Phase II study of gemcitabine plus epirubicin plus paclitaxel in metastatic breast cancer patients

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1 Turkish Journal of Cancer Volume 35, No.4, Phase II study of gemcitabine plus epirubicin plus paclitaxel in metastatic breast cancer patients MUTLU DEM RAY 1, TÜRKKAN EVRENSEL 1, MURAT ARSLAN 1, ÖZKAN KANAT 1, ENDER KURT 1, ÖZLEM SARAYDAROÚLU 2, LKER ERCAN 3, ÞEHSUVAR GÖKGÖZ 4, UÚUR TOPAL 5, ÞAHS NE TOLUNAY 2, SMET TAÞDELEN 4, OSMAN MANAVOÚLU 1 Uluda University Medical School, Departments of 1 Medical Oncology, 2 Pathology, 3 Biostatistics, 4 General Surgery and 5 Radiology, Bursa-Turkey ABSTRACT Although metastatic breast cancer is essentially incurable, patients achieving a complete response may be good candidates for long term survival. Gemcitabine, epirubicin and paclitaxel have different mechanisms of action. Therefore, we conducted this phase II study to assess efficacy and safety of gemcitabine plus epirubicin plus paclitaxel (GET) combination therapy in metastatic breast cancer. The study enrolled 21 women with pathologically confirmed and measurable metastatic breast cancer who were not previously treated with gemcitabine and paclitaxel and prior doxorubicin cumulative dosage was no more than 240 mg/m 2 and epirubicin cumulative dosage 360 mg/m 2. Median ECOG performance status was 0. Fifteen patients (71.4%) had visceral metastases and most of them had liver and lung involvement as the predominant site. Treatment schedule was as follows: gemcitabine 1000 mg/m 2 was administered intravenously in 30 minutes on days 1 and 4 and epirubicin 90 mg/m 2 was administered intravenously 30 minutes on day 1 following gemcitabine administration and paclitaxel 175 mg/m 2 was administered intravenously in 3 hours on day 1 starting immediately after epirubicin. Objective response rate was 57.1% with 14.2% CR, and 42.8% PR. Median time to progression and overall survivals were 11 and 19 months respectively. Treatment of five patients was discontinued due to toxicity. Grade 3-4 neutropenia, anemia and thrombocytopenia were observed in 100%, 52.3%, and 42.8% of patients respectively. First and second dose reductions due to myelotoxicity were performed in 66.6% and 42.8% of patients respectively. Only 33.3% of patients received scheduled dose. In our study, the GET regimen has comparable efficacy to anthracycline-alkylator or anthracycline-taxane combination but requires proportionally high dose modifications due to myelotoxicity. [Turk J Cancer 2005;35(4): ]. KEY WORDS: Gemcitabine, epirubicin, paclitaxel, metastatic breast cancer INTRODUCTION Despite all available treatment options, metastatic breast cancer (MBC) is essentially incurable and the median survival time is 12 to 24 months after documentation of metastasis (1). Although primary goals of treatment are prolongation of time to progression, disease free survival and overall survival, the chemotherapy is generally palliative in metastatic breast cancer. Nevertheless, the patients who achieve a complete remission after chemotherapy may remain in this state for prolonged period (2,3). Anthracyclines have been considered as one of the most active agents in the metastatic breast cancer and regimens containing anthracyclines provide 50% to 80% objective response and 15-20% clinical complete response rate in metastatic breast cancer (2-4). Paclitaxel plus epirubicin combination is effective with response rates of 50-70% and safe (5). The combination of paclitaxel and gemcitabine (GT) is challenging because of the different mechanisms of action and generally non-overlapping toxicity profiles. Phase I studies indicated that GT combination is well tolerated and can be administered with both drugs at full doses (6). GT doublet was evaluated in phase II and III

