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A Phase II evaluation of weekly topotecan as a single agent second line therapy in persistent or recurrent carcinoma of the cervix: A Gynecologic Oncology Group study
Gynecologic Oncology 115 (2009) 285–289
Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o
A Phase II evaluation of weekly topotecan as a single agent second line therapy in persistent or recurrent carcinoma of the cervix: A Gynecologic Oncology Group study☆ James V. Fiorica a,⁎, John A. Blessing b, Louis V. Puneky c, Angeles Alvarez Secord d, James S. Hoffman e, S. Diane Yamada f, Thomas E. Buekers g, Jeffrey Bell h, Jeanne M. Schilder i a
Sarasota Memorial Hospital, 1888 Hillview Street, Sarasota, FL 34239, USA Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY, USA c University of Mississippi, Jackson, MS, USA d Duke University Medical Center, Durham, NC, USA e The Hospital of Central Connecticut, New Britain, CT, USA f University of Chicago Medical Center, Chicago, IL, USA g University of Iowa, Iowa City, IA, USA h Riverside Methodist Hospital, Columbus, OH, USA i Indiana University Medical Center, Indianapolis, IN, USA b
a r t i c l e
i n f o
Article history: Received 19 May 2009 Available online 2 September 2009 Keywords: Topotecan hydrochloride Advanced and recurrent cervical cancer
a b s t r a c t Purpose. To estimate antitumor activity and toxicity of weekly topotecan hydrochloride in patients with persistent or recurrent cervical carcinoma who failed prior treatment. Patients and methods. Women entered on study had or failed one prior chemotherapy regimen in addition to radiosensitizing chemotherapy, performance status less than 3, and adequate hematologic, renal, hepatic, and neurological function. Topotecan was infused at 3.0 mg/m2 on days 1, 8, and 15 every 28 days. Results. Twenty-seven patients were enrolled onto this study with 25 evaluable. Twenty-two patients had received radiation and chemotherapy prior to study. A median of two and mean of three courses of chemotherapy was given (range, one to eight courses). The most frequently severe adverse events were grade 3 anemia (28%) and grade 4 (4%) along with grade 3 neutropenia (8%) and grade 4 (8%). Two patients had grade 4 thrombocytopenia. There were no complete or partial responders. Ten patients (40%) had stable disease, twelve (48%) had increasing disease, and response could not be assessed in three (12%). The median progression-free survival was 2.4 months for the patients with increasing disease and 6.2 months (3.5–8.8 months) for those with stable disease. Disease location was equally divided within and outside the irradiated field. The 12 patients with increasing disease were more likely to have disease outside the pelvic radiation field. Conclusion. There were no complete or partial responders to weekly topotecan among the 25 patients in this study. © 2009 Elsevier Inc. All rights reserved.
Introduction
☆ This study was supported by the National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA27469) and the Gynecologic Oncology Group Statistical Office (CA37517). The following Gynecologic Oncology Group member institutions participated in this study: Duke University Medical Center, University of Mississippi, University of Cincinnati, University of Iowa Hospitals and Clinic, Indiana University Medical Center, University of California Medical Center at Irvine, Washington University School of Medicine, Columbus Cancer Council/Ohio State, University of Oklahoma, University of Chicago, Woman and Infants, the Hospitals of Central Connecticut at New Britain General and Bradley Memorial, and CCOP. ⁎ Corresponding author. Fax: +1 941 917 3980. E-mail address: james-fi[email protected] (J.V. Fiorica). 0090-8258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2009.07.024
The mortality rates for advanced and metastatic cervical cancer have not changed significantly over the past 25 years [1]. This disease remains the second most frequent cause of cancer-related death in the world [2]. There have been an estimated 11,070 cases and 3870 deaths in 2008 in the United States [3]. While advances have been made with initial treatment—dramatic improvements in survival with combination chemoradiotherapy for locally advanced disease—a similar advantage has not been achieved for those with recurrent disease. Similarly, recurrence following initial chemoradiotherapy is virtually always incurable, and those who present with widely metastatic disease rarely achieve remission, much less cure. Initial treatment for these patients includes combination platinum-based chemotherapy
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[3]. Until recently, single agent cisplatin was the standard of care for treating patients with recurrent or advanced cervical cancer, with response rates of 20–30% and median survival time of six to seven months [4]. Topotecan is an S-phase specific cytotoxic agent that binds to the topoisomerase I-DNA complex and prevents relegation of induced single strand breaks. The combination of cisplatin plus topotecan has recently been shown to improve overall survival (OS) from 6.5 to 9.4 months in a randomized Phase III trial conducted by the Gynecologic Oncology Group (GOG) [5]. This randomized trial dosed topotecan at 0.75 mg/m2 on days 1, 2, and 3 and cisplatin at 50 mg/m2 on day 1. There has been evidence in vitro that prolonged exposure to topotecan may not be necessary in order to produce superior cytotoxicity [6]. In ovarian cancer, topotecan has been used at 4 mg/m2 as a once weekly regimen with lower toxicity [7,8]. Weekly administration was proposed in this study because of the potential for improved patient acceptance, lower toxicity, and the possibility of combination with other weekly agents. The purpose of this current Phase II trial was to evaluate weekly topotecan as a salvage agent in women with recurrent disease who failed primary therapy and also failed first line chemotherapy with recurrent disease. Patients with cancers of the cervix were evaluated for toxicity and response. Materials and methods This multicenter GOG study was approved by the National Cancer Institute and the Institutional Review Board of each participating institution. Written informed consent conforming to all federal, state, and local regulations was obtained from all patients prior to receiving protocol therapy. Patients were registered through the GOG Statistical and Data Center. Patients with recurrent or persistent squamous cell or other carcinomas of the cervix were eligible for this Phase II GOG study. Patients had to be recovered from the effects of recent surgery, radiotherapy, or chemotherapy prior to entry on the study. Patients must have had one prior systemic chemotherapeutic regimen. Chemotherapy administered in conjunction with primary radiation as a radiosensitizer was not considered as a systemic regimen. Patients may have received one additional non-cytotoxic (biologic or cytostatic) regimen including monoclonal antibodies, cytokines, or small-molecule inhibitors. Patients were required to have measurable disease, defined as at least one lesion ≥ 20 mm when measured by conventional techniques (palpation, plain x-ray, CT and MRI) or ≥10 mm when measured in one direction by spiral