|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2000 American Society for Clinical Oncology Phase I Study of Paclitaxel, Carboplatin, and Increasing Days of Prolonged Oral Etoposide in Ovarian, Peritoneal, and Tubal Carcinoma: A Gynecologic Oncology Group StudyFrom the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Case Western Reserve University, University Hospitals of Cleveland, Cleveland; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Ohio State University, James Cancer Hospital and Solove Research Institute, Columbus, OH; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL; Division of Gynecologic Oncology, University of Washington School of Medicine, Seattle, WA; Division of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA; University of Mississippi School of Medicine, Jackson, MS; and Chemotherapy Services, Gynecologic Cancer Center, Mercy Medical Center, Baltimore, MD. Address reprint requests to Gynecologic Oncology Group Administrative Office, Suite 1945, 1234 Market St, Philadelphia, PA 19107.
PURPOSE: Given the activity of prolonged oral etoposide in platinum and paclitaxel-resistant ovarian carcinoma, a phase I trial was conducted that combined increasing days of oral etoposide therapy with paclitaxel and carboplatin in chemotherapy-naive patients with ovarian peritoneal and tubal carcinoma to establish a maximum-tolerated dose (MTD) of this combination. PATIENTS AND METHODS: Paclitaxel at 175 mg/m2 given over 3 hours and carboplatin at an area under the curve of 5 were administered on day 1 followed by oral etoposide 50 mg/m2/d beginning on day 2. The number of days of etoposide therapy was escalated on the basis of toxicity. Toxicity end points included neutropenic sepsis, grade 4 thrombocytopenia, or grade 3 neutropenia or thrombocytopenia during etoposide administration. Cycles were repeated every 21 days for a maximum of six courses. Due to hematologic toxicity, the duration of the paclitaxel infusion was decreased to 1 hour for a second stage of accrual. RESULTS: Of 52 patients studied, 29 were in the first stage of accrual. Dose-limiting toxicity occurred with 8 days of oral etoposide, making the MTD six days of therapy. Twenty-three patients were entered into the second stage of accrual. Dose-limiting toxicity occurred at 12 days of oral etoposide, making the MTD 10 days of therapy. Three patients developed acute myeloid leukemia 16, 27, and 35 months after receiving a cumulative dose of 200 mg/m2, 1,200 mg/m2, and 2,400 mg/m2, respectively. CONCLUSION: One-hour paclitaxel, carboplatin, and oral etoposide at 50 mg/m2/d for 10 days is tolerable without supportive therapy. The leukemogenic potential is cause for concern and precludes its use in chemotherapy-naive ovarian carcinoma.
THE COMBINATION OF paclitaxel and cisplatin as primary chemotherapy in advanced ovarian cancer has demonstrated an improved response rate, progression-free interval, and survival advantage over cyclophosphamide and cisplatin.1,2 The combination of paclitaxel and a platinum compound has become the standard regimen for patients with advanced ovarian cancer. Nevertheless, platinum and paclitaxel resistance remains the primary cause of immediate or subsequent treatment failure for patients with advanced ovarian cancer. There is a need for additional active agents to treat this disease. Numerous phase II trials of prolonged oral etoposide as second-line therapy in ovarian cancer have been performed. Hoskins and Swenerton3 reported a response rate of 26% in platinum-resistant ovarian cancer, using a dose of 100 mg/d for 14 days every 3 weeks. A subsequent study by Seymour et al,4 again using a 100-mg/d dose for 14 days, confirmed this activity with a response rate of 25%. More recently, a Gynecologic Oncology Group (GOG) phase II study with prolonged oral etoposide using a 50 mg/m2/d dose for 21 of 28 days as second-line therapy was reported.5 Among platinum-resistant patients, a 26.8% response rate (7.3% complete response rate and 19.5% partial response rate) occurred. Among 25 of the 41 platinum-resistant patients who had previously received paclitaxel a 32% objective response rate was observed. Hoskins and Swenerton3 also reported an objective response in three of 11 patients (27.2%) who had previously received paclitaxel and experienced disease progression. These studies provide clinical evidence of non–cross-resistance to both the platinum and taxane agents. The activity of oral etoposide in platinum- and paclitaxel-resistant ovarian carcinoma suggested the potential for incorporating it with paclitaxel and platinum in a three-drug combination as first-line therapy. Preclinical studies have suggested a schedule dependency to paclitaxel and etoposide that favors sequential administration with either agent