Biweekly gemcitabine and cisplatin in platinum-resistant/refractory, paclitaxel-pretreated, ovarian and peritoneal carcinoma

OBJECTIVES: Synergism between gemcitabine and cisplatin is supported by preclinical and clinical data. The present study explores the efficacy of a biweekly regimen in platinum-resistant/refractory, paclitaxel-pretreated ovarian and peritoneal cancer. METHODS: 50 paclitaxel-pretreated patients with platinum-resistant/refractory ovarian or peritoneal carcinoma who had previously received paclitaxel chemotherapy, were treated with six cycles of gemcitabine 1000 mg/m(2) followed by cisplatin 40 mg/m(2) on days 1 and 15, repeated every 4 weeks. RESULTS: The median platinum-free interval (PFI) was 4 months while the median number of previous treatment lines was 2. Chemotherapy was well tolerated. Objective responses were observed in 31.5% of evaluable patients (n=35). CA125 response was observed in 68% of patients with elevated CA125 (n=41). Median overall survival (OS) was 13.2 months (95% Confidence Interval, CI: 10.2-16.2) while progression-free survival (PFS) was 4.9 months (95%CI: 3.5-6.4). A PFI of less than 3 months was associated with lower objective response rates (15.8% versus 50%, p=0.03). CONCLUSIONS: Biweekly gemcitabine and cisplatin is feasible for patients with platinum-resistant ovarian or peritoneal cancer and is associated with a favorable toxicity profile. In a population with recent exposure to platinum, a PFI of less than 3 months was the major factor influencing response to chemotherapy.     

Meta-analysis of cisplatin, doxorubicin, and cyclophosphamide versus cisplatin and cyclophosphamide chemotherapy of ovarian carcinoma.

OBJECTIVE: To compare the survival with cisplatin, doxorubicin (Adriamycin), and cyclophosphamide versus that of cisplatin and cyclophosphamide in women with advanced epithelial ovarian cancer, to evaluate the effect of dose intensity, and to evaluate meta-analysis methodology. METHODS: Meta-analysis was done on 30 studies of 2060 women with stages III and IV epithelial ovarian cancer. All had 3-year survival data, adequate follow-up, no other chemotherapy, no radiation therapy, and had information for various prognostic variables (age, stage, grade, and residual disease). We used four different methods of meta-analysis: pooled published data and modified effect-size analyses of the entire group (30 studies), and pooled published data and effect-size analyses of the subset of five prospective randomized studies. RESULTS: Three-year survival for the entire group was 43% for cisplatin, doxorubicin, and cyclophosphamide versus 36% for cisplatin and cyclophosphamide; for the five prospective randomized studies, the rates were 46 and 35%, respectively. The survival advantage of cisplatin, doxorubicin, and cyclophosphamide was statistically significant when analyzed by the pooled published data and modified effect-size meta-analysis of the entire group and the pooled published data meta-analysis of the five prospective randomized studies. The effect-size meta-analysis of the five prospective studies did not reach statistical significance. Total dose intensity and doxorubicin dose intensity were not significantly associated with survival advantage in cisplatin, doxorubicin, and cyclophosphamide use. CONCLUSIONS: There seems to be a survival advantage to treatment with cisplatin, doxorubicin, and cyclophosphamide versus treatment with cisplatin and cyclophosphamide. We believe this to be due to the properties of multiagent chemotherapy (the addition of doxorubicin) rather than to increased dose intensity. In addition, we believe that physicians need to familiarize themselves with meta-analysis methodology.     

A phase II study of pegylated liposomal doxorubicin oxaliplatin and cyclophosphamide as second-line treatment in relapsed ovarian carcinoma

Abstract.   Valerio MR, Tagliaferri P, Raspagliesi F, Fulfaro F, Badalamenti G, Arcara C, Cicero G, Russo A, Venuta S, Guarneri G, Gebbia N. A phase II study of pegylated liposomal doxorubicin oxaliplatin and cyclophosphamide as second-line treatment in relapsed ovarian carcinoma. Int J Gynecol Cancer 2006; 16(Suppl. 1): 79–85
We carried out a phase II nonrandomized study to examine the level of activity of oxaliplatin, pegylated liposomal doxorubicin, and cyclophosphamide in a patient population with relapsed ovarian cancer pretreated with platinum derivatives and paclitaxel. Patients received oxaliplatin (85 mg/m²), pegylated liposomal doxorubicin (30 mg/m²), and cyclophosphamide (750 mg/m²). A total of 49 patients (39 assessable for toxicity and response) were enrolled in this trial. Neutropenia grade 3 was observed in six patients (15%) and anemia grade 3 in one patient (0.2%). Fatigue grade 1–2 occurred in 26 patients (66%), nausea/vomiting grade 1 in 23 patients (58%), and alopecia grade 1–2 in 19 patients (48%). Twenty-one (53%) patients experienced grade 1–2 peripheral neuropathy. The overall response rate was 46% (95% CI 23.6–68.7). Median progression-free survival was 28 weeks (range 12–52 weeks) and median survival was 45 weeks (range 26–136+ weeks). The mean duration of response was 34 weeks (range 16–52 weeks). In platinum-resistant and -refractory ovarian cancer patients, the overall response rate was 37% (CI 95% 14.4–60.8) with a progression-free survival of 28 weeks (range 12–52 weeks) and a median survival of 42 weeks (range 28–84 weeks). This combination chemotherapy is generally well tolerated and is an active second-line regimen against ovarian cancer.     