CT. Target lesions were used to assess response. Tumors within the previously irradiated field were designated as “non-target” unless progression was documented or a biopsy confirmed persistence at least 90 days following completion of radiation therapy. Those patients with concomitant or previous malignancies (except non-melanoma skin carcinoma) were excluded. Pre-treatment laboratory eligibility requirements included the following: absolute neutrophil count (ANC) ≥ 1500/mcl, platelet count ≥ 100,000/mcl, bilirubin and creatinine b 1.5 times institutional upper limit of normal, SGOT and alkaline phosphatase b 2.5 times institutional upper limit of normal. Pre-treatment evaluation included physical examination, assessment of performance status, measurement of the indicator lesion(s), serum electrolytes, renal and hepatic function, complete blood count, and chest radiograph. If CT scan or MRI was used for identifying measurable disease, it was done at entry and repeated every other cycle for six months, then every six months thereafter. Topotecan hydrochloride was administered at a dose of 3.0 mg/m2 as an IV infusion over 30 min. This dose was repeated every seven days for 21 days followed by a seven-day recovery period. A cycle was defined as a 28-day period. The maximum body surface area for dose
calculation was 2.0 m2. Patients were to receive therapy until disease progression or unacceptable toxicity occurred. The dose of topotecan was reduced to 2.5 mg/m2 (one level) or 2.0 mg/m2 (2 levels) based on hematological and other criteria described in the protocol. Patients did not receive prophylactic growth factors unless they experienced recurrent hematological complications after dose reduction. Erythropoietin was administered only after documented hemoglobin was less than 10.0 g/dl. Amifostine and other protective reagents were not allowed for this study. The pre-treatment evaluation was repeated every 28 days with the exception of the chest radiograph and radiologic tumor measurements which were done every other cycle. A complete blood count (CBC) with differential and platelets was obtained weekly. Response to therapy was defined by standard GOG RECIST Criteria utilizing measurable disease, documentation of target and non-target lesions, and best response (complete response, partial response, stable disease, and increasing disease). Patients in whom response could not be assessed were included in response rate determination. Increasing disease was defined as a 20% or greater increase in the sum of the longest dimensions or the appearance of a new lesion within 8 weeks of study entry. If the only target lesion was nonradiologically measurable, a 50% increase in the longest diameter was required. The study employed a two-stage accrual design with an early stopping rule in the event that the treatment demonstrated insufficient activity [9]. During the first stage of accrual, 22–29 patients were to be entered and evaluated. If at least four responses were observed among the first 22–24 patients, or at least five responses out of 25–29 patients, a second phase of accrual was to be initiated which would increase accrual to 53–60 patients. The regimen would be considered active if at least 11 responses were observed among 53 patients, or at least 12 responses were observed among 54–57 patients, or at least 13 responses were observed among 58–60 patients. If the true response rate was 15%, the average probability of designating the treatment as active was limited to 10%. Conversely, if the true response rate was 30%, then the probability of correctly classifying the treatment as active is 90%. Results Twenty-seven patients were enrolled onto the study. Two patients were excluded; one was deemed ineligible (wrong disease site) and one patient was inevaluable (never treated), leaving 25 patients evaluable. All patients received prior first line chemotherapy and twenty-two patients (88%) received pelvic radiation and concurrent chemotherapy in addition to their first line chemotherapy, prior to enrollment into this study. The radiosensitizing chemotherapy was Cisplatin alone in 17 patients, Cisplatin/fluorouracil in one patient, and Cisplatin with gemcitabine in two patients. The amount of sensitizing chemotherapy varied with one patient receiving 10 cycles of cisplatin. In three patients, response could not be determined due to incomplete follow-up assessments. The progression-free interval prior to enrollment was 29.7 months (7–84) in patients with stable disease and 16.7 months (2–80) in the patients with progressive disease. The patient characteristics are listed in Table 1. The mean age was 50 years (range: 28 to 68 years). The first line chemotherapy regimens included cisplatin/paclitaxel (6); cisplatin/vinorelbine (GOG204) (5); carboplatin with paclitaxel (4); cisplatin/gemcitabine (3); cisplatin/cetuximab (2); carboplatin/etoposide (1); carboplatin/ fluorouracil (1); cisplatin/nalvalbine (1); paclitaxel alone (1); and carboplatin alone (1). The duration of prior chemotherapy ranged from 1 to 11 cycles. A total of 75 courses of topotecan chemotherapy were given in the current study (mean, 3.0 courses; range, one to eight courses). The toxicities that occurred during therapy are listed in Table 2. Anemia
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and neutropenia were the most frequently severe adverse events. Grade 3 anemia was seen in 28% and grade 4 in 4% of the 25 patients evaluable for toxicity. Grade 3 neutropenia occurred in 8% and grade 4 in 8% of patients. Grade 3 leukopenia occurred in five patients and grade 4 in one. The median WBC count nadir was 2400 for those 19 patients experiencing leukopenia (20% grade 3 and 4% grade 4). No grade 3 thrombocytopenia was observed and grade 4 thrombocytopenia occurred in two patients (8%). Grade 3 infection occurred in three patients and no grade 4 infections were seen. There were no treatment-related deaths on this trial. The incidence of nonhematologic toxicity was minimal. Gastrointestinal toxicity included nausea and vomiting (grade 3) in one patient (4%) and three patients experienced grade 3 “other” gastrointestinal effect and no grade 4 gastrointestinal toxicity was reported. Other less common grade 3 or 4 non-hematologic toxicity included neurotoxicity (n = 1), pain (n = 1), constitutional (G3 = 3, G4 = 2), vascular (n = 10), and lymphatics (n = 1). One patient required a dose reduction to 2.5 mg/m2 due to elevated creatinine and hydronephrosis, and was subsequently removed from trial after one cycle of chemotherapy. The remaining 24 patients continued at the starting dose throughout the trial. None of the 25 patients responded to the treatment. Ten patients (40%) had stable disease with a median progression-free survival (PFS) of 6.2 months (3.5–8.8 months). The measurable disease location was equally divided within the irradiated field and outside the irradiated field in the 10 stable disease patients (4 within field, 4 outside, and 2 both locations). Twelve patients (48%) had increasing disease; these patients were more likely to have disease outside the pelvic irradiated region. In three patients, response could not be assessed due to lack of follow-up. The median PFS for the entire group was 2.4 months (−6 days −8.5 months).
