© 2004 Foundation for Promotion of Cancer Research
Cisplatin, Paclitaxel and Escalating Doses of Doxorubicin (TAP) in Advanced Ovarian Cancer: a Phase I Trial
1 Division of Gynecological Oncology and 2 Department of Medical Oncology, National Cancer Center Hospital, Tokyo, 3 Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, 4 Department of Obstetrics and Gynecology, National Nagoya Hospital, Nagoya, 5 Department of Obstetrics and Gynecology, Sakai Hospital, Kinki University School of Medicine, Sakai, 6 Department of Obstetrics and Gynecology, National Kure Medical Center, Kure, Hiroshima, 7 Department of Obstetrics and Gynecology, Faculty of Medicine, Kyushu University, Fukuoka, 8 Department of Obstetrics and Gynecology, Kurume University School of Medicine, Kurume, Fukuoka, 9 Gynecology Service, National Kyushu Cancer Center, Fukuoka and 10 Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
For reprints and all correspondence: Takashi Onda, Division of Gynecological Oncology, National Cancer Center Hospital, 5–1–1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: taonda{at}ncc.go.jp
Received April 3, 2004; accepted June 10, 2004
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Abstract |
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Background: The objectives of this phase I trial were to determine the maximum tolerated dose (MTD) and the recommended dose (RD) for phase II/III trials of doxorubicin (DOX) combined with paclitaxel (PTX) and cisplatin (CDDP) in patients with advanced ovarian cancer (AOC).
Methods: Twenty-eight patients with stage III/IV AOC received fixed doses of PTX (110 mg/m2 over 24 h on day 1) and CDDP (75 mg/m2 on day 2) and an escalating dose of DOX (20, 30, 40 or 50 mg/m2 on day 1) every 3 weeks. The patients received up to six cycles of chemotherapy. At level 1, one of the original dose-limiting toxicities (DLTs), grade (G) 4 neutropenia lasting for 4 days or longer, occurred in four of six patients. The criterion for DLT was amended to ‘G4 neutropenia lasting for 8 days or longer accompanied with G4 leukopenia’ and four additional patients were evaluated at level 1.
Results: According to the new criteria, DLT was observed only in one of nine patients except one ineligible patient at level 1and two of six patients at level 4. G4 neutropenia and G4 leukopenia occurred in 85% and 44%, respectively, in the first course of chemotherapy. Non-hematological toxicity was generally mild or moderate. MTD was not determined at the planned dose levels. A clinical response was observed in 16 of 19 (84%) evaluable patients. Further dose escalation was not performed and RD was determined as level 4 because more than 30% of cycles required some modification of chemotherapy at level 4.
Conclusion: The combination of TAP including 50 mg/m2 of DOX is feasible and well tolerated as first line chemotherapy in AOC, warranting further study of this regimen.
Key Words: ovarian cancer • chemotherapy • doxorubicin • phase I study
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Since randomized trials have demonstrated the superiority of paclitaxel (PTX) plus cisplatin (CDDP) over cisplatin plus cyclophosphamide (CPA) in overall survival and progression-free survival (1,2) and subsequent trials demonstrated similar activity of PTX plus carboplatin (CBDCA) compared with PTX plus CDDP (3), the combination regimen of PTX plus platinum, such as CDDP or CBDCA, is considered the standard regimen for advanced ovarian cancer (AOC). The two-drug combination regimen of PTX and platinum yields a high response rate and improved survival for patients with AOC. In spite of chemotherapy development, the 5-year survival of patients with stage III/IV ovarian cancer is generally less than or around 20% (4), which is far from satisfactory. Therefore, several approaches, especially new agents or new drug combinations, are being examined in clinical studies to improve further the outcome of treatment for AOC.