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.     

Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers

Objectives

Currently, pegylated liposomal doxorubicin (PLD) is regarded as one of the standard treatment options in recurrent ovarian cancers (ROC). Bevacizumab has shown significant antitumor activity for ROC in single-agent or in combination with cytotoxic agents. We have conducted a preliminary study to investigate effects of combination of bevacizumab and PLD for heavily pretreated patients with ROC.

Methods

Thirty patients with ROC were treated with combination therapy with weekly bevacizumab and PLD, 2 mg/kg of continuous weekly bevacizumab and 10 mg/m² of PLD (3 weeks on, 1 week off). The treatment was continued until development of disease progression, or unmanageable adverse effects. Response evaluation was based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and Gynecologic Cancer Intergroup (GCIG) CA125 response criteria. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

Results

Overall response rate was 33%, and clinical benefit rate (CR + PD + SD) was 73%. Median progression-free survival was 6 months (range: 2-20 months), and a 6-months progression-free survival was 47%. Any hematological toxicities more than grade 3 were not observed. Two cases developed non-hematologic toxicities more than grade 2; a case with grade 3 hand-foot syndrome, another with grade 3 gastrointestinal perforation (GIP). The case with GIP was conservatively treated and recovered after 2 months, and there was no case with treatment-related death.

Conclusion

The present investigation suggested that combination therapy with bevacizumab and PLD was active and well tolerated for patients with ROC. We recommend the regimen be evaluated in further clinical studies.     

Treatment of advanced endometrial carcinoma with cisplatin, cyclophosphamide and doxorubicin

A patient with advanced adenocarcinoma of the endometrium was treated with cisplatin, cyclophosphamide and doxorubicin. This regimen achieved surgically proved complete remission. No severe drug-related toxicity occurred.     

Treatment of fallopian tube carcinoma with cisplatin, doxorubicin, and cyclophosphamide

Primary carcinoma of the fallopian tube is uncommon and is often treated using regimens active in ovarian carcinoma. Evidence is scant that such therapies benefit patients with fallopian tube carcinoma. Between December 1979 and July 1988, we treated 18 patients who had adenocarcinoma of the fallopian tube with the combination of cisplatin (50 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) administered intravenously on 1 day every 28 days. Histologic confirmation of fallopian tube carcinoma was obtained before entry in the study. Three patients had stage I disease, five had stage II, nine had stage III, and one had stage IV. Sixteen patients received the combination therapy as first-line treatment after cytoreductive surgery, and two patients received it for recurrent carcinoma. Seven patients had clinically measurable disease at the start of therapy. Two of these patients had a complete clinical response, two had stable disease, and three had progressive disease. Eight of the 15 patients with stages II-IV disease underwent second-look laparotomy; four had a complete response to therapy and four had a partial response, making the overall response rate 53%. The toxicity of the regimen was moderate. The median survival was 81 months. Patients with stages II-IV disease had a median survival of 43.9 months and a progression-free survival of 22.5 months. This regimen appears to be active in fallopian tube carcinoma and can result in response rates comparable to those reported for epithelial ovarian cancer.     

Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer

Objectives

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.

Methods

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.

Results

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 a PIK3CA mutation had stable disease (SD) for 4 months. Two other patients without apparent PI3K pathway aberrations achieved SD. Two patients with KRAS mutations demonstrated rapid progression. Decreased phosphorylated S6 correlated with ¹⁸F-FDG-PET responses.

Conclusions

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.     

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.     

