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Phase II study of weekly docetaxel in patients with recurrent or metastatic endometrial cancer: AGO Uterus-4
Gynecologic Oncology 104 (2007) 86 – 90 www.elsevier.com/locate/ygyno
Phase II study of weekly docetaxel in patients with recurrent or metastatic endometrial cancer: AGO Uterus-4 A.R. Günthert a , S. Ackermann b , M.W. Beckmann b , O. Camara c , L. Kiesel d , K. Rensing d , W. Schröder e , E. Steiner f , G. Emons a,⁎ on behalf of the Arbeitsgemeinschaft Gynaekologische Onkologie a
Georg-August-University, Dept. Obstet. and Gynaecol., Robert-Koch-Str. 40, 37075 Goettingen, Germany b Friedrich-Alexander-University, Erlangen, Germany c Friedrich-Schiller-University, Jena, Germany d Westfälische Wilhelms-University, Münster, Germany e Klinikum Bremen Mitte, Bremen, Germany f Johannes-Gutenberg-University, Mainz, Germany Received 9 May 2006 Available online 20 September 2006
Abstract Objective. The aim of this phase II multicenter study was to evaluate the safety, toxicity and efficacy of docetaxel administered weekly as first line chemotherapy in patients with recurrent or metastatic endometrial cancer. Patients and methods. Thirty five patients with recurrent or metastatic endometrial cancer without previous chemotherapy were enrolled to receive three 6-week cycles of docetaxel 35 mg/m2/week with 2-week breaks between the cycles. Therapy response was evaluated after every 6week cycle, and therapy was continued in case of at least stable disease. Final therapy response was evaluated after three 6-week cycles of docetaxel. Results. Thirty five patients with a median age of 65 years (range, 37–80 years) were evaluable for toxicity assessment, one patient presented with severe anaphylactic reaction during the second application of docetaxel and therapy was discontinued. Subsequently, this patient received doxorubicin–cisplatin combination chemotherapy. Another patient was initially documented with uterine papillary serous cancer but secondarily confirmed as uterine carcinosarcoma. Thus, 33 patients were assessable for response. Overall response rate was 21% (3 PR and 4 CR). Three patients showed stable disease. Median TTP and OAS were 12 weeks and 43 weeks, respectively. Therapy with weekly docetaxel was well tolerated; in particular, no grade 3 or 4 hematological toxicities occurred. Conclusion. Docetaxel weekly has a favorable toxicity profile, is well tolerated and shows encouraging activity in patients with advanced endometrial cancer. © 2006 Elsevier Inc. All rights reserved. Keywords: Endometrial cancer; Chemotherapy; Docetaxel; Taxanes
Introduction The majority of patients with endometrial cancer are diagnosed at early stage I and II, and most of them are cured with surgery plus/minus radiotherapy. However, a significant number of patients present initially with metastatic disease outside the pelvis or develop metastases after primary therapy. ⁎ Corresponding author. Fax: +49 551 396585. E-mail address: [email protected] (G. Emons). 0090-8258/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2006.07.026
The outcome for patients with advanced or recurrent disease which cannot be controlled by surgery and/or radiotherapy is poor. Current standard in estrogen/progesterone receptor positive advanced endometrial cancer are progestins alone or in combination with tamoxifen [1–3]. For patients with symptomatic metastases or receptor negative tumors, usually single agent or combination chemotherapy is used. Various single agent therapies, such as doxorubicin, cisplatin or paclitaxel, showed moderate activity in the treatment of advanced endometrial cancer [4–9]. Combination chemotherapy
A.R. Günthert et al. / Gynecologic Oncology 104 (2007) 86–90
regimens may improve response rates and progression-free survival (PFS), but also show increased toxicity. The Gynecologic Oncology Group trial compared the combination cisplatin–doxorubicin with doxorubicin alone and described a better response rate (42% vs. 25%) and PFS (5.7 vs. 3.8 months) for the combination regimen with a negligible impact on overall survival (OS) [10]. Addition of paclitaxel to the combination cisplatin–doxorubicin (TAP) significantly improved response rates, PFS and OAS but markedly increased neurotoxicity and hematologic toxicity and required G-CSF support. Thus, TAP cannot be considered as standard therapy regimen for patients with advanced or recurrent endometrial cancer [10,11]. Many of the patients with endometrial cancer are aged over 60 years, so that feasibility of combination therapies in these patients is difficult to compare with treatment strategies of cancers occurring at lower age. Recently, Katsumata et al. described good activity of docetaxel 70 mg/m2 in 3-week cycles in patients with recurrent or advanced endometrial cancer with an overall response rate of 31%, but grades 3–4 neutropenia occurred in 94% of the patients [12]. In patients with metastatic breast cancer, weekly docetaxel showed comparable activity to 3-week cycles with docetaxel, but had a more favorable toxicity profile [13]. The purpose of our study was to evaluate efficacy and toxicity of weekly docetaxel in patients with advanced or recurrent endometrial cancer.
