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Carboplatin and paclitaxel in advanced or metastatic endometrial cancer
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Gynecologic Oncology 109 (2008) 250 – 254 www.elsevier.com/locate/ygyno
Carboplatin and paclitaxel in advanced or metastatic endometrial cancer D. Pectasides a,⁎, N. Xiros a , G. Papaxoinis a , E. Pectasides a , C. Sykiotis b , A. Koumarianou a , A. Psyrri a , A. Gaglia a , D. Kassanos b , P. Gouveris a , J. Panayiotidis c , G. Fountzilas d , T. Economopoulos a a
Second Department of Internal Medicine, Propaedeutic, Oncology Section, University of Athens, “Attikon” University Hospital, Haidari, 1 Rimini, Athens, Greece b 3d Department of Gynecologic Oncology, University of Athens, “Attikon” University Hospital, Haidari, 1 Rimini, Athens, Greece c Second Department of Pathology, University of Athens, “Attikon” University Hospital, Haidari, 1 Rimini, Athens, Greece d Department of Medical, Oncology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece Received 13 December 2007 Available online 4 March 2008
Abstract Objectives. The purpose of this study was to evaluate the activity and toxicity of carboplatin and paclitaxel combination in advanced or recurrent endometrial carcinoma. Methods. Forty-seven eligible patients with measurable advanced or recurrent endometrial carcinoma were treated with carboplatin [area under the curve (AUC) 5] and paclitaxel 175 mg/m2 every 3 weeks for 6–9 cycles or until disease progression or unacceptable toxicity. Results. There were 10 complete responses (CRs) (21%) and 19 partial responses (PRs) (41%) for an overall response rate (RR) of 62% (29 patients) (95% confidence interval [CI], 47–76%). The median progression-free survival (PFS) was 15 months (95% CI, 7.3–22.7 months) and the median overall survival (OS) was 25 months (95% CI, 19.0–31.0 months). No difference was found in RR and OS in patients with primary advanced disease and those with recurrent tumors. Similarly, no difference was found in PFS and OS for patients with serous/clear tumors and those with endometrioid tumors. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 36% of patients and 6% experienced febrile neutropenia. One patient each developed grade 4 thrombocytopenia and anemia. Grade 3 sensory neuropathy was recorded in 6% of patients. Conclusion. The combination of carboplatin and paclitaxel appears to have activity in advanced or recurrent endometrial carcinoma with an acceptable toxicity profile. © 2008 Elsevier Inc. All rights reserved. Keywords: Carboplatin; Paclitaxel; Chemotherapy; Endometrial cancer
Introduction Endometrial cancer is the fourth most frequently occurring gynecological cancer in the western world. It is estimated that 39,080 new cases and 7400 deaths of endometrial cancer will be recorded in the United States [1]. Most women are diagnosed at an early stage leading to high cure rates with surgery with or without radiotherapy. Approximately 15% of patients are present with advanced stage disease and N 25% of all patients
⁎ Corresponding author. Fax: +30 210 5831666, +30 210 6008610. E-mail addresses: [email protected], [email protected] (D. Pectasides). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.01.028
will recur. For cases of primary advanced or recurrent disease, chemotherapy is the standard treatment option. Doxorubicin and cisplatin [2–6] have been the standard cytotoxic agents in advanced or recurrent endometrial cancer. Most of the responses are partial (30–45%) and are of short duration with median survival of b1 year. Recently, two large randomized phase III trials showed superiority of the combination of doxorubicin plus cisplatin over single-agent doxorubicin in terms of RRs (42% versus 25% and 43% versus 17%, respectively) and progression-free survival (PFS) (5.7 versus 3.8 months and 8 versus 7 months, respectively). However, the impact on survival was modest with the cost of considerable toxicity [7,8]. Due to the lack of prolonged benefit from currently
D. Pectasides et al. / Gynecologic Oncology 109 (2008) 250–254
available agents, new agents along with newer combinations are critical if progress is to be made in the treatment of advanced endometrial cancer. Carboplatin has been used as a less toxic alternative to cisplatin in endometrial cancer. Carboplatin given at a dose 300–400 mg/m2 has been associated with RRs of 24% to 29% [9,10]. Recently, prospective trials have shown that paclitaxel may be the most active agent in the treatment of endometrial cancer, with RRs ranging from 27% to 36% [11,12]. Based on the activity of paclitaxel, the combination of doxorubicin and cisplatin has been supplanted by the new standard of cisplatin, doxorubicin and paclitaxel in the treatment of advanced endometrial cancer. The combination of carboplatin at a dose of AUC (area under the curve) 5–7 and paclitaxel at a dose of 135–175 mg/m2 produced RRs ranging from 40 to 82%, complete response rates (CRs) from 0.5 to 35%, median progression-free survival (PFS) from 6 to 24 months and median survival (OS) from 14 to 27 months [13–16,18]. Based on these data, we report on our experience with the activity, tolerability and toxicity of carboplatin-paclitaxel combination in advanced or recurrent endometrial carcinoma. Patients and methods Between January 2004 and September 2007, 47 consecutive patients with advanced or recurrent endometrial carcinoma were included in the study. All patients received treatment at two departments of medical oncology. Data were collected from medical records and the electronic tumor registry. Inclusion criteria were the following: 1) histological documentation of endometrial carcinoma of any histology (except for malignant mixed mullerian tumors); 2) measurable disease by computerized tomography (CT) scan or magnetic resonance imagine (MRI); 3) no prior cytotoxic chemotherapy for advanced or recurrent disease, unless used only for radiosensitization or in adjuvant setting for high-risk tumors. Other eligibility requirements included Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; a granulocyte count of at least 1500/μl, a platelet count of at least 100,000/μl, a serum creatinine level b1.5 mg/dl, creatinine clearance measured by Cr EDTA ≥40 mL/min, a serum bilirubin b1.5 mg/dl, and transaminase values of no more than twice the upper normal limit. The ethics committees of the participating centers approved the study protocol and the patient informed consent. All patients provided informed consent according to institutional guidelines. Exclusion criteria were the following: history of malignancies, except for cured non-melanoma skin cancer, curatively treated in situ carcinoma of the cervix; known brain/leptomeningeal involvement of carcinoma; active uncontrolled infection; symptomatic, grade 2 of peripheral neuropathy; no prior radiotherapy within 4 weeks before initiation of treatment; severe intercurrent diseases.
