Sequential combination of paclitaxel-carboplatin and paclitaxel-liposomal doxorubicin as a first-line treatment in patients with ovarian cancer. A multicenter phase II trial

Cisplatin or carboplatin plus paclitaxel is considered the standard first-line treatment in ovarian cancer. Attempts to maximize tumor cytoreduction with first-line chemotherapy by incorporating new promising agents led to sequential drug administration with two or three doublets. In the present study, we aimed to evaluate the activity and the tolerance of two sequential doublets (paclitaxel/carboplatin and liposomal doxorubicin/carboplatin) administered as first-line treatment in patients with FIGO III/IV ovarian cancer. Treatment consisted of four cycles of carboplatin (6 AUC) plus paclitaxel (175 mg/m2; PC regimen) followed by four cycles with carboplatin (6 AUC) plus liposomal doxorubicin (40 mg/m(2); LD/C regimen) every 3 weeks. Forty-one patients in FIGO III or IV were enrolled. In an intention-to-treat analysis, 20 (49%) complete (CR) and 12 (29%) partial (PR) responses were achieved (overall response rate, ORR: 78%; 95% confidence interval, CI: 64.1-91.9%); with the PC regimen (164 cycles); 7 (17%) patients have stable (SD) and 2 (5%) progressive (PD) disease. The LD/C regimen (124 cycles) was administered in 36 (88%) patients because of 2 early deaths and 3 patient withdrawals. Three additional patients, 2 with PR and 1 with SD after PC chemotherapy) achieved a CR. Upon completion of the LD/C chemotherapy there were 18 (44%) patients with CR and 9 (22%) with PR (ORR=66%; 95% CI: 64-92%). The median duration of response was 27 months and the median time to progression 20 months. The probability of 2-year survival was 67%. Grade 3 and 4 neutropenia was observed in 34 and 14.6% of the patients, respectively, during the PC regimen, while during the treatment with LD/C the percentages for grade 3 and 4 neutropenia were 44.4 and 19.4%, respectively. Febrile neutropenia occurred only in patients treated with the PC regimen (4.9%). The incorporation of liposomal doxorubicin in this sequential doublet schedule of first-line treatment of ovarian carcinoma created a feasible and active regimen. Prospective randomized studies are required to assess its efficacy on patient survival.     

A systematic overview of chemotherapy effects in ovarian cancer.

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This overview on chemotherapy for epithelial ovarian cancer is based on a total of 176 scientific reports. Five meta-analyses including 17,291 patients, 33 prospective randomised studies including 12,340 patients, 36 prospective studies including 3,593 patients and one retrospective study including 421 patients. The studies include approximately 33,642 patients. The conclusions reached can be summarized into the following points: Radically operated patients with low-risk early ovarian cancer (stage IA or IB non-clear-cell well-differentiated carcinomas or borderline tumours) have a very good prognosis and there is no indication for adjuvant therapy. Radically operated patients with high-risk early ovarian cancer (clear cell carcinomas or FIGO stage IA or IB moderately or poorly differentiated carcinomas or stage IC) have a substantial risk for micrometastatic disease. However, the role of adjuvant chemotherapy is unclear and such therapy should, thus, only be used within clinical trials. The median overall survival for patients with advanced (FIGO stages II-IV) ovarian cancer randomised to paclitaxel/platinum-containing chemotherapy in three large studies ranged between 36-39 months. Compared with historical data, this represents a six to seven times longer median survival time than after surgery only. The probability for long-term survival for patients treated with a paclitaxel/platinum combination is too early to define. In two prospective randomised trials in advanced ovarian cancer, paclitaxel in combination with cisplatin has provided a survival benefit over cyclophosphamide/cisplatin. Based on these trials, paclitaxel/cisplatin is considered to be the standard treatment. This choice of standard therapy might, however, be questioned based on the results of the hitherto largest randomised study in advanced ovarian cancer, ICON3, which is, as yet only available in abstract form. It compared paclitaxel/carboplatin with carboplatin only or a platinum combination (cyclophosphamide/doxorubicin/cisplatin). There were no statistically significant differences in progression-free or overall survival. The drug regimen in the control arms of the previous studies showing superiority of the paclitaxel-cisplatin combination may not have been the optimal non-paclitaxel platinum-containing regimen. Three randomised studies have compared carboplatin/paclitaxel with cisplatin/paclitaxel. All three are hitherto only published as abstracts with short follow-up precluding survival analyses. None of them shows any difference in response rates. All three show less toxicity and one also better quality of life with carboplatin. Thus, there are preliminary data supporting the substitution of cisplatin with carboplatin. Intraperitoneal therapy with cisplatin caused improved survival compared with intravenous therapy in one ramdomised study. Further studies have shown trends to better survival and longer progression-free interval with intraperitoneal therapy. The accrual to studies on intraperitoneal chemotherapy has been poor reflecting that it is a cumbersome and not easily accepted treatment. In advanced ovarian cancer, no convincing advantage has been shown from more dose-intensive chemotherapy, without cytokines or bone marrow stem cell support, compared with standard doses. High response rates are achieved with high-dose chemotherapy with stem cell support in the salvage situation but response duration is short. Phase III studies evaluating high-dose chemotherapy in the first-line situation are ongoing. Until supportive controlled clinical trials are presented, high-dose chemotherapy should be confined to clinical trials. Tumour response is frequently observed on re-treatment with the same drugs as given first-line in patients sensitive to first-line platinum-based chemotherapy with a long progression-free interval. Thus, in these patients treatment with a platinum/paclitaxel combination might be recommended. albeit based on limited data. In patients resistant to first-line therapy, a number of single agents induce tumour responses in the range of 10-30%. The literature does not permit general treatment recommendations in these patients, which are recommended to be included in controlled clinical trials.     

