Maintenance Versus Observation After 6 Cycles of Gemcitabine Plus Paclitaxel in Pts With Advanced Breast Cancer
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Phase III, Multicenter, Randomized Trial of Maintenance Versus Observation After Achieving Clinical Response in Pts With Metastatic or Recurrent Breast Cancer Who Received 6 Cycles of Gemcitabine Plus Paclitaxel(GP) as 1st-line Chemotherapy|
- Progression free survival [ Time Frame: approximately 4 years ]
- a) overall survival b) quality of life c) toxicity of GP chemotherapy d) duration of response [ Time Frame: approximately 4 years ]
|Study Start Date:||May 2007|
|Study Completion Date:||December 2016|
|Primary Completion Date:||December 2016 (Final data collection date for primary outcome measure)|
No Intervention: Arm 1
Observation after 6 cycles of gemcitabine plus paclitaxel till progression
Experimental: Arm 2
Maintenance chemotherapy with gemcitabine plus paclitaxel after 6 cycles of gemcitabine plus paclitaxel till progression
Drug: gemcitabine , paclitaxel
Gemcitabine 1250 mg/m2 i.v. Day 1 & 8
Paclitaxel 175 mg/m2 i.v. day 1
repeat every 3 weeks
Hide Detailed Description
The primary goal of therapy in patients with metastatic breast cancer is palliation and prolongation of life with quality, because many if not most patients with metastatic breast cancer ultimately die of their disease. Although there are no randomized trials comparing chemotherapy with supportive care in women with metastatic breast cancer, chemotherapy clearly provides a survival benefit in early breast cancer and produces tumor shrinkage in metastatic disease. Institutional databases show an improvement in the survival of patients with metastatic disease over the past two decades, which may be due to diagnosis at earlier phases of metastatic disease and more effective therapies. The median survival of patients treated with modern taxane-based chemotherapy is now reaching approximately 2 years.
The duration of chemotherapy in patients responding or stable disease remains controversial, since quality of life is not usually adversely affected and may even be improved in many patients receiving cytotoxic chemotherapy. In addition, many commonly used chemotherapeutic agents are not limited by cumulative toxicity in metastatic breast cancer patients. Several trials have reported that continuous therapy generally prolonged the duration of remission, but the effect on survival and quality of life were less consistent.
Coates et al compared continuous therapy with AC or CMF with intermittent therapy using 3 cycles of the same regimen with reinstitution of therapy at the time of disease progression. Patients receiving continuous therapy had superior response rates, time to progression, and better quality of life, but no improvement in overall survival in this trial. A similar trial by the Peidmont Oncology Association randomly assigned patients who had responding or stable disease after six cycles of CAF to either CMF or observation, followed by reinstitution of CMF at disease progression . Although time to progression was more than twice as long for patients on continuous therapy than for those with interrupted treatment, overall survival was similar. Falkson et al randomly assigned 141 patients whose measurable disease showed a complete response after 6 cycles of CAF to receive either chemohormonal therapy or observation and found no difference in overall survival despite of prolongation of time to progression in treatment arm . In summary, these data suggest that maintenance chemotherapy is associated with superior time to progression but no survival gain. However, these randomized trials did not incorporate taxane-based chemotherapeutic regimens, the new standard of care in metastatic breast cancer patients these days.
In the 10 years since their initial licensing in Europe, the taxanes, paclitaxel and docetaxel, have emerged as critical drugs in the treatment of metastatic breast cancer patients. In TAX 303 trial, patients with prior alkylating agent exposure were randomly assigned to receive either docetaxel, 100 mg/m2, or doxorubicin, 75 mg/m2, every 3 weeks. Docetaxel produced a superior response rate (48% versus 33%, P=.008) and time to treatment failure. In addition, docetaxel was less marrow suppressive, with statistically significantly lower rates of thrombocytopenia, anemia, transfusions of blood and platelets, and neutropenic fever. Paclitaxel has been compared with doxorubicin in two randomized trials. In a European Organization for Research and Treatment of Cancer study, paclitaxel (200mg/m2 administered in a 3-hour infusion) was inferior to doxorubicin . In an Eastern Cooperative Oncology Group (ECOG) trial, 24-hour paclitaxel and doxorubicin produced equivalent results . Paclitaxel has also been shown to be equivalent to CMFP (cyclophosphamide, methotrexate, fluorouracil, prednisone) chemotherapy as first-line chemotherapy for metastatic breast cancer patients .