Doxorubicin (DOX), an anthracycline, is known to be an active agent for ovarian cancer and was used in combination with CDDP and CPA as a standard regimen for ovarian cancer before the introduction of PTX plus platinum. The benefit of adding DOX to CDDP and CPA was controversial. A phase III randomized trial of CDDP plus CPA with or without DOX conducted by the Gynecological Oncology Group (GOG) (5) showed no clear benefit of DOX in the pathological complete response rate and median survival time. However, three meta-analyses demonstrated that the incorporation of DOX into the CDDP-based regimen for ovarian cancer may improve the long-term survival of AOC by 7–10% (6–8). Therefore, the value of DOX in the treatment of ovarian cancer was re-examined.
The benefit of adding DOX to the current standard regimen, PTX and platinum, should be evaluated to improve further the outcome of patients with AOC. To evaluate the safety and efficacy of this combination regimen, we conducted a phase I trial in patients with AOC for first-line chemotherapy using a combination of fixed doses of CDDP and PTX with escalating doses of DOX given every 3 weeks.
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PATIENTS AND METHODS |
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SELECTION OF PATIENTS
The subjects of this study were untreated patients with stage IIIC or IV epithelial ovarian cancer. The histology of tumors included serous, mucinous, endometrioid, clear cell, mixed epithelial, undifferentiated, malignant Brenner, transitional cell and unclassified types. Patients with low potential malignancies were not included.
Other eligible criteria for entry into this study were as follows: (a) Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; (b) age 16–75 years; (c) adequate bone marrow function [white blood cell count (WBC) 
3000/mm3 or absolute neutrophil count (ANC) 1500/mm3 and platelet count 100 000/mm3], adequate hepatic function [total serum bilirubin 
1.5 mg/dl and serum aspartate aminotransferase (AST) 2.5 times the upper limit of normal], adequate renal function (serum creatinine 1.5 mg/dl and creatinine clearance 50 ml/min) and adequate cardiac function (normal or minor deviation in electrocardiogram); and (d) written informed consent. Patients were ineligible if they had (a) severe mental disorders; (b) uncontrolled hypertension; (c) history of cardiac failure, unstable angina, myocardial infarction within 6 months prior to the study; (d) liver cirrhosis; (e) diabetes mellitus, controlled with insulin; (f) history of severe hypersensitivity or hypersensitivity to drugs formulated with polyoxyethylated castor oil (Cremophor EL) as an ingredient (e.g. cyclosporine or vitamin K); (g) hepatitis B e antigen (HBeAg) or antibody against hepatitis C virus (HCV); or (h) if they were pregnant.
TREATMENT PLAN
All patients underwent staging laparotomy and, simultaneously, maximum cytoreductive surgery. Following surgery, eligible patients were enrolled into the study. Patients received up to six cycles of chemotherapy consisting of paclitaxel (PTX), doxorubicin (DOX) and cisplatin (CDDP). DOX was administered as a 30 min intravenous (IV) infusion on day 1. PTX was administered as a 24 h continuous i.v. infusion on day 1 following DOX administration. CDDP was administered as a 2 h i.v. infusion on day 2. Chemotherapy was repeated every 21 days, assuming recovery from the toxicity of the previous cycle. Four different dose levels were tested. The dose of DOX was escalated from 20 mg/m2 (level 1) to 50 mg/m2 (level 4) in increments of 10 mg/m2 in sequential cohorts and doses of PTX and CDDP were fixed at 110 and 75 mg/m2, respectively.
A pre-medication schedule consisted of a 20 mg intravenous dexamethasone infusion 12 and 6 h before chemotherapy, 50 mg oral diphenhydramine and 50 mg intravenous ranitidine administration 30 min before chemotherapy. No primary granulocyte colony-stimulating factor (G-CSF) prophylaxis was allowed. G-CSF use was allowed only when grade 4 leukopenia (<1000/m3) or grade 4 neutropenia (<500/m3) lasting for 3 days or longer or grade 2 fever (38°C) during grade 3 leukopenia (<2000/m3) or grade 3 neutropenia (<1000/m3) was observed.
TREATMENT MODIFICATION
Re-treatment was delayed until the following criteria were met. (a) WBC 2500/mm3 and platelet count 100 000/mm3; (b) total serum bilirubin 1.5 mg/dl, serum AST 2.5 times the upper limit of normal and serum creatinine 1.5 mg/dl; (c) more than 48 h passed after the final G-CSF use; and (d) absence of active infection. Patients were taken out of the study if the treatment interval exceeded 42 days.
