|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 22, No 13 (July 1), 2004: pp. 2635-2642 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.09.088 Topotecan Compared With No Therapy After Response to Surgery and Carboplatin/Paclitaxel in Patients With Ovarian Cancer: Multicenter Italian Trials in Ovarian Cancer (MITO-1) Randomized StudyFrom the Dipartimento di Endocrinologia e Oncologia Sperimentale e Clinica, Università Federico II di Napoli; Oncologia Medica, Ospedale Cardarelli; Oncologia Medica C, Oncologia Medica B, Ginecologia Oncologica, and Unità Operativa Sperimentazioni Cliniche, Istituto Nazionale Tumori di Napoli; Cattedra di Statistica Medica, Seconda Università di Napoli, Napoli; Istituto di Ginecologia ed Ostetricia, Policlinico Universitario Gemelli; Oncologia Medica, Azienda Ospedaliera S. Filippo Neri, Roma; Ginecologia II and I Clinica Ostetrica Ginecologica, Università di Bari; Oncologia Medica e Sperimentale, Istituto Nazionale Tumori di Bari, Bari; Clinica Malzoni, Avellino; Oncologia Medica, Ospedale Mariano Santo, Cosenza; Oncologia Medica, Azienda Ospedaliera S. Carlo, Potenza; Oncologia Medica, Ospedale Fatebenefratelli, Benevento; Oncologia Medica, Policlinico Giaccone, Palermo; and Ginecologia, Ospedale S Anna, Torino, Italy Address reprint requests to Sandro Pignata, MD, PhD, Istituto Nazionale Tumori, via M Semmola, 80131–Napoli, Italy; e-mail: sandro.pignata{at}fondazionepascale.it
PURPOSE: Topotecan is an active second-line treatment for advanced ovarian cancer. Its efficacy as consolidation treatment after first-line standard chemotherapy is unknown. PATIENTS AND METHODS: To investigate whether topotecan (1.5 mg/m2 on days 1 through 5, four cycles, every 3 weeks) prolonged progression-free survival (PFS) for patients responding to standard carboplatin (area under the curve 5) and paclitaxel (175 mg/m2 administered as a 3-hour infusion in six cycles; CP), a multicenter phase III study was performed with an 80% power to detect a 50% prolongation of median PFS. Patients were registered at diagnosis and randomized after the end of CP. RESULTS: Two hundred seventy-three patients were randomly assigned (topotecan, n = 137; observation, n = 136), with a median age of 56 years. Stage at diagnosis was advanced in three fourths of patients (stage III in 65% of patients; stage IV in 10%); after primary surgery, 46% had no residual disease and 20% were optimally debulked. After CP, 87% reached a clinical complete response, and 13% achieved a partial response. Neutropenia (grade 3/4 in 58% of the patients) and thrombocytopenia (grade 3 in 21%; grade 4 in 3%) were the most frequent toxicities attributed to topotecan. There was no statistically significant difference in PFS between the arms (P = .83; log-rank test): median PFS was 18.2 months in the topotecan arm and 28.4 in the control arm. Hazard ratio of progression for patients receiving topotecan was 1.18 (95% CI, 0.86 to 1.63) after adjustment for residual disease, interval debulking surgery, and response to CP. CONCLUSION: The present analysis indicates that consolidation with topotecan does not improve PFS for patients with advanced ovarian cancer who respond to initial chemotherapy with carboplatin and paclitaxel.