Pre-treatment evaluation Each patient before enrolment in the study had to have a medical history, medical examination, complete blood cell count, differential counts, biochemistry profile, serum CEA and CA-125, chest CT scan, and abdominal CT scan or MRI.
Treatment Chemotherapy consisted of paclitaxel 175 mg/m2 given as a 3-h infusion followed by carboplatin AUC 5 (area under the curve) in 500 ml D/W 5% over 1-h, with dose calculated according to the Calvert formula. Treatment was administered on an outpatient basis every 3 weeks for a minimum of 6 cycles and a maximum of 9 cycles. Appropriate pre-medication prior to paclitaxel and antiemetics were given before and after the administration of chemotherapy. Treatment was discontinued in case of progressive disease, unacceptable toxicity
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or patient's preference. To administer chemotherapy, patients were required to maintain a WBC N3.0 × 109/l, ANC N1.5 × 109/l, platelet count N100 × 109/l and serum creatinine b1.5 mg/m2. If WBC had decreased to b3.0 × 109/l or the platelet count to b75 × 109/l on the first day of next cycle, chemotherapy was withheld until hematological recovery for a maximum of two weeks. G-SCF was administered until recovery and G-CSF support was added for subsequent cycles. If grade 4 leukopenia, grade 4 neutropenia lasting for N7 days, neutropenic fever or grade 4 thrombocytopenia was noted, the doses of all drugs were reduced by 20% in all subsequent cycles. If the patient was already on GCSF, the dose was reduced by 20% a maximum of two times. If persistent toxicity was occurred which required more than two dose reductions, the patient was removed from the study. The carboplatin dose was re-calculated with each cycle. If patient experienced severe anaphylaxis on two occasions, the patient was taken off study. For neurotoxicity, dose was reduced 1 level for grade 3 toxicity and 2 dose levels for toxicity of grade 4.
Response evaluation Tumor in all patients was assessed with abdominal CT scan and/or MRI and chest CT scan at baseline, and thereafter every three treatment courses, within 4 weeks after the completion of chemotherapy and every 2 months during followup until tumor progression was documented. Serum CA125 was measured on day 1 of each cycle. Objective tumor response and toxicity was assessed according to the World Health Organization criteria [17]. Complete response (CR) was defined as disappearance of all known disease, determined by two observations not less than 4 weeks apart. Partial response (PR) was defined as 50% or more decrease in total tumor load of the lesions that have been measured to determine the effect of chemotherapy by two observations not less than 4 weeks apart. Stable disease (SD) was defined as less than 50% decrease in total tumor load and not more than 50% increase in size of 1 or more measurable lesions. No new lesions were detected. Progressive disease (PD) was defined as ≥25% increase in size of 1 or more measurable lesions or appearance of new lesions.
Statistical analysis This is a retrospective analysis of 47 patients with primary advanced and recurrent endometrial cancer. Overall survival (OS) was measured from the date of registration to the protocol until death from any cause. Surviving patients were censored at the date of last contact. Progression-free survival was measured from the date of registration until the date of evident of serological or objective progression. Kaplan Meier curves were used to calculate overall and progression-free survival and were compared between groups using log rank test. The Fisher's exact test was used to compare categorical values between different groups. Throughout the analysis a level of 5% was used to denote statistical significance. Analysis was conducted on an ‘intent to treat' basis.
Results The patient characteristics of the 47 patients included in the study are summarized in Table 1. All patients included in the study were eligible for toxicity and survival. The median age of patients at diagnosis was 65 years (range 39–80). There was no difference in the median age between the 15 patients with primary advanced disease and those 32 with recurrent disease. Similarly no difference was found between these two groups of patients concerning the median weight. Forty-three (91%) patients had primary surgery with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and surgical staging. Twentyfive (53%) patients had received adjuvant radiotherapy and 11 (23%) patients with high-risk tumors had a history of adjuvant chemotherapy (5 patients with papillary serous or clear cell types and the others with high grade or advanced stage tumors), consisting of cisplatin and doxorubicin (5 patients), doxorubicin and cyclophosphamide (2 patients), and doxorubicin only
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Table 1 Patient characteristics Characteristic Age Median 65 years (range 39–80) Recurrent cases Primary advanced cases Stage III Stage IV Histology Endometrioid UPSC⁎ Clear cell Adenosquamous Undifferentiated Grade Well differentiated Moderately differentiated Poorly differentiated Unknown Performance status 0 1 2 Unknown Prior radiotherapy Yes No Prior adjuvant chemotherapy Cisplatin+Doxorubicin Cyclophosphamide+Doxorubicin Doxorubicin Prior surgery Yes No Locoregional disease only Metastatic disease
No of pts
%
32 15 3 12
68 32 20 80
39 4 1 2 1
83 9 2 4 2
6 17 22 2
13 36 47 4
4 37 5 1
9 78 11 2
25 22 11 5 2 4
53 47 23 11 4 8
43 4 10 37
91 9 21 79
⁎UPSC: uterine papillary serous carcinoma.