For patients experiencing any of the following toxicities, the doses of all three drugs were reduced to 90% of the previous dose: (a) grade 4 leukopenia (<1000/m3); (b) grade 2 fever (38°C) lasting for 3 days and/or bacteremia during grade 3 leukopenia (<2000/m3) or neutropenia (<1000/m3); (c) grade 3 thrombocytopenia (<50 000/m3); and (d) grade 3 or 4 non-hematological toxicities other than nausea and vomiting. Toxicities were graded according to the Japan Clinical Oncology Group (JCOG) toxicity criteria (9), based on Common Toxicity Criteria of the National Cancer Institute (NCI-CTC, 1982) to extend and supplement the criteria.
Chemotherapy was discontinued if (a) response was revealed to be no change (NC) after three cycles of chemotherapy, (b) progressive disease (PD) was observed, (c) unacceptable toxicities were observed or (d) recovery from toxicities was prolonged.
DETERMINATION OF MAXIMUM TOLERATED DOSE AND RECOMMENDED DOSE
The primary objectives of the study were to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of DOX when combined with 110 mg/m2 of PTX and 75 mg/m2 of CDDP. Initially, six patients were sequentially enrolled into the lowest dose level. Dose-limiting toxicity (DLT) was evaluated in the first course of chemotherapy to determine MTD and in all courses of chemotherapy to determine the RD. If none or one of the six patients experienced DLT, then the following six patients would be enrolled into the next dose level. If four or more of the six patients experienced DLT and the dose level was higher than level 1, MTD was determined as the previous dose level. If two or three of the six patients experienced DLT, then an additional six patients would be enrolled into the same dose level at other than level 4. If three or fewer of 12 patients experienced DLT, then the next six patients would be enrolled into the next dose level. If four or more of 12 patients experienced DLT, then MTD was determined as that dose level. These steps were repeated until MTD was determined. RD was determined taking into account the DLT observed in the following courses of chemotherapy.
DLT was initially defined as (a) grade 4 leukopenia (<1000/m3) or grade 4 neutropenia (<500/m3) lasting for 4 days or longer; (b) grade 2 fever (38°C) lasting for 3 days and/or bacteremia during grade 3 leukopenia (<2000/m3) or neutropenia (<1000/m3); (c) grade 4 thrombocytopenia (<25 000/m3); and (d) grade 3 or 4 non-hematological toxicities other than nausea and vomiting. The criteria were subsequently amended as described in the next subsection.
AMENDMENT OF CRITERIA FOR DOSE-LIMITING TOXICITY
Among six patients enrolled into dose level 1, grade 4 neutropenia lasting for 4 days or longer [criterion (a)] was observed in four patients during the first course of chemotherapy and neutrophils were not counted in one patient with grade 2 leukopenia. Therefore, the study was discontinued and the toxicities were evaluated. Grade 4 neutropenia was observed for 6–7 days in three patients and observed for 11 days in one patient, although grade 4 leukopenia was not observed. However, all six patients recovered from the toxicity and could receive the subsequent course of chemotherapy without delay. No other DLT was observed in these six patients during the first and subsequent courses. Therefore, dose level 1 was evaluated to be safe and criterion (a) was considered to be too strict. Moreover, many phase I studies for ovarian cancer adopted a criterion of ‘grade 4 neutropenia lasting for 8 days or longer’ (10–14). Taken together, the following amendment of criteria and study design was permitted by the Data and Safety Monitoring Committee. (1) Criterion (a) was modified to ‘grade 4 neutropenia lasting for 8 days or longer accompanied by grade 4 leukopenia for at least 1 day during the period’. According to this amendment, none of the above-mentioned four patients met the criterion. (2) A patient whose neutrophils were not counted was determined to be ineligible. (3) An additional four patients would be enrolled to dose level 1 to determine the safety of the dose level. If DLT was observed in none or one of nine patients, the subsequent patients would be enrolled at dose level 2. If DLT was observed in two of nine patients, an additional three patients would be enrolled at dose level 1. If DLT was observed in three or four of nine patients, the study would be discontinued.
