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Journal of Clinical Oncology, Vol 18, Issue 24 (December), 2000: 4038-4044
© 2000 American Society for Clinical Oncology

Phase II Feasibility Study of Sequential Couplets of Cisplatin/Topotecan Followed by Paclitaxel/Cisplatin as Primary Treatment for Advanced Epithelial Ovarian Cancer: A National Cancer Institute of Canada Clinical Trials Group Study

By P. Hoskins, E. Eisenhauer, I. Vergote, J. Dubuc-Lissoir, B. Fisher, R. Grimshaw, A. Oza, M. Plante, G. Stuart, J. Vermorken

From the British Columbia Cancer Agency, Vancouver Clinic, Vancouver, British Columbia; National Cancer Institute of Canada Clinical Trials Group, Queen’s University, Kingston; Princess Margaret Hospital, Toronto, Ontario; Centre Hospitalier de l’Universite de Montreal–Pavillon Notre Dame, Montreal; Centre Hospitalier de l’Universite de Quebec–Pavillon Hotel Dieu de Quebec, Quebec City, Quebec; Queen Elizabeth II Health Science Centre, Halifax, Nova Scotia; Tom Baker Cancer Centre, Calgary, Alberta, Canada; University Hospital, Leuven; and University Hospital, Antwerp, Belgium.

Address reprint requests to Elizabeth Eisenhauer, MD, National Cancer Institute of Canada Clinical Trials Group, Queen’s University, 82–84 Barrie St, Kingston, Ontario K7L 3N6, Canada; email eeisenhauer@ ctg.queensu.ca.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: Despite the improved results in advanced ovarian cancer achieved with the addition of paclitaxel to frontline therapy, there remains room for improvement. One approach is to add new agents such as topotecan. Because myelosuppression limits the delivery of topotecan with paclitaxel/cisplatin in a three-drug combination, we explored giving sequential couplets of cisplatin/topotecan followed by paclitaxel/cisplatin.

PATIENTS AND METHODS: Forty-four patients with residual epithelial ovarian carcinoma after primary surgery were studied. Cisplatin 50 mg/m2 on day 1 and topotecan 0.75 mg/m2 on days 1 through 5 were administered at 21-day intervals for four cycles, followed by interval debulking surgery (if optimal debulking was not achieved with primary surgery), and then paclitaxel 135 mg/m2 over 24 hours on day 1 and cisplatin 75 mg/m2 on day 2 at 21-day intervals for four cycles.

RESULTS: Such sequential couplets are feasible. Myelotoxicity was the major toxic effect, but it was of short duration. The granulocyte nadir with topotecan/cisplatin occurred late (median, day 18), so retreatment on day 21 was not always possible. There was no unexpected nonhematologic toxicity. The regimen was active in this group of patients who had undergone largely suboptimal debulking surgery. In 34 patients with clinically measurable disease, the overall response rate was 78%, and 30 (77%) of the 39 patients with elevated CA 125 levels at baseline had normalization of CA 125 levels by the end of therapy.

CONCLUSION: Sequential couplets of cisplatin/topotecan followed by paclitaxel/cisplatin are feasible. The efficacy data in this suboptimal group of patients has encouraged us to proceed with a randomized study based on this approach.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
ADVANCED EPITHELIAL ovarian cancer is a frustrating disease. Despite the high initial response rates, relapse and death were almost inevitable after cisplatin-based combination chemotherapy in the era preceding paclitaxel.1-4 The addition of paclitaxel has improved the outcome, with an increase in median survival in two of the three randomized studies.5,6 The third study, the third International Collaborative Ovarian Neoplasm Study, is a negative study on the basis of preliminary reporting.7 However, these results are immature, and in the subset with suboptimal disease, the paclitaxel-containing arm was superior. It is clear that, although cisplatin/paclitaxel combinations represent an advance, there is still much room for improvement in the treatment of this disease, as most patients will relapse. A variety of different approaches are being studied in an attempt to further improve on these results. One such approach is to add other non–cross-resistant agents to the standard frontline combination of paclitaxel/cisplatin.