(4 patients). All these 11 patients were in the recurrent disease group. The median progression-free interval before recurrence was 4.0 months (range, 1.5–21 months). Endometrioid histology was the most frequent type (83%), while uterine papillary serous carcinoma (UPSC) and clear cell carcinoma were present in 4 (9%) and 1 (2%) cases, respectively. The vast majority of the cases were of poorly differentiated (47%) and of performance status (PS) of 1 (78%). The median number of cycles of chemotherapy delivered was 6 (range 3–9 cycles). Forty-three (91%) patients received 3 or more cycles of chemotherapy, and 39 (83%) completed 6 or more cycles. Three (6%) patients developed PD while on therapy and were taken off study. Eleven (23%) patients received 9 cycles of chemotherapy. Response, PFS, survival The overall response rate was 62% (29 patients) (95% CI, 47–76%) with 21% (10 patients) of patients achieving a complete remission and 41% (19 patients) of patients achieving a partial remission (Table 2). The overall response rate in patients with primary advanced disease was 73% (95% CI, 48–99%) and in those with recurrent disease was 56% (95% CI, 38–74%).
Fig. 1. Progression-free survival (PFS) and overall survival (0S) curves of the entire population.
This difference was not statistically significant (p = 0.343). The median PFS was 15 months (95% CI, 7.3–22.7) and the median overall survival was 25 months (95% CI, 19.0–31.0), as shown in Fig. 1. The median survival of patients with primary advanced disease was 19 months and for those with recurrent disease was 26 months (Table 2). This difference was not statistically significant ( p = 0.081). Similarly no difference was found in PFS and OS for patients with serous/clear tumors and those with endometrioid tumors [PFS: 13 months (95% CI, 0–33.3) versus 17 months (95% CI, 8.8–25.2)] ( p = 0.231), [OS 23 months (95% CI, 2.7–43.3) versus 27 months (95% CI, 18.0–36.0)] ( p = 0.124), respectively. Prior adjuvant chemotherapy did not have an impact on response rate (54% versus 64%, p = 0.726). Similarly, prior radiotherapy did not influence the response rate (56% versus 68%, p = 0.549), PFS (13 months versus 18 months, p = 0.115) and OS (22 months versus 28 months, p = 0.197). Nevertheless, it must be noticed that, although the differences in ORR, PFS and OS are not statistically significant, there is a big difference in actual numbers. This could be attributed to the small sample size. Toxicity Hematologic and non-hematologic toxicities are summarized in Table 3. Toxicity was generally mild except for myelotoxicity.
Table 2 0bjective response, OS RR⁎ (whole population): 62% RR⁎ (advanced disease): 73% RR⁎ (recurrent disease): 56% Median OS+ (whole population): 25 months Median OS (advanced disease): 19 months Median OS (recurrent disease): 26 months
CR⁎⁎: 21% CR⁎⁎: 30% CR⁎⁎: 9%
R⁎⁎⁎: 41% PR⁎⁎⁎: 43% PR⁎⁎⁎: 47%
RR⁎: response rate, CR⁎⁎: complete response, PR⁎⁎⁎: partial response, OS+: overall survival.
D. Pectasides et al. / Gynecologic Oncology 109 (2008) 250–254 Table 3 Toxicity Adverse effect
Grade 3
Grade 4
total n, %
Anemia Neutropenia Febrile neutropenia Thrombocytopenia Nausea Vomiting Neurotoxicity Diarrhea Mucositis/stomatitis Allergic reaction Constipation Thromboembolism
1 14 3 4 4 3 2 1 2 1 1 1
0 (0%) 3 (6%) 0 (0%) 1 (2%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
1 (2%) 17 (36%) 3 (6%) 5 (11%) 4 (9%) 3 (6%) 2 (4%) 1 (2%) 2 (4%) 1 (2%) 1 (2%) 1 (2%)
(2%) (30%) (6%) (9%) (9%) (6%) (4%) (2%) (4%) (2%) (2%) (2%)
The predominant toxicity reported was neutropenia, with 36% of patients experiencing grade 3/4 neutropenia. However, only 3 patients developed grade 3 febrile neutropenia, which successfully treated with broad spectrum antibiotics and G-CSF support. In total 12 (26%) patients required a G-CSF support. One patient each developed grade 4 thrombocytopenia and anemia. Three patients developed grade 3 sensory neuropathy. All these patients received N6 cycles of chemotherapy and two of these suffered from a diabetes mellitus. One patient each experienced grade 3 hypersensitivity reaction and deep vein thromboembolism of the left leg. Grade 3 mucositis/stomatitis was recorded in two patients. Discussion Patients with primary advanced and recurrent endometrial cancer still have poor prognosis and chemotherapy remains the major treatment option. The combination of carboplatin and paclitaxel has made a significant impact in the field of gynecological malignancies. Both carboplatin and paclitaxel have been used as single agents in patients with primary advanced and recurrent endometrial cancer. Overall RRs for single-agent paclitaxel range from 27% to 36% [11,12], while carboplatin alone achieves RRs of approximately 24% to 29% [9,10]. In the current report, we evaluated the activity and toxicity of the combination of carboplatin and paclitaxel in patients with primary advanced and recurrent endometrial cancer. In our experience using this combination, a 62% objective RR, a 15 months median PFS and a 25 months median OS, was observed. Our data about outcome were in line with other reports [13–20]. The Gynecologic Oncology Group (GOG) conducted a phase II trial to evaluate the combination of paclitaxel (175 mg/m2) and carboplatin (AUC 5-7) in 18 chemotherapy-naïve patients with recurrent endometrial cancer after surgery and/or radiotherapy [14]. A RR of 56% was achieved, with a median disease-free survival of 6 months and median OS of 15 months. Toxicity was manageable, reversible, and predominance hematologic. In another trial 47 eligible patients with bidimensionally measurable advanced, recurrent, or refractory endometrial cancer were treated with carboplatin (AUC = 6), paclitaxel (175 mg/m2) and amifostine (740 mg/m2) every 4 weeks for 6 cycles or until disease progression or unacceptable toxicity [15]. The overall RR was