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evaluations were done by the same methods used initially. Complete response (CR) was defined as the complete disappearance of all known tumor manifestations for a minimum of 4 weeks. Partial response (PR) was defined as a more than 50% reduction of the length–width products of target lesions for a minimum of 4 weeks. Progressive disease (PD) was defined as a more than 25% increase in the length–width products of target lesions and/or appearance of any new lesions and/or unequivocal progression of existing non-target lesions. Stable disease (SD) was defined as any situation after three six-week cycles of docetaxel that did not qualify as a response or progression. Thus, patients with criteria of SD needed to be without progressive disease for at least 21 weeks. Time to progression (TTP) was defined as the time from the first medication to the date of a PD event or death.
Statistical consideration All patients who met the eligibility criteria and received at least one application of docetaxel were analyzed. Assuming a response rate of 20%, the study was designed with 80% power such that the lower limit of the 95% confidence interval for the estimate of the response rate was greater than 0.05. A sample size of at least 32 evaluable patients was required. To increase safety, the study was performed in a modified 2-step Simon design: after recruitment of 12 patients, therapy response was evaluated prior to continuation of the study. At least two patients with confirmed documented partial or complete response were required to continue the study. The endpoints of the study were overall tumor response as described, toxicity and safety. Toxicity evaluations were based on WHO criteria.
Results Patient characteristics
Patients and methods Eligibility criteria Patients with recurrent or metastatic histologically confirmed endometrial cancer without previous chemotherapy were eligible for the study. Patients needed to have at least one tumor manifestation evaluable bidimensionally by computed tomography and/or ultrasound. Further eligibility criteria were WHO performance status of a at least 2, general health with no history of cardiac disorder or congestive heart failure, an expected survival of at least 3 months and tumor manifestations that were not controllable by surgery or radiotherapy. Before each docetaxel application, laboratory tests had to meet the following criteria: white blood cell count > 3000/μl, platelet count > 100,000/μl, hemoglobin >10 g/dl, aspartate amino transferase (AST) and alanine amino transferase (ALT) less than twice the normal upper limit and serum creatinine less than 1.5 mg/dl. Total blood cell counts, serum chemistry, liver function tests and electrocardiogram were monitored weekly. This study was approved by the Ethics Committee of the Medical Faculty of the University of Goettingen. All patients signed an informed consent document that described the investigational nature of the proposed treatment.
Treatment schedule Docetaxel 35 mg/m2 was infused over a 30 min period. To avoid hypersensitivity reactions, patients routinely received a premedication with 8 mg dexamethasone intravenously 30 min prior to docetaxel infusion [14]. The treatment was repeated weekly for 6 weeks (cycle I1–6) followed by a two-week break to evaluate response. If no tumor progression or unacceptable toxicity was detected, patients received a second six-week cycle (II1–6) and response was evaluated again before the third six-week cycle (III1–6).
Response and toxicity evaluation Toxicity evaluations were based on WHO criteria [15]. Individual target lesions were defined before entering the study and needed to be measurable bidimensionally by computed tomography and/or ultrasound. Follow-up
Between December 2000 and March 2004, 35 patients entered the study. The median age of the intent to treat population was 65 years (range 37–80). 60% of the patients had unfavorable histological characteristics, like grade 3 endometrioid carcinoma or uterine serous carcinomas with no expression of estrogen receptors and progesterone receptors. These patients were defined as high risk group. Patients with endometrioid endometrial cancer with grades 1 and 2 of differentiation and expression of estrogen and/or progesterone receptors were defined as low risk group. Seven patients had had prior therapy with progestins; one patient had had prior therapy with fulvestrant. The median performance status was 1 (range 0–2). Ten patients presented with primary stage IV endometrial carcinoma, 25 patients showed recurrent disease with local recurrence or distant metastases. The patients' sites of metastases as indicator lesions are listed in Table 1. These 35 patients received a total of 402 applications of weekly 35/mg2 docetaxel with an average of 11.5 administrations. None of the patients needed dose reduction or treatment delay caused by toxicity. Thirty five patients were evaluable for toxicity assessment. One woman had a severe anaphylactic reaction Table 1 Site of metastases as indicator lesions (n = 35) Tumor manifestation
No. of patients
%
Intraabdominal Lung Liver Paraaortic lymph nodes Pelvic recurrence (after surgery and radiotherapy)
8 13 6 5 3
23 37 17 14 9
88
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during the second application of docetaxel and therapy was discontinued. Subsequently, this patient received doxorubicin– cisplatin combination chemotherapy. Another patient was initially documented with uterine papillary serous cancer but secondarily confirmed as uterine carcinosarcoma, which was an exclusion criteria for the study. Thus, 33 patients were assessable for response. Toxicity and safety No treatment-related deaths occurred in this study. Two patients presented with thrombembolic complications, which were not associated with study drug. One patient presented with a severe anaphylactic reaction during the second application of docetaxcel and therapy was discontinued. Another patient experienced grade 3 epistaxis leading to emergency hospitalization. Another patient with latent diabetes mellitus experienced grade 3 hyperglycemia after prophylactic dexamethasone administration leading to prolonged hospitalization. Almost all grades 2–3 side effects occurred during cycle II and cycle III. Cycle I was very well tolerated. No grade 3 or 4 hematologic toxicity and no febrile neutropenia occurred; supportive treatment with granulocyte-colony stimulating factor (G-CSF) was not required. Nonhematologic and hematologic toxicities are listed in detail in Tables 2 and 3. Response Table 4 presents the assessment of response to treatment with weekly docetaxel in 33 evaluable patients. Endpoint of this study was to evaluate response rates after three completed sixweek cycles of docetaxel. Thus, cut-off for evaluation of response rate assessment was set after 21 weeks or in case of progressive disease earlier. The clinical response rate was 21% with three partial responses (9%) and four complete responses (12%). Three patients showed stable disease after completion of the third cycle (9%). After the first cycle, 24 patients (73%) showed at least stable disease and entered the second cycle. After the second cycle, 13 patients (39%) showed at least stable Table 2 Nonhematologic toxicities Toxicities
NCI-CTC grade (n = 35) 1
Anaphylaxis Alopecia Mucositis Noncharacteristic pain Onychodystrophy Epistaxis Nausea Local skin reaction Myalgia/Arthralgia Conjunctivitis
2
3
No. of patients
%
No. of patients
%
No. of patients
%
0 11 10 6
0 31 29 17
0 7 2 3
0 20 6 9
1 3 1 3
3 9 3 9
0 1 14 8 7 4
0 3 40 23 20 11
4 3 3 1 0 0
11 9 9 3 0 0
1 1 1 0 0 0
3 3 3 0 0 0
Grade 1/2 toxicities with at least four cases and all grade 3 toxicities are shown.