Topotecan is one such partially non–cross-resistant agent.8-13 However, combining topotecan with any platinum analog is problematic because the dose-limiting toxicity is myelosuppression and the dose of either of the drugs that can be given is markedly lower than the equivalent single-agent dose, even with granulocyte colony-stimulating factor support.14,15 The combination of cisplatin plus paclitaxel is also myelosuppressive.5 Therefore, it could be anticipated that combining all three drugs together in adequate doses would be problematic, and in fact, this is what was found. Doses were low, and thrombocytopenia was dose-limiting.16 We, therefore, took the approach of using the sequential administration of cisplatin-based couplets (two-drug combinations) that incorporated topotecan and paclitaxel in an attempt to maintain as high a dose as possible without using growth factors. This study in women with previously untreated advanced epithelial ovarian cancer is now complete, and this report outlines the feasibility of the regimen (ie, the ability to deliver the planned doses and its toxicity) and its efficacy (response rates, CA 125 normalization rates, and progression-free survival).


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility
Women aged 18 to 65 years with chemotherapy-naïve epithelial ovarian, primary peritoneal, or fallopian tube carcinomas were eligible. Each woman had to have undergone her planned primary surgery and have macroscopic residual disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, normal bilirubin and creatinine levels, a total granulocyte count of >= 2 x 109/L, and a platelet count >= 150 x 109/L. Patients were excluded if they had borderline malignancies, a previous malignancy except for in situ cervical cancer or nonmelanoma skin cancer, or contraindications to the use of either cisplatin (neuropathy, hearing impairment, or inability to tolerate a fluid load) or paclitaxel (second- or third-degree heart block or neuropathy).

Regimen
Four cycles of cisplatin/topotecan at 21-day intervals were followed by four cycles of paclitaxel/cisplatin, also at 21-day intervals. After completion of the four topotecan/cisplatin cycles, interval debulking surgery was permitted in those patients who had not undergone optimal debulking at their first operation. Cisplatin 50 mg/m2 in 500 mL of normal saline was given on day 1, immediately followed by topotecan 0.75 mg/m2 in 100 mL of normal saline over 30 minutes. The same dose of topotecan was then repeated on days 2 through 5. For the final four cycles, the Gynecologic Oncology Group (GOG) 111 regimen5 was used because this was the standard frontline combination in use at the time. Paclitaxel 135 mg/m2 in 1 L of normal saline was infused over 24 hours using a standard prepaclitaxel premedication regimen. Cisplatin 75 mg/m2 in 500 mL of normal saline was then given at the completion of the paclitaxel infusion. Pre- and posthydration according to institutional guidelines was given to ameliorate the nephrotoxic effects of cisplatin in all eight cycles.

The antiemetic prescription was at the treating physician’s discretion. A serotonin antagonist plus dexamethasone was always given before the cisplatin. The antiemetics to be used in the delayed phase were not mandated and were given as per the treating physician’s preference.

Dose Modification
A 25% decrease in topotecan or paclitaxel dose was mandated for neutropenia less than 0.5 x 109/L lasting for >= 7 days, thrombocytopenia <= 25 x 109/L, febrile neutropenia or neutropenic infection >= grade 3, or bleeding that required transfusion. Retreatment on this 21-day regimen was only allowed once the neutrophil count was >= 1.5 x 109/L and the platelet count was >= 100 x 109/L. Pragmatically, this translated into a week’s delay with cisplatin/topotecan, to allow it to be given during the 5-day work week.

