1 Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL; 2 Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY; 3 Pathology Department, Duke University Medical Center, Durham, NC; 4 Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, St Louis, MO; 5 Division of Gynecologic Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA; 6 Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Arthur James Cancer Hospital and Research Institute, Ohio State University, Columbus, OH; 7 Division of Gynecologic Oncology, University of Kentucky, Lexington, KY, USA
* Correspondence to: Dr G. F. Fleming, Section of Medical Oncology (MC2115), University of Chicago, 5841 S. Maryland Avenue (Room I-211), Chicago, IL 60637, USA. Tel: +1-773-702-6712; Fax: +1-773-702-0963; Email: gfleming{at}medicine.bsd.uchicago.edu
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Abstract |
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Patients and methods: Eligible chemotherapy-naïve patients were randomly assigned to doxorubicin 60 mg/m2 intravenously (i.v.) followed by cisplatin 50 mg/m2 i.v. (arm 1, n=157) or doxorubicin 50 mg/m2 i.v. followed 4 h later by paclitaxel 150 mg/m2 i.v. over 24 h plus filgrastim 5 µg/kg on days 312 (arm 2, n=160). Starting doses were reduced for prior pelvic radiotherapy and age >65 years. Both regimens were to be repeated every 3 weeks for a maximum of seven cycles.
Results: There was no significant difference in response rate (40% versus 43%), PFS (median 7.2 versus 6 months) or OS (median 12.6 versus 13.6 months) for arm 1 and arm 2, respectively. Toxicities were primarily hematological, with 54% (arm 1) and 50% (arm 2) of patients experiencing grade 4 granulocytopenia. Gastrointestinal toxicities were similar in both arms.
Conclusions: Doxorubicin and 24-h paclitaxel plus filgrastim was not superior to doxorubicin and cisplatin in terms of response, PFS or survival in advanced endometrial cancer.
Key words: chemotherapy, cisplatin, doxorubicin, endometrial cancer, paclitaxel
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Introduction |
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More recently, the GOG evaluated single-agent paclitaxel 250 mg/m2 as a 24-h continuous infusion with granulocyte colony-stimulating factor (G-CSF) support in chemotherapy-naïve patients with advanced endometrial carcinoma. Overall, 36% of patients responded, including 14% who experienced complete responses [6]. At the time this trial was planned, little information regarding activity using paclitaxel infusions of shorter duration in endometrial cancer was available. The goal of this study was to determine whether replacing cisplatin with a 24-h paclitaxel infusion would increase OS, progression-free survival (PFS) or objective response rate in patients with advanced endometrial cancer. The regimen combining doxorubicin with a 24-h paclitaxel infusion was developed by the Eastern Cooperative Oncology Group and tested in a large multicenter study of patients with metastatic breast cancer [7
]. Because prolonged infusion of paclitaxel results in greater myelosuppression, growth factor support was required on the experimental arm.
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Materials and methods |
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Patient evaluation and treatment
Pretreatment evaluation included a history and physical examination, complete blood cell count (CBC) with differential and platelet count, serum biochemistry, CA-125, baseline assessment of PS, tumor measurements, chest X-ray, electrocardiogram (EKG), measurement of LVEF and an audiogram, if clinically indicated. CBC, differential and platelet count was to be repeated weekly for all patients, and also on day 12 for patients on arm 2 receiving filgrastim. Physical examination, assessment of toxicity, serum biochemistry and CA-125 were to be repeated each cycle. Tumor measurements were to be repeated each cycle if obtained by physical exam, and every other cycle if by radiological evaluation. LVEF measurement was to be repeated every three cycles.
Treatment on arm 1, the standard treatment arm, consisted of doxorubicin 60 mg/m2 intravenously (i.v.) followed immediately by cisplatin 50 mg/m2 i.v. Cisplatin was diluted in 250 cm3 0.9% sodium chloride and infused over 1 h. Patients who had received prior pelvic radiotherapy or who were over the age of 65 years were to receive reduced starting doses of doxorubicin 45 mg/m2 and cisplatin 40 mg/m2.
The treatment plan for arm 2, the experimental treatment arm, consisted of 50 mg/m2 of doxorubicin on day 1 administered by i.v. bolus or brief infusion followed 4 h later by paclitaxel at a dose of 150 mg/m2 administered as a 24-h infusion. Filgrastim was to be given subcutaneously at a dose of 5 µg/kg on a daily basis, starting on day 3 of each cycle and continuing until day 12 or until the WBC was at least 10 000/mm3 (post nadir). Patients who had received prior pelvic radiotherapy or who were over the age of 65 years were to receive reduced starting doses of doxorubicin 40 mg/m2 and paclitaxel 120 mg/m2.