Surgery followed by systemic chemotherapy is the current standard treatment modality for epithelial ovarian cancer, particularly when diagnosis is made at an advanced stage.1,2 The combination of paclitaxel and cisplatin replaced schemes without paclitaxel after it was shown in the Gynecologic Oncology Group Trial 1113 and in a subsequent confirmatory trial4 that it was more effective than the combination of cyclophosphamide and cisplatin. Actually, paclitaxel combined with carboplatin is considered the standard first-line chemotherapy regimen worldwide because of its more favorable toxicity profile as compared with paclitaxel and cisplatin.5–7 Surgery and first-line systemic chemotherapy induce complete and partial response in up to 80% of patients, with a pathologic complete remission rate of approximately 25%.3,4 Unfortunately, recurrences occur in the majority of patients, and only 20% to 40% survive after a 5-year follow-up period, with survival being substantially dependant on the initial International Federation of Gynecology and Obstetrics stage.8,9 The selection of drug resistant cells is a major cause of failure of chemotherapy in many solid tumors, including ovarian cancer. Among the strategies used to overcome drug resistance, the addition of non–cross-resistant drugs is one of the most extensively studied, both as combination or with a sequential approach. The role of sequential consolidation chemotherapy in patients responding to first-line chemotherapy, however, has not been clearly defined in ovarian cancer, although some attempts have been made with several approaches, including chemotherapy and radiotherapy.10–13 Topotecan, introduced as the second-line treatment of ovarian cancer in 1996,14 acts by inhibiting topoisomerase I. It has a qualitatively different toxicity pattern as compared with carboplatin and paclitaxel and is non–cross-resistant with these agents.15 In phase II and III trials, topotecan has shown activity against ovarian cancer that is either refractory, resistant, or sensitive to initial carboplatin and paclitaxel treatment, producing a response rate ranging between 15% and 33%.14–16 Sequential administration of topotecan after the combination of carboplatin and paclitaxel has proved to be safe and active, inducing a 28% pathologic complete response rate in patients with residual disease after first-line chemotherapy.17,18 Postulating that consolidation chemotherapy with a non-cross-resistant drug might be beneficial, the aim of this study was to investigate whether four cycles of topotecan (1.5 mg/m2 days 1 through 5 every 21 days) could prolong progression-free survival (PFS) compared with observation in patients with ovarian cancer with complete or partial clinical response after initial treatment with surgery and paclitaxel plus carboplatin.
Selection of Patients Patients were registered at diagnosis and randomly assigned after six cycles of chemotherapy with carboplatin and paclitaxel, if eligible at that time.
At registration, patients with cytologic or histologic diagnosis of epithelial ovarian carcinoma (stage IC to IV according to International Federation of Gynecology and Obstetrics staging) and an Eastern Cooperative Oncology Group performance status
After the end of first-line treatment with six cycles of carboplatin and paclitaxel, patients were randomly assigned to observation or to receive consolidation chemotherapy with topotecan. At random assignment, eligibility criteria were as follows: complete response or partial response, including patients without evidence of cancer after primary surgery or interval debulking surgery; normal bone marrow function (neutrophils
Study Design The main end point of the study was to evaluate whether four cycles of consolidation treatment with topotecan prolonged PFS as compared with observation alone in patients responding to carboplatin plus paclitaxel. Secondary end points were overall survival, toxicity, and activity of topotecan.
Patients were randomly assigned to the standard or the experimental arm in a one-to-one ratio. Randomization was performed centrally at the Clinical Trials Unit of the National Cancer Institute in Naples by means of a computer-driven minimization procedure. Stratification factors were center, residual disease after primary surgery (absent v
Treatment Plan
Toxicity and Response Assessment Staging procedures included standard physical examinations, CA-125, ultrasound, and computed tomography scan of the abdomen and pelvis and two-view chest x-ray. Staging was scheduled at diagnosis, after primary surgery (to determine residual disease) at the end of the third and sixth cycle of carboplatin/paclitaxel (to assess response to first-line chemotherapy), and at the end of the fourth cycle of topotecan (to assess response to consolidation treatment). Response was categorized according to WHO criteria.19
Follow-Up
Statistical Considerations
All randomly assigned patients were evaluated for efficacy analysis, according to the intention-to-treat rule. PFS was defined as the interval from date of randomization to the date of progression or death, whichever occurred first, or last follow-up information for patients alive and progression-free as of July 15, 2003. Overall survival was defined as the interval from date of randomization to date of death or last follow-up information for alive patients. PFS and overall survival curves were drawn with the Kaplan-Meier product-limit method23 and compared with the Mantel-Haenszel test.24 According to the study design, a one-tailed P value was calculated for the primary analysis. In addition, the Cox model25 was applied to perform a multivariable analysis of the primary end point, including treatment (topotecan v observation), response to first-line treatment (partial v complete), interval debulking surgery (performed v not performed), and residual disease after primary surgery (
Patients Characteristics Between January 1998 and March 2002, 545 patients were entered onto the trial; 273 patients were eligible for randomization after six cycles of carboplatin plus paclitaxel. The study flow, according to consort rules, is shown in Fig 1.