Recent advances in ovarian cancer chemotherapy]

The standard approach for epithelial ovarian cancer has been maximum cytoreductive surgery followed by combination therapy. Several prospective control studies individually failed to demonstrate improved survival advantage for the Adriamycin containing combination compare with cisplatin plus cyclophosphamide. The two drug combination of carboplatin plus cyclophosphamide will be thought to become the treatment of choice, because it is equally effective as and less toxic than a regimen of cisplatin plus cyclophosphamide. Clinical trials are also in progress with more dose-intense regimens based on considerable retrospective evidence that survival is correlated with the dose intensity of platinum compounds. Currently, high dose carboplatin plus Gm-CSF, two-drug combination of carboplatin and cisplatin and super high dose carboplatin combined with autologous bone marrow transplantation are undergoing clinical trials. Taxol and taxotere, most important cancer drugs after emergence of cisplatin compound, has been shown to have clinical activity in drug resistant ovarian cancer patients. Majority of patients even with advanced germ cell tumors of the ovary is now cured because of the development of effective platinum-based combination chemotherapy of PVB or BEP.     

Comparison of Ifosfamide versus cyclophosphamide in combination with Cisplatin and Doxorubicin (adriamycin), as first-line therapy for advanced epithelial ovarian-cancer - report of a pilot-study

Cisplatin induction therapy followed by combination chemotherapy employing cisplatin, doxorubicin, and ifosfamide was administered to 25 consecutive patients with FIGO stage III:or IV epithelial ovarian cancer as first-line therapy following cytoreductive surgery. A median of seven (3-10) courses of combination chemotherapy were administered. Myelotoxicity necessitated dose attenuation in 20 (80%) patients. Microscopic hematuria was observed in one (4%) patient. Serious central neurotoxicity occurred in two (8%) patients. A surgically documentable response to therapy was observed in 16 of 19 (84%) patients who underwent second-look laparotomy. Thirteen (68%) patients had a surgical complete response, three (12%) patients had a surgical partial response, and three (12%) patients demonstrated progression of disease. The estimated two-year survival for the study population was 81%. The results observed in the current study were compared to those reported for a population of 40 patients with advanced ovarian cancer treated with cisplatin, doxorubicin, and cyclophosphamide (PAC). Patients treated with PAI had significantly (p=0.04) fewer episodes of sepsis, a significantly (p=0.02) greater percentage of patients requiring dose reduction secondary to myelotoxicity, and a significantly (p=0.02) higher surgical complete response rate. The two-year survival for patients treated with PAI of 81% and that for patients treated with PAC of 68%, do not differ significantly (p=0.39). The two-year disease-free survival for patients treated with PAI of 34% and the two-year disease-free survival of 55% for patients treated with PAC do not differ significantly (p=0.99). The combination of cisplatin, doxorubicin, and ifosfamide is effective as first-line therapy in the treatment of advanced epithelial ovarian cancer, but a significant advantage over the less costly standard regimen which employs cisplatin, doxorubicin and cyclophosphamide is not demonstrable in the current study.     