Table 1 Characteristics of patients assessable for response. Characteristic Age b 40 40–49 50–59 60–69 Performance status 0 1 2 Race White Black Asian Unknown Grade 1 2 3 Histology Squamous cell Adenocarcinoma Adenosquamous Mucinous Prior chemotherapy Prior radiotherapy Courses of chemotherapy 1 2 3 4 N4 Site of target lesion Pelvis Outside pelvis Both
Number of cases (n = 25) 4 10 8 3 14 8 3 18 5 1 1 3 11 11 16 5 3 1 25 22 5 12 2 1 5 5 20 N/A
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Table 2 Adverse effects. Adverse effects Leukopenia Thrombocytopenia Neutropenia Transfusions Anemia Hemorrhage Nausea/Vomiting Other gastrointestinal Genito urinary Neurotoxicity Pain Pulmonary Infection Constitutional Metabolic Dermatologic Alopecia Renal Alkaline phosphatase Vascular Lymphatics Lymphopenia
Grade (number of patients) 0
1
2
3
4
Total
6 16 9 24 1 24 13 12 22 19 19 24 22 8 22 22 17 21 23 24 24 24
4 4 8 0 4 1 7 4 2 3 4 0 0 5 2 3 7 3 2 0 0 0
9 3 4 0 12 0 4 6 1 2 1 0 0 7 1 0 1 1 0 0 0 1
5 0 2 1 7 0 1 3 0 0 0 1 3 3 0 0 0 0 0 1 1 0
1 2 2 0 1 0 0 0 0 1 1 0 0 2 0 0 0 0 0 0 0 0
25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25
No treatment-related deaths have been reported.
Discussion Recurrent cervical cancer is generally considered an incurable disease. Multiple clinical Phase II trials have been conducted in an attempt to improve response and median PFS and OS. However, response rates with current chemotherapy regimens are commonly in the range of 18–38%. Time to progression is less than three months, and median survival is less than seven months [10–12]. Until recently, single agent cisplatin has been the standard treatment of choice for metastatic cervical cancer. Other agents have been tried, but often toxicity limits the usefulness in these heavily pretreated and often previously irradiated patients. There is clearly a need to quantify and improve the acute and chronic toxicities, particularly since the response rates are often short with recurrent disease. Anemia is known to have an adverse effect on tolerance of treatment and on quality of life. Concomitant platinum-based chemotherapy with radiation is the gold standard for locally advanced cervical cancer and is often used either as a single agent or in combination for patients with recurrent disease. Cisplatin is the most widely used radiosensitizing agent and can contribute to long term renal compromise, limiting many future treatment options in heavily pretreated patients. Anti-tumor activity of topotecan against cervical cancer was first reported by Noda. Topotecan was given at 1.2 mg/m2 on days 1–5 of a 21-day course. The dose-limiting toxicity was myelosuppression with 33% grade 4 leukopenia and 25% grade 4 anemia reported in the previously treated patients [13]. Similar findings were reported by Abu-Rustum and Muderspach with myelosuppressive dose- limiting toxicity at doses of 1.0 mg/m2 on days 1–5 and 1.5 mg/m2 on days 1–5 of a 21-day cycle despite favorable response rates [14,15]. The GOG performed a confirmatory Phase II trial where 40 evaluable patients received one prior chemotherapy regimen at a topotecan dose of 1.5 mg/m2 on days 1–5 of a 21-day cycle. The overall response rate was 13%; 38% had stable disease. The progression-free interval was 2.1 months with an overall survival period of 6.6 months in the patients previously treated with one cycle of chemotherapy. Despite the favorable response and stable disease statistics, the dose-limiting toxicity was again myelosuppression, specifically grade 4 neutropenia (68%), and thrombocytopenia (39%) [16]. Based on Rowinsky's Phase I study combining dose topotecan with cisplatin, a Phase II trial was conducted in Florida where cisplatin 50 mg/m2/day 1 was combined with topotecan 0.75 mg/m2 on days
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Table 3 Response. Response Stable disease Increasing disease Unknown
Cases Number
Percent
10 12 3
40.0 48.0 12.0
1–3 on a 21-day cycle for first relapsed cervical cancer [17]. Nine of 32 evaluable patients (28%) responded and nine additional patients (28%) achieved stable disease with a median survival of 10 months. The frequency of neutropenia and thrombocytopenia was 30% and 10% respectively in a relatively chemo-naive group of patients [18]. GOG conducted a confirmatory Phase III randomized clinical trial comparing combination cisplatin and topotecan in the three-day regimen to either cisplatin alone, or a combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) in cervical cancer patients at the time of first recurrence. The MVAC arm was closed after four treatment-related deaths occurred among the 63 patients on trial. The other two treatment arms continued and a total of 294 patients were enrolled receiving either cisplatin alone or in combination with topotecan. Patients receiving cisplatin with topotecan (CT) had a statistically superior outcome with an OS of 9.4 versus 6.5 months (p = .017), a superior median PFS of 4.6 versus 2.9 months (p = .014), and a response rate of 27% versus 13% with cisplatin alone [5]. However, patients on the CT arm experienced an increase in hematologic toxicity, including substantial neutropenia (70%) as well as 18% febrile neutropenia. Quality of life became a critical concern due to the differences in toxicity profiles. Fortunately, there was no significant decrease in quality of life up to nine months after randomization to the trial, demonstrating that the combination of CT, although substantially more toxic, could achieve an improved survival without significantly impairing the patient's overall quality of life [19]. In this study, it was hypothesized that weekly topotecan may offer an improved toxicity profile for these pretreated patients with cervical cancer. A Phase I trial by Homesley and a Phase II trial by Morris using weekly topotecan for recurrent ovarian cancer demonstrated only rare hematologic side effects [20,21]. In this current trial, topotecan was administered weekly at a dose of 3.0 mg/m2 every 28 days in an attempt to diminish the hematologic toxicity seen with a five consecutive day regimen. Twenty-five patients were evaluated for toxicity in this multicenter trial conducted by the GOG. We included