Cisplatin was reduced for serum creatinine abnormalities as follows: if the serum creatinine level had increased to greater than the upper limit of normal, the patient was to be rehydrated. If the creatinine level was still greater than 1.5 x the upper limits of normal, then the protocol treatment was discontinued; for one to 1.5 times the upper limits of normal, a 25% reduction was made. For serum creatinine level less than the upper limit of normal, the full dose was given. Any other grade 3 toxicity, except for alopecia and emesis, resulted in a 25% decrease of the cisplatin along with its couplet partner.

Efficacy Measures
Clinical response was determined by computed tomography scan in the subset of patients with measurable disease at the start of chemotherapy. Scans were performed at baseline and repeated after the four cycles of cisplatin/topotecan (but before interval debulking was performed) and, finally, once all eight cycles of chemotherapy were completed. Patients who had interval debulking (between the cisplatin/topotecan and paclitaxel/cisplatin couplets) also had a surgical response assessment. Standard clinical response criteria were used. A complete clinical response (CR) was the disappearance of all disease plus normalization of CA 125 level and resolution of all cancer-related symptoms. A partial response (PR) was either a 50% or greater decrease in the sum of the products of measurable lesions or a CR without CA 125 or symptom normalization. Stable disease (SD) was either a decrease in disease of less than 50% or an increase in disease of less than 25%. Progressive disease was a greater than 25% increase in the sum of products or the appearance of new lesions. Patients classified as having no evidence of disease (NED) were those who had no evidence of disease by physical examination and computed tomography scanning at the start of therapy.

CA 125 levels were measured before each cycle of chemotherapy. The percentage normalizing during the four cycles of cisplatin/topotecan (and before any interval debulking) and again at the completion of the total program was calculated.

Progression-free survival for all patients was recorded from the start date of the first cycle of chemotherapy. Marker elevation alone in the absence of clinical evidence of relapse was not sufficient evidence for progression. Patients who did not otherwise complete the protocol were censored at the time of going off study. Progression-free and overall survival curves were constructed using the methodology of Kaplan and Meier.

Toxicity Measures
All patients who had received at least one cycle were assessable. Toxicity was graded using National Cancer Institute of Canada Clinical Trials Group expanded common toxicity criteria. When relevant, these criteria are given in Results.

Assessment of Feasibility and Sample Size
A planned sample size of 40 patients was targeted to obtain reliable information on the proportion of patients who could complete all eight cycles of therapy and to describe toxic effects with acceptable confidence intervals. Assuming that approximately one half of enrolled patients would have objectively measurable disease to observe for response, this number was also expected to yield at least 20 patients in whom objective response could be described. Because this regimen incorporated drugs known to be active in ovarian cancer, overall response rates in the range of 60% to 70% were expected; the observation of lower rates would have been of concern, but no criteria were established for a higher response rate of interest. In fact, it was intended that, provided the regimen was feasible, the previously documented activity of topotecan as a single agent in recurrent disease would make this triple-drug regimen of potential interest to pursue in a frontline randomized study.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients
Between June 1997 and May 1998, 44 patients were enrolled onto the study. The characteristics of all 44 patients are given in Table 1. These were not prognostically optimal patients. Twenty patients (45%) did not have primary debulking. Thirty-three (75%) were suboptimal in that they had >= 2 cm of residual (the 20 in whom debulking was not attempted plus an additional 13 who could not be debulked to < 2 cm), and 15 (34%) had stage IV disease. Thirty-four had documented measurable disease at baseline and are thus considered in the calculation of clinical response rates.


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  		Table 1. Patient Characteristics at Baseline (n = 44)
 
Nonhematologic Toxicity (Table 2)
There was neither undue nor unexpected toxicity with either the cisplatin/topotecan or the paclitaxel/cisplatin. No discrimination was made between toxicity resulting from the chemotherapy, antiemetics, or the cancer, and the frequencies reported are the overall percentages. The rate of sensory neuropathy was 52% (recorded at the completion of the protocol), and of these patients, only 5% had grade 3 disease. During the cisplatin/topotecan portion of the treatment, only 4% of patients had any form of renal toxicity (as shown by increased creatinine levels). At the completion of the regimen, this rate had risen to 19%. This toxicity was no greater than grade 2 in any patient.