Table 3 Hematologic toxicities Toxicities
NCI-CTC grade (n = 35) 1
Anemia Neutropenia Thrombopenia
2
No. of patients
%
No. of patients
%
7 4 0
20 11 0
2 1 0
6 3 0
disease and entered the third cycle. The four patients with complete response had all histological low risk tumors. Two of the three patients with partial response and also two of the three patients with stable disease had histological high risk tumors. No response occurred in patients with paraaortic lymph node metastases or pelvic recurrence. The median time to progression (TTP) was 12 weeks; the median overall survival (OAS) was 43 weeks (Fig. 1). In patients with partial or complete response, the median duration of response was 100 weeks (95% CI of mean 50–134 weeks). In two patients with stable disease, therapy with weekly docetaxel was continued after the third cycle. The first patient received a total of 44 administrations which were well tolerated. In this patient, therapy was stopped because of progressive disease. The second patient received a total of 33 administrations, and therapy was discontinued because of increased peripheral neuropathy. Discussion Patients with advanced or recurrent endometrial cancer are usually elderly patients who very often present with relevant co-morbidities. Feasibility of any chemotherapy regimens in these patients is lower compared to patients with other malignancies. Various single agent or combination chemotherapies show moderate response rates in patients with advanced endometrial cancer but until now it is unclear if chemotherapy offers any survival benefit [16]. The only randomized trial with statistically significant difference in survival in adjusted analyses compared doxorubicin + cisplatin versus doxorubicin + cisplatin + paclitaxel + G-CSF (12.3 months vs. 15.3 months), but toxicity was very high so that this combination was considered by the authors as optional therapy regimen in a small subgroup of patients with advanced endometrial cancer [10]. A recent systemic review published in this journal arrived at the same conclusion [17]. Although the combination of cisplatin and doxorubicin is currently regarded as standard chemotherapy regimen, two trials did not show any Table 4 Response rate (n = 33)
Complete response Partial response Overall response rate Stable disease Progressive disease
No. of patients
%
4 3 7 3 23
12 9 21 9 70
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89
Fig. 1. Time to progression (TTP) and overall survival (OAS) after enrollment to the study.
significant survival benefit for the combination therapy compared to doxorubicin alone [9,18]. Various oncology centers favor in analogy to the treatment of ovarian cancer the combination of carboplatin or cisplatin with paclitaxel for patients with advanced or recurrent endometrial cancer and reported retrospectively analyzed response rates of 47% to 87% [19–22]. Until now, this regimen has not been evaluated in prospective randomized trials. In addition, chemotherapy has never been explicitly proven to offer any clear survival benefit against best supportive care in these patients [16,23]. Regarding these points, toxicity and feasibility need to be the major criteria in the individual choice of a chemotherapy regimen. To minimize toxicity, therapies may be preferred in patients with advanced disease. Single agent therapies like doxorubicin, carboplatin or ifosfamide showed response rates about 15–24% and moderate toxicity [9,18,24–26]. One possible way to decrease the toxicity of treatment without reducing efficacy is to give lower doses more frequently. Tabernero et al. showed comparable efficacy of weekly docetaxel versus 3-weekly docetaxel in patients with metastatic breast cancer [27]. In this study, weekly docetaxel had a more favorable toxicity profile. Our study was conducted to investigate toxicity, safety and efficacy of first line chemotherapy with weekly docetaxel in patients with advanced endometrial cancer. Our study population showed an elderly average age (64 years), and 60% of the patients had unfavorable histology of their tumors. In addition, many patients presented with unfavorable sites of their metastases like local pelvic recurrence after surgery and radiation or paraaortic lymph node metastases. No grade 3 toxicities occurred during the first six-week cycle, so that patients tolerated the first chemotherapy cycle very well until assessment of treatment response was performed in order to decide whether to continue docetaxel treatment or not. Recently, Katsumata et al. reported an encouraging overall response rate of 31% of 3-weekly docetaxel (70 mg/m2) in patients with advanced or recurrent endometrial cancer, but these patients were younger (median age of 59 years) and showed a lower percentage of unfavorable histology [12]. Grades 3–4 neutropenia occurred in 94% of the patients in this study. Two studies with 3-weekly paclitaxel as first or second line chemotherapy showed overall response rates of 30% and 27%, respectively [6,8]. In these trials, adverse events were manageable, but