administered first.6 Clinical trials of combinations of paclitaxel and etoposide have used both etoposide followed by paclitaxel and paclitaxel followed by etoposide.7-9 In an effort to ensure paclitaxel administration was not altered by hematologic toxicity from etoposide in this phase I trial, it was elected to administer paclitaxel on day 1. A 3-hour paclitaxel infusion was chosen on the basis of the decreased hematologic toxicity without abrogation of efficacy observed with this schedule compared with 24-hour infusion.10 Carboplatin was administered after paclitaxel in view of the severe neurotoxicity reported with the combination of 3-hour paclitaxel and cisplatin.11 The carboplatin dose was calculated based on an area under the curve (AUC) of 5. This AUC was lower than that which had been determined to be the maximum-tolerated dose (MTD) in a prior GOG study.12 In view of the lack of a documented dose-response relationship for platinum and our intention to add a third agent, this seemed appropriate.13-15 After paclitaxel and carboplatin administration on day 1, oral etoposide 50 mg/m2 was administered orally beginning on day 2. Hainsworth et al16,17 have reported two phase I/II studies with paclitaxel at a dose of 200 mg/m2 over 1 hour, carboplatin at an AUC of 6, and etoposide 100 mg on day 1 alternating with 50 mg on day 2 for 10 days’ duration with good hematologic tolerance of this triplet. The current study was undertaken to determine the maximum number of days of oral etoposide therapy that would be tolerated after a regimen of paclitaxel 175 mg/m2 administered over 3 hours and carboplatin administered at an AUC of 5.
Patients were entered onto this Gynecologic Oncology Group study between August 1996 and August 1998. All patients had adenocarcinoma of the ovary, peritoneum, or fallopian tube diagnosed within 12 weeks and confirmed histologically by review of the GOG Pathology Committee. All stages of disease were eligible. Patients were required to have no history of other malignancy, chemotherapy, or radiation therapy; to have GOG performance status of 2 or better; and to have had recovered from prior surgery. In view of the limitations of commercially available oral dosing of etoposide, the patient was required to have at least 1 m2 of body-surface area and adequate intestinal function (ie, the patient could not require intravenous hydration or nutritional support). Excluded were patients with a GOG performance status of 3 or 4, tumors of low malignant potential (borderline tumors), active infection, hepatitis, gastrointestinal bleeding, a history of a myocardial infarction, abnormal cardiac conduction diagnosed within 6 months, or unstable angina.
Pretreatment laboratory eligibility requirements included the following: leukocyte count Pretreatment evaluation included assessment of performance status, measurement of the indicator lesion or lesions, serum CA-125, physical examination (including a pelvic examination), complete blood cell count and differential, serum electrolytes, bilirubin, AST, alkaline phosphatase, creatinine, blood urea nitrogen, chest radiograph, and microscopic urinalysis. Paclitaxel at a dose of 175 mg/m2 over 3 hours followed by carboplatin at an AUC of 5 and determined using the Calvert Formula based on a calculated creatinine clearance of Jelliffe was administered intravenously on day 1. Patients received standard premedication with dexamethasone and H1- and H2-receptor antagonists to avoid paclitaxel hypersensitivity reactions. Serotonin agonist antiemetics were routinely administered on day 1, with other antiemetics subsequently used as required. Etoposide was administered orally at a dosage of 50 mg/m2/d beginning on day 2 (Table 1). Because etoposide is available only in 50-mg capsules, some approximation in the calculated daily dose was necessary.
A complete blood cell count was performed weekly, and oral etoposide therapy was discontinued if the absolute granulocyte count was less than 1,000/µL or the platelet count less than 50,000/µL during a treatment course. Chemotherapy cycles were repeated every 21 days, pending hematologic recovery defined as an absolute granulocyte count  1,500/µL and platelet count 100,000/µL, for a maximum of six courses. There were no intrapatient dose-escalations. Dose reductions of paclitaxel were prescribed for grade 2 hepatotoxicity and discontinued for grade 3 or 4 hepatotoxicity or atrioventricular nodal block, including Mobitz type 1 or 2 or total heart block. Chemotherapy was to be delayed until adverse effects resolved to  grade 1 severity if the calculated creatinine clearance was less than 50 mL/min or the patient developed grade 3 or 4 peripheral neuropathy. If treatment delays were greater than 2 weeks, then the patient was removed from study.