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  		Table 2. Worst Nonhematologic Toxic Effects by Patient
 
Hematologic Toxicity (Table 3)
Myelotoxicity, specifically neutropenia, was the major toxicity encountered. Grade 4 neutropenia (absolute neutrophil count < 0.5 x 109/L) occurred in 79% of patients during the cisplatin/topotecan cycles and in 75% during the paclitaxel/cisplatin cycles. The mean nadir achieved in each couplet was 0.20 x 109/L. In all cases, it was of short duration and there was no evidence of a cumulative effect. The median time to reach the nadir was later with cisplatin/topotecan (day 18) than with paclitaxel/cisplatin (day 12). This observation explains the greater frequency of treatment delays during the first four cycles. Febrile neutropenia or neutropenic infection occurred in 14% and 10% of patients on the cisplatin/topotecan and paclitaxel/cisplatin couplets, respectively. There was one septic death that occurred after the first cycle of topotecan/cisplatin therapy, but in this case, antibiotics were not given for 3 days despite the fever and neutropenia. A second death unrelated to chemotherapy resulted from pulmonary emboli in the perioperative period. The degree of thrombocytopenia was greater with cisplatin/topotecan, with a nadir of 73 x 109/L (range, 6 to 403 x 109/L) compared with 131 x 109/L (range, 30 to 269 x 109/L) with paclitaxel/cisplatin, but this did not result in any clinical complications.


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  		Table 3. Hematologic Toxicity: Worst Ever by Patient
 
Drug Delivery and Treatment Delays (Table 4)
A total of 165 cycles of topotecan/cisplatin were given to the 44 patients enrolled. Forty patients went on to part two of the regimen and received a total of 159 cycles of paclitaxel/cisplatin. Dose reduction of topotecan or paclitaxel occurred in 17% and 9% of repeat cycles, respectively. Cisplatin was reduced in less than 1% of cisplatin/topotecan and 7% of paclitaxel/cisplatin repeat cycles.


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  		Table 4. Dose Reductions and Treatment Delays
 
Treatment delay, largely resulting from delayed nadir neutrophil count and subsequent failure to recover to 1.5 x 109/L by day 21, was the norm with cisplatin/topotecan. Sixty-three percent of the repeat cycles were delayed by 7 days, and a further 17% were delayed 3 to 6 days. In contrast, only 18% of the repeat cycles of paclitaxel/cisplatin were delayed. The data were examined to see whether there would have been greater on-time delivery if the required retreatment day neutrophil count had been decreased to 1.0 x 109/L, instead of 1.5 x 109/L. Only 6% more cycles would have been delivered on day 21 had we adopted such a revised retreatment criteria.

Three patients received only one cycle of therapy: one patient was removed from trial because of a flare of pre-existing Crohn’s disease, one died of neutropenic sepsis, and one had a fatal pulmonary embolus. Only the septic death was thought to be chemotherapy-related, although it is possible that chemotherapy may have contributed to the Crohn’s flare. A fourth patient received only four courses of therapy and declined further cancer treatment for nontoxicity reasons.

Response Assessment
At baseline, 34 patients had measurable disease and were observed for objective response. Of these, two were not assessable, both of whom received only one cycle of therapy before going off treatment without reassessment of disease (one with Crohn’s disease and one with septic death). The clinical response rate after the four cisplatin/topotecan cycles and before any further surgery was 66% (CR, five of 32; PR, 16 of 32) and 78% at the completion of the total regimen (CR, 16 of 32; PR, nine of 32). The other seven patients had either SD (n = 6) or progressive disease (n = 1).

The 10 patients with nonmeasurable disease were either NED (n = 4) or nonmeasurable (n = 6). All four patients with NED were continuing NED at the end of therapy, and four of the six nonmeasurable patients were NED at the end of therapy. Overall, the progression rate in the 41 patients who received more than one cycle of treatment was 2%.