Clinical Investigation of Efficacy of Albumin Bound Paclitaxel plus Platinum Compounds as First-line Chemotherapy for Stage Ⅲ/IV Squamous Non-small Cell Lung Cancer

Objective: To observe the efficacy and toxicity of nanoparticle albumin bound paclitaxel (nab-paclitaxel) plus platinum agent (cisplatin or carboplatin) as first line treatment for stage III/IV squamous non-small-cell lung cancer (NSCLC). Methods: Forty chemotherapy naive patients with stage III/IV squamous NSCLCreceived nab-paclitaxel 125 mg/m2 on day 1 and day 8, cisplatin 75 mg/m2 on day 1, carboplatin area under the concentration-time curve of 5 (AUC=5) on day 1. One cycle of treatment was 3 weeks, and at least two were completed in each case. Results: Of the 40 patients who participated in the study, 25 achieved partial responses (PR), 12 reached a stage of stable disease (SD), and 3 suffered progressive disease (PD). The overall response rate (ORR) was 62.5% and the disease control rate (DCR) was 92.5%. Of the 20 patients without surgery orradiotherapy, 10 achieved PR, 7 reached a stage of SD, and 3 PD. The ORR was 50.0% and the DCR was 85.0%. The median progression-free survival time (PFS) of patients without surgery or radiotherapy was 5.0 months. Of the 20 patients receiving surgery or radiotherapy, 15 had PR and 5 p had SD, with an ORR of 75.0% and a DCR of 85.0%. Specifically, the DDP arm demonstrated a significantly higher ORR than the CBP arm (100%vs54.5%, P<0.05). Common treatment related adverse events were myelosuppression, gastrointestinal response, baldness and neurotoxicity, most of which were grade 1 to 2. Conclusion: Nab-paclitaxel plus platinum agent (cisplatin or carboplatin) is effective as a first-line chemotheraphy for stage III/IV squamous NSCLC, and its adverse effects are tolerable.     

Extreme drug resistance assay and response to chemotherapy in patients with primary peritoneal carcinoma

BACKGROUND AND OBJECTIVES: The extreme drug resistance (EDR) assay is an in vitro chemoresistance assay performed on tumor samples grown in culture and is claimed to predict drugs unlikely to produce response. Its clinical value in patients with epithelial ovarian cancer (EOC) has recently been questioned. The aim of this study is to describe EDR assay results and responses to chemotherapy among women with primary peritoneal adenocarcinoma (PPA) and to compare them with those of women with EOC. METHODS: Fresh tumor specimens from 20 consecutive women with PPA were tested for EDR to the following drugs: cisplatin, carboplatin, paclitaxel, doxorubicin, cyclophosphamide, ifosfamide, etoposide, hexamethylmelamine, and topotecan. They were then treated with cisplatin-based combination chemotherapy. The results of the EDR assay and response to chemotherapy were compared with those among women with EOC. RESULTS: There was no significant difference in the incidence of EDR to cisplatin, carboplatin, paclitaxel, doxorubicin, cyclophosphamide, ifosfamide, etoposide, hexamethylmelamine, and topotecan among patients with PPA and those with EOC. The response rate of PPA patients to chemotherapy was 80.0% and unrelated to EDR to the individual drugs used in combination chemotherapy. CONCLUSIONS: The EDR profile and response to cisplatin-based chemotherapy among women with PPA were similar to those among women with EOC. These findings support treating both conditions similarly. EDR to individual drugs does not preclude response to combination chemotherapy.     

A phase II study of the combination of carboplatin and ifosfamide in previously untreated metastatic small cell lung carcinoma.

This Phase II study evaluated the combination of two active agents in small cell lung carcinoma (SCLC): carboplatin and ifosfamide. Thirty previously untreated patients (27 men and 3 women) with a median age of 59 years were included in this study. Twelve patients had one metastatic site and 18 had two or more metastatic sites. The median performance status was 80%. The chemotherapy (CT) regimen administered during the course of this study consisted of carboplatin (300 mg/m2) and ifosfamide (4 g/m2) plus mesna every 4 weeks. All 30 patients were evaluable: 1 achieved a complete remission (CR) and 18 achieved a partial remission (PR) (objective response rate, 63%). The median response time was 3 months and the median survival time was 8 months (range, 1 to 25+ months). Bone marrow toxicity was Grade III in three patients and Grade IV in four patients. The carboplatin and ifosfamide combination was well tolerated. No cross-resistance with the doxorubicin and etoposide regimen was established because 4 of 11 patients responded to this combination (+/- cisplatin) after failing to respond to the ifosfamide and carboplatin regimen. The ifosfamide and carboplatin combination may be considered for inclusion in non-cross-resistant alternating CT schedules.     

Salvage carboplatin therapy for advanced ovarian cancer after first-line treatment with cisplatin.

