in the oocytes.     

A phase I trial of prolonged oral etoposide and liposomal doxorubicin in ovarian, peritoneal, and tubal carcinoma: a gynecologic oncology group study

OBJECTIVES: In an effort to explore second-line therapy in ovarian, peritoneal, and tubal carcinoma, a phase I trial combining prolonged oral etoposide and liposomal doxorubicin was conducted by the Gynecologic Oncology Group. METHODS: Liposomal doxorubicin (20 mg/m(2)) was administered intravenously over 1 h followed by oral etoposide at 50 mg/m(2)/day beginning on day 2. In the first phase of accrual, the number of days of oral etoposide was increased until its maximum tolerated dose (MTD) was determined based on hematologic toxicity. In the second phase, etoposide was given at the MTD while the dose of liposomal doxorubicin was escalated until its maximum tolerated dose was reached based on hematologic or nonhematologic toxicity. Cycles were repeated every 28 days for a maximum of 12 courses. Dose-limiting toxicity was defined as neutropenic sepsis, grade 4 thrombocytopenia, absolute neutrophil count <1000/microl or platelets <50,000 during treatment with etoposide, or > or =grade 3 mucositis/stomatitis, palmar-plantar erythrodyesthesia, or rash. RESULTS: Fifteen patients were accrued to the study's first phase, and 3 were accrued to the second phase. Dose-limiting hematologic toxicity occurred with 14 days of oral etoposide in combination with liposomal doxorubicin at 20 mg/m(2). Efforts to escalate the dose of liposomal doxorubicin to 30 mg/m(2) in combination with 12 days of oral etoposide at 50 mg/m(2) resulted in dose-limiting hematologic toxicity. Five of 17 (29%; 95% CI: 13-53%) evaluable patients experienced a response. CONCLUSION: The regimen of oral etoposide at 50 mg/m(2)/day for 12 days in combination with liposomal doxorubicin at a dose of 20 mg/m(2) is tolerable without supportive therapy. While this dose of oral etoposide has demonstrated activity as a single agent in ovarian cancer, liposomal doxorubicin has only been effective in ovarian cancer at higher doses. There are no immediate plans to study this combination further.     

CDDP-ACR treatment in patients with recurrent ovarian cancer with prior chemotherapy containing CDDP--a preliminary study of a 14-day continuous infusion of CDDP with ACR

Six patients with recurrent ovarian cancer who had prior chemotherapy were studied for the clinical efficacy of CDDP-ACR treatment. Five out of the 6 had received CDDP a total doses of 1,320, 780, 750, 475, and 340 mg. CDDP-ACR therapy consisted of continuous infusion of CDDP at a daily dose of 10 mg/m2 over 14 days (total CDDP doses; 140 mg/m2) and of intermittent infusion of ACR (aclarubicin) at a dose of 20 mg/body every other day (total ACR doses: 140 mg). There were one CR and five PR and a response rate up to 100% was noted. Toxicity was manifested in slight nausea or vomiting, but there was no nephrotoxicity. However bone marrow was severe. Thrombocytopenia less than 50,000/mcl in 4 pts (67%) and leukopenia less than 1,000 mcl in 3 pts (50%). The mean filterable platinum exposure measured by area under the concentration-time curve (AUC) was as high as 19.7 +/- 6/0 mg.hr/ml. In conclusion the bone marrow toxicity in this regimen was severe, but the therapeutic efficacy was promising. Further studies on the appropriate infusion time and the minimum effective dose of CDDP are needed.     