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40%, the median PFS was 7 months and the median OS was 14 months. Toxicity was tolerable. While 79% of patients developed grade 3/4 neutropenia, there were no episodes of grade 4 febrile neutropenia and one episode of infection with grades 3–4 neutropenia. Akram et al. [13] retrospectively reviewed 18 consecutive patients with advanced or recurrent endometrial carcinoma who had been treated with outpatient carboplatin and paclitaxel. The overall RR was 63% with 28% of patients having a partial response and 35% of patients having a complete response. The median OS was 27 months and the median PFS was 24 months. Arimoto et al. [21] were treated 37 consecutive patients with advanced or recurrent endometrial carcinoma with paclitaxel (175 mg/m2) and carboplatin (AUC 5-6) at 4-week intervals. Five patients were received 50 Gy pelvic irradiation, and 7 were received 50 Gy pelvic and 50 Gy paraaortic irradiation, after adjuvant chemotherapy with paclitaxel plus carboplatin. Eleven patients (61%) achieved an objective RR. Toxicity was manageable, reversible, and predominance hematologic. Twenty-four patients were treated on an outpatient basis with paclitaxel 175 mg/m2 followed by cisplatin 75 mg/m2 with G-CSF support, every 3 weeks [22]. Sixteen patients (67%) achieved an objective RR. including seven complete responses and nine partial responses. The median PFS and OS were 8.4 and 17.6 months, respectively. Fleming et al. [23] compared doxorubicin (50 mg/m2) and paclitaxel (150 mg/m2/24 h) plus G-SCF with doxorubicin (60 mg/m2) and cisplatin (50 mg/m2). No significant differences in RRs, PFS, and OS were observed. Toxicity favoured the combination of doxorubicin and cisplatin. In a GOG study, Fleming et al. [24] compared an aggressive combination of doxorubicin, cisplatin, and paclitaxel (TAP) with the standard combination of doxorubicin and cisplatin (AP). The RR was significantly better in the TAP arm (57%) compared with that of AP arm (34%), ( p b 0.001). PFS and OS were also significantly improved in the TAP arm. It has to be emphasized that 5 treatment-related deaths were recorded in the TAP arm and none in the AP arm. The deaths included 1 case of acute myeloid leukemia, 1 related to mesenteric artery thrombus, 1 related to neutropenic sepsis, 1 attributed to a grade 3 infection and disease, and 1 from possible haemolytic uremic syndrome and disease. However, only 2 of the 5 deaths were clearly treatment-related. Peripheral sensory neuropathy was also more common in the TAP arm compared with that of AP arm (grade 2–3, 39% versus 5%). Type of histology did not influence outcome in our study. This is in agreement with the results of other reports [16,23]. Similarly, prior radiotherapy did not have an impact on the outcome of our patients. This is in line with the results of Sorbe et al. [16]. The GOG is currently comparing the combination of carboplatin and paclitaxel with the TAP regimen in patients with advanced or recurrent endometrial carcinoma. Toxicity with this regimen was tolerable, the most common one being hematologic side-effects. Forty-three (91%) patients received ≥ 3 cycles of chemotherapy, and 39 (83%) completed ≥ 6 cycles. Neutropenia and thrombocytopenia were not a problem, G-CSF support was administered in 26% of patients and neutropenic fever was recorded only in 6% of patients. Only 1 patient each with grade 4 anemia and thrombocytopenia required red cell blood and platelet transfusion, respectively.
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Clinically significant neuropathy was recorded in 6% of patients, probably due to 9 cycles of chemotherapy given and to comorbidities. Severe allergic reaction grade 3 was recorded in 1 patient. No treatment-related deaths were recorded in our series. An efficacious and low-toxic regimen is needed for this group of rather old and ill patients suffering from advanced or recurrent endometrial carcinoma. The results of our study indicated that the combination of carboplatin and paclitaxel in an effective and well tolerated regimen against primarily advanced or recurrent endometrial carcinoma, excluding patients with co-morbidities. Long-term follow-up and additional prospective studies probably in combination with molecular targeted therapies are necessary for the future.