grades 3–4 neutropenia occurred in 58% and 78% of the patients, respectively. Paclitaxel weekly in patients with advanced or recurrent endometrial cancer was tested in small groups and showed encouraging response rates accompanied by low toxicities, in particular only few grades 3–4 neutropenia [28,29]. Thus, taxanes are active single agent therapies in the treatment of advanced endometrial cancer. The strategy of 3weekly administrations of taxanes is accompanied by high rates of grades 3–4 toxicities, especially neutropenia. Weekly administrations of docetaxel or paclitaxel show comparable response rates but a much more favorable toxicity profile. The current standard combination of doxorubicin and cisplatin showed in randomized trials response rates of 26–46% in patients with advanced or recurrent endometrial cancer [17]. Three-weekly paclitaxel in combination with cisplatin and doxorubicin may improve both response rate and median survival, but it is accompanied by markedly increased toxicity [10,11]. Thus, the three-drug combination can only be offered to a subgroup of patients with advanced endometrial cancer. The use of less toxic combinations including the taxanes is of interest and requires further study [17,23]. The current review of the Cochrane Collaborations suggests that the optimum cytotoxic drug regimen for advanced endometrial cancer contains paclitaxel and/or platinum [23]. The authors also conclude that major factors should be symptom control, quality of life and co-morbidity. Our data of docetaxel weekly in elderly patients with a high percentage of unfavorable tumors show encouraging activity and a low toxicity profile. Higher doses of administered docetaxel may increase response rates, but also show increased toxicity. Probably a combination regimen including docetaxel weekly and an agent with a different toxicity profile will increase response rate with acceptable toxicity. Prospective trials of docetaxel weekly in combination with other agents in patients with advanced or recurrent endometrial cancer regarding progression-free survival, symptom control and quality of life are currently being prepared by our study group. References [1] Lentz SS, Brady MF, Major FJ, et al. High-dose megestrol acetate in advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 1996;14:357–61. [2] Thigpen JT, Brady MF, Alvarez RD, et al. Oral medroxyprogesterone
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A.R. Günthert et al. / Gynecologic Oncology 104 (2007) 86–90 acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose–response study by the Gynecologic Oncology Group. J Clin Oncol 1999;17:1736–44. Fiorica JV, Brunetto VL, Hanjani P, Lentz SS, Mannel R, Andersen W. Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. Gynecol Oncol 2004;1:1–10. Moore TD, Phillips PH, Nerenstone SR, Cheson BD. Systemic treatment of advanced and recurrent endometrial carcinoma: current status and future directions. J Clin Oncol 1991;9:1071–88. 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. 1989;33:68–70. Lincoln S, Blessing JA, Lee RB, Rocereto TF. Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2003;88:277–81. Lissoni A, Zanetta G, Losa G, Gabriele A, Parma G, Mangioni C. Phase II study of paclitaxel as salvage treatment in advanced endometrial cancer. Ann Oncol 1996;7:861–3. Hirai Y, Hasumi K, Onose R, Kuramoto H, Kuzuya K, Hatae M, et al. Phase II trial of 3-h infusion of paclitaxel in patients with adenocarcinoma of endometrium: Japanese Multicenter Study Group. Gynecol Oncol 2004;94:471–6. 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;19:3902–8. Fleming GF, Brunetto VL, Cella D, Look KY, Reid GC, Munkarah AR, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 2004;11:2159–66. Fleming GF, Filiaci VL, Bentley RC, Herzog T, Sorosky J, Vaccarello L, et al. Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study. Ann Oncol 2004;15:1173–8. Katsumata N, Noda K, Nozawa S, Kitagawa R, Nishimura R, Yamaguchi S, et al. Phase II trial of docetaxel in advanced or metastatic endometrial cancer: a Japanese Cooperative Study. Br J Cancer 2005;93:999–1004. Tabernero J, Climent MA, Lluch A, Albanell J, Vermorken JB, Barnadas A, et al. A multicentre, randomised phase II study of weekly or 3-weekly docetaxel in patients with metastatic breast cancer. Ann Oncol 2004;15:1358–65. Piccart MJ, Klijn J, Paridaens R, Nooij M, Mauriac L, Coleman R, et al. Corticosteroids significantly delay the onset of docetaxel-induced fluid retention: final results of a randomized study of the European Organization for Research and Treatment of Cancer Investigational Drug Branch for Breast Cancer. J Clin Oncol 1997;15:3149–55. WHO handbook for reporting results of cancer treatment. Offset Publication, vol. 48. Geneva (Switzerland): World Health Organization; 1979.