Phase 2 Trial of Liposomal Doxorubicin (40 mg/m) in Platinum/Paclitaxel-Refractory Ovarian and Fallopian Tube Cancers and Primary Carcinoma of the Peritoneum

Background. Several studies have demonstrated liposomal doxorubicin (Doxil) to be an active antineoplastic agent in platinum-resistant ovarian cancer, with dose limiting toxicity of the standard dosing regimen (50 mg/m² q 4 weeks) being severe erythrodysesthesia (“hand–foot syndrome”) and stomatitis. We wished to develop a more tolerable liposomal doxorubicin treatment regimen and document its level of activity in a well-defined patient population with platinum/paclitaxel-refractory disease.Methods and Materials. Patients with ovarian or fallopian tube cancers or primary peritoneal carcinoma with platinum/paclitaxel-refractory disease (stable or progressive disease following treatment with these agents or previous objective response <3 months in duration) were treated with liposomal doxorubicin at a dose of 40 mg/m² q 4 weeks.Results. A total of 49 patients (median age: 60; range 41–81) entered this phase 2 trial. The median number of prior regimens was 2 (range: 1–6). Six (12%) and 4 (8%) patients experienced grade 2 hand–foot syndrome and stomatitis, respectively (no episodes of grade 3). One patient developed grade 3 diarrhea requiring hospitalization for hydration. Six (12%) individuals required dose reductions. The median number of courses of liposomal doxorubicin administered on this protocol was 2 (range: 1–12). Four of 44 patients (9%) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy.Conclusion. This modified liposomal doxorubicin regimen results in less toxicity (stomatitis, hand–foot syndrome) than the standard FDA-approved dose schedule. Definite, although limited, antineoplastic activity is observed in patients with well-defined platinum- and paclitaxel-refractory ovarian cancer.     

Liposomal doxorubicin in ovarian, peritoneal, and tubal carcinoma: a retrospective comparative study of single-agent dosages

PURPOSE: The aim of this study was to evaluate the relative activity and tolerance of liposomal doxorubicin in recurrent ovarian, peritoneal, and tubal carcinoma at an initial dose of 40 or 50 mg/m(2) every 4 weeks. METHODS: A retrospective single-institution study was performed on patients who received liposomal doxorubicin from 1/97 to 12/00. Demographic data, liposomal doxorubicin dose, dose reductions, response, and progression-free and overall survival were recorded. RESULTS: Seventy-eight patients, 38 treated at 40 mg/m(2) and 40 treated at 50 mg/m(2), were identified. There was no difference with respect to patient age, performance status, percentage of patients who were platinum resistant or paclitaxel resistant, or tumor bulk. The response rate in this highly resistant population was 13.5 and 7.7% for liposomal doxorubicin at 40 and 50 mg/m(2) every 4 weeks, respectively. Stable disease was observed in 49 and 51% of patients treated with liposomal doxorubicin at a dose of 40 and 50 mg/m(2) every 4 weeks, respectively. The progression-free survival for patients with responding and stable disease was similar. Dose reductions were required in 27.5% of patients treated at 50 mg/m(2) versus no patients treated at 40 mg/m(2) (P < 0.001). Treatment delays due to toxicity were required in 32.5% of patients treated at 50 mg/m(2) versus 16% of patients treated at 40 mg/m(2) (P = 0.14). CONCLUSION: Liposomal doxorubicin at a dose of 40 mg/m(2) appears to be as active as liposomal doxorubicin at a dose of 50 mg/m(2) in ovarian, peritoneal, and tubal carcinoma and is better tolerated based on the frequency of dose reductions and treatment delays.     

Efficacy and toxicity of the novel chemotherapeutic agent KW-2170 in recurrent epithelial ovarian cancer