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[15]
References [1] Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. CA Cancer J Clin 2007;57(1):43–66. [2] Thigpen JT, Buchsbaum HJ, Mangan C, Blessing JA. Phase II trial of adriamycin in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Cancer Treat Rep 1979;63(1):21–7. [3] Thigpen JT, Blessing JA, DiSaia PJ, Yordan E, Carson LF, Evers C. A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1994;12(7):1408–14. [4] Thigpen JT, Blessing JA, Homesley H, Creasman WT, Sutton G. Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study. Gynecol Oncol 1989;33(1):68–70. [5] Seski JC, Edwards CL, Herson J, Rutledge FN. Cisplatin chemotherapy for disseminated endometrial cancer. Obstet Gynecol 1982;59(2):225–8. [6] Thigpen JT, Blessing JA, Lagasse LD, DiSaia PJ, Homesley HD. Phase II trial of cisplatin as second-line chemotherapy in patients with advanced or recurrent endometrial carcinoma. A Gynecologic Oncology Group study. Am J Clin Oncol 1984;7(3):253–6. [7] Thigpen JT, Brady MF, Homesley HD, Malfetano J, DuBeshter B, Burger RA, et al. Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 2004;22(19):3902–8. [8] Aapro MS, van Wijk FH, Bolis G, Chevallier B, van der Burg ME, Poveda A, et al. European organisation for research and treatment of cancer Gynaecological Cancer Group. Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group. Ann Oncol 2003;14(3):441–8. [9] Burke TW, Munkarah A, Kavanagh JJ, Morris M, Levenback C, Tornos C, et al. Treatment of advanced or recurrent endometrial carcinoma with single-agent carboplatin. Gynecol Oncol 1993;51(3):397–400. [10] van Wijk FH, Lhommé C, Bolis G, Scotto di Palumbo V, Tumolo S, Nooij M, et al. European organization for research and treatment of cancer.
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Gynecologic Oncology 109 (2008) 250 – 254 www.elsevier.com/locate/ygyno
Carboplatin and paclitaxel in advanced or metastatic endometrial cancer D. Pectasides a,⁎, N. Xiros a , G. Papaxoinis a , E. Pectasides a , C. Sykiotis b , A. Koumarianou a , A. Psyrri a , A. Gaglia a , D. Kassanos b , P. Gouveris a , J. Panayiotidis c , G. Fountzilas d , T. Economopoulos a a
Second Department of Internal Medicine, Propaedeutic, Oncology Section, University of Athens, “Attikon” University Hospital, Haidari, 1 Rimini, Athens, Greece b 3d Department of Gynecologic Oncology, University of Athens, “Attikon” University Hospital, Haidari, 1 Rimini, Athens, Greece c Second Department of Pathology, University of Athens, “Attikon” University Hospital, Haidari, 1 Rimini, Athens, Greece d Department of Medical, Oncology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece Received 13 December 2007 Available online 4 March 2008
Abstract Objectives. The purpose of this study was to evaluate the activity and toxicity of carboplatin and paclitaxel combination in advanced or recurrent endometrial carcinoma. Methods. Forty-seven eligible patients with measurable advanced or recurrent endometrial carcinoma were treated with carboplatin [area under the curve (AUC) 5] and paclitaxel 175 mg/m2 every 3 weeks for 6–9 cycles or until disease progression or unacceptable toxicity. Results. There were 10 complete responses (CRs) (21%) and 19 partial responses (PRs) (41%) for an overall response rate (RR) of 62% (29 patients) (95% confidence interval [CI], 47–76%). The median progression-free survival (PFS) was 15 months (95% CI, 7.3–22.7 months) and the median overall survival (OS) was 25 months (95% CI, 19.0–31.0 months). No difference was found in RR and OS in patients with primary advanced disease and those with recurrent tumors. Similarly, no difference was found in PFS and OS for patients with serous/clear tumors and those with endometrioid tumors. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 36% of patients and 6% experienced febrile neutropenia. One patient each developed grade 4 thrombocytopenia and anemia. Grade 3 sensory neuropathy was recorded in 6% of patients. Conclusion. The combination of carboplatin and paclitaxel appears to have activity in advanced or recurrent endometrial carcinoma with an acceptable toxicity profile. © 2008 Elsevier Inc. All rights reserved. Keywords: Carboplatin; Paclitaxel; Chemotherapy; Endometrial cancer
Introduction Endometrial cancer is the fourth most frequently occurring gynecological cancer in the western world. It is estimated that 39,080 new cases and 7400 deaths of endometrial cancer will be recorded in the United States [1]. Most women are diagnosed at an early stage leading to high cure rates with surgery with or without radiotherapy. Approximately 15% of patients are present with advanced stage disease and N 25% of all patients
⁎ Corresponding author. Fax: +30 210 5831666, +30 210 6008610. E-mail addresses: [email protected], [email protected] (D. Pectasides). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.01.028
will recur. For cases of primary advanced or recurrent disease, chemotherapy is the standard treatment option. Doxorubicin and cisplatin [2–6] have been the standard cytotoxic agents in advanced or recurrent endometrial cancer. Most of the responses are partial (30–45%) and are of short duration with median survival of b1 year. Recently, two large randomized phase III trials showed superiority of the combination of doxorubicin plus cisplatin over single-agent doxorubicin in terms of RRs (42% versus 25% and 43% versus 17%, respectively) and progression-free survival (PFS) (5.7 versus 3.8 months and 8 versus 7 months, respectively). However, the impact on survival was modest with the cost of considerable toxicity [7,8]. Due to the lack of prolonged benefit from currently
D. Pectasides et al. / Gynecologic Oncology 109 (2008) 250–254
available agents, new agents along with newer combinations are critical if progress is to be made in the treatment of advanced endometrial cancer. Carboplatin has been used as a less toxic alternative to cisplatin in endometrial cancer. Carboplatin given at a dose 300–400 mg/m2 has been associated with RRs of 24% to 29% [9,10]. Recently, prospective trials have shown that paclitaxel may be the most active agent in the treatment of endometrial cancer, with RRs ranging from 27% to 36% [11,12]. Based on the activity of paclitaxel, the combination of doxorubicin and cisplatin has been supplanted by the new standard of cisplatin, doxorubicin and paclitaxel in the treatment of advanced endometrial cancer. The combination of carboplatin at a dose of AUC (area under the curve) 5–7 and paclitaxel at a dose of 135–175 mg/m2 produced RRs ranging from 40 to 82%, complete response rates (CRs) from 0.5 to 35%, median progression-free survival (PFS) from 6 to 24 months and median survival (OS) from 14 to 27 months [13–16,18]. Based on these data, we report on our experience with the activity, tolerability and toxicity of carboplatin-paclitaxel combination in advanced or recurrent endometrial carcinoma. Patients and methods Between January 2004 and September 2007, 47 consecutive patients with advanced or recurrent endometrial carcinoma were included in the study. All patients received treatment at two departments of medical oncology. Data were collected from medical records and the electronic tumor registry. Inclusion criteria were the following: 1) histological documentation of endometrial carcinoma of any histology (except for malignant mixed mullerian tumors); 2) measurable disease by computerized tomography (CT) scan or magnetic resonance imagine (MRI); 3) no prior cytotoxic chemotherapy for advanced or recurrent disease, unless used only for radiosensitization or in adjuvant setting for high-risk tumors. Other eligibility requirements included Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; a granulocyte count of at least 1500/μl, a platelet count of at least 100,000/μl, a serum creatinine level b1.5 mg/dl, creatinine clearance measured by Cr EDTA ≥40 mL/min, a serum bilirubin b1.5 mg/dl, and transaminase values of no more than twice the upper normal limit. The ethics committees of the participating centers approved the study protocol and the patient informed consent. All patients provided informed consent according to institutional guidelines. Exclusion criteria were the following: history of malignancies, except for cured non-melanoma skin cancer, curatively treated in situ carcinoma of the cervix; known brain/leptomeningeal involvement of carcinoma; active uncontrolled infection; symptomatic, grade 2 of peripheral neuropathy; no prior radiotherapy within 4 weeks before initiation of treatment; severe intercurrent diseases.
