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Clinical Evidence for Topotecan-Paclitaxel Non–Cross-Resistance in Ovarian Cancer

From the Royal Marsden Hospital; Department of Oncology, North Middlesex Hospital, London; CRC Department of Clinical Oncology, City Hospital, Nottingham; YCRC Department of Clinical Oncology, Weston Park Hospital, Sheffield; SmithKline Beecham Pharmaceuticals, Harlow, United Kingdom; Netherlands Cancer Institute, Amsterdam, The Netherlands; Texas Oncology PA, Dallas, TX; Institute of Obstetrics and Gynaecology, University School of Medicine, Poznan, Poland; Centre François Baclesse, Caen; Centre Oscar Lambret, Lille, France; Obstetric and Gynaecology Clinic, University of Milan, Milan; Department of Gynaecology, Civile Hospital, Voghera, Italy; Gynaecology and Oncology Department, University Hospital, Linköping, Sweden; Department of OB/GYN, Division of GYN Oncology, Albany Medical College of Union University, Albany, NY; and SmithKline Beecham Pharmaceuticals, Collegeville, PA.

Address reprint requests to Martin Gore, MD, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK; email: Martin.Gore{at}rmh .nthames.nhs.uk.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: A large, randomized study comparing the efficacy and safety of topotecan versus paclitaxel in patients with relapsed epithelial ovarian cancer showed that these two compounds have similar activity. In this study, a number of patients crossed over to the alternative drug as third-line therapy, ie, from paclitaxel to topotecan and vice versa. We therefore were able to assess the degree of non–cross-resistance between these two compounds.

PATIENTS AND METHODS: Patients who had progressed after one platinum-based regimen were randomized to either topotecan (1.5 mg/m²/d) x 5 every 21 days (n = 112) or paclitaxel (175 mg/m² over 3 hours) every 21 days (n = 114). A total of 110 patients received cross-over therapy with the alternative drug (61 topotecan, 49 paclitaxel) as third-line therapy.

RESULTS: Response rates to third-line cross-over therapy were 13.1% (8 of 61 topotecan) and 10.2% (5 of 49 paclitaxel; P = .638). Seven patients who responded to third-line topotecan and four patients who responded to paclitaxel had failed to respond to their second-line treatment. Median time to progression (from the start of third-line therapy) was 9 weeks in both groups, and median survival was 40 and 48 weeks for patients who were receiving topotecan or paclitaxel, respectively. The principal toxicity was myelosuppression; grade 4 neutropenia was more frequent with topotecan (81.4% of patients) than with paclitaxel (22.9% of patients).

CONCLUSION: Topotecan and paclitaxel have similar activity as second-line therapies with regard to response rates and progression-free and overall survival. We demonstrated that the two drugs have a degree of non–cross-resistance. Thus, there is a good rationale for incorporating these drugs into future first-line regimens.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
OVARIAN CANCER is one of the most common malignancies of the female genital tract and is the leading cause of death from gynecological cancer in Western industrial countries. This is because in early stage ovarian cancer, symptoms frequently are absent and therefore most patients present with advanced disease. The disease initially is sensitive to platinum-based cytotoxic chemotherapy, but the majority of women eventually relapse and die of progressive drug-resistant disease.^1-4 Phase II studies of second-line single agents such as anthracyclines,^5,6 hexamethylmelamine,⁷ ifosfamide,⁸ and etoposide⁹ have shown response rates of 14% to 20%, but in some of these trials, the timing of the relapse was not defined precisely and responses were not verified independently. In the 1990s, a number of newer drugs with activity in ovarian cancer were introduced, including paclitaxel,¹⁰ docetaxel,¹¹ gemcitabine,¹² liposomal doxorubicin,¹³ vinorelbine,¹⁴ and more recently, oxaliplatin.¹⁵ These compounds have demonstrated response rates of 14% to 37% in phase II studies performed in patients with disease refractory to or relapsing after platinum-based therapy.