All patients with a body surface area (BSA) >2 m2 were dosed as though their BSA was 2 m2. Treatment was continued for seven cycles, or until disease progression or unacceptable toxicity necessitated therapy discontinuation. Doses were reduced for grade 3 or 4 WBC, granulocyte or platelet toxicity, and could be re-escalated if subsequent cycles produced toxicity of no more than grade 1. Filgrastim was to be added for patients on arm 1 who had persistent grade 4 hematological toxicity or treatment delays despite dose reduction. Grade 3 peripheral neuropathy required discontinuation of therapy until the severity of symptoms was no worse than grade 1, with the paclitaxel or cisplatin dose reduced for subsequent cycles. Grade 3 or 4 mucositis or diarrhea required dose reduction. If creatinine was >1.6 mg/dl on the day of therapy, cisplatin was discontinued. Protocol prescribed therapy was discontinued in patients experiencing a drop in LVEF to <50%, or a 20% decrease from baseline value, or for any toxicity-related delay in therapy of >3 weeks.
Response was measured according to standard GOG criteria. A complete response was defined as the disappearance of all gross evidence of disease for at least 4 weeks. Partial response was a 50% reduction in the product of perpendicular diameters obtained from measurement of each lesion for at least 4 weeks. Increasing disease was defined as a
50% increase in the product of perpendicular diameters of any lesion or the appearance of any new lesion within 8 weeks of study entry. Stable disease was disease meeting none of the above criteria. Survival was defined as observed length of life from entry on study to death or date of last contact. PFS was defined as date from entry on study to date of reappearance or increasing parameters of disease, death or date of last contact. Standard GOG common toxicity criteria were used to grade the severity of adverse events.
Pharmacokinetics
During cycle 1 only, blood samples for paclitaxel levels were taken at 0 (pre-infusion), 3, 22 and 27 h after the start of the paclitaxel infusion. Ten milliliters of blood were drawn in a heparinized tube and centrifuged within 60 min of collection. The plasma was then separated out and frozen at 20°C until shipping to a central laboratory for analysis. One hundred and twenty-nine women had at least one sample drawn after start of infusion, which could be used for pharmacokinetic analysis. Full results of a population pharmacokinetic analysis will be published elsewhere. Results were consistent with published literature on paclitaxel pharmacokinetics for total paclitaxel following long infusion, and demonstrated decreased total paclitaxel clearance with increased age, increased aspartate aminotransferase, or lower weight (David Spriggs, personal communication).
Statistical methods
The primary end point of the study was frequency of objective response (complete and partial). Secondary end points include duration of PFS and OS. A total sample size of 290 patients was targeted to detect an overall relative odds of response of 1.9 with type I error set at 0.05 in one tail and type II error of 0.20 [8]. This sample size would also allow an 83% chance of detecting a 40% increase in survival duration with 12 months of follow-up (240 deaths) and type I error of 0.05 in one tail [9
]. Additionally, this sample size would permit an 88% chance of detecting a similar increase in duration of PFS with 12 months of follow-up (280 failures) [9
].
The GOG Statistical and Data Center (SDC) carried out randomization with equal probabilities balancing the sequence of assigned regimens within institutions and strata. The stratification classified the patients into two groups: patients 65 years old and no history of radiation therapy, and patients >65 years old or with a history of radiation therapy. The sequence of treatment assignments was concealed. After patient eligibility was verified by the SDC, random treatment assignment was provided. Data were collected and reviewed centrally at the SDC. The study chair reviewed patient data to assess protocol compliance, toxicity, eligibility and end points. Pathology materials were collected at the SDC and reviewed by the GOG Pathology Committee, including slides documenting the primary and metastatic disease. The Gynecologic Oncology Committee centrally reviewed all patient eligibility data.
An interim futility analysis of response was planned and carried out after a minimum of 75 patients had been evaluated in each arm. Accrual termination was to be considered if the odds of response in the experimental arm were less than that in the standard arm [10]. The GOG Data Monitoring Committee opted to continue accrual after reviewing response and toxicity data
22 months after study activation.