RESPONSE EVALUATION
A secondary objective of the study was to evaluate the efficacy of the TAP regimen. The World Health Organization (WHO) criteria (15) were employed in this study. Complete response (CR) was defined as the disappearance of all gross evidence of disease for at least 4 weeks. Partial response (PR) was defined as a 50% reduction in the sum of the products of the two largest perpendicular dimensions of all two-dimensionally measurable lesions and no evidence of new lesions for at least 4 weeks. No change (NC) was defined as a <25% increase or a <50% reduction in the sum of the aforementioned products and no evidence of new lesions for at least 4 weeks. Progressive disease (PD) was defined as a 25% increase in the sum of the above-mentioned products or the appearance of any new lesions. Not evaluable (NE) was defined when insufficient data for response evaluation are available.
Before enrolling the patients into the study, the original protocol was approved by the Institutional Review Board (IRB) in each participating institute. The new protocol including the above-mentioned amendment was also approved by IRB in all participating institutes before restarting the study.
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RESULTS |
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PATIENTS' CHARACTERISTICS
Between December 1998 and December 2000, 28 patients with advanced ovarian cancer were enrolled in this study. One patient was excluded from the study because sufficient laboratory data were not available for analysis. The median age of the 27 eligible patients was 56 years (range, 24–71 years) and 27 patients received 3–6 courses of chemotherapy (mean, 5.4 courses). Additional patients' characteristics are summarized in Table 1.
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DOSE ESCALATION AND DOSE-LIMITING TOXICITY
Excluding one ineligible patient, whose neutrophils were not counted during the first course of chemotherapy, nine patients were enrolled into dose level 1. Among these nine patients, only one developed DLT, grade 4 diarrhea, so the dose escalation was allowed. The following six patients were enrolled into dose level 2. These six patients developed no DLT and further dose escalation was performed. The next six patients enrolled into dose level 3 did not develop DLT and the dose was escalated to level 4. Six subsequent patients were enrolled into dose level 4. Two patients developed DLT; one patient developed febrile neutropenia matching criterion (b) and grade 4 diarrhea and another patient developed prolonged grade 4 neutropenia matching criterion (a). The MTD defined in the protocol had not been reached even at dose level 4. Therefore, it was decided to determine RD taking into account the toxicities of all cycles, the necessity of G-CSF support, the actual dose delivery and efficacy.
HEMATOLOGICAL TOXICITY
The hematological toxicity results are summarized in Table 2. The major toxicities observed were neutropenia and leukopenia. Grade 4 neutropenia was observed frequently even during the first course of chemotherapy [85% (23/27)] and almost all patients developed grade 4 neutropenia during all courses of chemotherapy [96% (26/27)]. The dose level was not correlated with the frequency of neutropenia (100% in level 1 and 83% in level 4 during the first course of chemotherapy). Grade 4 leukopenia was observed in 44% (12/27) of patients during the first course and in 52% (14/27) of patients during all courses of chemotherapy. The toxicity did not seem to increase from the second to sixth courses of chemotherapy. However, the frequency of grade 4 leukopenia was correlated with the dose level during the first course [22% (2/9) in level 1 to 83% (5/6) in level 4] and all courses of chemotherapy [22% (2/9) in level 1 to 83% (5/6) in level 4]. Among these grade 4 hematological toxicities observed during the first course of chemotherapy, toxicity developed by one patient in level 4 matched the dose-limiting toxicity criterion (a). As for other hematological toxicity, grade 3 anemia was rarely observed during the first course of chemotherapy [11% (3/27)]; however, nearly half of patients developed grade 3 anemia during all courses of chemotherapy [44% (12/27)]. Grade 4 thrombocytopenia was never observed during the first course of chemotherapy and only one patient developed grade 4 thrombocytopenia during all courses of chemotherapy [4% (1/27)].