The two drugs most extensively studied in relapsed ovarian cancer over the last 10 years have been paclitaxel and topotecan. Initial phase II trials of paclitaxel reported response rates of approximately 30% in patients with relapsed disease although a large randomized, multicenter study of paclitaxel, in which responses were confirmed by independent review, showed response rates of between 14% and 24%, depending on the dose and schedule.¹⁶ Similar response rates (14% to 16%) were obtained in multicenter noncomparator studies with topotecan in patients with relapsed ovarian cancer.^17-19 A phase III randomized trial was subsequently performed comparing the efficacy and safety of topotecan with paclitaxel in patients. This study has been reported and showed that the two drugs have similar activity when given as second-line therapy²⁰ (response rates: 20% topotecan, 13% paclitaxel).

This randomized study of second line therapy has allowed us to assess the degree of non–cross-resistance between topotecan and paclitaxel because a number of patients crossed over to the alternative agent as third-line therapy. We present here our analysis of this cross-over treatment and discuss the evidence for non–cross-resistance between these two compounds. We also update the progression-free and overall survival data of the original phase III trial.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients who had advanced epithelial ovarian cancer were enrolled in a randomized phase III trial of second-line treatment comparing topotecan with paclitaxel. The study was multicenter, involving institutions in both the United States and Europe. A full description of the patient population has been reported.²⁰ Patients were permitted to cross over and receive the alternative drug as third-line therapy, ie, patients who were randomized to topotecan crossed over to receive paclitaxel and those who were treated with paclitaxel crossed over to receive topotecan. This cross-over occurred at the investigator’s discretion but was usually for one of three reasons: (1) failure to respond to second-line therapy, (2) relapse after an initial response to second-line therapy, or (3) toxicity.

All patients had received platinum as first-line treatment. Their sensitivity to platinum was recorded as being either refractory (ie, progression during chemotherapy) or relapsing disease. Relapse was classified as early (relapse within 3 months), interim (relapse between 3 and 6 months), or late (relapse more than 6 months) after the end of first-line therapy.

Treatment
Topotecan 1.5 mg/m²/d was administered as a 30-minute intravenous infusion for 5 consecutive days, every 21 days. Paclitaxel 175 mg/m² was administered as a 3-hour infusion every 21 days. The topotecan dose could be increased or decreased in the range 1.0 to 2.0 mg/m²/d, depending on toxicity. Reductions in the dose of paclitaxel were permitted to a minimum dose of 135 mg/m², but no dose increases were allowed. Each course of treatment began on schedule provided the bone marrow had recovered, neutrophils 1,000/mm³ (topotecan) or 1,500/mm³ (paclitaxel) and platelets 100,000/mm³, and there was no clinically significant nonhematologic toxicity (except grade 3 nausea or alopecia). To maintain dose intensity, granulocyte colony-stimulating factor (G-CSF) filgrastim (Neupogen; Amgen Inc, Thousand Oaks, CA) could be added, if required, to either treatment regimen after the first course of therapy. Patients who were to receive paclitaxel were premedicated with dexamethasone and both H₁- and H₂-receptor antagonists to prevent severe hypersensitivity reactions. No premedication was required for patients who were to be treated with topotecan.

Events Measured
The events measured in both the randomized (second-line treatment) and the cross-over (third-line treatment) studies were response rate, time to response, duration of response, time to progression, and overall survival.

Methods of Assessment
Lesions were measured by computed tomographic or magnetic resonance imaging scan, ultrasound, x-ray, or physical examination, and the same technique for individual lesion assessment was used throughout the study. Measurements were performed before each course of treatment for lesions evaluated by ultrasound, x-ray, or physical examination and before each alternative course for those who were evaluated by computed tomographic or magnetic resonance imaging scan.

Responses were determined according to standard World Health Organization (WHO) criteria,²¹ and all claimed responses underwent independent review and confirmation by a radiologist who was blinded to treatment. Complete response was defined as the complete disappearance of all known measurable and evaluable disease for at least 4 weeks, and partial response was defined as a 50% reduction in measurable disease for at least 4 weeks and with no new lesions or progression of evaluable disease. All patients who crossed over to the alternative treatment as third-line therapy were included in the analysis.