2 160 GET in Metastatic Breast Cancer trials where the objective response rates were reported as % with % CR (7-11). Heavily pretreated and chemonaive patients were evaluated in this trial and GT combination was found to be efficient in both groups. The mechanism of action and main adverse effects of gemcitabine and anthracyclines do not overlap. Limited number of studies shows that gemcitabine and anthracycline doublet was feasible and well tolerated (12-14). Anthracycline and taxanes belong to most active agents used in breast cancer treatment. Single-agent gemcitabine is moderately active and well tolerated (14). Gemcitabine, epirubicin and paclitaxel have different mechanism of action, thus GET is an attractive regimen for metastatic breast cancer. Therefore, we conducted this phase II study to assess the efficacy and safety of gemcitabine plus epirubicin plus paclitaxel (GET) triplet combination therapy in metastatic breast cancer. PATIENTS AND METHODS Histologicaly confirmed metastatic breast cancer patients with at least one bidimensionally measurable disease were eligible for study enrollment. Patients had to meet the following additional eligibility criteria: age years, life expectancy >3 months, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, normal left ventricular ejection fraction by echocardiography, adequate marrow, renal and hepatic function (absolute neutrophil count 2000/µL, platelet count 100,000/µL, and total bilirubin and serum creatinine 1.25 x upper normal limit (UNL). Prior chemotherapy for metastatic disease or adjuvant/neoadjuvant treatment were stopped at least 6 months non-anthracycline containing regimens and anthracycline containing regimens for at least 12 months. A prior doxorubicin cumulative dosage was no more than 240 mg/m2 and epirubicin cumulative dosage 360 mg/m 2. Patients who could not have been treated with taxane and gemcitabine were eligible for the study. Concurrent hormonal therapy during the study was not allowed. Before initiation of therapy, all patients underwent staging work-up which included a complete history and physical examination, a complete blood cell count with differential, chemistry profile, ECG, echocardiography, and tumor measurement with appropriate radiographic or computed tomography scan for disease assessment. Complete blood cell counts with differential were performed on day 1 and 4 and subsequently weekly. Cardiac toxicity was evaluated by echocardiography. Chemistry profile (urea, creatinine, electrolytes, and liver function tests) and toxicity assessment were performed every 3 weeks. Lesions were evaluated for response at every two cycles with repeated measures performed as the original means of assessment. However, the evaluation was repeated in case of any disease related symptoms or signs. Exclusion criteria included bone metastases as the only site of disease, previous radiation therapy on target lesion, symptomatic brain metastases, significant cardiac disease, a past or concurrent history of other neoplasm (except nonmelanoma skin cancer or cervical carcinoma in situ), previously irradiation to a field encompassing more than %30 of bone marrow, pregnancy, breast feeding. Patients with other serious medical conditions potentially compromising study participation were also excluded. All patients were required to provide written informed consent. Treatment regimen consisted of gemcitabine 1000 mg/m2, epirubicin 90 mg/m 2 and paclitaxel 175 mg/m 2. Gemcitabine was administered intravenously in 30 minutes on days 1 and 4. Epirubicin was administered intravenously in 30 minutes on day 1 following gemcitabine administration. Paclitaxel was administered intravenously in 3 hours on day 1 starting immediately after epirubicin. Each paclitaxel administration included premedication with dexamethasone 20 mg p.o. 12 and 6 hours before therapy; diphenhydramine 50 mg, and ranitidine 50 mg i.v. 30 minutes before paclitaxel. Treatment regimen was given at every 21 days for a maximum of six cycles. Dose modifications were based on weekly monitoring of complete blood count and assessment of other toxicities. If absolute neutrophil count were less than 1500/µL, and/or the platelet count less than /µL on day 21, the treatment was delayed by weekly intervals. If hematologic recovery was not achieved after six weeks, the treatment was discontinued. Prophylactic hematopoietic growth