Pre-treatment evaluation Each patient before enrolment in the study had to have a medical history, medical examination, complete blood cell count, differential counts, biochemistry profile, serum CEA and CA-125, chest CT scan, and abdominal CT scan or MRI.
Treatment Chemotherapy consisted of paclitaxel 175 mg/m2 given as a 3-h infusion followed by carboplatin AUC 5 (area under the curve) in 500 ml D/W 5% over 1-h, with dose calculated according to the Calvert formula. Treatment was administered on an outpatient basis every 3 weeks for a minimum of 6 cycles and a maximum of 9 cycles. Appropriate pre-medication prior to paclitaxel and antiemetics were given before and after the administration of chemotherapy. Treatment was discontinued in case of progressive disease, unacceptable toxicity
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or patient's preference. To administer chemotherapy, patients were required to maintain a WBC N3.0 × 109/l, ANC N1.5 × 109/l, platelet count N100 × 109/l and serum creatinine b1.5 mg/m2. If WBC had decreased to b3.0 × 109/l or the platelet count to b75 × 109/l on the first day of next cycle, chemotherapy was withheld until hematological recovery for a maximum of two weeks. G-SCF was administered until recovery and G-CSF support was added for subsequent cycles. If grade 4 leukopenia, grade 4 neutropenia lasting for N7 days, neutropenic fever or grade 4 thrombocytopenia was noted, the doses of all drugs were reduced by 20% in all subsequent cycles. If the patient was already on GCSF, the dose was reduced by 20% a maximum of two times. If persistent toxicity was occurred which required more than two dose reductions, the patient was removed from the study. The carboplatin dose was re-calculated with each cycle. If patient experienced severe anaphylaxis on two occasions, the patient was taken off study. For neurotoxicity, dose was reduced 1 level for grade 3 toxicity and 2 dose levels for toxicity of grade 4.
Response evaluation Tumor in all patients was assessed with abdominal CT scan and/or MRI and chest CT scan at baseline, and thereafter every three treatment courses, within 4 weeks after the completion of chemotherapy and every 2 months during followup until tumor progression was documented. Serum CA125 was measured on day 1 of each cycle. Objective tumor response and toxicity was assessed according to the World Health Organization criteria [17]. Complete response (CR) was defined as disappearance of all known disease, determined by two observations not less than 4 weeks apart. Partial response (PR) was defined as 50% or more decrease in total tumor load of the lesions that have been measured to determine the effect of chemotherapy by two observations not less than 4 weeks apart. Stable disease (SD) was defined as less than 50% decrease in total tumor load and not more than 50% increase in size of 1 or more measurable lesions. No new lesions were detected. Progressive disease (PD) was defined as ≥25% increase in size of 1 or more measurable lesions or appearance of new lesions.
Statistical analysis This is a retrospective analysis of 47 patients with primary advanced and recurrent endometrial cancer. Overall survival (OS) was measured from the date of registration to the protocol until death from any cause. Surviving patients were censored at the date of last contact. Progression-free survival was measured from the date of registration until the date of evident of serological or objective progression. Kaplan Meier curves were used to calculate overall and progression-free survival and were compared between groups using log rank test. The Fisher's exact test was used to compare categorical values between different groups. Throughout the analysis a level of 5% was used to denote statistical significance. Analysis was conducted on an ‘intent to treat' basis.