A log rank test stratified by PS was used to test the independence of treatment with survival and PFS [11]. The KaplanMeier method was used to obtain estimates of PFS and survival [12
]. A proportional hazards model was used to provide an estimate of the relative hazard stratified by PS for both PFS and survival [13
]. An exact test stratified by PS [14
] was used to test the benefit of the experimental arm with respect to response, and the conditional maximum likelihood estimate of the common relative odds ratio is reported with exact 95% confidence bounds [15
]. The intention-to-treat principle was applied in the analysis of response, survival and PFS. Tabulation of adverse effects includes only treated patients.
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Results |
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Response
No improvement in response was observed for the experimental arm. The overall response rate was 40% in arm 1 and 43% in arm 2. The common odds of response ratio in arm 2 relative to arm 1 stratified by PS was 1.12 [95% confidence interval (CI) 0.691.79; P=0.36, one-tailed]. Including the 11 ineligible patients in the analysis did not appreciably change the results. Patients with prior pelvic radiotherapy were overall less likely to respond (35%, both arms combined) than were patients with no prior pelvic radiotherapy (48%, both arms combined). Statistically significant factors related to poorer response included PS of 2, prior radiotherapy, liver metastases, and disease that was recurrent after presentation at an earlier stage.
There were no significant differences in PFS (Figure 1) or OS (Figure 2) between the treatment arms. Median PFS was 7.2 months on arm 1 and 6 months on arm 2. Adjusting for PS, the hazard ratio relative to arm 1 is 1.01 (95% CI 0.801.28; P=0.46, one-tailed). Median OS was 12.6 months on arm 1 and 13.6 months on arm 2. Adjusting for PS, the death hazard ratio relative to arm 1 is 1.00 (95% CI 0.781.27; P=0.49, one-tailed). Statistically significant factors predicting for longer OS include good PS, grade 1 histology, extrapelvic disease other than lung and abdomen but including the liver, and months to first recurrence.
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Discussion |
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Toxicities in the two arms were similar, but the paclitaxel arm required the use of filgrastim. The rate of neuropathy was fairly low (8% and 9% grade 2 or higher in arm 1 and arm 2, respectively) and was similar to that seen in previous GOG endometrial cancer trials using doxorubicincisplatin [20]. These rates may increase in the adjuvant setting where a higher percentage of patients receive a full course of therapy. Of note is the single case of AML. Because relatively few patients with metastatic or recurrent endometrial cancer live long enough to develop AML, this raises concern about the potential frequency of such events when regimens are moved to the adjuvant setting. Estimates of the risk of secondary leukemia after adjuvant anthracycline-based therapy for breast cancer are in the range of 0.2% to 2.5% at 10 years, and may be increased in those women who also receive radiotherapy [21
, 22
]. While it is possible that G-CSF or taxane contributes to the risk of AML, one case of AML was also reported on the previous randomized GOG trial for advanced/recurrent endometrial cancer [20
]. In that trial both arms received doxorubicincisplatin with no G-CSF. The patient reported here, as well as the patient treated on the previous randomized GOG trial, had received prior pelvic radiotherapy, and it is possible that this may contribute to the risk of development of AML. This will be of concern in adjuvant endometrial cancer trials using both pelvic radiotherapy and doxorubicin-containing regimens.
Subsequent to the design of this trial, a 3-h paclitaxel infusion has been shown to have substantial activity in endometrial cancer and shorter, less myelotoxic infusions have replaced more prolonged infusions in treating most tumor types [2325
]. However, shorter infusions may be more neurotoxic [26
, 27
] and may interact with doxorubicin to increase its cardiac toxicity [28
]. The GOG has recently completed a trial randomizing therapy in women with advanced endometrial cancer between the doublet doxorubicincisplatin and the triplet doxorubicincisplatin3-h paclitaxel [29
]. Results from that trial, in which paclitaxel is separated from the doxorubicin and cisplatin by 24 h to minimize possible adverse cardiac and neurological interactions, show increased response rate and survival, but also increased neurotoxicity, with the triplet therapy. Other investigators have combined 3-h paclitaxel with carboplatin, which is less neurotoxic than cisplatin and also has activity in endometrial cancer [30
]; preliminary results of that combination are also encouraging [31
33
]. The GOG is currently comparing the combination of paclitaxel and carboplatin with the three-drug regimen of cisplatin, doxorubicin and paclitaxel.
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Acknowledgements |
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Notes |
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Received for publication April 6, 2004. Accepted for publication April 15, 2004.
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