3 Demiray et al. 161 factors were not administered routinely. The chemotherapy doses were reduced at 20% if there was febrile neutropenia, documented infection, severe bleeding, grade 3-4 thrombocytopenia, grade 4 neutropenia, or grade 3 nonhematologic toxicity (except alopecia, vomiting, musculoskeletal pain). If same toxicities were repeated, second dose modification was made. Only epirubicin dose was reduced to 20% in the second dose modification. Treatment was discontinued in case of progressive disease or unacceptable toxicity. Toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria. Tumor response was graded according to the WHO criteria. Complete response (CR) was defined as the disappearance of all clinical evidence of tumor, and the absence of any disease-related symptoms for a minimum four weeks. Partial response (PR) was defined as a 50% reduction in the sum of the products of the perpendicular diameters of all measurable lesions, without the appearance of any new lesions for at least four weeks. Stable disease (SD) was defined as a less than 50% decrease or a less than 25% increase in tumor size for at least four weeks. Progressive disease (PD) was defined as a 25% increase in the sum of the products of the perpendicular diameters of any measurable lesions or in the estimated size of an immeasurable lesions or any new lesion. In the case of bone metastases, CR was defined as a disappearance of all lesions on X-ray or scan for at least four week, PR was defined as partial decrease in size of lytic lesions, recalcification of lytic lesions or decreased density of blastic lesions for at least 4 weeks. After the last course of chemotherapy, patients were followed every 3 months until death to monitor progression and survival. Statistical method Patients, who received at least two cycles of therapy, were considered assessable for response. Patients who received at least one course of therapy were assessable for toxicity. Time to progression was considered from the beginning of therapy to the date of disease progression. Overall survival was measured from the date of the first course of therapy to the date of death or last follow-up examination. Survival curves were plotted according to the Kaplan Meier method and confidence intervals for response rates were calculated using methods for exact binominal confidence intervals (15,16). RESULTS A total of 21 patients were enrolled in the study. Pretreatment characteristics of patients are listed in table 1. All patients were considered eligible for response and toxicity evaluations. Mean age was 50.2 years (range: years). Median ECOG performance status was 0. Fifteen patients (71.4%) had visceral metastases and most of them had liver and lung involvement as the predominant site. Fifteen patients had previously received adjuvant or neoadjuvant anthracycline based chemotherapy and 9 patients had previously received hormonotherapy. A total of 21 patients received 105 courses of chemotherapy, with a median of 6 courses per patients (range: 2-6 courses). In twenty one evaluable patients, the objective response rate was 57.1% (12 patients; 95% CI: 35.9% %) with 14.2 (3 patients; 95% CI: 0% %) CR, and 42.8% (9 patients; 95% CI: 21.6% %) PR. Additionally, stable and progressive disease was observed in 28.5% (6 patients) and 14.2% (3 patients) respectively (Table 2). The median time to progression (TTP) was 11 months (range: 2-28 months; 95% CI: 7% - 15%) (Figure 1) and the median overall survival (OS) was 19 months (range: months; 95% CI 16% - 22%) (Figure 2). One and two year survival rates were 71.4% and 9.5%, respectively. All patients were assessable for toxicity. Toxicity data is listed in table 3. Hematologic toxicities were the major dose-limiting toxicities. Treatment of five patients was discontinued due to toxicity. Grade 3-4 neutropenia, anemia and thrombocytopenia was observed in 21 (100%), 11 (52.3%), and 9 (42.8) patients respectively. First and second dose reductions due to myelotoxicity were performed in 14 (66.6%) and 9 (42.8%) patients, respectively. Seven (33.3) patients received scheduled dose. Major hematologic toxicities were observed in 20 patients after the first two cycles. In addition, 7 (33.3%) patients developed febrile neutropenia. Twelve patients required G-CSF support. Grade 3 or 4 bleeding, cardiotoxicity, hepatotoxicity were not observed. Toxicity related death was not observed.

4 162 GET in Metastatic Breast Cancer Table 1 Pretreatment characteristics of patients and tumors (N=21) Characteristics Mean age(years) 50.2 Range ECOG performance status No % Number of organs involved Site of metastasis Lung Liver Bone Soft tissue/skin Lymph node Other* Hormonal receptor status Positive Negative Prior therapy Adjuvant therapy only Metastatic therapy only Both adjuvant and metastatic therapy No prior chemotherapy Prior chemotherapy Adjuvant or neoadjuvant FEC Adjuvant CMF Adjuvant CMF plus metastatic first line FEC First-line metastatic FEC No prior chemotherapy Prior hormonotherapy Adjuvant therapy only Metastatic therapy only Both adjuvant and metastatic therapy Table 2 Response rates N patients % Objective Response Complete response Partial response Stable disease Progressive disease Fig 1. Kaplan-Meier analysis of time to progression. Median TTP=11 months *Surrenal gland and pleura FEC: fluorouracil 500mg/m2, epirubicin 50 mg/m 2, cyclophosphamide 500 mg/m 2 ; CMF: fluorouracil 600mg/m 2, methotrexate 40 mg/m 2, Cyclophosphamide 500 mg/m 2 Fig 2. Kaplan-Meier analysis of overall survival. Median overall survival=19 months