Time to response was measured from the start of treatment (second or third line) to initial response, and the duration of response was measured from the time of documented response to the first sign of disease progression. The time to progression was measured from the time of first administration of therapy (second or third line) to documented progressive disease. Survival was measured from the time of first administration of therapy (second or third line) to death.

Blood samples were taken before each cycle of third-line therapy for full blood counts and biochemistry. Hematologic and nonhematologic toxicities were assessed by the common toxicity criteria.

Statistical Analysis
Objective response was compared between treatment groups using Pearson’s uncorrected ² statistic, and the estimated percentage difference in response rates between treatments was calculated with 95% confidence intervals. Data from patients who received alternative treatment could not be combined with those from patients who received randomized treatment as the study was not of a true cross-over design. Time- to-event variables (time to response, response duration, time to progression, and overall survival) were compared between treatments using the Cox regression model, and the results were presented as the hazard ratio, with a 95% confidence interval, for patients who received topotecan relative to those who received paclitaxel.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
A total of 226 patients received second-line therapy with topotecan or paclitaxel: 112 patients were randomized to receive topotecan, and 114 patients were randomized to receive paclitaxel. A total of 110 patients subsequently crossed over to the alternative drug as third-line therapy: 61 patients crossed over from paclitaxel to topotecan, and 49 patients crossed over from topotecan to paclitaxel. Demographic characteristics of patients in the randomized (second-line) and cross-over (third-line) phases of this study are listed in Table 1. There were no major differences in the demographic characteristics of the two groups of patients who crossed over at the third-line phase. There were differences, however, in the two groups’ potential chemoresponsiveness, as demonstrated in Table 2. This Table shows the best response to randomized second-line therapy for patients who crossed over to third-line treatment; the data suggest that patients who crossed over to topotecan were less likely to respond to further chemotherapy than were those who were treated at the third-line phase with paclitaxel. This was because the topotecan group contained fewer partial responders to second-line therapy (3% v 14%) and more patients with progressive disease (57% v 45%), although these differences were not statistically significant.

Response and Survival Results for Cross-Over (Third-Line) Therapy
Response to cross-over treatment is listed in Table 3. The overall response rate to topotecan after paclitaxel was 13% (8 of 61; all partial responses) and to paclitaxel after topotecan was 10% (5 of 49; 2 complete responses, 3 partial responses; P = .638). Seven of the eight patients who responded to topotecan as third-line treatment had disease that was refractory to second-line paclitaxel, three of whom had actually progressed on this treatment ( Table 4). Similarly, only one of the patients who responded to third-line paclitaxel had responded to second-line topotecan ( Table 5).

We also analyzed response to third-line treatment according to patients’ sensitivity to first-line platinum therapy. Only those patients who had a treatment-free interval of more than 6 months after completion of first-line platinum therapy responded to third-line topotecan, although four patients who relapsed within 6 months of their first-line platinum therapy responded to paclitaxel at the third-line phase. However, there were no responders to any third-line treatment in patients who had platinum-refractory disease (relapse within 4 months or no response or progressive disease to first-line therapy).

Toxicity to Cross-Over (Third-Line) Therapy
The 61 patients who were treated with topotecan received 270 courses of treatment, and the 49 patients who were treated with paclitaxel received 223 courses. Patients who were in the topotecan group received a median of 3 courses of treatment (range, 1 to 23), and those who were in the paclitaxel group received a median of 4 courses (range, 1 to 12). The planned dose was maintained in 95% of courses of topotecan and 94% of courses of paclitaxel. Hematologic toxicity caused dose delays of more than 7 days in only 1.4% of topotecan courses and in none of the paclitaxel courses.