patients with measurable disease who failed their initial treatment (surgery and/or radiation therapy with concomitant chemotherapy sensitizers) and failed subsequent systemic chemotherapy. We were able to administer chemotherapy on an outpatient basis, with only one patient requiring a dose reduction. All other patients were treated with a full dose without treatment delays for a total of 75 chemotherapy courses. Anemia occurred in 32% of patients (seven patients with grade 3 and one patient with grade 4). Neutropenia was seen in 16% of patients (two patients with grade 3 and two patients with grade 4). This included 22 patients who received previous chemo-irradiation prior to their other first line chemotherapy regimen. Filgrastim was not necessary in any of the 25 patients. Only one patient experienced grade 4 neurotoxicity; she had a cerebral vascular accident and was taken off study after three courses of chemotherapy. One patient developed an inferior vena caval thrombosis and was taken off study after three cycles of chemotherapy. Forty percent (n = 10) of patients had stable disease with a mean time of 5.25 months. However, stable disease was not the primary endpoint of this study. Twelve patients (48%) had increasing disease (Table 3). Four of these patients with new lesions were discovered within six weeks of study enrollment. Patients with increasing disease received a mean of 1.75 cycles of chemotherapy (range 1–2) before being taken off study. Two additional patients were taken off the trial for global deterioration. One patient elected to receive palliative care and declined further therapy after only one cycle of topotecan and the other was enrolled while in the hospital and died after a five week protracted hospital course. There were no responders to weekly topotecan among the 25 patients in this study. This lack of response included 22 patients with prior radiation and 20 with chemosensitizing radiation treatment. According to GOG response criteria four responses were required to initiate a second phase of accrual. This criteria was not met. Therefore, there is no evidence based rationale to recommend this therapy in this patient population as topotecan is not an active drug as a single agent as defined by the GOG. Other combinations are being evaluated by the GOG. In GOG 169 (Table 4), cisplatin was compared to cisplatin together with paclitaxel in first relapse cervical cancer. The combination chemotherapy arm achieved a superior response (36% versus 19%) and median PFS (4.8 versus 2.8 months) [22]. GOG 204 (Table 4) is a randomized 4-arm trial attempting to find the best drug combination for advanced and recurrent cervical cancer evaluating both response and quality of life. In GOG 179 (Table 4), an improved OS from 6.5 to 9.4 months was observed when topotecan was
Table 4 Schematic of GOG 179, 169, and 204. GOG 179 Randomize Regimen I Cisplatin 50 mg/m2 IV Courses repeated every 3 weeks × 6
Regimen II Topotecan 0.75 mg/m2 IV over 30 min days 1, 2, and 3 Cisplatin 50 mg/m2 IV day 1 Courses repeated every 3 weeks × 6
GOG 169 Randomize Regimen I Cisplatin 50 mg/m2 IV courses repeated every 3 weeks × 6
Regimen II Paclitaxel 135 mg/m2 IV over 24 h Cisplatin 50 mg/m2 IV courses repeated every 3 weeks × 6
GOG 204 Randomize Regimen I Paclitaxel 135 mg/m2 IV over 24 h and cisplatin 50 mg/m2 IV day 2 cycles repeated q 3 weeks × 6 Regimen III Gemcitabine 1000 mg/m2 IV days 1 and 8 and cisplatin 50 mg/m2 IV day 1 cycles repeated q 3 weeks × 6
Regimen II Vinorelbine 30 mg/m2 IV days 1 and 8 and cisplatin 50 mg/m2 IV day 1 repeated q 3 weeks × 6 Regimen IV Topotecan 0.75 mg/m2 IV over 30 min days 1, 2, and 3 and cisplatin 50 mg/m2 IV day 1 cycles repeated q 3 weeks × 6
Regimen III (Closed to patient entry 7/23/2001) Methotrexate 30 mg/m2 m2 Vinblastine 3 mg/m2 m2 Doxorubicin 30 mg/m2 m2 Cisplatin 70 mg/m2
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administered for three consecutive days together with cisplatin, compared to cisplatin alone. As a result of this study, there appears to be no activity for topotecan in the treatment of recurrent cervical cancer as a second line agent using this schedule. Conflict of interest statement Drs. James Fiorica and Angeles Alvarez Secord are both on the GlaxoSmithKline Speaker's Bureau.
References [1] Fiorica JV. The role of topotecan in the treatment of advanced cervical cancer. Gynecol Oncol 2003;90:S16–21. [2] Saslow D, Castle PE, Cox T, Davey DD, Einstein MH, Ferris DG, et al. American Cancer Society guidelines for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin 2007;57:7–28. [3] Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics 2008. CA Cancer J Clin 2008;58:71–96. [4] Berek JS, Hacker NF. Practical gynecologic oncology US.4. Philadelphia, PA: Lippincott Williams and Wilkins; 2005. p. 385–6. [5] Long HJ, Bundy BN, Grendys EC, Benda JA, McMeekin DS, Sorosky J, et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group study. J Clin Oncol 2005;23:4626–33. [6] Bence AK, Mattingly CA, Burke TG, Adams VR. The effect of DB-67, a lipophilic camptothecin derivative, on topoisomerase I levels in non-small cell lung cancer cells. Cancer Chemother Pharmacol 2004;54:354–60. [7] Safra T, Menczar J, Bernstein R, Shpigel S, Inbar MJ, Grisaru D, et al. Efficacy and toxicity of weekly topotecan in recurrent epithelial ovarian and primary peritoneal cancer. Gynecol Oncol 2007;105:205–10. [8] Morris R, Munkarah A. Alternate dosing schedules for topotecan in the treatment of recurrent ovarian cancer. Oncologist 2002;7:29–35. [9] Chen TT, Ng TH. Optimal flexible designs in phase II clinical trials. Stat Med 1998; 17:2301–12.