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NON-HEMATOLOGICAL TOXICITY
The results of non-hematological toxicity are listed in Table 3. Generally, non-hematological toxicity was mild or moderate. The observed grade 3 toxicities during the first course or all courses of chemotherapy were nausea and vomiting in 11% (3/27) or 11% (3/27), diarrhea in 7% (2/27) or 11% (3/27) and febrile neutropenia in 19% (5/27) or 22% (6/27), respectively. The frequency of above grade 3 toxicities did not increase during the second to sixth courses of chemotherapy and was not correlated with the dose levels. Among these grade 3 toxicities observed during the first course of chemotherapy, two cases of diarrhea, one in level 1 and one in level 4 and one febrile neutropenia in level 4 matched the dose-limiting toxicity criteria (d) and (b). Other than these toxicities, alopecia was the most frequently observed toxicity: 85% (23/27) of patients developed grade 2 alopecia during all courses of chemotherapy. Grade 2/3 hypersensitivity and any grade renal toxicity (rise of serum creatinine) were not observed during the study. It was noteworthy that grade 2/3 sensory neuropathy was not observed during the first course of chemotherapy and only one patient [4% (1/27)] developed grade 2 sensory neuropathy during all courses of chemotherapy.
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CLINICAL RESPONSE
Eight patients had no measurable disease at entry. In the other 19 patients with two-dimensionally measurable disease, the response to chemotherapy was evaluated (Table 4). Twelve patients achieved complete response and four achieved partial response. The overall response rate was 84% (16/19) among patients with measurable disease. The remaining three patients had progressive disease. The response rate at dose levels 1–4 was 100, 100, 67 and 80%, respectively, suggesting no correlation between the dose level and response rate.
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RECOMMENDED DOSE
Table 5 summarizes the characteristics of chemotherapy at each level. In level 4, the majority of cycles [91% (30/33)] required G-CSF support and more than 30% of chemotherapy cycles required some modification in the dose or starting date of chemotherapy. However, chemotherapy could be continued until the planned cycle was completed or disease progression in most cases [83% (5/6)]. Moreover, 93.4% of the planned doses of agents could be administered at level 4. Considering all the factors, such as hematological and non-hematological toxicities, clinical responses and actual dose deliveries at dose level 4, RD for further study was decided as dose level 4 consisting of 110 mg/m2 of PTX, 50 mg/m2 of DOX and 75 mg/m2 of CDDP.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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In this study, we evaluated the safety and efficacy of a combination regimen of PTX, DOX and CDDP (TAP) as first-line chemotherapy for AOC. Because of the bone marrow toxicity of both CBDCA and DOX, CDDP seems to be safer than CBDCA to combine with DOX as a platinum analog. On the other hand, the combination of CDDP and PTX may produce severe and irreversible neurotoxicity (2,16,17). To avoid this adverse effect and to reduce cardiac toxicity, PTX was administered in a 24 h continuous infusion (18). The PTX dose was set at 110 mg/m2 as the minimum dose at which sufficient response could be expected, because there is no dose–response relationship in a range of 110 mg/m2 or more (19). The dose of CDDP was decided as the standard dose of 75 mg/m2 (20). The DOX dose was increased from 20 to 50 mg/m2 and was expected to improve efficacy over the standard combination of PTX and platinum. To avoid excessive toxicity, PTX was administered following DOX (21,22) and CDDP was administered following PTX (23). The regimen therefore consisted of 20–50 mg/m2 increasing doses of DOX followed by 24 h infusion of 110 mg/m2 of PTX followed by 75 mg/m2 of CDDP.