The toxicity seen in patients who received cross-over treatment was similar to that recorded in the randomized study. The principal side effect was myelosuppression ( Table 6); grade 4 neutropenia occurred in a higher proportion of patients who received topotecan (81% patients, 39% courses) than paclitaxel (23% patients, 14% courses). Mean neutrophil nadirs were 0.9 x 10⁹/L (range, 0.0 to 6.2) in the topotecan group and 2.9 x 10⁹/L (range, 0.1 to 54.0) in the paclitaxel group. The incidence of grade 4 neutropenia in the topotecan group was highest during course 1 (59.3% patients) and decreased in subsequent courses with no apparent cumulative effects, although the use of G-CSF was permitted after course 1. The incidence of grade 4 neutropenia with paclitaxel was 10.4% during course 1 and remained relatively constant. Despite the high incidence of neutropenia, complications were not common; fever and infection (grade 2) associated with grade 4 neutropenia occurring in only 7.0% of topotecan courses (21% patients) and 4.0% of paclitaxel courses (16% patients), with sepsis occurring in an additional 1.1% of courses (5% patients) in the topotecan group. Prophylactic G-CSF was administered to 23% of patients (22% courses) in the topotecan group and 12% of patients (6% courses) in the paclitaxel group. Treatment with G-CSF was administered to 8% and 2% of patients (3% and 0% courses) in the topotecan and paclitaxel groups, respectively. Intravenous antibiotics were administered to 26% of patients in the topotecan group and 12% of patients in the paclitaxel group. Thirteen patients (21%) who received topotecan and one who received paclitaxel (2%) were hospitalized because of infection.

Nonhematologic toxicity associated with topotecan ( Table 7) generally was mild or moderate (grade 1/2) and consisted mainly of gastrointestinal disturbances. Nonhematologic toxicities associated with paclitaxel were consistent with the established profile of this drug. Nausea and vomiting were greater for topotecan patients, but patients who received paclitaxel were premedicated with dexamethasone, which may have reduced the incidence of nausea and vomiting. The incidences of arthralgia, myalgia, and paresthesia were greater with paclitaxel (37%, 33%, and 31%, respectively) than with topotecan (15%, 18%, and 8%, respectively).

Response and Survival Update of Randomized (Second-Line Therapy) Trial of Topotecan Versus Paclitaxel
We have updated the analysis of the data from the original randomized phase III study of second-line chemotherapy. The response rate was 20.5% for patients who were treated with topotecan compared with 14.0% for those who were treated with paclitaxel (P = .196). These figures are based on data of independent radiologic review of all responses. At this review, 15 claimed topotecan responses and 12 claimed paclitaxel responses were not confirmed. Thus, without independent verification of responses, the response rates would have been 34% and 25%, respectively. The median duration of response was 26 weeks (range, 7 to 84 weeks) and 22 weeks (range, 9 to 67 weeks) for topotecan and paclitaxel, respectively. The median time to progression for patients randomized to topotecan was 19 weeks (range, < 1 to 93 weeks) versus 15 weeks (range, <1 to 77 weeks) for those who were randomized to paclitaxel. The median survival was 63 weeks (range, <1 to 122 weeks) versus 53 weeks (range, <1 to 130 weeks) for topotecan and paclitaxel, respectively. None of these differences was statistically significant.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In the early 1990s, paclitaxel became the major second-line treatment for ovarian cancer and subsequently became established as standard first-line therapy in combination with a platinum compound.^1,22 The final results of the randomized phase III trial of topotecan versus paclitaxel show that topotecan is at least as active as paclitaxel as second-line treatment of epithelial ovarian cancer after platinum-based therapy. These updated findings therefore suggest that there is justification to explore the role of topotecan as part of a first-line treatment regimen.