Twenty patients did not have primary debulking surgery. Sixteen (88%) went on to interval debulking. Responses assessed surgically, at the start of the interval debulking operation, were as follows: PR, 8; SD, 1; progression, 2; and unknown, 5 (because of unknown status at baseline). At the completion of the surgery, responses were as follows: CR, 8; PR, 6; and SD, 2 (all compared with the status at the start of the interval debulking). Four of the 20 did not go on to interval debulking for the following reasons: one died of sepsis after one cycle, one went off because of Crohn’s disease after one cycle, and two had no clinical response to treatment after four cycles. Neither of these last two patients responded to paclitaxel/cisplatin.

CA 125 Measurements
CA 125 levels were measured before each cycle of treatment. Thirty-nine patients had a baseline elevation of CA 125 level and at least one follow-up determination. Of these, 25 (64%) had CA 125 normalization within 3 months (ie, while on cisplatin/topotecan) and 30 (77%) had normalization by the end of their chemotherapy.

Survival (Fig 1)
As of July 27, 1999, the median follow-up was 15.5 months. The median overall survival was not yet reached at the time of this writing. Eight patients died, two from toxicity and six from disease. Twenty-one patients progressed. The estimated median progression-free survival was 14.8 months (range, 2 to 20+ months).



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  		Fig 1. Overall (solid line) and progression-free (dashed line) survival.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Sequential couplets of cisplatin/topotecan followed by paclitaxel/cisplatin are feasible as primary treatment for advanced ovarian cancer. Only one patient did not complete the planned eight cycles of treatment for toxicity-related reasons: she died of neutropenic sepsis cycle 1. A second patient went off study after cycle 1 when she had a flare of underlying Crohn’s disease that may have been exacerbated by chemotherapy. There was no unexpected or undue nonhematologic toxicity. Renal toxicity, as evidenced by elevated serum creatinine level, was infrequent and never severe. The rate of sensory neuropathy for the total regimen was 52%, and only 5% were grade 3. This is within the expected range, given that the total dose of cisplatin was 500 mg/m2 and the paclitaxel was given by the less frequently neurotoxic 24-hour infusion.17 Reversible, short-term, noncumulative myelotoxicity was standard, occurring equally often with each couplet. The degree of myelotoxicity was comparable to that reported on the GOG 111 protocol, which used 24-hour paclitaxel.5 There was no evidence that this regimen led to either more frequent or severe hematologic or nonhematologic toxicities in the paclitaxel/cisplatin cycles, which reassured us that there was no unexpected biologic effect resulting from the preceding cisplatin/topotecan treatments. Febrile neutropenia or neutropenic infection occurred in 14% of patients while they were receiving topotecan/cisplatin and in 10% of patients while they were receiving paclitaxel/cisplatin. The median day to granulocyte nadir during cisplatin/topotecan cycles was day 18. Because of this, retreatment was delayed by a week in 63% of repeat cycles. We still recommend using a 21-day cycle as opposed to a 28-day cycle to maximize the treatment intensity, recognizing that many patients will need to change to a 28-day cycle. Given the short duration of granulocytopenia, we do not recommend the routine use of growth factors.