Main characteristics of the 273 randomized patients are listed in Table 1. Age, stage at diagnosis, residual disease after primary surgery, interval debulking surgery, and response to carboplatin/paclitaxel were well balanced between the two study arms. Median patient age was 56 years. The majority of patients had an advanced stage of disease at diagnosis (65% of patients had stage III disease; 10% of patients had stage IV disease). Most patients had no residual disease after primary surgery (46%) or were optimally debulked (< 1 cm, 20%). Twenty-two percent of the patients underwent interval debulking surgery after three cycles of carboplatin/paclitaxel. At randomization, the majority of patients (238 of 273) had a complete response, with this prevalence influenced by refusal of almost all participating centers to randomize partial responders because of a presumed risk of undertreatment in case of allocation to the observation arm.
Compliance to Treatment Six patients (four in the control arm and two in the experimental arm) were lost to follow-up immediately after randomization. In the control arm, one patient received topotecan before disease progression. In the experimental arm, 18 patients never started treatment because of refusal after randomization (11 patients), lack of minimal hematologic criteria on day 1 (five patients), accidental bone fracture (one patient), and progressive disease (one patient). The median number of cycles given was four (range, one to four cycles). Treatment was discontinued before the fourth cycle in 10 patients because of toxicity (five patients), progression (one patient), or other reasons (four patients).
Toxicity
Time to Progression and Survival All randomized patients were included in efficacy analysis. As of July 15, 2003, 153 patients (56%) had experienced disease progression, and 73 (26.7%) had died. Of the 153 cases of disease progression, 18 (11.8%) were characterized by an isolated increase in CA-125 values (nine in observation arm; nine in topotecan arm). Median follow-up of patients who were alive at analysis was 28 months. PFS curves (Fig 2) did not differ between the two arms (P = .83), with a median time to progression of 18.2 and 28.4 months in the topotecan and control arms, respectively. One-year PFS probability was 60.4% and 65.4% in the two arms, respectively. There was no significant difference between the arms, even if the 18 patients with disease progression diagnosed solely on the basis of CA-125 increase were censored at the date of progression. The multivariable analysis (Table 3), adjusted by residual disease, interval debulking surgery, and response to surgery and carboplatin plus paclitaxel, showed a hazard ratio of progression for patients receiving topotecan of 1.18 (95% CI, 0.86 to 1.63). Unadjusted hazard ratios of progression, calculated for exploratory aims and graphically displayed in Figure 3, show that there was no apparent effect of topotecan in any prognostic subgroup. Similarly, there was no significant effect (P = .30) of topotecan on patient survival (Fig 4).
Aggressive surgical cytoreduction followed by six cycles of carboplatin plus paclitaxel actually represents the standard of care for ovarian cancer, from stage IC to IV.1,2,5–7 Despite the high response rate reported with this strategy, most of the patients who achieve an objective response experience relapse and ultimately die of ovarian cancer.8 Several types of consolidation treatments have been tested, such as radiotherapy,12,13 hormonal therapy,26 and immunotherapy.27,28 Most of these studies had small sample size and insufficient power; all of them produced negative results. Recently, two studies have been reported on the use of systemic chemotherapy as consolidation treatment with paclitaxel and epirubicin.11,29 Markman et al11 showed that 12 cycles of single-agent paclitaxel, compared with three cycles of the same drug, significantly prolonged PFS in patients with clinical complete response to first-line carboplatin and paclitaxel. This study was discontinued early after an interim analysis showed a statistically significant improvement in time to progression with a 7-month advantage for the arm receiving 12 cycles compared with that receiving three cycles only. This is the first randomized study that suggested that maintenance chemotherapy may impact survival. Another trial with apparently opposite results has been reported in abstract form by Bolis et al,29 comparing four cycles of epirubicin (120 mg/m2) with no treatment in the same setting of patients. Preliminary results (presented at the 2002 Annual Meeting of the American Society of Clinical Oncology) indicate that there was no advantage in time to progression for patients treated with epirubicin. The rationale of using topotecan in the Multicenter Italian Trials in Ovarian Cancer (MITO)–1 study was based on clinical trials that had shown the activity of topotecan in second-line treatment of advanced ovarian cancer14,16 and on the data showing the absence of cross-resistance with carboplatin and paclitaxel.15 The trial was designed as having PFS as the primary end point because of the risk that subsequent treatment approaches could