[16] Polyzos NP, Pavlidis N, Paraskevaidis E, Ioannidis JP. Randomized evidence on chemotherapy and hormonal therapy regimens for advanced endometrial cancer: an overview of survival data. Eur J Cancer 2006;42:319–26. [17] Carey MA, Gawlik C, Funk-Kee-Fung M, Chambers A, Oliver T. Systematic review of systemic therapy for advanced or recurrent endometrial cancer. Gynecol Oncol 2006 [published Epub ahead of print]. [18] Aapro MS, van Wijk FH, Bolis G, et al. Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group. Ann Oncol 2003;14:441–8. [19] Akram T, Maseelall P, Fanning J. Carboplatin and paclitaxel for the treatment of advanced or recurrent endometrial cancer. Am J Obstet Gynecol 2005;192:1365–7. [20] Michener CM, Peterson G, Kulp B, Webster KD, Markman M. Carboplatin and paclitaxel in the treatment of advanced or recurrent endometrial cancer. J Cancer Res Clin Oncol 2005;131:581–4. [21] Sovak MA, Chuai S, Anderson R, et al. Paclitaxel and carboplatin (TP) for treatment of advanced or recurrent endometrial cancer: a retrospective study. J Clin Oncol 2005 [ASCO Meeting Abstracts 23:5020]. [22] Dimopoulos MA, Papadimitriou CA, Georgoulias V, et al. Paclitaxel and cisplatin in advanced or recurrent carcinoma of the endometrium: long-term results of a phase II multicenter study. Gynecol Oncol 2000;78: 52–7. [23] Humber C, Tierney J, Symonds P, Collingwood M, Kirwan J, Williams C, et al. Chemotherapy for advanced, recurrent or metastatic endometrial carcinoma. The Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No: CD003915.pub3. DOI:10.1002/146511858.CD003915.pub3. [24] Hoskins PJ, Swenerton KD, Pike JA, Lim P, Aquino-Parsons C, Wong F, et al. Small-cell carcinoma of the cervix: fourteen years of experience at a single institution using a combined-modality regimen of involved-field irradiation and platinum-based combination chemotherapy. J Clin Oncol 2001;19:4048–53. [25] Sutton GP, Blessing JA, DeMars LR, Moore D, Burke TW, Grendys EC. A phase II Gynecologic Oncology Group trial of ifosfamide and mesna in advanced or recurrent adenocarcinoma of the endometrium. Gynecol Oncol 1996;63:25–7. [26] van Wijk FH, Lhomme C, Bolis G, Scotto di Palumbo V, Tumolo S, Nooij M, et al. European Organization for Research and Treatment of Cancer. Gynaecological Cancer Group. Phase II study of carboplatin in patients with advanced or recurrent endometrial carcinoma. A trial of the EORTC Gynaecological Cancer Group. Eur J Cancer 2003;39:78–85. [27] Tabernero J, Climent MA, Lluch A, et al. A multicentre, randomised phase II study of weekly or 3-weekly docetaxel in patients with metastatic breast cancer. Ann Oncol 2004;15:1358–65. [28] Nishio S, Ota S, Sugiyama T, et al. Weekly 1-h paclitaxel infusion in patients with recurrent endometrial cancer: a preliminary study. Int J Clin Oncol 2003;8:45–8. [29] Markman M, Fowler J. Activity of weekly paclitaxel in patients with advanced endometrial cancer previously treated with both a platinum agent and paclitaxel. Gynecol Oncol 2004;92:180–2.
Phase II study of weekly docetaxel in patients with recurrent or metastatic endometrial cancer: AGO Uterus-4 A.R. Günthert a , S. Ackermann b , M.W. Beckmann b , O. Camara c , L. Kiesel d , K. Rensing d , W. Schröder e , E. Steiner f , G. Emons a,⁎ on behalf of the Arbeitsgemeinschaft Gynaekologische Onkologie a
Georg-August-University, Dept. Obstet. and Gynaecol., Robert-Koch-Str. 40, 37075 Goettingen, Germany b Friedrich-Alexander-University, Erlangen, Germany c Friedrich-Schiller-University, Jena, Germany d Westfälische Wilhelms-University, Münster, Germany e Klinikum Bremen Mitte, Bremen, Germany f Johannes-Gutenberg-University, Mainz, Germany Received 9 May 2006 Available online 20 September 2006
Abstract Objective. The aim of this phase II multicenter study was to evaluate the safety, toxicity and efficacy of docetaxel administered weekly as first line chemotherapy in patients with recurrent or metastatic endometrial cancer. Patients and methods. Thirty five patients with recurrent or metastatic endometrial cancer without previous chemotherapy were enrolled to receive three 6-week cycles of docetaxel 35 mg/m2/week with 2-week breaks between the cycles. Therapy response was evaluated after every 6week cycle, and therapy was continued in case of at least stable disease. Final therapy response was evaluated after three 6-week cycles of docetaxel. Results. Thirty five patients with a median age of 65 years (range, 37–80 years) were evaluable for toxicity assessment, one patient presented with severe anaphylactic reaction during the second application of docetaxel and therapy was discontinued. Subsequently, this patient received doxorubicin–cisplatin combination chemotherapy. Another patient was initially documented with uterine papillary serous cancer but secondarily confirmed as uterine carcinosarcoma. Thus, 33 patients were assessable for response. Overall response rate was 21% (3 PR and 4 CR). Three patients showed stable disease. Median TTP and OAS were 12 weeks and 43 weeks, respectively. Therapy with weekly docetaxel was well tolerated; in particular, no grade 3 or 4 hematological toxicities occurred. Conclusion. Docetaxel weekly has a favorable toxicity profile, is well tolerated and shows encouraging activity in patients with advanced endometrial cancer. © 2006 Elsevier Inc. All rights reserved. Keywords: Endometrial cancer; Chemotherapy; Docetaxel; Taxanes
Introduction The majority of patients with endometrial cancer are diagnosed at early stage I and II, and most of them are cured with surgery plus/minus radiotherapy. However, a significant number of patients present initially with metastatic disease outside the pelvis or develop metastases after primary therapy. ⁎ Corresponding author. Fax: +49 551 396585. E-mail address: [email protected] (G. Emons). 0090-8258/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2006.07.026