The most important aspect of this report is the demonstration that topotecan and paclitaxel have a degree of non–cross-resistance. Patients who have disease that is "refractory" to topotecan or paclitaxel may respond to the other drug. It is striking that three patients who had progressive disease on second-line paclitaxel responded to topotecan and that two patients who were progressing on second-line topotecan responded to paclitaxel as third-line therapy. These data provide further rationale for investigating topotecan as part of first-line treatment, in combination with paclitaxel and platinum or as part of a non–cross-resistance alternating/sequential strategy. This lack of complete cross-resistance is perhaps not surprising, because paclitaxel resistance is due partly to the overexpression of p-glycoprotein²³ but p-glycoprotein overexpression does not seem to affect the cytotoxicity of camptothecin analogues such as topotecan.²⁴ Although patients who are platinum refractory (ie, progressive disease, no response, or relapse within 4 months) can respond to paclitaxel or topotecan as second-line therapy, we did not see responses to subsequent third-line therapy with the alternative drug in this population.

Neutropenia was the major hematologic toxicity associated with both third-line treatments, but it was more frequent and more severe with topotecan, although it was noncumulative and there were few clinically significant sequelae from hematologic toxicities when G-CSF was used. There was, however, one death associated with hematologic toxicity, although this was reported by the investigator as probably unrelated to treatment with topotecan. Nonhematologic toxicity with either agent generally was mild or moderate, not dose limiting, and a high percentage of patients received the planned dose.

A phase I study was carried out to evaluate the maximum tolerated doses of the combination of topotecan with paclitaxel, and doses of 0.75 and 135 mg/m², respectively, are recommended for phase II studies.²⁵ In a phase II study of patients with chemotherapy-naive advanced epithelial ovarian cancer, sequential couplets of treatment were investigated; cisplatin/topotecan was given for four cycles followed by cisplatin/paclitaxel for four cycles. In 20 evaluable patients, the response rate was 85%, and although myelotoxicity was severe, it was manageable and treatment was delivered successfully.²⁶ There are also preliminary data on an alternating regimen of carboplatin/topotecan and carboplatin/paclitaxel.²⁷ High-dose topotecan, carboplatin, and paclitaxel with progenitor cell support was also evaluated in a phase I study of patients with advanced disease that was previously untreated with chemotherapy.²⁸ Patients received two cycles of carboplatin/paclitaxel then three cycles of topotecan/paclitaxel/carboplatin; in 13 patients who had second surgery, 12 showed a response to treatment. Other sequential regimens using topotecan with paclitaxel and carboplatin are being developed for advanced ovarian cancer, eg, paclitaxel/carboplatin for a number of cycles followed by topotecan for additional cycles.^29,30 This sequential approach is being evaluated in a phase III study.

Paclitaxel combined with carboplatin is now standard first-line therapy in advanced epithelial ovarian cancer. However, the majority of patients still relapse and die from their disease, and there continues to be a need for more effective first-line therapies. In addition, treatments for recurrent ovarian cancer that is potentially non–cross-resistant to first-line therapy have an important role to play in the treatment of patients. Topotecan has a different mode of action from paclitaxel and has been shown to be active in the treatment of ovarian cancer after failure of initial therapy. The criteria on which new drug combinations are developed depend on a demonstration that compounds have different toxicity profiles, that they have different mechanisms of action, and, if possible, that clinical non–cross-resistance has been demonstrated. These three criteria are met when topotecan and paclitaxel are considered; thus, there is a good rationale for using these two drugs together in combination or sequentially in any new ovarian cancer regimen.

APPENDIX
The following individuals contributed to this study: Antonio Anton, MD, Paseo De Isabel La Catolica, Hospital Miguel Servet, Zaragoza, Spain; Thomas Bauknecht, MD, Universitäts-Frauenklinik, Freiburg, Germany; Jean Pierre Bergerat, MD, Hôpital Civil, Strasbourg, France; Laurent Cals, MD, Centre Hospitalier Intercommunal, Toulon, France; Jim Cassidy, MD, Department of Medicine and Therapeutics, Aberdeen Royal Infirmary, Aberdeen, UK; Francesco Cavalli, MD, Ospedale San Giovanni, Bellinzona, Switzerland; Stephen Chan, MD, Department of Clinical Oncology, Nottingham City Hospital, Nottingham, UK; Daniel Clarke-Pearson, MD, DUMC Morris Cancer Center, Durham, NC; Hervé Curé, MD, Centre