Concerning the safety of the regimen, the three-drug combination regimen seemed to be sufficiently safe to use as first-line chemotherapy for patients with ovarian cancer. The major toxicities observed in our study were neutropenia and leukopenia. Grade 4 neutropenia and leukopenia were observed in 85% (23/27) and 44% (12/27) in the first course of chemotherapy. However, these toxicities rarely lasted long enough to be counted as DLT and were not cumulative in the 2nd to 6th courses of chemotherapy. Thus, these hematological toxicities seemed manageable. Moreover, non-hematological toxicities were generally mild or moderate. The grade 3 toxicities observed were nausea and vomiting in 11% (3/27), diarrhea in 11% (3/27) and febrile neutropenia in 22% (6/27), during all courses of chemotherapy. Grade 3 sensory neuropathy was not observed during all courses of chemotherapy. To our knowledge, seven phase I or I/II studies (10,24–29), evaluating the value of anthracyclines in a taxane and platinum-based regimen for previously untreated AOC, have been published. The major toxicities observed throughout the studies were hematological toxicities, such as neutropenia, leukopenia and thrombocytopenia. In particular, neutropenia was reported in 100% in some studies (25,27,28). However, the toxicity was readily managed using G-CSF and was rarely complicated with serious infection or sepsis. Non-hematological toxicities, excluding nausea, vomiting and alopecia, were generally mild and manageable. No severe cardiac toxicity or neuropathy was observed throughout the previous studies.
As for the efficacy of the triplet combination in our study, a response rate (RR) of 84% (16/19), including 63% (12/19) complete response (CR), was observed. Even in level 1, 100% RR was achieved and there was no correlation between the dose level and response rate. In the previous studies, that using docetaxel (DOC) as the taxane (28) showed a relatively lower response rate of 36%, but studies using PTX as the taxane showed a higher response rate of 83–100%. In studies using PTX, there were no apparent differences in the response rate between studies using CDDP (86–100%) (25,26) and those using CBDCA (83–100%) (10,24,29) as platinum compound and between studies using DOX (100%) (24,25) and those using EpiDOX (83–86%) (10,26,29) as anthracycline.
In summary, the combination regimen of DOX with PTX and CDDP is highly active and hematological toxicities are readily manageable and non-hematological toxicities, including cardiac toxicity and sensory neuropathy, were mild or moderate. From our study and previous studies, we conclude that the addition of anthracyclines to PTX plus a platinum-based regimen may provide an effective and safe regimen for patients with untreated ovarian cancer. However, the hematological toxicities seem to be relatively severe compared with those reported with a PTX/CBDCA combination (3,30,31). At present, AGO–GINECO (Arbeitsgemeinschaft Gynäkologische Onkologie–Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens) (32) and NSGO–EORTC–NCIC CTG (Nordic Society of Gynecological Oncology–European Organization for Research and Treatment of Cancer–National Cancer Institute of Canada Clinical Trials Group) (33) are conducting phase III studies comparing epirubicin/paclitaxel/carboplatin vs. paclitaxel/carboplatin. To assess the usefulness of anthracyclines, the results of these studies are awaited.
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Acknowledgments |
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We thank Dr Nagahiro Saijo for his support and suggestions as a member of Data and Safety Monitoring Committee of this study.
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References |
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1 McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1–6.
2 Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, et al. Randomized intergroup trial of cisplatin–paclitaxel versus cisplatin–cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000;92:699–708.
3 Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, et al. 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. J Clin Oncol 2003;21:3194–200.
4 Nguyen HN, Averette HE, Hoskins W, Sevin BU, Penalver M, Steren A. National survey of ovarian carcinoma. VI. Critical assessment of current International Federation of Gynecology and Obstetrics staging system. Cancer 1993;72:3007–11.[CrossRef][Web of Science][Medline]
5 Omura GA, Bundy BN, Berek JS, Curry S, Delgado G, Mortel R. Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1989;7:457–65.[Abstract]
6 Cyclophosphamide plus cisplatin versus cyclophosphamide, doxorubicin and cisplatin chemotherapy of ovarian carcinoma: a meta-analysis. The Ovarian Cancer Meta-Analysis Project. J Clin Oncol 1991;9:1668–74.[Abstract]
7 Fanning J, Bennett TZ, Hilgers RD. Meta-analysis of cisplatin, doxorubicin and cyclophosphamide versus cisplatin and cyclophosphamide chemotherapy of ovarian carcinoma. Obstet Gynecol 1992;80:954–60.[Web of Science][Medline]
8 A'Hern RP, Gore ME. Impact of doxorubicin on survival in advanced ovarian cancer. J Clin Oncol 1995;13:726–32.
9 Tobinai K, Kohno A, Shimada Y, Watanabe T, Tamura T, Takeyama K, et al. Toxicity grading criteria of the Japan Clinical Oncology Group. The Clinical Trial Review Committee of the Japan Clinical Oncology Group. Jpn J Clin Oncol 1993;23:250–7.