OBJECTIVES: KW-2170 is a novel DNA intercalating agent whose mechanism of action is similar to doxorubicin HCl, yet is associated with less cardiac toxicity. The objective of this study was to evaluate the activity and toxicity of this novel chemotherapeutic agent in patients with recurrent ovarian carcinoma. METHODS: A prospective phase II trial was performed in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma and measurable disease. Patients could have platinum-sensitive or refractory disease and could have received any number of prior treatments. One treatment cycle consisted of KW-2170 administered at a dose of 18 mg/m(2) weekly for 3 weeks followed by a 21-day rest period. Toxicity was assessed using the NCI Common Toxicity Criteria (Version 2.0), and dose reduction was allowed for significant toxicity. Response to therapy was assessed in patients who completed at least 2 cycles using RECIST criteria. RESULTS: A total of 28 patients were enrolled in this phase II trial at 5 separate centers. Of the 28 patients evaluated, all had stage III/IV disease at initial diagnosis. The median number of prior therapeutic regimens in these patients was 4 (range 1-8). The median number of KW-2170 cycles administered was 2 (range 1-5). Treatment-related toxicity in this heavily pretreated population was acceptable as only 6 patients (21%) had grade 3-4 neutropenia. Dose reductions occurred in 6 patients (21%) for grades 1-4 neutropenia, and no patient had febrile neutropenia. Four patients completed less than 1 cycle; 3 secondary to progressive disease, and one due to Gram-positive sepsis. Of patients receiving at least 2 full cycles, 10 patients (55%) had stable disease with a median of 4.5 months (range 3-10) to disease progression. All other patients were removed from the study after 1-2 cycles of therapy with no significant clinical effect noted. CONCLUSIONS: Although associated with relatively little toxicity, KW-2170 at the dose and schedule evaluated demonstrated little clinical activity in this heavily pretreated population of recurrent ovarian cancer patients. Whether KW-2170 would have greater clinical activity in a more treatment naive group of patients at an increased dose awaits clinical trial evaluation.     

Renal toxicity by intraperitoneal administration of CDDP

Renal toxicity following intraperitoneal (ip) CDDP therapy after laparotomy in twenty patients with ovarian cancer was examined. Four patients had renal toxicity. Patients who received CDDP at a dose of 150 mg (2/2) had a statistically higher incidence of toxicity than those who received less than 100 mg (2/18) (p less than 0.05). Patients who underwent ip therapy on the same day as laparotomy had a statistically higher incidence of the toxicity (4/15) than those underwent it on the fourth day after (0/5) (p less than 0.05). Renal toxicity was revealed in the mean urine volume of 1,100 ml on the day of therapy, but the toxicity did not appeared in those with a mean urine volume of 2,131 ml, whose volume was statistically different (p less than 0.01). These data suggest maintenance of renal blood flow during CDDP treatment plays an important role in preventing renal toxicity even following ip therapy. By investigating preoperative laboratory data, it is seen that patients with FDP values higher than 32 micrograms/ml have a higher risk of renal toxicity.     

Phase II study of the combination of pegylated liposomal doxorubicin and topotecan in platinum-resistant ovarian cancer

The combination of liposomal doxorubicin and topotecan was evaluated in a phase II study in patients with platinum-resistant ovarian cancer. Twenty-seven patients received liposomal doxorubicin (30 mg/m(2)) infused at day 1, followed by topotecan (1 mg/m(2)) infusion daily for 5 days. Cycles were repeated every 21 days. This combination regimen showed an overall response rate of 28%. Median time to progression was 30 weeks, with a median overall survival of 40 weeks. Grade 3/4 neutropenia was shown in 70% of patients and grade 3/4 thrombopenia in 41% of patients. Neutropenic fever was reported in 11% of patients. After reviewing the first 12 patients, the internal review board decided to administer topotecan at a dose of 0.75 mg/m(2) and liposomal doxorubicin at 40 mg/m(2) for the remainder of the study. However, this adjustment did not lead to reduction in bone marrow toxicity nor to an improvement in dose intensity. Palmar-plantar erythrodysesthesia and mucositis were more reported in the second cohort but usually mild. The combination of liposomal doxorubicin and topotecan demonstrates favorable response data in platinum-resistant ovarian cancer. However, substantial bone marrow toxicity limits further clinical use.     