APPENDIX (Cont’d)
Jean Perrin, Clermont-Ferrant, France; Andreas Dubois, MD, St. Vincentius Krankenhauser, Karlsruhe, Germany; Peter Eisenberg, MD, Marin Oncology Associates, Greenbrae, CA; Helen Lloyd Frederickson, MD, Pharmatech, Inc., Denver, CO; Holly Gallion, MD, University of Kentucky, Department of OB/GYN, Lexington, KY; John Graham, MD, Bristol Oncology Centre, Bristol, UK; Jean Paul Guastalla, MD, Centre Léon Bérard, Lyon, France; Vincente Guillem, MD, Instituto Valenciano De Oncologia, Valencia, Spain; Steve Gwyther, MD, East Surrey Hospital, Redhill, UK; Don J. Hall, MD, Baptist Regional Cancer Center, Knoxville, TN; James Hall, MD, Cancer Center, Carolina’s Medical Center, Bristol, TN; Howard D. Homesley, MD, Bowman Gray School of Medicine, Section on Gynecologic Oncology, Bristol, TN; Faress Husseini, MD, Centre Hospitalier de Colmar, Colmar, France; Angel Jimenez-Lacave, MD, Hospital General De Asturias, Oviedo, Spain; Glen Justice, MD, Pacific Coast Hematology/Oncology Medical Group, Fountain Valley, CA; WooShin Kim, MD, Henry Ford Hospital, Detroit, MI; Henery Kitchener, MD, Aberdeen Royal Infirmary, Aberdeen, UK; Richard C. Kline, MD, Ochsner Cancer Institute, Alton Ochsner Medical Foundation, New Orleans, LA; Heinz Koelbl, MD, Universitäts Frauenklinik Wien, Wien, Austria; Laffargue, MD, Hôpital Arnaud de Villeneuve, Montpellier, France; Manfred Lahousen, MD, Gynaekologie, Universitätsklinik Graz, Graz, Austria; John R. Lurain, MD, Prentice Women’s Hospital, Chicago, IL; William McGuire, MD, The Emory Clinic, Medical Oncology Program, Atlanta, GA; Hervé Naman, MD, Clinique du Méridien, Cannes la Bocca, France; Jose J. Noy, MD, Pharm Research, Inc., Miami, FL; Gilles Prevot, MD, Centre Hospitalier de Mulhouse, Hôpital du Hasenrain, Mulhouse, France; Eric Pujade-Lauraine, MD, Hotel Dieu de Paris, Paris, France; R. Kevin Reynolds, MD, University of Michigan, Ann Arbor, MI; Dirk Johannes Richel, MD, Department of Internal Medicine, Medical Spectre Twente, Enschede, the Netherlands; Gordon Rustin, MD, Mount Vernon Hospital, Northwood, UK; John Savage, MD, United Hospital, St. Paul, MN; Pieter HTJ Slee, MD, Sint Antonius Ziekenhuis, Nieuwegein, the Netherlands; Bengt Sorbe, MD, Region Hospital, Orebro, Sweden; Paul Unger, MD, Oncology Associates, Inc., Colchester, VT; Michel Untereiner, MD, Hôpital Clinique Claude Bernard, Metz, France; Luis Vaccarello, MD, Ohio State University, Columbus, OH; Eugenio Vadora, MD, Obstetrics and Gynaecological Clinic, Parma University, Parma, Italy; and Allan T. Van Oosterom, MD, Dienst Oncologie, UIA, Edegem, Belgium.

	ACKNOWLEDGMENTS

 
Supported by a grant from SmithKline Beecham Pharmaceuticals.

	NOTES

 
S.Z.F. and G.R. are employees of SmithKline Beecham Pharmaceuticals.

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Submitted August 18, 2000; accepted December 19, 2000.

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