From April 1989 to August 1990, 17 patients with Stage 3 or 4 epithelial ovarian cancer (EOC) were treated with intravenous carboplatin (160-400 mg/m2) for refractory or recurrent disease after first-line treatment with cisplatin-based combination chemotherapy. Of fifteen patients evaluable for activity, two complete responses and two partial responses were seen, for a response rate of 27%. The duration of response was 4.5, 5, 8, and 9.2 months, respectively, and responders survived longer than nonresponders. Of the nine evaluable patients receiving carboplatin as the first salvage treatment, four responses were seen. Dose selection for the first cycle of carboplatin was based on previous treatment, and adjustments were made on the basis of myelosuppression. In general, treatment was well tolerated--severe myelosuppression occurred after 6 of 73 cycles. This review confirms previous reports of anti-tumor activity of carboplatin in patients with refractory or recurrent advanced EOC who respond to first-line treatment with cisplatin. Further evaluation may help define the toxicity and efficacy of salvage treatment with carboplatin compared to cisplatin in patients who recur after a prolonged disease-free interval after first-line cisplatin-based therapy.     

Significance and effects of intraperitoneal cisplatin administration for ovarian cancer

We studied the efficacy and safety of combination chemotherapy in which a high-dose platinum agent was administered intraperitoneally (i.p.) plus intravenously (i.v.) to 22 patients with stage III ovarian cancer. The chemotherapy consisted of etoposide (i.p.), cisplatin (i.p.), and carboplatin (i.v.). Each course was repeated every 4 weeks and a maximum of 5 courses was given in the 6 months following the initial surgery. As a control, 13 patients received different chemotherapy (CAP etc.) in which cisplatin, cyclophosphamide and doxorubicin pirarubicin hydrochloride were administered. The mean (SD) total dose of cisplatin in the patient group group (790.6 +/- 317.0 mg/m2) over the 6 months was significantly higher than in the control group (377.2 +/- 215.1 mg/m2). The overall response rate (CR + PR) 6 months after the completion (95.5%) was significantly higher in the study patients than in the control group (53.1%). The 1, 3, 5-year survival rates were significantly higher in the EPJ group (91.0, 59.0, 42.1%) than in the control group (53.8, 15.4, 15.4%). There was no significant difference in renal toxicity or bone marrow suppression (leukopenia and thrombocytopenia) between the two groups. EPJ therapy allowed an increased dose of cisplatin in the treatment of ovarian cancer without enhancing renal toxicity, resulting in higher response and survival rates. This study demonstrated that this therapy is an effective and well-tolerated regimen.     

A randomised study of carboplatin vs sequential ifosfamide/carboplatin for patients with FIGO stage III epithelial ovarian carcinoma. The London Gynaecologic Oncology Group.

In a study designed to compare response rates of patients with stage III epithelial ovarian carcinoma to ifosfamide and carboplatin, 152 patients were randomised to receive either sequential therapy with three cycles of ifosfamide followed by three cycles of carboplatin, or to six cycles of single agent carboplatin. Ifosfamide was given every 3 weeks in a dose of 5 gm m-2 as a 24 h infusion with mesna, 1 gm m-2 by i.v. bolus prior to ifosfamide, 3 gm m-2 with ifosfamide, and 1 gm m-2 as an 8 h infusion after ifosfamide. Carboplatin was given in a dose of 400 mg m-2 by short i.v. infusion every 4 weeks. Sixty-eight evaluable patients were randomised to sequential ifosfamide/carboplatin, and 67 to single agent carboplatin. Median follow-up is 36 months (range 5.5-82.3). After three cycles of treatment two patients in the ifosfamide/carboplatin arm achieved complete remission (CR), and 12 partial remission (PR) for an overall response rate of 29%, whereas in the carboplatin arm ten patients achieved CR, and 23 PR, for an overall response rate of 63% (P = 0.0008). Seven of 15 patients with progressive disease, and nine of 20 patients with stable disease at the initial response evaluation, following three cycles of ifosfamide, subsequently responded to carboplatin therapy so that the final response rate to the complete regimen was 65% for the ifosfamide/carboplatin arm, compared to 71% for the carboplatin arm (NS). For the ifosfamide/carboplatin arm, median recurrence free survival and overall survival were 14.1 months and 18.7 months. Corresponding figures for the carboplatin arm were 14.5 months and 21.5 months (NS). Both treatments were generally well tolerated. However 47% of patients in the ifosfamide/carboplatin arm developed alopecia sufficient to require a wig, compared to only 2% in the carboplatin arm. Ifosfamide is clearly less effective, and more toxic than carboplatin. Ifosfamide failures can however be effectively salvaged by subsequent carboplatin treatment. Ifosfamide cannot be recommended for single agent therapy in ovarian carcinoma, however the combination of carboplatin plus ifosfamide might be a suitable treatment to be tested in a future randomised study against carboplatin alone.     