Interleukin-6 (IL-6) does not change the expression of Bcl-2 protein in the prevention of cisplatin-induced apoptosis in ovarian cancer cell lines

OBJECTIVE: To study whether interleukin-6 (IL-6) changes the expression of the anti-apoptic Bcl-2 protein in the prevention of cis-diaminedichloroplatinum (II) (CDDP)-induced apoptosis of human ovarian cancer cells. METHODS: Comparative studies were performed on 3 ovarian cancer cell lines after 48 hours of exposure to 0.5-50 ng/ml IL-6, 2 micrograms/ml anti-IL-6 monoclonal antibody (anti-IL-6 mAb), 10 microM CDDP, 10 microM CDDP + 0.5-50 ng/ml IL-6, and 10 microM CDDP + 2 micrograms/ml anti-IL-6 mAb. Apoptosis was measured morphologically and by a DNA fragmentation assay. Bcl-2 protein levels were measured by an ELISA. RESULTS: An increase in apoptosis was observed for each cell line after 48 hours of exposure to 10 microM CDDP. Although high doses of IL-6 decreased the percentage of apoptotic cells, this cytokine did not change the expression of the Bcl-2 protein. CONCLUSION: CDDP-induced apoptosis was negatively controlled by IL-6. However, the anti-apoptic Bcl-2 protein level was not changed by IL-6 in the process of apoptosis in the ovarian cancer cell lines.     

不同年龄妇女卵母细胞质量差异的分析

目的 从细胞凋亡探讨不同年龄妇女卵母细胞的质量差异。方法 应用细胞培养技术,和原位ＤＮＡ片段末端标记（ＩＳＥＬ）方法,对５８例卵巢囊肿、畸胎瘤患者的２０６个卵母细胞按不同年龄组进行观察和研究。结果 卵母细胞的凋亡过程与其它细胞一样,开始细胞容积缩小,形态不规则,最后凋亡小体形成等;４１￣５０岁年龄组妇女卵母细胞凋亡较２１￣３０岁与３１￣４０岁年龄组进展快（凋亡过程时间短,Ｐ〈０．００５）及凋亡率高     

Grade 3 liposomal-doxorubicin-induced skin toxicity in a patient following complete resolution of moderately severe sunburn

PURPOSE: Palmar-plantar erythrodysesthesia (PPE) is a potentially serious toxicity of a number of cytotoxic chemotherapeutic agents, including liposomal doxorubicin. Activities that may increase the risk of this toxicity should be avoided. CASE REPORT: A patient with platinum-resistant ovarian cancer, responded to, and tolerated (including no skin rash) an initial cycle of liposomal doxorubicin (40 mg/m(2)). Unfortunately, several days before her next scheduled cycle, she developed significant sunburn (intense erythema without blistering). Despite an additional 1-week delay (total of 5 weeks from the prior liposomal doxorubicin), and complete visual recovery from the effects of the sunburn, the patient developed severe (grade 3) PPE involving both hands (pain, pronounced erythema, blistering, without ulceration), and a slightly less extensive reaction of both feet, following subsequent treatment with a 25% reduced dose of the agent (30 mg/m(2)). CONCLUSION: Caution is advised when considering the administration of liposomal doxorubicin following a major sunburn, despite total resolution of the visible effects on the skin. A delay of several weeks may be appropriate to avoid exacerbation by the chemotherapeutic agent of persistent subclinical damage to normal epithelial cells.     

The effect of bismuth subnitrate on cisplatin toxicity

Bismuth subnitrate (BSN), a bismuth compound medically used for antidiarrheics, was orally administered to see whether it can reduce CDDP nephrotoxicity or not. Thirteen patients aged 19 approximately 60 with ovarian cancer entered this BSN-CDDP trial. A total of thirty three courses of BSN-CDDP treatment was undergone. BSN was administered orally at a dose of 50 mg/kg for five days before CDDP therapy. CDDP was infused for two hours. No vigorous hydration or diuresis was performed. Only 2,000 ml of saline with 20 mEq per liter of KCl was given for post-hydration. The median dose of CDDP was 100 mg/m2. The renal toxicity of BSN-CDDP treatment was minimum. 82% of the courses at the sixth day after the treatment had creatinine clearance levels which were more than 80% of those before the treatment. But twenty-four hour NAG and beta 2-microglobulin excretion were significantly increased. Bone marrow suppression and gastrointestinal disturbance were commonly observed. The results of our study indicate that BSN pretreatment reduces the renal toxicity of CDDP to some extent.     