5 Demiray et al. 163 Table 3 Toxicities (105 cycles) WHO grade (number of patients, %) Neutropenia (42.8) 12 (57.1) Anemia - 3 (14.2) 7 (33.3) 8 (38.0) 3 (14.2) Thrombocytopenia - 4 (19.0) 8 (38.0) 3 (14.2) 6 (28.5) Infection 17 (80.9) 2 (9.5) 1 (4.7) 1 (4.7) - Nausea/vomiting 5 (23.8) 7 (33.3) 5 (23.8) 3 (14.2) 1 (4.7) Diarrhea 9 (42.8) 8 (38.0) 2 (9.5) 2 (9.5) - Mucositis - 5 (23.8) 9 (42.8) 5 (23.8) 1 (4.7) Neurotoxicity 2 (9.5) 7 (33.3) 12 (57.1) - - Cardiac 16 (76.1) 3 (14.2) 2 (9.5) - - DISCUSSION In our phase II study, we evaluated the efficacy and tolerability of 3-weekly paclitaxel 175 mg/m 2 (3-hour infusion) and gemcitabine 1000 mg/m 2 on day 1 and 4 and epirubicin 90 mg/m 2 at every 21 days regimen in metastatic breast cancer. The overall response rate was 57.1% with a 14.2% CR, and 42.8% PR. Time to progression and overall survivals were 11 and 19 months respectively. Early phase II trials which evaluate anthracycline paclitaxel combination in metastatic breast cancer, have shown that this combination is very active, with overall response rates ranging 75-95% and with CR rates as high as 40% (17-19). Phase III trials that compared anthracycline-paclitaxel combinations with standard anthracycline-alkylator regimens were not to support these results (20-24). Only one trial demonstrated a survival advantage for the paclitaxel containing regimens (24). However, the CR rates in all this phase III trials were lower than expected. The response rate and overall survival of our phase II study were similar to paclitaxel and anthracycline containing phase III trial results. The authors who take high CR as a goal conducted GET tripled chemotherapy trials (25,26). The first phase II monocenter trial showed that the response rate was 92% with 31% CR (27). After the impressive results, multicenter phase II trial was conducted. In this trial overall response rate was 71% with 15% CR (27). In a recently declared phase III study comparing gemcitabine plus epirubicin plus paclitaxel and fluorouracil plus epirubicin plus cyclophosphamide, Zielinski et al. (28) found the response rates as 62.3% and 51.2% respectively with an insignificant difference. In phase II and III, GET trial grade III-IV neutropenia, thrombocytopenia, anemia and febrile neutropenia were observed in 62-93%, 4-28%, 2-21% and 6-12% respectively. Neutropenia, leukopenia, febrile neutropenia, thrombocytopenia, anemia, allergy polyneuropathy, and mucositis were significantly higher in GET arm in phase III trial reported by Zielinski et al. Other toxicities were similar in two arms. In our study, major dose limiting toxicities were hematologic toxicities which neutropenia (100%), thrombocytopenia (42.8%), anemia (52.3%). Treatment of five patients was discontinued due to toxicity. Fourteen patients required dose reduction due to toxicity. Nine patients required first and second dose reduction and only seven (33.3%) patients completed the full treatment course. In anthracycline plus paclitaxel combination trials, grade 3 or 4 neutropenia and febrile neutropenia were similar in GET triplet but thrombocytopenia was less common (20-24). However, in gemcitabine plus paclitaxel combination trials, grade 3 or 4 neutropenia, thrombocytopenia, and febrile neutropenia were observed in 15-28%, 5-5.4% and % of the patients, respectively (7-11).