The outcome for patients with advanced or recurrent disease which cannot be controlled by surgery and/or radiotherapy is poor. Current standard in estrogen/progesterone receptor positive advanced endometrial cancer are progestins alone or in combination with tamoxifen [1–3]. For patients with symptomatic metastases or receptor negative tumors, usually single agent or combination chemotherapy is used. Various single agent therapies, such as doxorubicin, cisplatin or paclitaxel, showed moderate activity in the treatment of advanced endometrial cancer [4–9]. Combination chemotherapy
A.R. Günthert et al. / Gynecologic Oncology 104 (2007) 86–90
regimens may improve response rates and progression-free survival (PFS), but also show increased toxicity. The Gynecologic Oncology Group trial compared the combination cisplatin–doxorubicin with doxorubicin alone and described a better response rate (42% vs. 25%) and PFS (5.7 vs. 3.8 months) for the combination regimen with a negligible impact on overall survival (OS) [10]. Addition of paclitaxel to the combination cisplatin–doxorubicin (TAP) significantly improved response rates, PFS and OAS but markedly increased neurotoxicity and hematologic toxicity and required G-CSF support. Thus, TAP cannot be considered as standard therapy regimen for patients with advanced or recurrent endometrial cancer [10,11]. Many of the patients with endometrial cancer are aged over 60 years, so that feasibility of combination therapies in these patients is difficult to compare with treatment strategies of cancers occurring at lower age. Recently, Katsumata et al. described good activity of docetaxel 70 mg/m2 in 3-week cycles in patients with recurrent or advanced endometrial cancer with an overall response rate of 31%, but grades 3–4 neutropenia occurred in 94% of the patients [12]. In patients with metastatic breast cancer, weekly docetaxel showed comparable activity to 3-week cycles with docetaxel, but had a more favorable toxicity profile [13]. The purpose of our study was to evaluate efficacy and toxicity of weekly docetaxel in patients with advanced or recurrent endometrial cancer.
87
evaluations were done by the same methods used initially. Complete response (CR) was defined as the complete disappearance of all known tumor manifestations for a minimum of 4 weeks. Partial response (PR) was defined as a more than 50% reduction of the length–width products of target lesions for a minimum of 4 weeks. Progressive disease (PD) was defined as a more than 25% increase in the length–width products of target lesions and/or appearance of any new lesions and/or unequivocal progression of existing non-target lesions. Stable disease (SD) was defined as any situation after three six-week cycles of docetaxel that did not qualify as a response or progression. Thus, patients with criteria of SD needed to be without progressive disease for at least 21 weeks. Time to progression (TTP) was defined as the time from the first medication to the date of a PD event or death.
Statistical consideration All patients who met the eligibility criteria and received at least one application of docetaxel were analyzed. Assuming a response rate of 20%, the study was designed with 80% power such that the lower limit of the 95% confidence interval for the estimate of the response rate was greater than 0.05. A sample size of at least 32 evaluable patients was required. To increase safety, the study was performed in a modified 2-step Simon design: after recruitment of 12 patients, therapy response was evaluated prior to continuation of the study. At least two patients with confirmed documented partial or complete response were required to continue the study. The endpoints of the study were overall tumor response as described, toxicity and safety. Toxicity evaluations were based on WHO criteria.
Results Patient characteristics
Patients and methods Eligibility criteria Patients with recurrent or metastatic histologically confirmed endometrial cancer without previous chemotherapy were eligible for the study. Patients needed to have at least one tumor manifestation evaluable bidimensionally by computed tomography and/or ultrasound. Further eligibility criteria were WHO performance status of a at least 2, general health with no history of cardiac disorder or congestive heart failure, an expected survival of at least 3 months and tumor manifestations that were not controllable by surgery or radiotherapy. Before each docetaxel application, laboratory tests had to meet the following criteria: white blood cell count > 3000/μl, platelet count > 100,000/μl, hemoglobin >10 g/dl, aspartate amino transferase (AST) and alanine amino transferase (ALT) less than twice the normal upper limit and serum creatinine less than 1.5 mg/dl. Total blood cell counts, serum chemistry, liver function tests and electrocardiogram were monitored weekly. This study was approved by the Ethics Committee of the Medical Faculty of the University of Goettingen. All patients signed an informed consent document that described the investigational nature of the proposed treatment.
Treatment schedule Docetaxel 35 mg/m2 was infused over a 30 min period. To avoid hypersensitivity reactions, patients routinely received a premedication with 8 mg dexamethasone intravenously 30 min prior to docetaxel infusion [14]. The treatment was repeated weekly for 6 weeks (cycle I1–6) followed by a two-week break to evaluate response. If no tumor progression or unacceptable toxicity was detected, patients received a second six-week cycle (II1–6) and response was evaluated again before the third six-week cycle (III1–6).