However, even though a regimen is feasible, it does not imply that it should be pursued further. For that efficacy data are needed. The results from this study in a cohort of women with predominantly suboptimal disease indicate that this is an active treatment. The median time to progression was 14.8 months, which is similar to the 15.3 months seen in the paclitaxel/cisplatin arm of the recent European-Canadian Intergroup trial, which included a much larger proportion (38%) of patients who had undergone optimal debulking.6 In the recently reported GOG 132 trial,18 which enrolled only patients who had undergone suboptimal debulking, the time to progression in the combination paclitaxel/cisplatin arm was 14 months. Because the median survival of our trial had not been reached at the time of this report, its comparability in terms of that outcome is uncertain. We did observe, however, an overall clinical response rate of 78% (95% confidence limits, 60% to 91%), which is encouraging, because the clinical response rate of the paclitaxel + cisplatin arm in GOG 132 was 66%, and in the European-Canadian Intergroup trial, it was 58.6% (78% if unconfirmed responses were included). Comparing efficacy parameters between trials is fraught with problems, however, so no definitive conclusions can be reached except that our results show this regimen to be active. To determine whether it will lead to improved survival compared with paclitaxel/cisplatin (or paclitaxel/carboplatin) will require a randomized trial. Such trials are in the planning stages in North America and Europe.

A concern that was voiced in the planning stage for this study was that suboptimal doses of cisplatin (50 mg/m2) and topotecan (0.75 mg/m2) were to be used in the cisplatin/topotecan couplets. The in vitro evidence of synergy when the cisplatin was given before or at the same time as the topotecan was sufficiently reassuring to allow for us to proceed.19,20 The CA 125 normalization data support this decision. Sixty-four percent of patients with initially elevated CA 125 levels had marker normalization during the four cisplatin/topotecan cycles, and 77% had normalized by the end of treatment. This result is similar to, if not better than, CA 125 normalization rates seen with other regimens. However, whether it is an indicator of superiority is not yet known and will depend on randomized results. It seems that greater myelosuppression is seen when cisplatin precedes topotecan, and similar enhanced cytotoxicity could be seen in the tumor as well. The underlying basis for this observation is not known, but it depends on the sequence of administration of the two drugs. Possible explanations for this include a subclinical renal effect by cisplatin altering the topotecan pharmacokinetics or a biologic effect such that topotecan, which inhibits topoisomerase I and thus DNA replication/repair, decreases the ability of the cell to repair cisplatin-induced DNA damage. However, studies to date, including a recently published report, have not been able to define the precise mechanism.21 An additional reassurance that we were not undertreating our patients was that the total dose of cisplatin used was comparable (500 mg/m2) to that which is routinely given (six cycles of cisplatin at 75 mg/m2 = 425 mg/m2). Given that the total dose of cisplatin may be important for outcome, we were not underdosing our patients.22

In summary, the approach of using sequential couplets of cisplatin/topotecan followed by paclitaxel/cisplatin is feasible, and the efficacy data is encouraging. Because the standard treatment of ovarian cancer, which was paclitaxel plus cisplatin when we began this pilot study, has since been replaced by paclitaxel plus carboplatin, we are repeating this study, in a smaller number of patients, with a regimen in which the paclitaxel/cisplatin couplet is replaced by a couplet of paclitaxel 175 mg/m2 over 3 hours plus carboplatin (area under the curve, 5). Our intent is that this will then become the experimental arm (versus paclitaxel plus carboplatin) in an upcoming international phase III study.


   NOTES
 
Presented in part at the Thirty-Fifth Annual American Society of Clinical Oncology Meeting, Atlanta, GA, May 15-18, 1999.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Neijt JP, ten Bokkel Huinink WW, van der Burg ME, et al: Long-term survival in ovarian cancer. Mature data from the Netherlands Joint Study Group for Ovarian Cancer. Eur J Cancer 27: 1367-1372, 1991

2. Hoskins PJ, O’Reilly SE, Swenerton KD, et al: Ten-year outcome of patients with advanced epithelial ovarian carcinoma treated with cisplatin-based multimodality therapy [see comments]. J Clin Oncol 10: 1561-1568, 1992[Abstract/Free Full Text]

3. Sutton GP, Stehman FB, Einhorn LH, et al: Ten-year follow-up of patients receiving cisplatin, doxorubicin, and cyclophosphamide chemotherapy for advanced epithelial ovarian carcinoma. J Clin Oncol 7: 223-229, 1989[Abstract]