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[10] Thigpen JT, Shingleton H, Homesley H, Lagasse L, Blessing J. Cis-platinum in treatment of advanced or recurrent squamous carcinoma of the cervix to cisplatin. Cancer 1981;48:899–903. [11] Long HJ. Management of metastatic cervical cancer: review of the literature. J Clin Oncol 2007;25:2966–74. [12] Bonomi P, Blessing JA, Stehman FB, DiSaia PJ, Walton L, Major FJ. Randomized trial of three cisplatin dose schedules in squamous cell carcinoma of the cervix. A Gynecologic Oncology Group study. J Clin Oncol 1985;3:1079–85. [13] Noda K, Sasaki H, Yamamoto T, et al. Phase II trial of topotecan for cervical cancer of uterus (abstract 754). Proc Am Soc Clin Oncol 1996;15:280. [14] Abu-Rustum NR, Lee S, Massad LS. Topotecan for recurrent cervical cancer after platinum-based therapy. Int J Gynecol Cancer 2000;10:285–8. [15] Muderspach LI, Blessing JA, Levenback C, Moore Jr JL. Phase II study of topotecan in patients with squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol 2001;81:213–5. [16] Bookman MA, Blessing JA, Hanjani P. Topotecan in squamous cell carcinoma of the cervix: a Phase II study of the Gynecologic Oncology Group. Gynecol Oncol 2000; 77:446–9. [17] Rowinsky EK, Verweij J. Review of phase I clinical studies with topotecan. Semin Oncol 1997;24 S20-3–S20-10. [18] Fiorica JV, Holloway R, Ndubisi B, Orr J, Grendys E, Boothby R, et al. Phase II trial of topotecan and cisplatin in persistent or recurrent squamous and non squamous carcinoma of the cervix. Gynecol Oncol 2002;85:89–94. [19] Monk BJ, Huang H, Cella D, Long III HJ. Quality of life outcomes from a randomized phase III trial of cisplatin with or without topotecan in advanced carcinoma of the cervix, a Gynecologic Oncology Group study. J Clin Oncol 2005;23:4617–25. [20] Homesley HD, Hall DJ, Martin DA, Lewandowski GS, Vaccarello L, Nahhas Wam A, et al. A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients. Gynecol Oncol 2001;83:394–9. [21] Morris R, Munkarah A. Alternating dosing schedules for topotecan in the treatment of recurrent ovarian cancer. Oncologist 2002;7(Suppl 5):29–35. [22] Moore D, Blessing J, McQuellon R, Thaler H, Cella D, Benda J, et al. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Clin Oncol 2004;22:3113–9.
Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o
A Phase II evaluation of weekly topotecan as a single agent second line therapy in persistent or recurrent carcinoma of the cervix: A Gynecologic Oncology Group study☆ James V. Fiorica a,⁎, John A. Blessing b, Louis V. Puneky c, Angeles Alvarez Secord d, James S. Hoffman e, S. Diane Yamada f, Thomas E. Buekers g, Jeffrey Bell h, Jeanne M. Schilder i a
Sarasota Memorial Hospital, 1888 Hillview Street, Sarasota, FL 34239, USA Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY, USA c University of Mississippi, Jackson, MS, USA d Duke University Medical Center, Durham, NC, USA e The Hospital of Central Connecticut, New Britain, CT, USA f University of Chicago Medical Center, Chicago, IL, USA g University of Iowa, Iowa City, IA, USA h Riverside Methodist Hospital, Columbus, OH, USA i Indiana University Medical Center, Indianapolis, IN, USA b
a r t i c l e
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Article history: Received 19 May 2009 Available online 2 September 2009 Keywords: Topotecan hydrochloride Advanced and recurrent cervical cancer
a b s t r a c t Purpose. To estimate antitumor activity and toxicity of weekly topotecan hydrochloride in patients with persistent or recurrent cervical carcinoma who failed prior treatment. Patients and methods. Women entered on study had or failed one prior chemotherapy regimen in addition to radiosensitizing chemotherapy, performance status less than 3, and adequate hematologic, renal, hepatic, and neurological function. Topotecan was infused at 3.0 mg/m2 on days 1, 8, and 15 every 28 days. Results. Twenty-seven patients were enrolled onto this study with 25 evaluable. Twenty-two patients had received radiation and chemotherapy prior to study. A median of two and mean of three courses of chemotherapy was given (range, one to eight courses). The most frequently severe adverse events were grade 3 anemia (28%) and grade 4 (4%) along with grade 3 neutropenia (8%) and grade 4 (8%). Two patients had grade 4 thrombocytopenia. There were no complete or partial responders. Ten patients (40%) had stable disease, twelve (48%) had increasing disease, and response could not be assessed in three (12%). The median progression-free survival was 2.4 months for the patients with increasing disease and 6.2 months (3.5–8.8 months) for those with stable disease. Disease location was equally divided within and outside the irradiated field. The 12 patients with increasing disease were more likely to have disease outside the pelvic radiation field. Conclusion. There were no complete or partial responders to weekly topotecan among the 25 patients in this study. © 2009 Elsevier Inc. All rights reserved.