6 164 GET in Metastatic Breast Cancer The toxicity of our previous gemcitabine (1000 mg/m 2 d1,8) and paclitaxel (175 mg/m 2 d1) studies were lower than this study. Grade 3 or 4 toxicity was observed in 34.6% of patients and 76.9% of the patients completed the full treatment course (in press; Cancer Investigation). Although GET combination was not superior to standard anthracycline-alkylator regimen, these agents are already under consideration by the NSABP for inclusion in an adjuvant trial, where GT would follow the anthracyclinealkylator regimen (personal communication). In conclusion, our small numbered study shows that the GET regimen was effective but requires high proportional dose modification due to myelotoxicity. References 1. Bergh J, Jonsson PE, Glimelius B, et al. A systematic overview of chemotherapy effects in breast cancer. Acta Oncol 2001;40: Tomiak E, Piccart M, Mignolet F, et al. Characterisation of complete responders to combination chemotherapy for advanced breast cancer: a retrospective EORTC Breast Group study. Eur J Cancer 1996;32A: Rahman ZU, Frye DK, Smith TL, et al. Results and long term follow-up for 1581 patients with metastatic breast carcinoma treated with standard dose doxorubicin-containing chemotherapy: A reference. Cancer 1999;85: Hortobagyi GN. Treatment of breast cancer. N Engl J Med 1998;339: Razis ED, Fountzilas G. Paclitaxel: Epirubicin in metastatic breast cancer - a review. Ann Oncol 2001;12: Rinaldi DA, Lormand NA, Brierre JE, et al. Phase I trial of gemcitabine, administered as a standard and constant doserate infusion, in combination with paclitaxel in patients with advanced solid tumors (LOA-2). Am J Clin Oncol 2002;25: Sanchez-Rovira P, Medina MB, Mohendano N, et al. Results from a phase II study of gemcitabine in combination with paclitaxel in metastatic breast cancer. Ann Oncol 1998;9(suppl 4):77 (abstr) 8. Murad AM, Guimaraes RC, Aragao BC, et al. Phase II trial of the use of paclitaxel and gemcitabine as a salvage treatment in metastatic breast cancer. Am J Clin Oncol 2001:24: Colomer R, Llombart-Cussac A, Lluch A, et al. Biweekly paclitaxel plus gemcitabine in advanced breast cancer: phase II trial and predictive value of HER2 extracellular domain. Ann Oncol 2004;15: Delfino C, Caccia G, Gonzales LR, et al. Gemcitabine plus paclitaxel as first-line chemotherapy for patients with advanced breast cancer. Oncology 2004;66: O'Shaughnessy J, Nag S, Calderillo-Ruiz G, et al. Gemcitabine plus paclitaxel (GT) versus paclitaxel (T) as first-line treatment for anthracycline pre-treated metastatic breast cancer (MBC): Interim results of a global phase III study. Proc Am Soc Clin Oncol 2003;22: Perez-Manga G, Lluch A, Alba E, et al. Gemcitabine in combination with doxorubicin in advanced breast cancer: Final results of a phase II pharmacokinetic trial. J Clin Oncol 2000;8: Fumoleau P, Viens P, Dieras V, et al. Final results of gemcitabine (G) and epirubicin (E) phaseii trial in metastatic breast cancer (MBC) patients (pts). Program and Abstracts of the 25th Annual San Antonio Breast Cancer Symposium; December 11-14, 2002;25: Heinemann V. Role of gemcitabine in the treatment of advanced and metastatic breast cancer. Oncology 2003;64: Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1959;53: Cox DR. The analysis of binary data. London, UK: Methuen, Gianni L, Munzone E, Capri G, et al. Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequencefinding study. J Clin Oncol 1995;13: Gehl J, Boesgaard M, Paaske T, et al. Combined doxorubicin and paclitaxel in advanced breast cancer: Effective and cardiotoxic. Ann Oncol 1996;7: Conte PF, Baldini E, Gennari A, et al. Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: a regimen with high activity and low cardiotoxicity in advanced breast cancer. J Clin Oncol 1997;15: Luck H, Thomssen C, Untch M, et al.. Multicentric Phase III Study in First Line Treatment of Advanced Metastatic Breast Cancer (ABC). Epirubicin/Paclitaxel (ET) Vs Epirubicin/Cyclophosphamide (EC). A Study of the Ago Breast Cancer Group. Proc Am Soc Clin Oncol 2000;18:280.

7 Demiray et al Sledge GW, Neuberg D, Bernardo P, et al. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 2003;21: Biganzoli L, Cufer T, Bruning P, et al. Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as firstline chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer Multicenter Phase III Trial. J Clin Oncol 2002;20: Carmichael J. UKCCCR Trial of Epirubicin and Cyclophosphamide (EC) vs. Epirubicin and Taxol (ET) in the First Line Treatment of Women with Metastatic Breast Cancer (MBC). Am Soc Clin Oncol 2001;20: Jassem J, Pienkowski T, Pluzanska A, et al; Central & Eastern Europe and Israel Paclitaxel Breast Cancer Study Group. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: Final results of a randomized phase III multicenter trial. J Clin Oncol 2001;19: Sanchez-Rovira P, Jaen A, Gonzalez E, et al. Phase II trial of gemcitabine/doxorubicin/paclitaxel administered every other week in patients with metastatic breast cancer. Clin Breast Cancer 2000;1: Conte PF, Gennari A, Donati S, et al. Gemcitabine plus epirubicin plus taxol (GET) in advanced breast cancer: A phase II study. Breast Cancer Res Treat 2001;68: Cappuzzo F, Mazzoni F, Gennari A, et al. Multicentric phase II trial of gemcitabine plus epirubicin plus paclitaxel as firstline chemotherapy in metastatic breast cancer. Br J Cancer 2004;90: Zielinski C, Beslija S, Mrsic-Krmpotic Z, et al. Gemcitabine/epirubicin/paclitaxel (GET) vs 5- fluorouracil/epirubicin/cyclophosphamide (FEC) as firstline treatment in metastatic breast cancer (MBC): Demographics of a randomized, multicenter phase III trial of the Central European Cooperative Oncology Group (CECOG). Proc Am Soc Clin Oncol 2003;22:26.

Taxane/Anthracycline Combinations: Setting a New Standard in Breast Cancer?

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