卵巢上皮癌淋巴结转移化疗的临床疗效分析

背景与目的：卵巢上皮癌属化疗中度敏感肿瘤,随着肿瘤细胞减灭术及铂类联合化疗的应用,其疗效有明显改善,但其淋巴结转移病灶对化疗的敏感性尚存异议。本研究通过回顾性分析临床资料,以评价卵巢上皮癌患者淋巴结转移对化疗的敏感性及其预后,方法：对1986年6月－2001年2月收治的50例卵巢上皮癌淋巴结转移患者进行回顾性分析,其中Ⅲ-Ⅳ期32例,治疗后复发18例,50例均有可评价疗交的淋巴结转移灶,其中38例有可评价的盆腔,腹腔肿瘤。46例接受术前化疗1－3疗程,肿瘤细胞减灭术、术后化疗。化疗疗效评价按实体瘤疗效评价标准。化疗包括术前、术后或复发患者的化疗,其中45例接受含铂类联合化疗,包括CP（环磷酰胺＋顺铂）,CAP（环磷酰胺＋顺铂＋阿霉素或表阿霉素）,TC（紫杉醇＋卡铂）,TP（紫杉醇＋顺铂）,吉西他滨＋卡铂及IEP（顺铂＋异环磷酰胺＋足叶乙甙）方案,1例用美法仑,1例用CF（环磷酰胺和5－氟尿嘧啶）方案,3例用IFO＋VP－16（异环磷酰胺＋足叶乙甙）,结果：全组淋巴结转移灶和肿瘤的有效率分别为68．0％、71．1％,Ⅲ-Ⅳ期初治患者淋巴结转移和盆腹腔肿瘤有效率分别为78．1％,76．6％,而复发组两者有效率均为50．0％,结论：卵巢上皮癌的淋巴结转移,无论Ⅲ-Ⅳ期还是复发患者,其对化疗敏感性与盆腹腔肿瘤相近,Ⅲ-Ⅳ期患者预后与减瘤术是否彻底,以及化疗的疗程数多少有明显的相关性。     

Carboplatin and cyclophosphamide salvage therapy for ovarian cancer patients relapsing after cisplatin combination chemotherapy

30 ovarian cancer patients with a relapse after prior cisplatin combination chemotherapy were treated in a phase II study with cyclophosphamide 100 mg/m² orally on days 1–7 and carboplatin 300 mg/m² intravenously on day 8. Treatment was well tolerated. The major side-effect was thrombocytopenia. 28 patients were evaluable for response. The response was 5 CRs (18%), 4 PRs (14%) 15 SDs (53%) and 4 PDs (14%), for an overall response rate of 32%. The overall progression-free survival lasted from 2 to 23 months, median 8 months. Overall survival ranged from 2 to 35+ months, median 12 months. Patients with a therapy-free interval of more than 1 year showed a higher response rate (46%) than patients with a shorter therapy-free interval (20%). It is concluded that platinum containing second-line chemotherapy, after treatment that already contained cisplatin, is only warranted to palliate symptoms.     

Dose intensification of platinum compounds with glutathione protection as induction chemotherapy for advanced ovarian carcinoma.

Based on previous clinical experience indicating the tolerability and efficacy of high-dose cisplatin with glutathione protection in the treatment of advanced ovarian cancer, this study was undertaken to explore the efficacy and feasibility of an alternative high-dose, platinum-based approach including a combination of high-dose cisplatin plus carboplatin as induction chemotherapy of advanced ovarian carcinoma and intervention surgery. Fifty consecutive eligible patients with untreated stage III or IV epithelial ovarian cancer received 40 mg/m(2) cisplatin daily on days 1-4 and 160 mg/m(2) carboplatin on day 5. The cycle was repeated after 28 days. Patients received glutathione (2,500 mg) before each cisplatin or carboplatin administration and standard intravenous hydration. After 2 courses of induction chemotherapy, the patients underwent surgical reevaluation with debulking, when possible, followed by a further 3 cycles of 120 mg/m(2) cisplatin (i.e. 40 mg/m(2) daily for 3 consecutive days plus 600 mg/m(2) cyclophosphamide on day 3) except in instances of lack of response. All eligible patients were assessed for response and toxicity. The toxicity was moderate with lack of significant nephrotoxicity. Neurotoxicity and ototoxicity were acceptable and in no patient was treatment discontinued for those toxic effects. Myelotoxicity was somewhat more severe than that observed with our previous study with high-dose cisplatin and probably related to the addition of carboplatin. Of the 40 responsive patients, 23 (46%) had a pathological complete response and 4 (8%) had a clinical complete response (without second-look laparotomy). The efficacy of the present protocol was also documented by overall survival (median survival >48 months), which appeared to be better than expected with the current therapy in this group with advanced/bulky disease. The impressive efficacy suggests a possible contribution of reduced glutathione itself in improving the outcome, as supported by preclinical studies. The results of this study should be placed in context with current platinum-based therapy including paclitaxel.     