bias overall survival analysis. Planning that the control arm could have had a median survival after randomization of approximately 18 months, the MITO investigators agreed that the increase in therapy duration of approximately 3 months could be justified only if it prolonged PFS by at least 9 months. Indeed, soon after the beginning of the study, many institutions decided that they would have enrolled only patients with complete response, because they preferred to avoid the risk of no treatment in patients with partial response (ie, with known residual disease after the end of first-line treatment). As a result, fewer than 20% of the randomized patients had a partial response, and the observed PFS in the control arm largely exceeded that which was planned; however, this does not affect the overall interpretation of results. Unfortunately, consolidation with four cycles of topotecan did not produce any advantage in PFS as compared with observation alone. This result is consistent with that reported by the Arbeitsgemeinschaft Gynäkologische Onkologie group at the 2003 Annual Meeting of the American Society of Clinical Oncology.30 The survival curves and the number of events recorded to date make the probability that such negative results can be modified by longer follow-up extremely low. There are some possible explanations for our negative findings, which are in contrast with the positive data reported by Markman et al.11 It has been postulated that administration of paclitaxel over a prolonged period of treatment may exert an antiangiogenic effect that may be particularly important in prolonging PFS of these patients.31 No similar effect has been demonstrated for topotecan. In the study of Markman et al,11 12 cycles of chemotherapy were used in the experimental arm, whereas in our study, only four cycles of topotecan were given. However, the maximal antiproliferative activity of antiblastic agents is usually obtained during initial cycles of treatment, and there are no published data suggesting that a prolongation of topotecan for more than four cycles could dramatically improve its efficacy. Furthermore, the population treated in our study, including patients with stage IC to IV ovarian cancer, is different than that enrolled in the Gynecologic Oncology Group study that consisted only of patients with stage III and IV disease. Finally, it could be considered that in the study by Markman et al,11 consolidation was performed with a drug (paclitaxel) that was also included in the first-line chemotherapy regimen; thus complete responding patients that entered the consolidation treatment could have been a favorable subset for paclitaxel effect. In the MITO study, on the contrary, we randomly assigned a population that was not selected for sensitivity to topotecan and could have been primarily resistant to topotecan at a large extent. In conclusion, the MITO study indicates that consolidation treatment with topotecan given at full dose for four cycles does not prolong PFS of patients with advanced ovarian cancer who achieve a complete response after surgery and first-line chemotherapy with carboplatin plus paclitaxel.
Participating MITO Institutions and coauthors include the following: Istituto Nazionale Tumori di Napoli (Oncologia Medica B: S. Pignata, R. Tambaro, E. Ferrari, R.V. Iaffaioli; Ginecologia: F. Iodice, G. Casella, S. Greggi; Oncologia Medica C: A. de Matteis, G. Landi; Unità Operativa Sperimentazioni Cliniche: F. Perrone, M. Di Maio); Università Federico II di Napoli (Dipartimento di Endocrinologia Sperimentale e Clinica: A.R. Bianco, S. De Placido, R. Lauria, M. De Laurentiis, M. Pensabene, G. Tortora; Ginecologia: G. De Placido, C. Nappi); Istituto di Ginecologia ed Ostetricia, Policlinico Universitario Gemelli, Roma (G. Scambia, D. Lorusso, G.R. D'Agostino, M. Ludovisi); Ginecologia II, Università di Bari (G. DiVagno, L. Selvaggi, G. Cormio, M.T. Lapresa); Ospedale Oncologico di Bari (G. Colucci, G. Fanizza, E. Naglieri, F. Giotta, M. diBisceglie); Clinica Malzoni, Avellino (A. Vernaglia Lombardi, M. Balestrino, C. Malzoni, M. Malzoni); Oncologia Medica, Ospedale Mariano Santo, Cosenza (R. Biamonte, S. Palazzo, A. Rovito, A. Filice); I Clinica Ostetrica Ginecologica, Università di Bari (M. Marinaccio, S. Shonauer, V. De Robertis); Oncologia Medica, Ospedale Cardarelli, Napoli (G. Cartenì, T. Guida, R. D'Antonio); Oncologia Medica, Azienda Ospedaliera S. Carlo, Potenza (G. Manzione, D. Germano, R. Romano); Oncologia Medica, Ospedale Fatebenefratelli, Benevento (A. Febbraro, T. Pedicini, C. Corbo); Oncologia Medica, Azienda Ospedaliera S. Filippo Neri, Roma (G. Gasparini, A. Morabito); Oncologia Medica, Policlinico Giaccone, Palermo (M.R. Valerio, E. Bajardi); Ginecologia, Ospedale S. Anna, Torino (S. Danese, E. Bertone); Cattedra di Statistica Medica, Seconda Università di Napoli (C. Gallo); Oncologia Medica Ospedale S. Spirito, Pescara (D. Natale); Oncologia Medica Ospedale M. Ascoli, Palermo (B. Agostara); Oncologia Medica Ospedale S. Francesco, Paola (G. Filippelli); Oncologia Medica, Università di Cagliari, Cagliari (B. Massidda); Oncologia Medica, Ospedale di Reggio Calabria, Reggio di Calabria (M. Nardi).