Feasibility study of concurrent weekly cisplatin and whole abdominopelvic irradiation followed by doxorubicin/cisplatin chemotherapy for advanced stage endometrial carcinoma: a Gynecologic Oncology Group trial

PURPOSE: A prospective Phase I study to determine toxicity of concurrent weekly intravenous cisplatin/whole abdominopelvic radiation therapy followed by four cycles of intravenous doxorubicin/cisplatin chemotherapy. MATERIALS AND METHODS: Ten patients with advanced endometrial cancer confined to the abdominal cavity and/or paraaortic lymph nodes with small residual disease were treated postoperatively with 3000 cGy whole abdominopelvic irradiation combined with 1500 cGy boost to the pelvis or pelvic and aortic fields. Cisplatin 15 mg/m(2) was given every week during irradiation. After completing radiotherapy, patients were to receive doxorubicin 50 mg/m(2) and cisplatin 50 mg/m(2) every 3 weeks for four cycles. Graduated dose reduction and acceleration of the doxorubicin dose were specified depending upon hematologic toxicity. Toxicities were monitored with weekly laboratory studies during treatment and frequent examinations. RESULTS: Five patients with Stage IIIC (paraaortic node involvement) and five with Stage IVB disease were treated on this study. Acute toxicity during chemoirradiation included one patient with grade 4 neutropenia and one patient with persistent grade 1 thrombocytopenia. Seven patients received chemotherapy after completing radiation therapy, two progressed before chemotherapy, and one had thrombocytopenia. Toxicity during chemotherapy included grade 4 neutropenia in all patients with four having five episodes of febrile neutropenia. Despite doxorubicin dose reductions for hematologic toxicity, three patients exhibited grade 4 neutropenia after both the second and third cycles. One patient developed a small bowel obstruction from radiation therapy that required surgery. There were no treatment-related deaths. Overall median survival was 14 months, with only one long-term survivor free of disease at 58 months. CONCLUSIONS: Without cytokine support, whole abdominopelvic irradiation and concurrent weekly cisplatin followed by doxorubicin/cisplatin chemotherapy without cytokine support has prohibitive hematologic toxicity.     

Cyclic high dose CAP therapy by short-stay admission for ovarian malignancies--to increase total dose of CDDP and to improve quality of life of patients

Since 1986, attempts have been made to improve the anti-cancer effect of Cisplatin (CDDP) in malignant ovarian tumor patients and their quality of life (QOL), by increasing single and total dose of CDDP and by short-stay cyclic treatment at our institution. In this study, the side effects of CDDP at high and low doses were compared and the effect on the QOL was analysed. Twenty ovarian malignant tumor patients who underwent adjuvant chemotherapy (CDDP 70 mg/m2, Adriamycin (ADR) 20 mg/m2, Cyclophosphamide (CPM) 200 mg/m2 given every 4 weeks for a total of 5 times and every 8-12 weeks thereafter for 5 times) after initial surgery were compared with non randomized control patients who received the old regimen of of our institution (CDDP 35 mg/m2, ADR 20 mg/m2, CRP 200 mg/m2, 5-FU 150 mg/m2 for 5 days given every 4 weeks for a total of 5 times without discharge from hospital). There was no significant difference between the groups in the white blood cell (WBC) count and creatinine clearance (Ccr) throughout the treatment, although a slight drop was observed after the second course in both groups. The QOL was examined by interviewing the patients on their physical and mental condition. Although the total amount of CDDP was increased from 175 mg/m2 to as much as 700 mg/m2, no severe nephrotoxicity or myelosuppression was seen and patients felt better and preserved a good QOL during a short hospital stay. These results clearly indicate the efficacy of our new regimen.     