Results The patient characteristics of the 47 patients included in the study are summarized in Table 1. All patients included in the study were eligible for toxicity and survival. The median age of patients at diagnosis was 65 years (range 39–80). There was no difference in the median age between the 15 patients with primary advanced disease and those 32 with recurrent disease. Similarly no difference was found between these two groups of patients concerning the median weight. Forty-three (91%) patients had primary surgery with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and surgical staging. Twentyfive (53%) patients had received adjuvant radiotherapy and 11 (23%) patients with high-risk tumors had a history of adjuvant chemotherapy (5 patients with papillary serous or clear cell types and the others with high grade or advanced stage tumors), consisting of cisplatin and doxorubicin (5 patients), doxorubicin and cyclophosphamide (2 patients), and doxorubicin only
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Table 1 Patient characteristics Characteristic Age Median 65 years (range 39–80) Recurrent cases Primary advanced cases Stage III Stage IV Histology Endometrioid UPSC⁎ Clear cell Adenosquamous Undifferentiated Grade Well differentiated Moderately differentiated Poorly differentiated Unknown Performance status 0 1 2 Unknown Prior radiotherapy Yes No Prior adjuvant chemotherapy Cisplatin+Doxorubicin Cyclophosphamide+Doxorubicin Doxorubicin Prior surgery Yes No Locoregional disease only Metastatic disease
No of pts
%
32 15 3 12
68 32 20 80
39 4 1 2 1
83 9 2 4 2
6 17 22 2
13 36 47 4
4 37 5 1
9 78 11 2
25 22 11 5 2 4
53 47 23 11 4 8
43 4 10 37
91 9 21 79
⁎UPSC: uterine papillary serous carcinoma.
(4 patients). All these 11 patients were in the recurrent disease group. The median progression-free interval before recurrence was 4.0 months (range, 1.5–21 months). Endometrioid histology was the most frequent type (83%), while uterine papillary serous carcinoma (UPSC) and clear cell carcinoma were present in 4 (9%) and 1 (2%) cases, respectively. The vast majority of the cases were of poorly differentiated (47%) and of performance status (PS) of 1 (78%). The median number of cycles of chemotherapy delivered was 6 (range 3–9 cycles). Forty-three (91%) patients received 3 or more cycles of chemotherapy, and 39 (83%) completed 6 or more cycles. Three (6%) patients developed PD while on therapy and were taken off study. Eleven (23%) patients received 9 cycles of chemotherapy. Response, PFS, survival The overall response rate was 62% (29 patients) (95% CI, 47–76%) with 21% (10 patients) of patients achieving a complete remission and 41% (19 patients) of patients achieving a partial remission (Table 2). The overall response rate in patients with primary advanced disease was 73% (95% CI, 48–99%) and in those with recurrent disease was 56% (95% CI, 38–74%).
Fig. 1. Progression-free survival (PFS) and overall survival (0S) curves of the entire population.
This difference was not statistically significant (p = 0.343). The median PFS was 15 months (95% CI, 7.3–22.7) and the median overall survival was 25 months (95% CI, 19.0–31.0), as shown in Fig. 1. The median survival of patients with primary advanced disease was 19 months and for those with recurrent disease was 26 months (Table 2). This difference was not statistically significant ( p = 0.081). Similarly no difference was found in PFS and OS for patients with serous/clear tumors and those with endometrioid tumors [PFS: 13 months (95% CI, 0–33.3) versus 17 months (95% CI, 8.8–25.2)] ( p = 0.231), [OS 23 months (95% CI, 2.7–43.3) versus 27 months (95% CI, 18.0–36.0)] ( p = 0.124), respectively. Prior adjuvant chemotherapy did not have an impact on response rate (54% versus 64%, p = 0.726). Similarly, prior radiotherapy did not influence the response rate (56% versus 68%, p = 0.549), PFS (13 months versus 18 months, p = 0.115) and OS (22 months versus 28 months, p = 0.197). Nevertheless, it must be noticed that, although the differences in ORR, PFS and OS are not statistically significant, there is a big difference in actual numbers. This could be attributed to the small sample size. Toxicity Hematologic and non-hematologic toxicities are summarized in Table 3. Toxicity was generally mild except for myelotoxicity.
Table 2 0bjective response, OS RR⁎ (whole population): 62% RR⁎ (advanced disease): 73% RR⁎ (recurrent disease): 56% Median OS+ (whole population): 25 months Median OS (advanced disease): 19 months Median OS (recurrent disease): 26 months
CR⁎⁎: 21% CR⁎⁎: 30% CR⁎⁎: 9%
R⁎⁎⁎: 41% PR⁎⁎⁎: 43% PR⁎⁎⁎: 47%
RR⁎: response rate, CR⁎⁎: complete response, PR⁎⁎⁎: partial response, OS+: overall survival.