A phase-ii study testing weekly platinum derivative combination chemotherapy as 2nd-line treatment in patients with advanced small-cell lung-cancer

A phase II trial was conducted to determine the effectiveness of weekly administration of cisplatin (25 mg/m(2) on day 1) and carboplatin (100 mg/m(2) on day 1) as salvage chemotherapy for patients with small cell lung cancer after first-line chemotherapy without platinum derivatives. Of 40 eligible patients, 38 were evaluable for response. Interval between last course of first-line chemotherapy and first course of salvage therapy was less than 3 months in 34 and greater in 4. Five partial responses (13%; confidence interval at 95%:0.01-0.25) were documented (including 4 in patients with a treatment-free interval <3 months) as well as 8 no change, 21 progressions and 4 early deaths due to malignant disease. Toxicity consisted mainly of moderate thrombopenia and leucopenia. Grade I nephrotoxicity was observed in 6 patients. In conclusion, weekly administration of moderate doses of cisplatin and carboplatin as salvage chemotherapy for small cell lung cancer appeared feasible and was associated with a moderate but definitive anticancer activity.     

Options for first- and second-line therapy in small cell lung cancer--a workshop discussion

In a case study-based workshop, physicians were asked to discuss various aspects of patient management in small cell lung cancer (SCLC). For first-line chemotherapy, most investigators recommended treatment with etoposide/cisplatin, with possible dosing variations according to tolerability and convenience. In France (but not elsewhere), medical oncologists tend to use a four-drug regimen (etoposide/cisplatin/cyclophosphamide/epirubicin), based on the results of an extensive-stage SCLC trial. Alternative first-line regimens, such as vincristine/ifosfamide/carboplatin/etoposide (VICE) and topotecan/platinum, are currently being explored. Options for therapy in patients with recurrent disease are more varied, although there was consensus that active treatment at relapse should be considered. Regimens include topotecan (alone or in combination), cyclophosphamide/doxorubicin/vincristine (CAV) and re-induction with the earlier first-line agents. Studies are also investigating the potential benefits of other combinations, including topotecan/vinorelbine and paclitaxel/carboplatin. For patients with relapsed extensive-stage SCLC and brain metastases, whole brain radiation therapy was considered appropriate for both palliative and therapeutic reasons. The potential role of combination therapy with topotecan/temozolomide, both of which cross the blood-brain barrier, is currently being investigated.     

The E3 ubiquitin ligase EDD is an adverse prognostic factor for serous epithelial ovarian cancer and modulates cisplatin resistance in vitro

Despite a high initial response rate to first-line platinum/paclitaxel chemotherapy, most women with epithelial ovarian cancer relapse with recurrent disease that becomes refractory to further cytotoxic treatment. We have previously shown that the E3 ubiquitin ligase, EDD, a regulator of DNA damage responses, is amplified and overexpressed in serous ovarian carcinoma. Given that DNA damage pathways are linked to platinum resistance, the aim of this study was to determine if EDD expression was associated with disease recurrence and platinum sensitivity in serous ovarian cancer. High nuclear EDD expression, as determined by immunohistochemistry in a cohort of 151 women with serous ovarian carcinoma, was associated with an approximately two-fold increased risk of disease recurrence and death in patients who initially responded to first-line chemotherapy, independently of disease stage and suboptimal debulking. Although EDD expression was not directly correlated with relative cisplatin sensitivity of ovarian cancer cell lines, sensitivity to cisplatin was partially restored in platinum-resistant A2780-cp70 ovarian cancer cells following siRNA-mediated knockdown of EDD expression. These results identify EDD as a new independent prognostic marker for outcome in serous ovarian cancer, and suggest that pathways involving EDD, including DNA damage responses, may represent new therapeutic targets for chemoresistant ovarian cancer.     