Response and toxicity evaluation Toxicity evaluations were based on WHO criteria [15]. Individual target lesions were defined before entering the study and needed to be measurable bidimensionally by computed tomography and/or ultrasound. Follow-up
Between December 2000 and March 2004, 35 patients entered the study. The median age of the intent to treat population was 65 years (range 37–80). 60% of the patients had unfavorable histological characteristics, like grade 3 endometrioid carcinoma or uterine serous carcinomas with no expression of estrogen receptors and progesterone receptors. These patients were defined as high risk group. Patients with endometrioid endometrial cancer with grades 1 and 2 of differentiation and expression of estrogen and/or progesterone receptors were defined as low risk group. Seven patients had had prior therapy with progestins; one patient had had prior therapy with fulvestrant. The median performance status was 1 (range 0–2). Ten patients presented with primary stage IV endometrial carcinoma, 25 patients showed recurrent disease with local recurrence or distant metastases. The patients' sites of metastases as indicator lesions are listed in Table 1. These 35 patients received a total of 402 applications of weekly 35/mg2 docetaxel with an average of 11.5 administrations. None of the patients needed dose reduction or treatment delay caused by toxicity. Thirty five patients were evaluable for toxicity assessment. One woman had a severe anaphylactic reaction Table 1 Site of metastases as indicator lesions (n = 35) Tumor manifestation
No. of patients
%
Intraabdominal Lung Liver Paraaortic lymph nodes Pelvic recurrence (after surgery and radiotherapy)
8 13 6 5 3
23 37 17 14 9
88
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during the second application of docetaxel and therapy was discontinued. Subsequently, this patient received doxorubicin– cisplatin combination chemotherapy. Another patient was initially documented with uterine papillary serous cancer but secondarily confirmed as uterine carcinosarcoma, which was an exclusion criteria for the study. Thus, 33 patients were assessable for response. Toxicity and safety No treatment-related deaths occurred in this study. Two patients presented with thrombembolic complications, which were not associated with study drug. One patient presented with a severe anaphylactic reaction during the second application of docetaxcel and therapy was discontinued. Another patient experienced grade 3 epistaxis leading to emergency hospitalization. Another patient with latent diabetes mellitus experienced grade 3 hyperglycemia after prophylactic dexamethasone administration leading to prolonged hospitalization. Almost all grades 2–3 side effects occurred during cycle II and cycle III. Cycle I was very well tolerated. No grade 3 or 4 hematologic toxicity and no febrile neutropenia occurred; supportive treatment with granulocyte-colony stimulating factor (G-CSF) was not required. Nonhematologic and hematologic toxicities are listed in detail in Tables 2 and 3. Response Table 4 presents the assessment of response to treatment with weekly docetaxel in 33 evaluable patients. Endpoint of this study was to evaluate response rates after three completed sixweek cycles of docetaxel. Thus, cut-off for evaluation of response rate assessment was set after 21 weeks or in case of progressive disease earlier. The clinical response rate was 21% with three partial responses (9%) and four complete responses (12%). Three patients showed stable disease after completion of the third cycle (9%). After the first cycle, 24 patients (73%) showed at least stable disease and entered the second cycle. After the second cycle, 13 patients (39%) showed at least stable Table 2 Nonhematologic toxicities Toxicities
NCI-CTC grade (n = 35) 1
Anaphylaxis Alopecia Mucositis Noncharacteristic pain Onychodystrophy Epistaxis Nausea Local skin reaction Myalgia/Arthralgia Conjunctivitis
2
3
No. of patients
%
No. of patients
%
No. of patients
%
0 11 10 6
0 31 29 17
0 7 2 3
0 20 6 9
1 3 1 3
3 9 3 9
0 1 14 8 7 4
0 3 40 23 20 11
4 3 3 1 0 0
11 9 9 3 0 0
1 1 1 0 0 0
3 3 3 0 0 0
Grade 1/2 toxicities with at least four cases and all grade 3 toxicities are shown.
Table 3 Hematologic toxicities Toxicities
NCI-CTC grade (n = 35) 1
Anemia Neutropenia Thrombopenia
2
No. of patients
%
No. of patients
%
7 4 0
20 11 0
2 1 0
6 3 0
disease and entered the third cycle. The four patients with complete response had all histological low risk tumors. Two of the three patients with partial response and also two of the three patients with stable disease had histological high risk tumors. No response occurred in patients with paraaortic lymph node metastases or pelvic recurrence. The median time to progression (TTP) was 12 weeks; the median overall survival (OAS) was 43 weeks (Fig. 1). In patients with partial or complete response, the median duration of response was 100 weeks (95% CI of mean 50–134 weeks). In two patients with stable disease, therapy with weekly docetaxel was continued after the third cycle. The first patient received a total of 44 administrations which were well tolerated. In this patient, therapy was stopped because of progressive disease. The second patient received a total of 33 administrations, and therapy was discontinued because of increased peripheral neuropathy. Discussion Patients with advanced or recurrent endometrial cancer are usually elderly patients who very often present with relevant co-morbidities. Feasibility of any chemotherapy regimens in these patients is lower compared to patients with other malignancies. Various single agent or combination chemotherapies show moderate response rates in patients with advanced endometrial cancer but until now it is unclear if chemotherapy offers any survival benefit [16]. The only randomized trial with statistically significant difference in survival in adjusted analyses compared doxorubicin + cisplatin versus doxorubicin + cisplatin + paclitaxel + G-CSF (12.3 months vs. 15.3 months), but toxicity was very high so that this combination was considered by the authors as optional therapy regimen in a small subgroup of patients with advanced endometrial cancer [10]. A recent systemic review published in this journal arrived at the same conclusion [17]. Although the combination of cisplatin and doxorubicin is currently regarded as standard chemotherapy regimen, two trials did not show any Table 4 Response rate (n = 33)
Complete response Partial response Overall response rate Stable disease Progressive disease
No. of patients
%
4 3 7 3 23
12 9 21 9 70
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89
Fig. 1. Time to progression (TTP) and overall survival (OAS) after enrollment to the study.