Introduction
☆ This study was supported by the National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA27469) and the Gynecologic Oncology Group Statistical Office (CA37517). The following Gynecologic Oncology Group member institutions participated in this study: Duke University Medical Center, University of Mississippi, University of Cincinnati, University of Iowa Hospitals and Clinic, Indiana University Medical Center, University of California Medical Center at Irvine, Washington University School of Medicine, Columbus Cancer Council/Ohio State, University of Oklahoma, University of Chicago, Woman and Infants, the Hospitals of Central Connecticut at New Britain General and Bradley Memorial, and CCOP. ⁎ Corresponding author. Fax: +1 941 917 3980. E-mail address: james-fi[email protected] (J.V. Fiorica). 0090-8258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2009.07.024
The mortality rates for advanced and metastatic cervical cancer have not changed significantly over the past 25 years [1]. This disease remains the second most frequent cause of cancer-related death in the world [2]. There have been an estimated 11,070 cases and 3870 deaths in 2008 in the United States [3]. While advances have been made with initial treatment—dramatic improvements in survival with combination chemoradiotherapy for locally advanced disease—a similar advantage has not been achieved for those with recurrent disease. Similarly, recurrence following initial chemoradiotherapy is virtually always incurable, and those who present with widely metastatic disease rarely achieve remission, much less cure. Initial treatment for these patients includes combination platinum-based chemotherapy
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[3]. Until recently, single agent cisplatin was the standard of care for treating patients with recurrent or advanced cervical cancer, with response rates of 20–30% and median survival time of six to seven months [4]. Topotecan is an S-phase specific cytotoxic agent that binds to the topoisomerase I-DNA complex and prevents relegation of induced single strand breaks. The combination of cisplatin plus topotecan has recently been shown to improve overall survival (OS) from 6.5 to 9.4 months in a randomized Phase III trial conducted by the Gynecologic Oncology Group (GOG) [5]. This randomized trial dosed topotecan at 0.75 mg/m2 on days 1, 2, and 3 and cisplatin at 50 mg/m2 on day 1. There has been evidence in vitro that prolonged exposure to topotecan may not be necessary in order to produce superior cytotoxicity [6]. In ovarian cancer, topotecan has been used at 4 mg/m2 as a once weekly regimen with lower toxicity [7,8]. Weekly administration was proposed in this study because of the potential for improved patient acceptance, lower toxicity, and the possibility of combination with other weekly agents. The purpose of this current Phase II trial was to evaluate weekly topotecan as a salvage agent in women with recurrent disease who failed primary therapy and also failed first line chemotherapy with recurrent disease. Patients with cancers of the cervix were evaluated for toxicity and response. Materials and methods This multicenter GOG study was approved by the National Cancer Institute and the Institutional Review Board of each participating institution. Written informed consent conforming to all federal, state, and local regulations was obtained from all patients prior to receiving protocol therapy. Patients were registered through the GOG Statistical and Data Center. Patients with recurrent or persistent squamous cell or other carcinomas of the cervix were eligible for this Phase II GOG study. Patients had to be recovered from the effects of recent surgery, radiotherapy, or chemotherapy prior to entry on the study. Patients must have had one prior systemic chemotherapeutic regimen. Chemotherapy administered in conjunction with primary radiation as a radiosensitizer was not considered as a systemic regimen. Patients may have received one additional non-cytotoxic (biologic or cytostatic) regimen including monoclonal antibodies, cytokines, or small-molecule inhibitors. Patients were required to have measurable disease, defined as at least one lesion ≥ 20 mm when measured by conventional techniques (palpation, plain x-ray, CT and MRI) or ≥10 mm when measured in one direction by spiral CT. Target lesions were used to assess response. Tumors within the previously irradiated field were designated as “non-target” unless progression was documented or a biopsy confirmed persistence at least 90 days following completion of radiation therapy. Those patients with concomitant or previous malignancies (except non-melanoma skin carcinoma) were excluded. Pre-treatment laboratory eligibility requirements included the following: absolute neutrophil count (ANC) ≥ 1500/mcl, platelet count ≥ 100,000/mcl, bilirubin and creatinine b 1.5 times institutional upper limit of normal, SGOT and alkaline phosphatase b 2.5 times institutional upper limit of normal. Pre-treatment evaluation included physical examination, assessment of performance status, measurement of the indicator lesion(s), serum electrolytes, renal and hepatic function, complete blood count, and chest radiograph. If CT scan or MRI was used for identifying measurable disease, it was done at entry and repeated every other cycle for six months, then every six months thereafter. Topotecan hydrochloride was administered at a dose of 3.0 mg/m2 as an IV infusion over 30 min. This dose was repeated every seven days for 21 days followed by a seven-day recovery period. A cycle was defined as a 28-day period. The maximum body surface area for dose
calculation was 2.0 m2. Patients were to receive therapy until disease progression or unacceptable toxicity occurred. The dose of topotecan was reduced to 2.5 mg/m2 (one level) or 2.0 mg/m2 (2 levels) based on hematological and other criteria described in the protocol. Patients did not receive prophylactic growth factors unless they experienced recurrent hematological complications after dose reduction. Erythropoietin was administered only after documented hemoglobin was less than 10.0 g/dl. Amifostine and other protective reagents were not allowed for this study. The pre-treatment evaluation was repeated every 28 days with the exception of the chest radiograph and radiologic tumor measurements which were done every other cycle. A complete blood count (CBC) with differential and platelets was obtained weekly. Response to therapy was defined by standard GOG RECIST Criteria utilizing measurable disease, documentation of target and non-target lesions, and best response (complete response, partial response, stable disease, and increasing disease). Patients in whom response could not be assessed were included in response rate determination. Increasing disease was defined as a 20% or greater increase in the sum of the longest dimensions or the appearance of a new lesion within 8 weeks of study entry. If the only target lesion was nonradiologically measurable, a 50% increase in the longest diameter was required. The study employed a two-stage accrual design with an early stopping rule in the event that the treatment demonstrated insufficient activity [9]. During the first stage of accrual, 22–29 patients were to be entered and evaluated. If at least four responses were observed among the first 22–24 patients, or at least five