Controversies in chemotherapy — what is standard treatment?

This paper discusses some current controversies regarding optimal first-line treatment for patients with advanced ovarian cancer.Despite improvements seen in median and overall survival using platinum-based chemotherapy, longterm survival rates for patients with advanced epithelial ovarian carcinoma remain disappointing and several efforts have been made recently to develop more effective primary therapy. In the early 1990s, paclitaxel was first tested in ovarian cancer. In GOG111, the cisplatin+paclitaxel regimen was judged to be superior compared with the platinum-cyclophosphamide control arm, with an improvement of overall response rate, median progression-free interval and overall median survival. These favourable data were confirmed by the OV 10 trial. In contrast, in a further GOG trial (GOG132), there was no difference in survival between cisplatin alone and the combination of paclitaxel and cisplatin. ICON3, the first and only trial comparing paclitaxel plus carboplatin against carboplatin alone or a (non-taxane) cisplatin-based control arm, again failed to demonstrate any advantage for the platinum-taxane arm, either in progression-free survival or in overall survival. The results of ICON3, in accordance with the GOG132 study, appear to contradict the earlier positive results seen for paclitaxel and cisplatin in the GOG111 and OV10. Several hypotheses have been raised to explain this discrepancy including differences in the extent and timing of crossover to taxanes in the control group, differences in the type of patients included, differences in the efficacy of research regimens or in the efficacy of the control regimens. A meta-analysis with individual patient data demonstrated a substantial heterogeneity between groups using different control arms, possibly indicating that the cyclophosphamide/cisplatin regimen used in the two “positive” trials may be less effective than the control regimen used in the other trials. It will be almost impossible to achieve an agreement on these proposed explanations. However, this meta-analysis provides evidence that the introduction of taxanes can lead to a survival advantage vastly inferior to that expected after the results of the GOG111 and OV10 trials.Ongoing research is focusing on the addition of a third drug to platinum/taxane in regimens consisting of triplets or sequential doublets.Determining the characteristics to define the patient population with relapse is important to evaluate the therapeutic options with the greatest likelihood of success. Appropriate salvage therapy is based on the timing and nature of the recurrence and the extent of prior chemotherapy. The main objectives of salvage chemotherapy include (1) improvement in quality of life and symptoms, (2) tumour load reduction and survival advantage, and (3) evaluation of potentially active new drugs to be included in first-line treatment.Since the goal is palliation in most cases, monotherapy is generally indicated. Unfortunately, durable responses to salvage chemotherapy are rare and cure almost impossible. The sequential use of the agents currently available for salvage treatment in monotherapy may transform ovarian cancer into a chronic disease and increase the length of survival. Perhaps the most interesting role of second-line chemotherapy is to identify, new potentially active drugs, which can then be used upfront.For patients with platinum-sensitive disease, it was unclear, until recently, whether the platinum-based combination was superior to single-agent platinum at the time of relapse. The recent results of ICON4 seem to indicate an advantage in both survival and progression-free survival for patients with relapsing platinum-sensitive ovarian cancer treated with the combination platinum/taxane compared with conventional platinum-based chemotherapy.     

Ovarian cancer, Part II: Treatment.

The death rate from epithelial ovarian cancer has only slightly decreased in the past decade. In contrast, there have been dramatic improvements in the treatment of germ cell tumors of the ovary and the majority of patients even with advanced disease is now cured because of the development of effective platinum-based combination chemotherapy. Unfortunately, most patients with ovarian cancer have the epithelial histologic type, and only one third of these patients can be cured with standard approaches. It has recently been shown that a subset of patients with early stage ovarian cancer has a greater than 90% cure rate without chemotherapy. Consequently, a major focus of current research is to develop effective screening modalities in order to diagnose epithelial tumors when they are still confined to the ovaries and pelvis. Currently, three fourths of patients are diagnosed at the time the disease has spread throughout the peritoneal cavity, and the standard approach has been cytoreductive surgery followed by combination chemotherapy. The two-drug combination of carboplatin plus cyclophosphamide has now become the treatment of choice, although it is equally effective as and less toxic than a regimen of cisplatin plus cyclophosphamide. In addition, Taxol has been identified as an extremely active agent against this disease, and new Taxol-containing combinations are under clinical investigation. Clinical trials are also in progress with hexamethylmelamine and ifosfamide combinations as well as with more dose-intense regimens based on considerable retrospective evidence that survival is correlated with the dose intensity of platinum compounds. New agents such as WR2721, IL-3, and IL-1 alpha are undergoing clinical evaluation to determine whether the toxicities of platinum compounds can be decreased and lead to further exploitation of the dose response relationship. After induction chemotherapy, approximately 50% of patients will be in a clinical complete remission. Unfortunately, 30% to 50% of these patients will have recurrent disease; clinical trials are currently in progress to determine whether any form of therapy following the initial induction regimen can prevent or delay recurrences. Based on laboratory investigations in relevant models of human ovarian cancer, clinical trials are also in progress with novel new agents that may be capable of reversing drug resistance to platinum compounds and alkylating agents. For patients with germ cell tumors of the ovary, platinum-based combination chemotherapy has produced the same dramatic effects as in testicular cancer. Clinical trials are now focused on retaining therapeutic efficacy but decreasing the toxicity of treatment in these tumors that frequently affect women in their reproductive ages.     

Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study.

PURPOSE: In randomized trials the combination of cisplatin and paclitaxel was superior to cisplatin and cyclophosphamide in advanced-stage epithelial ovarian cancer. Although in nonrandomized trials, carboplatin and paclitaxel was a less toxic and highly active combination regimen, there remained concern regarding its efficacy in patients with small-volume, resected, stage III disease. Thus, we conducted a noninferiority trial of cisplatin and paclitaxel versus carboplatin and paclitaxel in this population. PATIENTS AND METHODS: Patients with advanced ovarian cancer and no residual mass greater than 1.0 cm after surgery were randomly assigned to receive cisplatin 75 mg/m2 plus a 24-hour infusion of paclitaxel 135 mg/m2 (arm I), or carboplatin area under the curve 7.5 intravenously plus paclitaxel 175 mg/m2 over 3 hours (arm II). RESULTS: Seven hundred ninety-two eligible patients were enrolled onto the study. Prognostic factors were similar in the two treatment groups. Gastrointestinal, renal, and metabolic toxicity, as well as grade 4 leukopenia, were significantly more frequent in arm I. Grade 2 or greater thrombocytopenia was more common in arm II. Neurologic toxicity was similar in both regimens. Median progression-free survival and overall survival were 19.4 and 48.7 months, respectively, for arm I compared with 20.7 and 57.4 months, respectively, for arm II. The relative risk (RR) of progression for the carboplatin plus paclitaxel group was 0.88 (95% confidence interval [CI], 0.75 to 1.03) and the RR of death was 0.84 (95% CI, 0.70 to 1.02). CONCLUSION: In patients with advanced ovarian cancer, a chemotherapy regimen consisting of carboplatin plus paclitaxel results in less toxicity, is easier to administer, and is not inferior, when compared with cisplatin plus paclitaxel.     

Consolidation with intraperitoneal cisplatin in first-line therapy of advanced ovarian cancer

Seventy-five patients with advanced epithelial ovarian cancer were treated with a combined modality regimen of systemic, induction chemotherapy followed by intraperitoneal therapy (IPT). All patients underwent initial surgery for staging and/or cytoreduction followed by cisplatin 20 mg/m2 intravenously (IV) for 5 days and cyclophosphamide 600 mg/m2 on day 4 every 3 to 4 weeks for two to four cycles. Patients were then evaluated for IPT and, if eligible, had an intraperitoneal (IP) catheter placed. IPT consisted of cisplatin 60 mg/m2 in 2 L on day 1 and IV cyclophosphamide 600 mg/m2 on day 2 every 3 weeks for three to six cycles. Patients who demonstrated a clinical complete response (CCR) were then referred for second-look laparotomy (SLL). Of 71 patients who completed the induction phase, 53 (75%) were eligible for IPT, and 49 patients entered the therapy phase. Toxicity of the combined modality approach was acceptable and did not differ from our previous experience using the same drugs systemically. Thirty-two of the 49 patients who completed IPT achieved a CCR, which was confirmed by SLL in 20 patients. Twenty recurrences were documented in the 32 CCR patients, 13 occurred in patients after SLL. Projected median survival of all patients is 38 months. Median survival correlated with amount of residual disease following initial surgery (23 months for bulky v 45 months for minimal residual; P less than .001) and with performance status ([PS]; 24 months for PS 2, 3 v greater than 46 months for PS O; P less than .001). Patients who presented with bulky tumors were less likely to reach the consolidation IPT phase. Incorporation of IP cisplatin into the first-line regimen for treatment of ovarian cancer does not appear to have major impact on the survival of all treated patients when compared with our historical control series. Combined IV and IPT cisplatin and cyclophosphamide is feasible with acceptable toxicity. Its impact on response and survival may be limited to only "good-prognosis" patients.