significant survival benefit for the combination therapy compared to doxorubicin alone [9,18]. Various oncology centers favor in analogy to the treatment of ovarian cancer the combination of carboplatin or cisplatin with paclitaxel for patients with advanced or recurrent endometrial cancer and reported retrospectively analyzed response rates of 47% to 87% [19–22]. Until now, this regimen has not been evaluated in prospective randomized trials. In addition, chemotherapy has never been explicitly proven to offer any clear survival benefit against best supportive care in these patients [16,23]. Regarding these points, toxicity and feasibility need to be the major criteria in the individual choice of a chemotherapy regimen. To minimize toxicity, therapies may be preferred in patients with advanced disease. Single agent therapies like doxorubicin, carboplatin or ifosfamide showed response rates about 15–24% and moderate toxicity [9,18,24–26]. One possible way to decrease the toxicity of treatment without reducing efficacy is to give lower doses more frequently. Tabernero et al. showed comparable efficacy of weekly docetaxel versus 3-weekly docetaxel in patients with metastatic breast cancer [27]. In this study, weekly docetaxel had a more favorable toxicity profile. Our study was conducted to investigate toxicity, safety and efficacy of first line chemotherapy with weekly docetaxel in patients with advanced endometrial cancer. Our study population showed an elderly average age (64 years), and 60% of the patients had unfavorable histology of their tumors. In addition, many patients presented with unfavorable sites of their metastases like local pelvic recurrence after surgery and radiation or paraaortic lymph node metastases. No grade 3 toxicities occurred during the first six-week cycle, so that patients tolerated the first chemotherapy cycle very well until assessment of treatment response was performed in order to decide whether to continue docetaxel treatment or not. Recently, Katsumata et al. reported an encouraging overall response rate of 31% of 3-weekly docetaxel (70 mg/m2) in patients with advanced or recurrent endometrial cancer, but these patients were younger (median age of 59 years) and showed a lower percentage of unfavorable histology [12]. Grades 3–4 neutropenia occurred in 94% of the patients in this study. Two studies with 3-weekly paclitaxel as first or second line chemotherapy showed overall response rates of 30% and 27%, respectively [6,8]. In these trials, adverse events were manageable, but
grades 3–4 neutropenia occurred in 58% and 78% of the patients, respectively. Paclitaxel weekly in patients with advanced or recurrent endometrial cancer was tested in small groups and showed encouraging response rates accompanied by low toxicities, in particular only few grades 3–4 neutropenia [28,29]. Thus, taxanes are active single agent therapies in the treatment of advanced endometrial cancer. The strategy of 3weekly administrations of taxanes is accompanied by high rates of grades 3–4 toxicities, especially neutropenia. Weekly administrations of docetaxel or paclitaxel show comparable response rates but a much more favorable toxicity profile. The current standard combination of doxorubicin and cisplatin showed in randomized trials response rates of 26–46% in patients with advanced or recurrent endometrial cancer [17]. Three-weekly paclitaxel in combination with cisplatin and doxorubicin may improve both response rate and median survival, but it is accompanied by markedly increased toxicity [10,11]. Thus, the three-drug combination can only be offered to a subgroup of patients with advanced endometrial cancer. The use of less toxic combinations including the taxanes is of interest and requires further study [17,23]. The current review of the Cochrane Collaborations suggests that the optimum cytotoxic drug regimen for advanced endometrial cancer contains paclitaxel and/or platinum [23]. The authors also conclude that major factors should be symptom control, quality of life and co-morbidity. Our data of docetaxel weekly in elderly patients with a high percentage of unfavorable tumors show encouraging activity and a low toxicity profile. Higher doses of administered docetaxel may increase response rates, but also show increased toxicity. Probably a combination regimen including docetaxel weekly and an agent with a different toxicity profile will increase response rate with acceptable toxicity. Prospective trials of docetaxel weekly in combination with other agents in patients with advanced or recurrent endometrial cancer regarding progression-free survival, symptom control and quality of life are currently being prepared by our study group. References [1] Lentz SS, Brady MF, Major FJ, et al. High-dose megestrol acetate in advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 1996;14:357–61. [2] Thigpen JT, Brady MF, Alvarez RD, et al. Oral medroxyprogesterone
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