responses out of 25–29 patients, a second phase of accrual was to be initiated which would increase accrual to 53–60 patients. The regimen would be considered active if at least 11 responses were observed among 53 patients, or at least 12 responses were observed among 54–57 patients, or at least 13 responses were observed among 58–60 patients. If the true response rate was 15%, the average probability of designating the treatment as active was limited to 10%. Conversely, if the true response rate was 30%, then the probability of correctly classifying the treatment as active is 90%. Results Twenty-seven patients were enrolled onto the study. Two patients were excluded; one was deemed ineligible (wrong disease site) and one patient was inevaluable (never treated), leaving 25 patients evaluable. All patients received prior first line chemotherapy and twenty-two patients (88%) received pelvic radiation and concurrent chemotherapy in addition to their first line chemotherapy, prior to enrollment into this study. The radiosensitizing chemotherapy was Cisplatin alone in 17 patients, Cisplatin/fluorouracil in one patient, and Cisplatin with gemcitabine in two patients. The amount of sensitizing chemotherapy varied with one patient receiving 10 cycles of cisplatin. In three patients, response could not be determined due to incomplete follow-up assessments. The progression-free interval prior to enrollment was 29.7 months (7–84) in patients with stable disease and 16.7 months (2–80) in the patients with progressive disease. The patient characteristics are listed in Table 1. The mean age was 50 years (range: 28 to 68 years). The first line chemotherapy regimens included cisplatin/paclitaxel (6); cisplatin/vinorelbine (GOG204) (5); carboplatin with paclitaxel (4); cisplatin/gemcitabine (3); cisplatin/cetuximab (2); carboplatin/etoposide (1); carboplatin/ fluorouracil (1); cisplatin/nalvalbine (1); paclitaxel alone (1); and carboplatin alone (1). The duration of prior chemotherapy ranged from 1 to 11 cycles. A total of 75 courses of topotecan chemotherapy were given in the current study (mean, 3.0 courses; range, one to eight courses). The toxicities that occurred during therapy are listed in Table 2. Anemia
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and neutropenia were the most frequently severe adverse events. Grade 3 anemia was seen in 28% and grade 4 in 4% of the 25 patients evaluable for toxicity. Grade 3 neutropenia occurred in 8% and grade 4 in 8% of patients. Grade 3 leukopenia occurred in five patients and grade 4 in one. The median WBC count nadir was 2400 for those 19 patients experiencing leukopenia (20% grade 3 and 4% grade 4). No grade 3 thrombocytopenia was observed and grade 4 thrombocytopenia occurred in two patients (8%). Grade 3 infection occurred in three patients and no grade 4 infections were seen. There were no treatment-related deaths on this trial. The incidence of nonhematologic toxicity was minimal. Gastrointestinal toxicity included nausea and vomiting (grade 3) in one patient (4%) and three patients experienced grade 3 “other” gastrointestinal effect and no grade 4 gastrointestinal toxicity was reported. Other less common grade 3 or 4 non-hematologic toxicity included neurotoxicity (n = 1), pain (n = 1), constitutional (G3 = 3, G4 = 2), vascular (n = 10), and lymphatics (n = 1). One patient required a dose reduction to 2.5 mg/m2 due to elevated creatinine and hydronephrosis, and was subsequently removed from trial after one cycle of chemotherapy. The remaining 24 patients continued at the starting dose throughout the trial. None of the 25 patients responded to the treatment. Ten patients (40%) had stable disease with a median progression-free survival (PFS) of 6.2 months (3.5–8.8 months). The measurable disease location was equally divided within the irradiated field and outside the irradiated field in the 10 stable disease patients (4 within field, 4 outside, and 2 both locations). Twelve patients (48%) had increasing disease; these patients were more likely to have disease outside the pelvic irradiated region. In three patients, response could not be assessed due to lack of follow-up. The median PFS for the entire group was 2.4 months (−6 days −8.5 months).
Table 1 Characteristics of patients assessable for response. Characteristic Age b 40 40–49 50–59 60–69 Performance status 0 1 2 Race White Black Asian Unknown Grade 1 2 3 Histology Squamous cell Adenocarcinoma Adenosquamous Mucinous Prior chemotherapy Prior radiotherapy Courses of chemotherapy 1 2 3 4 N4 Site of target lesion Pelvis Outside pelvis Both
Number of cases (n = 25) 4 10 8 3 14 8 3 18 5 1 1 3 11 11 16 5 3 1 25 22 5 12 2 1 5 5 20 N/A
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Table 2 Adverse effects. Adverse effects Leukopenia Thrombocytopenia Neutropenia Transfusions Anemia Hemorrhage Nausea/Vomiting Other gastrointestinal Genito urinary Neurotoxicity Pain Pulmonary Infection Constitutional Metabolic Dermatologic Alopecia Renal Alkaline phosphatase Vascular Lymphatics Lymphopenia
Grade (number of patients) 0
1
2
3
4
Total
6 16 9 24 1 24 13 12 22 19 19 24 22 8 22 22 17 21 23 24 24 24
4 4 8 0 4 1 7 4 2 3 4 0 0 5 2 3 7 3 2 0 0 0
9 3 4 0 12 0 4 6 1 2 1 0 0 7 1 0 1 1 0 0 0 1
5 0 2 1 7 0 1 3 0 0 0 1 3 3 0 0 0 0 0 1 1 0
1 2 2 0 1 0 0 0 0 1 1 0 0 2 0 0 0 0 0 0 0 0
25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25
No treatment-related deaths have been reported.
Discussion Recurrent cervical cancer is generally considered an incurable disease. Multiple clinical Phase II trials have been conducted in an attempt to improve response and median PFS and OS. However, response rates with current chemotherapy regimens are commonly in the range of 18–38%. Time to progression is less than three months, and median survival is less than seven months [10–12]. Until recently, single agent cisplatin has been the standard treatment of choice for metastatic cervical cancer. Other agents have been tried, but often toxicity limits the usefulness in these heavily pretreated and often previously irradiated patients. There is clearly a need to quantify and improve the acute and chronic toxicities, particularly since the response rates are often short with recurrent disease. Anemia is known to have an adverse effect on tolerance of treatment and on quality of life. Concomitant platinum-based chemotherapy with radiation is the gold standard for locally advanced cervical cancer and is often used either as a single agent or in combination for patients with recurrent disease. Cisplatin is the most widely used radiosensitizing agent and can contribute to long term renal compromise, limiting many future treatment options in heavily pretreated patients. Anti-tumor activity of topotecan against cervical cancer was first reported by Noda. Topotecan was given at 1.2 mg/m2 on days 1–5 of a 21-day course. The dose-limiting toxicity was myelosuppression with 33% grade 4 leukopenia and 25% grade 4 anemia reported in the previously treated patients [13]. Similar findings were reported by Abu-Rustum and Muderspach with myelosuppressive dose- limiting toxicity at doses of 1.0 mg/m2 on days 1–5 and 1.5 mg/m2 on days 1–5 of a 21-day cycle despite favorable response rates [14,15]. The GOG performed a confirmatory Phase II trial where 40 evaluable patients received one prior chemotherapy regimen at a topotecan dose of 1.5 mg/m2 on days 1–5 of a 21-day cycle. The overall response rate was 13%; 38% had stable disease. The progression-free interval was 2.1 months with an overall survival period of 6.6 months in the patients previously treated with one cycle of chemotherapy. Despite the favorable response and stable disease statistics, the dose-limiting toxicity was again myelosuppression, specifically grade 4 neutropenia (68%), and thrombocytopenia (39%) [16]. Based on Rowinsky's Phase I study combining dose topotecan with cisplatin, a Phase II trial was conducted in Florida where cisplatin 50 mg/m2/day 1 was combined with topotecan 0.75 mg/m2 on days