Dose-limiting toxicities were defined as neutropenic fever, grade 4 thrombocytopenia, absolute neutrophil count less than 1,000/µL or platelet count less than 50,000/µL during treatment with etoposide, or a delay in starting a subsequent course of more than 14 days based on the first cycle of chemotherapy. In the absence of dose-limiting toxicity, escalation of the number of days of therapy was prescribed using cohorts of three patients (Table 1). In the presence of dose-limiting toxicity, the dose level was expanded to include up to six patients to better define the toxicity. The maximum-tolerated dose was defined as the highest dose level at which The pretreatment evaluation was repeated every 3 weeks with the exception of the chest radiograph (unless pulmonary metastases were present). Therapy was discontinued in the presence of disease progression. Response to therapy was defined by standard criteria. Written informed consent was obtained from all patients before entry on study fulfilling all institutional, state, and federal regulations.
Fifty-two patients were entered onto the study, and patient characteristics are listed in Table 2. Twenty-nine patients were entered in the first stage of accrual. Dose-limiting toxicity with neutropenic sepsis occurred at 8 days of oral etoposide, making the MTD 6 days of therapy.
To decrease the hematologic toxicity of the regimen, the duration of paclitaxel infusion was decreased to 1 hour. Twenty-three patients were entered into the second stage of accrual. Dose-limiting toxicity occurred at 12 days of oral etoposide, making the MTD 10 days of therapy. Thirteen patients were accrued at the MTD for a total of six cycles to better define cumulative toxicity. The adverse effects of this dose schedule are listed in Table 3. One patient was removed for cardiotoxicity and one refused therapy after two courses despite the absence of toxicity, leaving 11 patients assessable. Dose reductions were required in four patients on cycles 1 through 5 and two patients required dose reductions twice.
Three patients developed acute myeloid leukemia (AML). The first case occurred 16 months after the patient received a cumulative etoposide dose of only 200 mg/m2. Bone marrow cytogenetics demonstrated a [inv(16)(p13q22)] defect consistent with acute nonlymphocytic leukemia French-American-British type M4Eo. A second patient developed myelofibrosis 27 months after initiating therapy, receiving a cumulative etoposide dose of 1,200 mg/m2. Two bone marrow aspirates were acellular; she subsequently developed leukemia 5 months later and died. A third patient developed acute nonlymphocytic leukemia 35 months after initiating therapy, receiving a cumulative etoposide dose of 2,400 mg/m2. An acellular bone marrow aspirate precluded cytogenetics. At the time of death, two of these patients had no evidence of recurrent ovarian cancer. All early-stage patients and 37 (79%) of 47 patients with stage III or IV disease normalized their CA-125 levels and were in clinical remission after therapy. Partial response was seen in nine of the remaining patients. Second-look laparotomy was performed in five patients, four of whom had optimal residual disease after primary surgery. Four demonstrated microscopic disease and one demonstrated gross residual disease. The median progression-free survival is 17 months (range, 5 to 40+ months). Sixteen of 52 patients have died; 13 deaths were tumor-related.
In the last 5 years, a number of second-line chemotherapy agents have demonstrated activity in ovarian cancer. Oral etoposide, pegylated liposomal doxorubicin, topotecan, and gemcitabine are moderately active in platinum-resistant ovarian cancer and therefore are of greater interest for combination with platinum and paclitaxel in first-line therapy. The GOG is conducting multiple phase I studies of three-drug combinations in chemotherapy-naive patients to determine the toxicity profiles of these regimens. In the current phase I trial, it was our objective to combine paclitaxel, carboplatin. and increasing days of oral etoposide without growth-factor support.