Pegylated liposomal doxorubicin treatment in recurrent gynecologic cancer patients with renal dysfunction

OBJECTIVES: A paucity of data exists regarding the efficacy and toxicity of pegylated liposomal doxorubicin (PLD) in cancer patients with chronic kidney disease (CKD). We sought to investigate the toxicity and efficacy of PLD in gynecologic cancer patients with CKD. METHODS: The clinical records of all patients with recurrent gynecological cancer and CKD at the University of Texas M.D. Anderson Cancer Center from 08/1999 to 08/2006 were reviewed retrospectively to identify patients who received PLD. RESULTS: Twenty-eight patients were identified, which included 14 with epithelial ovarian cancer, 4 with peritoneal cancer, and 10 with other gynecologic cancers. CKD was defined as a creatinine clearance (CrCl) of <90 ml/min/1.73 m(2) and classified as mild (5 patients), moderate (16 patients), or severe (7 patients) (CrCl 60-89, 30-59, and <30 ml/min/1.73 m(2), respectively). The initial doses of PLD were classified into regular initial dose (40 mg/m(2)/4 weeks) and lower initial dose (30-35 mg/m(2)/4 weeks). The median cycle was 4.5 (range 1-17). The incidence of grade 3-4 palmar-plantar erythrodysesthesia, stomatitis, and hematologic toxicity was 11.1% (2/18), 5.6% (1/18), and 16.7% (3/18) among 18 patients with an initial dose of 40 mg/m(2)/4 weeks, which included 5, 10, and 3 patients with mild, moderate, and severe CKD, respectively. Dose reduction due to toxicities occurred in 33.3% (6/18) patients. In 18 patients with ovarian and peritoneal cancer (all platinum-resistant), the rates of complete response, partial response, stable disease, and progression were 0%, 11.1%, 44.4%, and 44.4%, respectively. CONCLUSIONS: Patients with CKD who received PLD therapy at an initial dose of 40 mg/m(2)/4 weeks may require greater subsequent dose reduction mainly secondary to mucocutaneous and hematologic toxicities. Treatment response in this population with ovarian and peritoneal cancer was similar to that of patients with normal renal function.     

The clinical utility of liposomal doxorubicin in recurrent ovarian cancer

OBJECTIVES: The aim of this study was to determine the efficacy and toxicity of single agent off-protocol, liposomal doxorubicin (Doxil Alza), in consecutive patients with recurrent ovarian cancer and to investigate the influence of HER-2/neu expression on response to liposomal doxorubicin. PATIENTS AND METHODS: Retrospective analysis of 72 consecutive patients treated, typically with liposomal doxorubicin 40 mg/m(2) q28 days between January 1997 and December 1998. Results. Twenty-nine patients (40%) had platinum- and taxane-resistant tumors. Nineteen patients (27%) responded with clinical or radiological evidence of response with reduction in CA-125 of >50%. One complete response (CR) and 7 partial responses (PRs) occurred in platinum- and taxane-resistant patients (radiological response (RR) 29%) and 8 PRs occurred in patients with visceral metastases (RR 28%). Time to progression was 5.3 (2.1-12.1) months. Only 7 dose delays (3%) and 20 dose reductions (8%) were necessary in 265 cycles of treatment. Hematological toxicity was generally mild with grade (Gr) > or =III neutropenia in 1 (2%), Gr > or =III thrombocytopenia in 1 (1%), and Gr > or =III anemia in 8 patients (11%). One patient (1%) was admitted with fever and neutropenia. Other toxicity was minimal with Gr > or =III mucositis occurring in 3 patients (4%). Gr > or =III cutaneous toxicity was seen in 6 patients (8%). Three patients (4%) had a >10% fall in ejection fraction but there was no unequivocal clinical heart failure. CONCLUSIONS: The data suggest that liposomal doxorubicin is an active drug in both taxane- and platinum-sensitive and resistant recurrent ovarian cancer. Liposomal doxorubicin is associated with tolerable toxicity and is particularly well tolerated in patients with multiple prior lines of treatment.     