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Received more than $2,000 per year from a company for either of the last 2 years: Francesco Perrone, GlaxoSmithKline; Ciro Gallo, GlaxoSmithKline; Sandro Pignata, GlaxoSmithKline.
We thank Gruppo Oncologico Italia Meridionale and Gruppo Oncologico Centro-Sud-Isole for promoting the study and Giuliana Canzanella, Federika Crudele, and Fiorella Romano for assistance in the registration and randomization process.
The Unità Operativa Sperimentazioni Cliniche, Istituto Nazionale Tumori di Napoli, is supported by Associazione Italiana per la Ricerca sul Cancro and Clinical Trials Promoting Group. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Berek JS, Bertelsen A, Du Bois A, et al: Advanced epithelial ovarian cancer: 1998 consensus statements. Ann Oncol 10:87–92, 1999 (suppl 1)
2. Bristow RE: Survival effect of maximal cytoreductive surgery for advance ovarian cancer in the platinum era: A meta-analysis. J Clin Oncol 20:1248–1259, 2002
3. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1–6, 1996
4. Piccart MJ, Bertelsen K, James K, 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 92:674–675, 2000
5. Ozols RF, Bundy BN, Greer BE, 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 21:3194–3200, 2003
6. Neijt JP, Engelolm SA, Tuxen MK, et al: Exploratory phase III study of cisplatin and paclitaxel versus carboplatin and paclitaxel in advanced ovarian cancer. J Clin Oncol 18:3084–3092, 2000
7. Du Bois A, Luck HJ, Meier W, et al: A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95:1320–1329, 2003 8. Rubin SC, Randall TC, Armstrong KA, et al: Ten-year follow-up of ovarian cancer patients after second-look laparotomy with negative findings. Obstet Gynecol 93:21–24, 1999[CrossRef][Medline] 9. Ries LAG, Eisner MP, Kosary CL, et al (eds): SEER Cancer Statistics Review, 1973-1999. Bethesda, MD, National Cancer Institute. http://seer.cancer.gov/csr/1973_1999/, 2002 10. Bertelsen K, Jakobsen A, Stroyer I, et al: Randomized prospective trial of 5 versus 10 cycles of cyclophosphamide, adriamycin, and cisplatin in advanced epithelial ovarian cancer: A Danish Ovarian Study Group Trial (DACOVA). Gynecol Oncol 49:30–36, 1993[CrossRef][Medline]
11. Markman M, Liu PY, Wilczynski S, et al: Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group Trial. J Clin Oncol 21:2460–2465, 2003 12. MacGibbon A, Bucci J, MacLeod C, et al: Whole abdominal radiation following second-look laparotomy for ovarian carcinoma. Gynecol Oncol 75:62–67, 1999[CrossRef][Medline]
13. Varia MA, Stehman FB, Bundy BN, et al: Intraperitoneal radioactive phosphorus(32P) versus observation after negative second-look laparotomy for stage III ovarian carcinoma: A randomized trial of the Gynecologic Oncology Group. J Clin Oncol 21:2849–2855, 2003
14. ten Bokkel Huinink W, Gore M, Carmichael J, et al: Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 15:2183–2193, 1997
15. Gore M, ten Bokkel Huinink W, Carmichael J, et al: Clinical evidence for topotecan-paclitaxel non–cross-resistance in ovarian cancer. J Clin Oncol 19:1893–1900, 2001