10 du Bois A, Luck HJ, Bauknecht T, Meier W, Richter B, Kuhn W, et al. First-line chemotherapy with epirubicin, paclitaxel and carboplatin for advanced ovarian cancer: a phase I/II study of the Arbeitsgemeinschaft Gynäkologische Onkologie Ovarian Cancer Study Group. J Clin Oncol 1999;17:46–51.
11 Siddiqui N, Boddy AV, Thomas HD, Bailey NP, Robson L, Lind MJ, et al. A clinical and pharmacokinetic study of the combination of carboplatin and paclitaxel for epithelial ovarian cancer. Br J Cancer 1997;75:287–94.[Web of Science][Medline]
12 Bolis G, Scarfone G, Villa A, Acerboni S, Siliprandi V, Guarnerio P. A phase I trial with fixed-dose carboplatin and escalating doses of paclitaxel in advanced ovarian cancer. Semin Oncol 1997;24, No 1, Suppl 2:23–5.[Web of Science]
13 Huizing MT, van Warmerdam LJ, Rosing H, Schaefers MC, Lai A, Helmerhorst TJ, et al. Phase I and pharmacologic study of the combination paclitaxel and carboplatin as first-line chemotherapy in stage III and IV ovarian cancer. J Clin Oncol 1997;15:1953–64.
14 ten Bokkel Huinink WW, Veenhof C, Huizing M, Rodenhuis S, Helmerhorst T, Dubbelman R, et al. Carboplatin and paclitaxel in patients with advanced ovarian cancer: a dose-finding study. Semin Oncol 1997;24, No 1, Suppl 2:31–3.
15 Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207–14.[CrossRef][Web of Science][Medline]
16 Rowinsky EK, Chaudhry V, Forastiere AA, Sartorius SE, Ettinger DS, Grochow LB, et al. Phase I and pharmacologic study of paclitaxel and cisplatin with granulocyte colony-stimulating factor: neuromuscular toxicity is dose-limiting. J Clin Oncol 1993;11:2010–20.
17 Chaudhry V, Rowinsky EK, Sartorius SE, Donehower RC, Cornblath DR. Peripheral neuropathy from taxol and cisplatin combination chemotherapy: clinical and electrophysiological studies. Ann Neurol 1994;35:304–11.[CrossRef][Web of Science][Medline]
18 Smith RE, Brown AM, Mamounas EP, Anderson SJ, Lembersky BC, Atkins JH, et al. Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26. J Clin Oncol 1999;17:3403–11.
19 Rowinsky EK, Mackey MK, Goodman SN. Meta analysis of paclitaxel dose–response and dose–intensity in recurrent or refractory ovarian cancer. Proc Am Soc Clin Oncol 1996;15:Meeting Abstract.
20 Kaye SB, Paul J, Cassidy J, Lewis CR, Duncan ID, Gordon HK, et al. Mature results of a randomized trial of two doses of cisplatin for the treatment of ovarian cancer. Scottish Gynecology Cancer Trials Group. J Clin Oncol 1996;14:2113–9.