Role of pegylated liposomal doxorubicin in ovarian cancer

OBJECTIVES: Safe, effective treatments are needed for relapsed ovarian cancer. Goals include improving symptoms, enhancing quality of life, and prolonging survival. The plethora of agents currently available present difficult choices for physicians. The present effort seeks to examine the role of one of these agents, pegylated liposomal doxorubicin. METHODS: A roundtable meeting of experts in the management of ovarian carcinoma was held to build consensus around the present and future role of pegylated liposomal doxorubicin for ovarian cancer and other gynecologic malignancies. RESULTS: Pegylated liposomal doxorubicin is effective and well tolerated in relapsed ovarian cancer. When compared with topotecan in a phase III randomized trial, pegylated liposomal doxorubicin showed several advantages: improved quality of life, fewer severe adverse events, fewer dose modifications, less hematologic support, and lower total cost per patient. In platinum-sensitive patients, pegylated liposomal doxorubicin also produced a survival advantage. Results from prospective and retrospective studies further demonstrate the improved cardiac safety of pegylated liposomal doxorubicin compared to conventional anthracyclines. CONCLUSIONS: Based on survival and toxicity advantages and a once-monthly administration schedule, pegylated liposomal doxorubicin is the first-choice nonplatinum agent for relapsed ovarian cancer. Pegylated liposomal doxorubicin may also have clinical application in combination regimens for platinum-sensitive ovarian cancer, as consolidation/maintenance therapy for ovarian cancer, as a component of first-line therapy for ovarian cancer, and in the treatment of other gynecologic malignancies. Future clinical trials will further define and maximize the role of pegylated liposomal doxorubicin in the treatment of ovarian cancer and other gynecologic malignancies.     

Paclitaxel, carboplatin and pegylated liposomal doxorubicin in ovarian and peritoneal carcinoma: a phase I study of the Gynecologic Oncology Group

PURPOSE: Based on the activity and tolerability of liposomal doxorubicin in platinum- and paclitaxel-resistant ovarian carcinoma, we conducted a phase I trial of pegylated liposomal doxorubicin with paclitaxel and carboplatin to determine the maximum tolerated dose (MTD) in chemotherapy naive ovarian, peritoneal and tubal carcinoma patients. METHODS: Three schedules were studied: paclitaxel, carboplatin and pegylated liposomal doxorubicin every 28 days; paclitaxel and carboplatin every 21 days with liposomal doxorubicin every 42 days; and weekly paclitaxel, carboplatin (AUC=5) every 21 days and liposomal doxorubicin every 42 days. The paclitaxel dose was 175 mg/m(2) over 3 h on an every 3-4 week schedule and 60 mg/m(2) when administered weekly. Based on the frequency of neutropenic sepsis, grade 4 thrombocytopenia and > or =grade 3 non-hematologic toxicity, the starting dose of liposomal doxorubicin of 20 mg/m(2) was escalated to determine the MTD. RESULTS: A total of 210 (21-day) cycles were administered to 37 patients. Dose-limiting toxicity (DLT) occurred when liposomal doxorubicin was administered at 40 mg/m(2). Because of treatment-related delays resulting in decreased paclitaxel/carboplatin dose intensity, administration was modified to be given every 21 days, with liposomal doxorubicin given every 42 days. Since neutropenia was the DLT of this schedule, the schema was further modified to administer paclitaxel weekly; however, weekly administration was inconsistent because of toxicity. CONCLUSION: Paclitaxel 175 mg/m(2), carboplatin (AUC=5) and pegylated liposomal doxorubicin 30 mg/m(2) are tolerable without supportive therapy. The usual dose intensity of paclitaxel/carboplatin was maintained by administering liposomal doxorubicin every other cycle.     