D. Pectasides et al. / Gynecologic Oncology 109 (2008) 250–254 Table 3 Toxicity Adverse effect
Grade 3
Grade 4
total n, %
Anemia Neutropenia Febrile neutropenia Thrombocytopenia Nausea Vomiting Neurotoxicity Diarrhea Mucositis/stomatitis Allergic reaction Constipation Thromboembolism
1 14 3 4 4 3 2 1 2 1 1 1
0 (0%) 3 (6%) 0 (0%) 1 (2%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
1 (2%) 17 (36%) 3 (6%) 5 (11%) 4 (9%) 3 (6%) 2 (4%) 1 (2%) 2 (4%) 1 (2%) 1 (2%) 1 (2%)
(2%) (30%) (6%) (9%) (9%) (6%) (4%) (2%) (4%) (2%) (2%) (2%)
The predominant toxicity reported was neutropenia, with 36% of patients experiencing grade 3/4 neutropenia. However, only 3 patients developed grade 3 febrile neutropenia, which successfully treated with broad spectrum antibiotics and G-CSF support. In total 12 (26%) patients required a G-CSF support. One patient each developed grade 4 thrombocytopenia and anemia. Three patients developed grade 3 sensory neuropathy. All these patients received N6 cycles of chemotherapy and two of these suffered from a diabetes mellitus. One patient each experienced grade 3 hypersensitivity reaction and deep vein thromboembolism of the left leg. Grade 3 mucositis/stomatitis was recorded in two patients. Discussion Patients with primary advanced and recurrent endometrial cancer still have poor prognosis and chemotherapy remains the major treatment option. The combination of carboplatin and paclitaxel has made a significant impact in the field of gynecological malignancies. Both carboplatin and paclitaxel have been used as single agents in patients with primary advanced and recurrent endometrial cancer. Overall RRs for single-agent paclitaxel range from 27% to 36% [11,12], while carboplatin alone achieves RRs of approximately 24% to 29% [9,10]. In the current report, we evaluated the activity and toxicity of the combination of carboplatin and paclitaxel in patients with primary advanced and recurrent endometrial cancer. In our experience using this combination, a 62% objective RR, a 15 months median PFS and a 25 months median OS, was observed. Our data about outcome were in line with other reports [13–20]. The Gynecologic Oncology Group (GOG) conducted a phase II trial to evaluate the combination of paclitaxel (175 mg/m2) and carboplatin (AUC 5-7) in 18 chemotherapy-naïve patients with recurrent endometrial cancer after surgery and/or radiotherapy [14]. A RR of 56% was achieved, with a median disease-free survival of 6 months and median OS of 15 months. Toxicity was manageable, reversible, and predominance hematologic. In another trial 47 eligible patients with bidimensionally measurable advanced, recurrent, or refractory endometrial cancer were treated with carboplatin (AUC = 6), paclitaxel (175 mg/m2) and amifostine (740 mg/m2) every 4 weeks for 6 cycles or until disease progression or unacceptable toxicity [15]. The overall RR was
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40%, the median PFS was 7 months and the median OS was 14 months. Toxicity was tolerable. While 79% of patients developed grade 3/4 neutropenia, there were no episodes of grade 4 febrile neutropenia and one episode of infection with grades 3–4 neutropenia. Akram et al. [13] retrospectively reviewed 18 consecutive patients with advanced or recurrent endometrial carcinoma who had been treated with outpatient carboplatin and paclitaxel. The overall RR was 63% with 28% of patients having a partial response and 35% of patients having a complete response. The median OS was 27 months and the median PFS was 24 months. Arimoto et al. [21] were treated 37 consecutive patients with advanced or recurrent endometrial carcinoma with paclitaxel (175 mg/m2) and carboplatin (AUC 5-6) at 4-week intervals. Five patients were received 50 Gy pelvic irradiation, and 7 were received 50 Gy pelvic and 50 Gy paraaortic irradiation, after adjuvant chemotherapy with paclitaxel plus carboplatin. Eleven patients (61%) achieved an objective RR. Toxicity was manageable, reversible, and predominance hematologic. Twenty-four patients were treated on an outpatient basis with paclitaxel 175 mg/m2 followed by cisplatin 75 mg/m2 with G-CSF support, every 3 weeks [22]. Sixteen patients (67%) achieved an objective RR. including seven complete responses and nine partial responses. The median PFS and OS were 8.4 and 17.6 months, respectively. Fleming et al. [23] compared doxorubicin (50 mg/m2) and paclitaxel (150 mg/m2/24 h) plus G-SCF with doxorubicin (60 mg/m2) and cisplatin (50 mg/m2). No significant differences in RRs, PFS, and OS were observed. Toxicity favoured the combination of doxorubicin and cisplatin. In a GOG study, Fleming et al. [24] compared an aggressive combination of doxorubicin, cisplatin, and paclitaxel (TAP) with the standard combination of doxorubicin and cisplatin (AP). The RR was significantly better in the TAP arm (57%) compared with that of AP arm (34%), ( p b 0.001). PFS and OS were also significantly improved in the TAP arm. It has to be emphasized that 5 treatment-related deaths were recorded in the TAP arm and none in the AP arm. The deaths included 1 case of acute myeloid leukemia, 1 related to mesenteric artery thrombus, 1 related to neutropenic sepsis, 1 attributed to a grade 3 infection and disease, and 1 from possible haemolytic uremic syndrome and disease. However, only 2 of the 5 deaths were clearly treatment-related. Peripheral sensory neuropathy was also more common in the TAP arm compared with that of AP arm (grade 2–3, 39% versus 5%). Type of histology did not influence outcome in our study. This is in agreement with the results of other reports [16,23]. Similarly, prior radiotherapy did not have an impact on the outcome of our patients. This is in line with the results of Sorbe et al. [16]. The GOG is currently comparing the combination of carboplatin and paclitaxel with the TAP regimen in patients with advanced or recurrent endometrial carcinoma. Toxicity with this regimen was tolerable, the most common one being hematologic side-effects. Forty-three (91%) patients received ≥ 3 cycles of chemotherapy, and 39 (83%) completed ≥ 6 cycles. Neutropenia and thrombocytopenia were not a problem, G-CSF support was administered in 26% of patients and neutropenic fever was recorded only in 6% of patients. Only 1 patient each with grade 4 anemia and thrombocytopenia required red cell blood and platelet transfusion, respectively.
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Clinically significant neuropathy was recorded in 6% of patients, probably due to 9 cycles of chemotherapy given and to comorbidities. Severe allergic reaction grade 3 was recorded in 1 patient. No treatment-related deaths were recorded in our series. An efficacious and low-toxic regimen is needed for this group of rather old and ill patients suffering from advanced or recurrent endometrial carcinoma. The results of our study indicated that the combination of carboplatin and paclitaxel in an effective and well tolerated regimen against primarily advanced or recurrent endometrial carcinoma, excluding patients with co-morbidities. Long-term follow-up and additional prospective studies probably in combination with molecular targeted therapies are necessary for the future.
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