The effect of regional cooling on toxicity associated with intravenous infusion of pegylated liposomal doxorubicin in recurrent ovarian carcinoma

OBJECTIVE: The purpose of this study is to determine if regional cooling reduces palmar-plantar erythrodysesthesia (PPE) associated with intravenous infusion of pegylated liposomal doxorubicin (PLD). METHODS: A retrospective review over 3 years identified 20 women who were treated with single-agent intravenous PLD for recurrent ovarian carcinoma. During PLD infusion, patients kept ice packs around their wrists and ankles, and consumed iced liquids. These steps were continued for 24 h after completion of chemotherapy. All patients were instructed not to ingest hot food or liquids, to avoid contact with hot water, and to minimize friction on the hands and feet for 72 h posttreatment. RESULTS: Seventeen of the twenty patients (85%) followed the regional cooling protocol, and three of twenty (15%) did not. In the group who underwent regional cooling, 16/17 (94%) had none to mild PPE (grades 0-2), and 1/17 (6%) had moderate to severe PPE (grades 3-4). Of the three patients without regional cooling, 1/3 (33%) had grades 0-2 PPE and 2/3 (67%) had grades 3-4 PPE (P = 0.047). CONCLUSIONS: Regional cooling may reduce the frequency and severity of PPE associated with intravenous PLD infusion for recurrent ovarian carcinoma. Prospective, randomized evaluation is needed to confirm this observation.     

Randomized prospective trial of 5 versus 10 cycles of cyclophosphamide, doxorubicin, and cisplatin in advanced ovarian carcinoma

Five versus ten cycles of cyclophosphamide, doxorubicin, and cisplatin (CAP) were compared in advanced ovarian carcinoma by a prospective randomized study of 78 patients, 41 receiving 5 cycles (CAP5) and 37 receiving 10 cycles (CAP10) of chemotherapy. Patients were stratified by histologic grade and size of residual disease. Cyclophosphamide, 600 mg/m2, doxorubicin, 40 mg/m2, and cisplatin, 100 mg/m2, were administered every 4 weeks for 5 or 10 cycles. Second-look laparotomy was performed to evaluate response and plan further therapy. CAP5 patients found a second-look laparotomy to have partially responded to chemotherapy were treated with 5 additional cycles of CAP. CAP10 was more toxic than CAP5 with respect to myelosuppression, hospital admissions for nadir fever, median elevation of creatinine, and degree of peripheral neuropathy. Median follow-up is 64 months. CAP5 and CAP10 were equivalent in surgically documented complete responses (34 versus 35%) and survival (P = 0.41). Twelve partial responders to CAP5 received additional CAP chemotherapy; one complete response resulted. We conclude that CAP5 is preferable to CAP10 in treatment of advanced ovarian cancer as it is equally effective and less toxic.     

脂质体多柔比星联合卡铂治疗复发性卵巢上皮性癌的临床研究

目的 评价脂质体多柔比星+卡铂方案治疗复发性卵巢上皮性癌(卵巢癌)的疗效和副反应.方法 2003年7月-2007年12月间北京肿瘤医院妇瘤科共收治67例卵巢癌(包括原发性腹膜腺癌8例,因其生物学行为和治疗同卵巢癌,故列入本研究)患者,所有患者初次治疗均接受了肿瘤细胞减灭术及以铂类为基础的联合化疗,复发后使用脂质体多柔比星(35～40 ms/m2)+卡铂(血浆浓度时间曲线下面积=5,每4周为1个疗程)作为一线或二线及以上化疗方案治疗,观察其有效率和生存率,并且评估其化疗副反应的发生率.结果 67例患者中,49例患者可进行疗效评估,其中完全缓解23例(47%),部分缓解13例(27%),病情平稳3例(6%),疾病进展10例(20%),有效(完全缓解+部分缓解)率为73%;中位疾病无进展生存时间为8个月;1年和2年生存率分别为73%和55%.67例患者中,2例因过敏样输液反应终止治疗;4例出现胸闷为主要症状的急性输液反应(因停药后再次使用时无任何不良反应发生,所以未终止治疗);2级和3级手足综合征分别为2例(3%)和3例(4%);2例(3%)患者出现4级121腔炎;3级白细胞减少8例(12%).无一例发生4级白细胞减少或与药物相关的心脏毒性反应.结论 脂质体多柔比星+卡铂方案治疗复发性卵巢癌具有一定的疗效,患者对治疗的耐受性良好,可作为治疗复发性卵巢癌的选择之一.     