Human ovarian cancer cell lines resistant to cisplatin, doxorubicin, and L-phenylalanine mustard are sensitive to delta 7-prostaglandin A1 and delta 12-prostaglandin J2

The antitumor activity of delta 7-prostaglandin A1 (delta 7-PGA1) or delta 12-prostaglandin J2 (delta 12-PGJ2) on human ovarian cancer cell lines resistant to cisplatin (CDDP), doxorubicin (ADR), and L-phenylalanine mustard (l-PAM) was studied in vitro. A2780AD, A2780 (parent cells of A2780AD), 2008DDP, and 2008 cells (parent cells of 2008DDP) were used. The antitumor activities of the drugs were defined with 50% inhibitory concentration (IC50) estimated from growth inhibition curves, which were obtained by an indirect colorimetric method. Drug-resistance ratios obtained from IC50 values, by comparing A2780AD and A2780 cells, were 62.5 for ADR, 4.6 for CDDP, 4.9 for l-PAM, 1.5 for delta 7-PGA1, and 1.8 for delta 12-PGJ2. Those obtained by comparing 2008DDP and 2008 cells were 1.1 for ADR, 16.0 for CDDP, 2.9 for l-PAM, 2.3 for delta 7-PGA1, and 3.2 for delta 12-PGJ2. Thus some human ovarian cancer cells resistant to ADR, CDDP, and l-PAM remain sensitive to antitumor PGs.     

Intraperitoneal versus intravenous cisplatin in combination with intravenous cyclophosphamide and epidoxorubicin in optimally cytoreduced advanced epithelial ovarian cancer: a randomized trial of the Gruppo Oncologico Nord-Ovest

Intraperitoneal chemotherapy has a strong biological and pharmacological rationale in the treatment of ovarian cancer. From 1989 to 1996 the present study included 113 patients with FIGO stage II-IV ovarian cancer with residual disease less than 2 cm who were randomly allocated to receive 50 mg/m(2) intraperitoneal cisplatin (CDDP) plus 60 mg/m(2) intravenous epidoxorubicin (EPIDOX) and 600 mg/m(2) intravenous cyclophosphamide (CTX) (ipPEC arm) or 50 mg/m(2) intravenous CDDP plus 60 mg/m(2) intravenous EPIDOX and 600 mg/m(2) intravenous CTX (ivPEC arm). Chemotherapy was repeated every 4 weeks for six cycles. Treatment protocol was changed in 22 patients, 2 from the iv arm (who received single-agent carboplatin) and 20 from the ip arm (who were crossed to systemic chemotherapy, ivPEC, or single-agent carboplatin). At the end of chemotherapy, a second-look was performed in 33 of the 54 patients from the ip arm and in 34 of the 57 patients from the systemic arm. The pathologic complete response rate was 41% of all entered patients and 69% of patients submitted to second-look. No significant difference in pathologic response rate as well as in hematologic and nonhematologic toxicities was seen between the two arms. Up to September 1998, 72 patients showed a disease recurrence (33 treated with ipPEC and 39 treated with ivPEC), 55 died (22 ipPEC and 30 ivPEC), and 10 were lost to follow-up (6 ipPEC and 4 ivPEC). Median progression-free survival was 42 and 25 months for ipPEC and ivPEC, respectively (p = 0.13). Median overall survival was 67 and 51 months for ipPEC and ivPEC, respectively (p = 0.14). In conclusion, besides confirming that intraperitoneal chemotherapy is feasible with acceptable toxicity but with poor compliance in community hospitals, this trial showed that intraperitoneal CDDP compared with intravenous CDDP in combination with EPIDOX and CTX obtained a slight (not significant) improvement in progression-free survival and overall survival of optimally cytoreduced advanced ovarian cancer patients.