4. Hainsworth JD, Grosh WW, Burnett LS, et al: Advanced ovarian cancer: Long-term results of treatment with intensive cisplatin-based chemotherapy of brief duration. Ann Intern Med 108: 165-170, 1988

5. 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[Abstract/Free Full Text]

6. 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[Abstract/Free Full Text]

7. Harper P: A randomized comparison of paclitaxel (T) and carboplatin (J) versus a control arm of single agent carboplatin (J) or CAP (cyclophosphamide, doxorubicin and cisplatin): 2075 patients randomised into the 3rd International Collaborative Ovarian Neoplasm Study (ICON3). Proc Am Soc Clin Oncol 18: 356a, 1999 (abstr 1375)

8. Kudelka AP, Tresukosol D, Edwards CL, et al: Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol 14: 1552-1557, 1996[Abstract/Free Full Text]

9. Carmichael J, Gordon A, Malfetano J, et al: Topotecan, a new active drug, vs paclitaxel in advanced epithelial ovarian carcinoma: International Topotecan Study Group trial. Proc Am Soc Clin Oncol 15: 283a, 1996 (abstr 765)

10. Bokkel Huinink W, Gore M, Carmichael J, et al: Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer [see comments]. J Clin Oncol 15: 2183-2193, 1997[Abstract/Free Full Text]

11. Bookman MA, Malmstrom H, Bolis G, et al: Topotecan for the treatment of advanced epithelial ovarian cancer: An open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J Clin Oncol 16: 3345-3352, 1998[Abstract]

12. Armstrong D, Rowinsky E, Donehower R, et al: A phase II trial of topotecan as salvage therapy in epithelial ovarian cancer. Proc Am Soc Clin Oncol 14: 275a, 1995 (abstr 769)

13. Hoskins P, Eisenhauer E, Beare S, et al: Randomized phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: A National Cancer Institute of Canada Clinical Trials Group study. J Clin Oncol 16: 2233-2237, 1998[Abstract]

14. de Jonge MJ, Sparreboom A, Verweij J: The development of combination therapy involving camptothecins: A review of preclinical and early clinical studies. Cancer Treat Rev 24: 205-220, 1998[Medline]

15. Rowinsky EK, Kaufmann SH: Topotecan in combination chemotherapy. Semin Oncol 24: S20-11-S20-26, 1997

16. Herben VM, Panday VR, Richel DJ, et al: Phase I and pharmacologic study of the combination of paclitaxel, cisplatin, and topotecan administered intravenously every 21 days as first-line therapy in patients with advanced ovarian cancer. J Clin Oncol 17: 747-755, 1999[Abstract/Free Full Text]

17. Eisenhauer E, ten Bokkel Huinink W, Swenerton K, 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 Classic Papers Curr Comments 3: 171-184, 1998

18. Muggia FM, Braly PS, Brady MF, et al: Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III and IV ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 18: 106-115, 2000[Abstract/Free Full Text]

19. Ma J, Maliepaard M, Nooter K, et al: Synergistic cytotoxicity of cisplatin and topotecan or SN-38 in a panel of eight solid-tumor cell lines in vitro. Cancer Chemother Pharmacol 41: 307-316, 1998[Medline]

20. Romanelli S, Perego P, Pratesi G, et al: In vitro and in vivo interaction between cisplatin and topotecan in ovarian carcinoma systems. Cancer Chemother Pharmacol 41: 385-390, 1998[Medline]

21. de Jonge MJA, Loos WJ, Gelderblom H, et al: Phase I pharmacologic study of oral topotecan and intravenous cisplatin: Sequence dependent hematologic side effects. J Clin Oncol 18: 2104-2115, 2000[Abstract/Free Full Text]

22. Hoskins PJ: Treatment of advanced epithelial ovarian cancer: Past, present and future. Crit Rev Oncol Hematol 20: 41-59, 1995[Medline]

Submitted December 28, 1999; accepted June 16, 2000.


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