21 Sledge GW Jr, Robert N, Sparano JA, Cobeligh M, Goldstein LJ, Neuberg D, et al. Paclitaxel (taxol)/doxorubicin combinations in advanced breast cancer: the Eastern Cooperative Oncology Group experience. Semin Oncol 1994;21:15–8.[Web of Science][Medline]
22 Sledge GW Jr, Robert N, Sparano JA, Cogleigh M, Goldstein LJ, Neuberg D, et al. Eastern Cooperative Oncology Group studies of paclitaxel and doxorubicin in advanced breast cancer. Semin Oncol 1995;22:105–8.[Web of Science][Medline]
23 Rowinsky EK, Gilbert MR, McGuire WP, Noe DA, Grochow LB, Forastiere AA, et al. Sequences of taxol and cisplatin: a phase I and pharmacologic study. J Clin Oncol 1991;9:1692–703.[Abstract]
24 Hill M, Macfarlane V, Moore J, Gore ME. Taxane/platinum/anthracycline combination therapy in advanced epithelial ovarian cancer. Semin Oncol 1997;24, No 1, Suppl 2:34–7.
25 Naumann RW, Alvarez RD, Omura GA, Segars E, Kilgore LC, Partridge EE. A phase I study of paclitaxel, doxorubicin and cisplatin in patients with previously untreated epithelial ovarian cancer. Gynecol Oncol 1998;71:450–3.[CrossRef][Web of Science][Medline]
26 Papadimitriou CA, Moulopoulos LA, Vlahos G, Voulgaris Z, Kiosses E, Georgoulias N, et al. Paclitaxel, cisplatin and epirubicin first-line chemotherapy in stage III and IV ovarian carcinoma: long-term results of a phase II study. Cancer 2000;89:1547–54.[CrossRef][Web of Science][Medline]
27 Gregory RK, Hill ME, Moore J, A'Hern RP, Johnston SR, Blake P, et al. Combining platinum, paclitaxel and anthracycline in patients with advanced gynaecological malignancy. Eur J Cancer 2000;36:503–7.[CrossRef][Web of Science][Medline]
28 O'Neill VJ, Kaye SB, Reed NS, Paul J, Davis JA, Vasey PA. A dose-finding study of carboplatin–epirubicin–docetaxel in advanced epithelial ovarian cancer. Br J Cancer 2002;86:1385–90.[CrossRef][Web of Science][Medline]
29 Romanini A, Tanganelli L, Carnino F, Fanucchi A, Lionetto R, Pastorino S, et al. First-line chemotherapy with epidoxorubicin, paclitaxel and carboplatin for the treatment of advanced epithelial ovarian cancer patients. Gynecol Oncol 2003;89:354–9.[CrossRef][Web of Science][Medline]
30 Neijt JP, Engelholm SA, Witteveen PO, Tuxen MK, Sorensen PG, Hansen M, et al. Paclitaxel (175 mg/m2 over 3 h) with cisplatin or carboplatin in previously untreated ovarian cancer: an interim analysis. Semin Oncol 1997;24, No 5, Suppl 15:36–9.[Web of Science]
31 du Bois A, Luck HJ, Meier W, Mobus V, Costa S, Richter B, et al. Carboplatin/paclitaxel versus cisplatin/paclitaxel as first-line chemotherapy in advanced ovarian cancer: an interim analysis of a randomized phase III trial of the Arbeitsgemeinschaft Gynakologische Onkologie Ovarian Cancer Study Group. Semin Oncol 1997;24, No 5, Suppl 15:44–52.
32 du Bois A, Weber B, Pfisterer J, Goupil A, Wagner U, Barats J, et al. Epirubicin/paclitaxel/carboplatin (TEC) vs. paclitaxel/carboplatin (TC) in first-line treatment of ovarian cancer FIGO stages IIb/IV. Interim results of an AGO/GINECO Intergroup Phase III trial. Proc Am Soc Clin Oncol 2001;20:Abstract 805.
33 Kristensen G, Vergote I, Stuart G, Izqiuerdo Delso M, Mirza MR, Aavall-Lundquist E, et al. First line treatment of ovarian cancer FIGO stages IIb–IV with paclitaxel/epirubicin/carboplatin (TEC) vs. paclitaxel/carboplatin (TC). Interim results of an NSGO–EORTC–NCIC CTG Gynecological Cancer Intergroup phase III trial. Proc Am Soc Clin Oncol 2002;21:Abstract 805.
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