16. Gordon AN, Fleagle JT, Guthrie D, et al: Recurrent epithelial ovarian carcinoma: A randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19:3312–3322, 2001 17. Bolis G, Scarfone G, Tateo S, et al: Response and toxicity to topotecan in sensitive ovarian cancer cases with small residual disease after first-line treatment with carboplatinum and paclitaxel. Gynecol Oncol 80:13–15, 2001[CrossRef][Medline] 18. Chan S, Carmichael J, Ross G, et al: Sequential hycamtin following paclitaxel and carboplatin in advanced ovarian cancer. Proc Am Soc Clin Oncol 18:372, 1999 (abstr 1436) 19. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207–214, 1981[CrossRef][Medline]
20. Lan KK, DeMets DL: Discrete sequential boundaries for clinical trials. Biometrika 70:659–663, 1983 21. O'Brien PC, Fleming TR: A multiple testing procedure for clinical trials. Biometrics 35:549–556, 1979[CrossRef][Medline] 22. Pignata S, Deplacido S, Scambia G, et al: Topotecan vs nihil after response to carboplatin and paclitaxel in advanced ovarian cancer. Early results of the MITO-1 (Multicenter Italian Trials in Ovarian Cancer) study. Proc Am Soc Clin Oncol 22:446, 2003 (abstr 1791) 23. Kaplan EL, Meier P: Non parametric estimation from incomplete observation. J Am Stat Assoc 53:457–481, 1958[CrossRef] 24. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163–170, 1966[Medline] 25. Cox DR: Regression models and life tables. J R Stat Soc B 34:187–220, 1972 26. Perez-Gracia JL, Carrasco EM: Tamoxifen therapy for ovarian cancer in the adjuvant and advanced setting: Systematic review of the literature and implications for future research. Gynecol Oncol 84:201–209, 2002[CrossRef][Medline] 27. Hall G, Coleman R, Stead M, et al: Maintenance treatment with interferon for advanced ovarian cancer. Proc Am Soc Clin Oncol 19:386, 2000 (abstr 1529) 28. Berek J, Ehlen T, Gordon A, et al: Interim analysis of a double blind study of Ovarex mAB B43,13 (OV) versus placebo (PBO) in patients with ovarian cancer. Proc Am Soc Clin Oncol 20:210, 2001 (abstr 837) 29. Scarfone G, Merisio C, Garavaglia E, et al: A phase III trial of consolidation versus nihil (nil) for advanced epithelial ovarian cancer (AEOC) after complete remission. Proc Am Soc Clin Oncol 21:204, 2002 (abstr 812) 30. Pfisterer J, Lortholary A, Kimmig R, et al: Paclitaxel/carboplatin (TC) vs paclitaxel/carboplatin followed by topotecan (TC-Top) in first line treatment of ovarian cancer FIGO stage IB-IV: Interim results of a Gynecologic Cancer Intergroup phase III trial of the AGO Ovarian Cancer Study Group and GINECO. Proc Am Soc Clin Oncol 21:446, 2003 (abstr 1793)
31. Browder T, Butterfield C, Kraling B, et al: Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60:1878–1886, 2000 Submitted September 16, 2003; accepted April 1, 2004.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 were eligible, after written informed consent was obtained, to receive systemic chemotherapy with paclitaxel and carboplatin. Exclusion criteria were age 
75 years, prior or concurrent malignant cancer (except for nonmelanomatous skin cancer and for in situ carcinoma of the uterine cervix, if treated adequately), brain metastases, inadequate bone marrow function (neutrophils < 1,500/µL, platelets < 100,000/µL, or hemoglobin < 9g/dL), abnormal renal function (total serum creatinine level > 1.25 times the upper level of institutional norm), and abnormal liver function (AST, ALT, or total serum bilirubin levels > 1.25 time the upper level of institutional norm, except if caused by liver metastases). 