The antitumor activity of oral etoposide is both schedule- and dose-dependent. Slevin et al18 previously demonstrated that the efficacy of oral etoposide is correlated with a serum level Because hematologic toxicity was the dose-limiting toxicity with prolonged oral etoposide, this phase I study initially used paclitaxel administered as a 3-hour infusion and a moderate dose of carboplatin (an AUC of 5). Despite these dose and schedule modifications, the MTD of oral etoposide was only 6 days of therapy. Given the previous reports by Hainsworth et al16,17 showing tolerance using paclitaxel at a dose of 200 mg/m2 delivered over 1 hour, carboplatin at an AUC of 6, and 10 days of oral etoposide at a dose of 50 mg/m2, the protocol was modified to a 1-hour paclitaxel infusion. Our goal was to further increase the number of days of etoposide therapy by using lower doses of paclitaxel and carboplatin than those used by Hainsworth et al. Hematologic toxicity was reduced with a 1-hour paclitaxel infusion allowing further escalation of the number of days of oral etoposide. The dose-limiting toxicity was reached at 12 days of therapy, making the MTD 10 days of therapy. A cohort of 11 assessable patients were then treated at the MTD to determine the tolerance of six courses of therapy. Dose reductions were required in four patients, of whom two required dose reductions on two occasions. Hainsworth et al16,17 had previously reported administering this combination for up to four courses for small-cell lung cancer and unknown primary tumor, but in both reports only 64% and 84% of patients received the planned therapy, most often owing to disease progression. The acute adverse effects seen with this regimen are comparable to those seen with paclitaxel and carboplatin at identical doses, for which the incidence of grade 3 or 4 neutropenia was 82% and the incidence of grade 3 or 4 thrombocytopenia was 16%.21 Neuropathy, myalgia, and arthralgia were mild despite the use of a 1-hour paclitaxel infusion. Of most concern were the cases of AML that occurred (5.8%). These occurred at an extremely low total dosages of oral etoposide of 200 mg/m2, 1,200 mg/m2, and 2,400 mg/m2 at 16, 32, and 35 months after the initiation of therapy, respectively. Risk of etoposide-associated AML has been related to cumulative etoposide doses greater than 2,000 mg/m2.22,23 For the two patients we have previously reported with etoposide-related AML after prolonged oral administration, the cumulative etoposide doses were 8,697/m2 and 7,375/m2.5,24 Both patients had recurrent cancer when AML was found. To decrease the risk of treatment-associated AML, the total etoposide dosage was limited in this trial. The chromosomal aberration seen, a [inv(16)(p13q22)] defect, has rarely been reported as a treatment-related AML after topoisomerase II inhibitors (ie, etoposide).25 This defect is more common after therapy with both topoisomerase II inhibitors and alkylating agents (ie, platinum).26 Nevertheless, etoposide-related AML in children has been reported after low cumulative etoposide exposure.27 Additionally, a recent review of secondary leukemias and myelodysplasia in 12 National Cancer Institute–supported cooperative group trials found the highest incidence of AML (3.3%) in patients who received the lowest cumulative etoposide dose (less than 1.5 mg/m2).28 Recently, Yagita et al29 reported treatment-related AML or myelodysplasia occurring in three of 24 heavily pretreated breast cancer patients after treatment with oral etoposide for 5 to 7 days every 4 weeks. Although platinum analogs are also leukemogenic, this is a less frequent event (0.33%) and their latency period is longer than 48 months.30 The impact of this adverse effect is more tragic by the absence of recurrent ovarian cancer in two of these patients. In our opinion, further studies with oral etoposide should be limited to recurrent ovarian carcinoma until the risk of treatment-related AML can be determined. Although response is not the primary intent of a phase I study, 79% of patients with advanced-stage disease were in clinical complete remission after therapy. Although not required, second-look surgery was performed in five patients, with no pathologic complete responders. The progression-free survival of 17 months is similar to the progression-free survival of 18 months for 3-hour paclitaxel and cisplatin reported by Stuart et al.2 To date, efforts to incorporate a third active agent into the paclitaxel/platinum doublet in chemotherapy-naive ovarian, peritoneal, and tubal cancer patients have been limited by hematologic toxicity. Limited data are currently available for an ongoing phase I GOG trial of topotecan, cisplatin, and paclitaxel in a similar patient population.31 In this trial, a 3-hour infusion of paclitaxel at 175 mg/m2 is being used to abrogate hematologic toxicity of previously reported 24-hour paclitaxel infusion with topotecan.32 Further, the less myelosuppressive platinum analog, cisplatin, is also being used at a decreased dose to minimize severe neurotoxicity seen with 3-hour paclitaxel in combination with cisplatin. To date, topotecan at a dose of 0.5 mg/m2/d on days 1 to 5 with granulocyte colony-stimulating factor is well tolerated. Efforts to combine gemcitabine with paclitaxel and carboplatin have been associated with hematologic toxicity requiring dose reductions of paclitaxel. Because of the limited hematologic toxicity of liposomal doxorubicin, an ongoing paclitaxel/carboplatin/liposomal doxorubicin regimen is under investigation. In conclusion, this phase I study demonstrated that the regimen of 1-hour paclitaxel, carboplatin, and oral etoposide for 10 days is tolerable without supportive therapy. However, the leukemogenic potential is of concern and limits the usefulness of the regimen in chemotherapy-naive ovarian carcinoma.