Phase II study of pegylated liposomal doxorubicin and oxaliplatin in relapsed advanced ovarian cancer

OBJECTIVE: This phase II study evaluated the efficacy and safety of pegylated liposomal doxorubicin (PLD) 30 to 35 mg/m(2) plus oxaliplatin 70 mg/m(2) every 28 days in women with advanced ovarian cancer that recurred or progressed after a platinum-based regimen. METHODS: 43 women received a median of 6 courses of treatment. RESULTS: Objective response was 54% in the evaluable population and was higher in women with platinum-sensitive (67%) compared with platinum-resistant disease (29%). At a median duration of follow-up of 15.5 months, median overall survival was 15.8 months and time to tumor progression 7.3 months. Most toxicity was no greater than grade 1 or 2. There was no grade 3 or 4 palmar-plantar erythrodysesthesia. After 264 cycles administered, neutropenia was the most common cause of severe toxicity and required one patient to withdraw from the study. No cardiotoxicity was reported. CONCLUSION: PLD plus oxaliplatin is active and well tolerated in women with relapsed advanced ovarian cancer, regardless of platinum sensitivity.     

Chemotherapy-induced dyspareunia: a case study of vaginal mucositis and pegylated liposomal doxorubicin injection in advanced stage ovarian carcinoma

BACKGROUND: Chemotherapy can cause vaginal irritation and mucositis, although rarely reported. CASE: A 62-year-old patient with ovarian cancer reported vaginal burning associated with dyspareunia, which emerged 3-5 days after her initial chemotherapy and persisted throughout her treatment. Her discomfort persisted until she was evaluated by our sexual health service and interventions were implemented. On examination, her vaginal vault was erythematous, with mild signs of vaginal atrophy. Her management schema consisted of the following: avoidance of intercourse 3-5 days after chemotherapy, intravaginal vitamin E suppositories three times per week, intravaginal estrogen tablets (initial course of 14 days followed by twice weekly usage), use of lubricants (Astroglide) during coitus, and counseling. Once interventions were introduced, she subsequently resumed sexual intercourse during the remainder of her chemotherapy treatments. CONCLUSION: Patients with sexual complaints during or following cancer treatment can be treated by their community gynecologists or gynecology oncologists or can be treated through a comprehensive sexual health program with restoration of sexual function.     

Prospective treatment of advanced or recurrent endometrial carcinoma with cisplatin, doxorubicin, and cyclophosphamide

Both single-agent cisplatin and the combination of doxorubicin and cyclophosphamide demonstrated moderate activity against endometrial carcinoma in earlier salvage trials. Since January 1979, 102 patients with advanced primary (n = 42) or recurrent (n = 60) endometrial carcinoma were prospectively treated with cisplatin (50 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2) (PAC). PAC was administered monthly until disease progression or toxicity precluded additional therapy. Patients received a median of five treatment cycles (range 1-13). Of the 87 patients with measurable disease, 12 had a complete clinical response, while 27 had a partial clinical response, for an overall objective response rate of 45%. No differences in response rates between primary and recurrent disease patients were noted. Median time to response was 2.5 months with a median response duration of 4.8 months. Nonresponders included 33 patients with stable disease and 15 with progression. Median progression-free survival for all patients was 6 months. Dose escalation was possible in 25% of patients; however, 52% of patients required dose reductions during treatment. Clinically significant toxicities included neutropenia (65%), anemia (47%), emesis (21%), nephrotoxicity (17%), and neurotoxicity (4%). Our study indicates that endometrial cancer is significantly responsive to PAC. Enthusiasm for this regimen should be tempered by the limited duration of response and substantial treatment toxicity.     

Prospective treatment of advanced or recurrent endometrial carcinoma with cisplatin, doxorubicin, and cyclophosphamide

Both single-agent cisplatin and the combination of doxorubicin and cyclophosphamide demonstrated moderate activity against endometrial carcinoma in earlier salvage trials. Since January 1979, 102 patients with advanced primary (n = 42) or recurrent (n = 60) endometrial carcinoma were prospectively treated with cisplatin (50 mg/m²), doxorubicin (50 mg/m²), and cyclophos-phamide (500 mg/m²) (PAC). PAC was administered monthly until disease progression or toxicity precluded additional therapy. Patients received a median of five treatment cycles (range 1–13). Of the 87 patients with measurable disease, 12 had a complete clinical response, while 27 had a partial clinical response, for an overall objective response rate of 45%. No differences in response rates between primary and recurrent disease patients were noted. Median time to response was 2.5 months with a median response duration of 4.8 months. Nonresponders included 33 patients with stable disease and 15 with progression. Median progression-free survival for all patients was 6 months. Dose escalation was possible in 25% of patients; however, 52% of patients required dose reductions during treatment. Clinically significant toxicities included neutropenia (65%), anemia (47%), emesis (21%), nephrotoxicity (17%), and neurotoxicity (4%). Our study indicates that endometrial cancer is significantly responsive to PAC. Enthusiasm for this regimen should be tempered by the limited duration of response and substantial treatment toxicity.     

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.