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Table 3 Response. Response Stable disease Increasing disease Unknown
Cases Number
Percent
10 12 3
40.0 48.0 12.0
1–3 on a 21-day cycle for first relapsed cervical cancer [17]. Nine of 32 evaluable patients (28%) responded and nine additional patients (28%) achieved stable disease with a median survival of 10 months. The frequency of neutropenia and thrombocytopenia was 30% and 10% respectively in a relatively chemo-naive group of patients [18]. GOG conducted a confirmatory Phase III randomized clinical trial comparing combination cisplatin and topotecan in the three-day regimen to either cisplatin alone, or a combination of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) in cervical cancer patients at the time of first recurrence. The MVAC arm was closed after four treatment-related deaths occurred among the 63 patients on trial. The other two treatment arms continued and a total of 294 patients were enrolled receiving either cisplatin alone or in combination with topotecan. Patients receiving cisplatin with topotecan (CT) had a statistically superior outcome with an OS of 9.4 versus 6.5 months (p = .017), a superior median PFS of 4.6 versus 2.9 months (p = .014), and a response rate of 27% versus 13% with cisplatin alone [5]. However, patients on the CT arm experienced an increase in hematologic toxicity, including substantial neutropenia (70%) as well as 18% febrile neutropenia. Quality of life became a critical concern due to the differences in toxicity profiles. Fortunately, there was no significant decrease in quality of life up to nine months after randomization to the trial, demonstrating that the combination of CT, although substantially more toxic, could achieve an improved survival without significantly impairing the patient's overall quality of life [19]. In this study, it was hypothesized that weekly topotecan may offer an improved toxicity profile for these pretreated patients with cervical cancer. A Phase I trial by Homesley and a Phase II trial by Morris using weekly topotecan for recurrent ovarian cancer demonstrated only rare hematologic side effects [20,21]. In this current trial, topotecan was administered weekly at a dose of 3.0 mg/m2 every 28 days in an attempt to diminish the hematologic toxicity seen with a five consecutive day regimen. Twenty-five patients were evaluated for toxicity in this multicenter trial conducted by the GOG. We included
patients with measurable disease who failed their initial treatment (surgery and/or radiation therapy with concomitant chemotherapy sensitizers) and failed subsequent systemic chemotherapy. We were able to administer chemotherapy on an outpatient basis, with only one patient requiring a dose reduction. All other patients were treated with a full dose without treatment delays for a total of 75 chemotherapy courses. Anemia occurred in 32% of patients (seven patients with grade 3 and one patient with grade 4). Neutropenia was seen in 16% of patients (two patients with grade 3 and two patients with grade 4). This included 22 patients who received previous chemo-irradiation prior to their other first line chemotherapy regimen. Filgrastim was not necessary in any of the 25 patients. Only one patient experienced grade 4 neurotoxicity; she had a cerebral vascular accident and was taken off study after three courses of chemotherapy. One patient developed an inferior vena caval thrombosis and was taken off study after three cycles of chemotherapy. Forty percent (n = 10) of patients had stable disease with a mean time of 5.25 months. However, stable disease was not the primary endpoint of this study. Twelve patients (48%) had increasing disease (Table 3). Four of these patients with new lesions were discovered within six weeks of study enrollment. Patients with increasing disease received a mean of 1.75 cycles of chemotherapy (range 1–2) before being taken off study. Two additional patients were taken off the trial for global deterioration. One patient elected to receive palliative care and declined further therapy after only one cycle of topotecan and the other was enrolled while in the hospital and died after a five week protracted hospital course. There were no responders to weekly topotecan among the 25 patients in this study. This lack of response included 22 patients with prior radiation and 20 with chemosensitizing radiation treatment. According to GOG response criteria four responses were required to initiate a second phase of accrual. This criteria was not met. Therefore, there is no evidence based rationale to recommend this therapy in this patient population as topotecan is not an active drug as a single agent as defined by the GOG. Other combinations are being evaluated by the GOG. In GOG 169 (Table 4), cisplatin was compared to cisplatin together with paclitaxel in first relapse cervical cancer. The combination chemotherapy arm achieved a superior response (36% versus 19%) and median PFS (4.8 versus 2.8 months) [22]. GOG 204 (Table 4) is a randomized 4-arm trial attempting to find the best drug combination for advanced and recurrent cervical cancer evaluating both response and quality of life. In GOG 179 (Table 4), an improved OS from 6.5 to 9.4 months was observed when topotecan was
Table 4 Schematic of GOG 179, 169, and 204. GOG 179 Randomize Regimen I Cisplatin 50 mg/m2 IV Courses repeated every 3 weeks × 6
Regimen II Topotecan 0.75 mg/m2 IV over 30 min days 1, 2, and 3 Cisplatin 50 mg/m2 IV day 1 Courses repeated every 3 weeks × 6
GOG 169 Randomize Regimen I Cisplatin 50 mg/m2 IV courses repeated every 3 weeks × 6
Regimen II Paclitaxel 135 mg/m2 IV over 24 h Cisplatin 50 mg/m2 IV courses repeated every 3 weeks × 6
GOG 204 Randomize Regimen I Paclitaxel 135 mg/m2 IV over 24 h and cisplatin 50 mg/m2 IV day 2 cycles repeated q 3 weeks × 6 Regimen III Gemcitabine 1000 mg/m2 IV days 1 and 8 and cisplatin 50 mg/m2 IV day 1 cycles repeated q 3 weeks × 6
Regimen II Vinorelbine 30 mg/m2 IV days 1 and 8 and cisplatin 50 mg/m2 IV day 1 repeated q 3 weeks × 6 Regimen IV Topotecan 0.75 mg/m2 IV over 30 min days 1, 2, and 3 and cisplatin 50 mg/m2 IV day 1 cycles repeated q 3 weeks × 6
Regimen III (Closed to patient entry 7/23/2001) Methotrexate 30 mg/m2 m2 Vinblastine 3 mg/m2 m2 Doxorubicin 30 mg/m2 m2 Cisplatin 70 mg/m2
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administered for three consecutive days together with cisplatin, compared to cisplatin alone. As a result of this study, there appears to be no activity for topotecan in the treatment of recurrent cervical cancer as a second line agent using this schedule. Conflict of interest statement Drs. James Fiorica and Angeles Alvarez Secord are both on the GlaxoSmithKline Speaker's Bureau.
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