The following Gynecologic Oncology Group institutions participated in this study: Emory University Clinic, University of Washington Medical Center, Indiana University Medical Center, Cleveland Clinic Foundation, Columbus Cancer Council, University of Chicago, and Case Western Reserve University.
Supported by National Cancer Institute grants of the Gynecologic Oncology Group Administrative Office (grant no. CA 27469) and the Gynecologic Oncology Group Statistical Office (grant no. CA 37517).
1. 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
2.
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 92:699–708, 2000 3. Hoskins PJ, Swenerton KD: Oral etoposide is active against platinum-resistant epithelial ovarian cancer. J Clin Oncol 12:60–63, 1994[Abstract] 4. Seymour MT, Mansi JL, Gallagher CJ, et al: Protracted oral etoposide in epithelial ovarian cancer: A phase II study in patients with relapsed or platinum resistant disease. Br J Cancer 69:191–195, 1994[Medline] 5. Rose PG, Blessing JA, Mayer AR, et al: Prolonged oral etoposide as second line therapy for platinum resistant and platinum sensitive ovarian carcinoma: A Gynecologic Oncology Group study. J Clin Oncol 16:405–410, 1998[Abstract] 6. Perez EA, Buckwalter CA: Sequence-dependent cytotoxicity of etoposide and paclitaxel in human breast and lung cancer cell lines. Cancer Chemother Pharmacol 41:448–452, 1998[Medline] 7. Ukena D, Berg M, Leutz M, et al: A phase I study of paclitaxel in combination with etoposide in patients with stage IIIB/IV non-small cell lung cancer (NSCLC). Lung Cancer 19:31–36, 1998[Medline] 8. Lilenbaum RC, MacManus D, Engstrom C, et al: Phase I study of paclitaxel and etoposide for metastatic or recurrent malignancies. Am J Clin Oncol 21:129–134, 1998[Medline] 9. Perez EA, Buckwalter CA, Reid JP: Combinations of paclitaxel and etoposide in the treatment of lung cancer. Semin Oncol 23:21–25, 1996[Medline]
10.
Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al: European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus low-dose and long versus short infusion. J Clin Oncol 12:2654–2666, 1994 11. Rowinsky EK, Gilbert MR, McGuire WP, et al: Sequences of Taxol and cisplatin: A phase I and pharmacologic Study. J Clin Oncol 9:1692–1703, 1991[Abstract]
12.
Bookman MA, McGuire WP, Kilpatrick D, et al: Carboplatin and paclitaxel in ovarian carcinoma: A phase I study of the Gynecologic Oncology Group. J Clin Oncol 14:1895–1902, 1996 13. Gore ME, Mainwaring PN, Macfarlane V, et al: A randomized study of high versus standard dose carboplatin in patients (pts) with advanced epithelial ovarian cancer (eoc). Proc Am Soc Clin Oncol 15:284a, 1996 (abstr)
14.
Jacobsen A, Bertelson K, Anderson JE, et al: Dose-effect study of carboplatin in ovarian cancer: A Danish Ovarian Cancer Study Group study. J Clin Oncol 15:193–198, 1997
15.
Jodrell DI, Egorin MJ, Canetta RM, et al: Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer. J Clin Oncol 10:520–528, 1992 16. Hainsworth JD, Stroup SL, Greco FA: Paclitaxel, carboplatin, and extended schedule etoposide in the treatment of small cell lung carcinoma. Cancer 77:2458–2463, 1996[Medline]
17.
Hainsworth JD, Erland JB, Kalman LA, et al: Carcinoma of unknown primary site: Treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide. J Clin Oncol 15:2385–2393, 1997 18. Slevin ML, Clark PI, Joel SP, et al: A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung. J Clin Oncol 7:1333–1340, 1989[Abstract] 19. Markman M, Hakes T, Reichman B, et al: Phase 2 trial of chronic low-dose oral etoposide as salvage therapy of platinum-refractory ovarian cancer. J Cancer Res Clin Oncol 119:55–57, 1992[Medline] 20. Clark PI, Cottier B: The activity of 10-, 14-, 21-day schedules of single-agent etoposide in previously untreated patients with extensive small-cell lung cancer. Semin Oncol 19:36–39, 1992 (suppl 14) 21. Neijt JP, Hansen SW, Hansen PG, et al: Randomized phase III study in previously untreated epithelial ovarian cancer FIGO stage IIB, III, IV comparing paclitaxel-cisplatin and paclitaxel-carboplatin. Proc Am Soc Clin Oncol 16:352a, 1997 (abstr 1259) 22. Pedersen-Bjergaard J, Daugaard G, Hansen SW, et al: Increased risk of myelodysplasia and leukemia after etoposide, cisplatin and bleomycin for germ cell tumors. Lancet 338:359–363, 1991[Medline] 23. Kollmannsberger C, Beyer J, Droz JP, et al: Secondary leukemia following high cumulative doses of etoposide in patients treated for advanced germ cell tumors. J Clin Oncol 16:3386–3391, 1998[Abstract] 24. Rose PG, Blessing JA, Soper JT, et al: Prolonged oral etoposide in recurrent or advanced leiomyosarcoma of the uterus: A Gynecologic Oncology Group Study. Gynecol Oncol 70:267–271, 1998[Medline] 25. Dissing M, Le Beau MM, Pedersen-Bjergaard J: Inversion of chromosome 16 and uncommon rearrangements of the CBFB and MYH11 genes in therapy-related acute myeloid leukemia: Rare events related to DNA-topoisomerase II inhibitors? J Clin Oncol 16:1890–1896, 1998[Abstract] 26. Pedersen-Bjergaard J, Andersen MK, Johansson B: Balanced chromosome aberrations in leukemia following chemotherapy with DNA-topisomerase II inhibitors. J Clin Oncol 16:1897–1898, 1998[Medline] 27. Stine KC, Saylors RL, Sawyer JR, et al: Secondary acute myelogenous leukemia following safe exposure to etoposide. J Clin Oncol 15:1583–1586, 1997[Abstract]
28.
Smith MA, Rubinstein L, Anderson JR, et al: Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 17:569–577, 1999 29. Yagita M, Ieki Y, Onishi R, et al: Therapy-related leukemia and myelodysplasia following oral administration of etoposide for recurrent breast cancer. Int J Oncol 13:91–96, 1998[Medline]
30.
Travis LB, Holowaty EJ, Bergfeldt K, et al: Risk of leukemia after platinum-based chemotherapy for ovarian cancer. N Engl J Med 340:351–357, 1999 31. Armstrong DK, O’Reilly S, Bookman M, et al: A phase I study of topotecan, cisplatin and paclitaxel in newly diagnosed epithelial ovarian cancer: A Gynecologic Oncology Group study. Proc Am Soc Clin Oncol 17:350a, 1998 (abstr 1351)
32.
O’Reilly S, Fleming GF, Baker SD, et al: Phase I trial and pharmacologic trial of sequences of paclitaxel and topotecan in previously treated ovarian epithelial malignancies: A Gynecologic Oncology Group study. J Clin Oncol 15:177–186, 1997 Submitted December 20, 1999; accepted April 12, 2000.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