The survival advantage of combination chemotherapy has not been firmly established in breast cancer patients yet. No trial has shown a convincing survival advantage from combination therapy over single agents given in sequence. However, all published trials have been criticized for being underpowered and unable to demonstrate survival differences as high as 20% . A 1998 metaanalysis of 1,986 patients randomly assigned between combination chemotherapy and single-agent therapy in metastatic breast cancer patients demonstrated a survival advantage to combination chemotherapy, with a hazard ratio of 0.82 (range, 0.75 to 0.90). Two recently published studies, capecitabine and docetaxel versus docetaxel alone and paclitaxel and gemcitabine versus paclitaxel alone , have shown significant survival advantages of combination chemotherapy.
In the capecitabine/docetaxel study, 511 patients with measurable metastatic breast cancer who had received a prior anthracycline were randomly assigned to receive either docetaxel and oral capecitabine or docetaxel alone . The combination of docetaxel and capecitabine demonstrated a higher response rate (42% vs 30%, P=.006), longer time to progression (6.1 vs 4.2 months, P=.0001), and longer overall survival (14.5 vs 11.5 months, P=.0126). The gemcitabine/paclitaxel study randomized 529 women with chemo-naïve, measurable metastatic breast cancer to receive either paclitaxel (175 mg/m2 over 3 hours every 3 weeks) and gemcitabine (1,250 mg/m2 over 30 minutes, on days 1 and 8 every 3 weeks), or paclitaxel (175 mg/m2 over 3 hours every 3 weeks) alone. The combination arm showed higher response rates (41% vs 22%, P<.0001), longer time to progression (5.2 vs 2.9 months, P<.0001), and longer survival (18.5 vs 15.8 months, P=.018).
At the ASCO meeting 2005, Chan and colleagues reported the results of a European phase III study comparing gemcitabine/docetaxel versus capecitabine/docetaxel for anthracycline-pretreated metastatic breast cancer patients . 305 patients were randomized to receive gemcitabine/docetaxel over capecitabine/docetaxel and there were no significant difference in response rate, PFS, or survival between the two arms. However, gemcitabine/docetaxel had a better risk-benefit profile in terms of less drug-related discontinuation, less gastrointestinal toxicity, and less skin toxicities.
Although there are several randomized trials showing negative results for survival gain in patients who received maintenance chemotherapy, the role of maintenance chemotherapy with newer agents, such as docetaxel or paclitaxel, have not been established yet. The Italian MANTA trial has registered 451 metastatic breast cancer patients to receive induction chemotherapy with epirubicin or doxorubicin/paclitaxel and further randomized 253 responders (CR, PR, SD) to receive maintenance therapy with paclitaxel or observation . Although this trial demonstrated no difference in PFS or survival between the two arms, their metaanalysis advocated survival benefit of maintenance therapy. Since gemcitabine/paclitaxel (GP) combination chemotherapy is one of the two regimens which showed definite survival gain from a randomized trial, we plan to randomize patients who responded to six cycles of GP induction chemotherapy to receive additional maintenance GP chemotherapy until disease progression versus observation. We hypothesize that patients who receive maintenance GT chemotherapy will do better in terms of progression free survival.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00561119
|Korea, Republic of|
|Hanlym University Hospital|
|Anyang, Kyeongki-Do, Korea, Republic of, 431-070|
|Bundang Seoul National University Hospital|
|Bundang, Kyeongki-Do, Korea, Republic of, 463-707|
|Ajou University University Hospital|
|Suwon, Kyungki-Do, Korea, Republic of|
|Yeungnam University Hospital|
|Kyungsan, Kyungsangbuk-Do, Korea, Republic of|
|Daegu Patima Hospital|
|Daegu, Korea, Republic of, 701-600|
|Inha University School of Medicine|
|Inchon, Korea, Republic of, 400-711|
|Seoul National University Hospital|
|Seoul, Korea, Republic of, 110-744|
|Yonsei University Hospital|
|Seoul, Korea, Republic of, 120-752|
|Samsung Medical Center|
|Seoul, Korea, Republic of, 135-710|
|National Cancer Center|
|Seoul, Korea, Republic of, 140-320|
|Kunkuk University Hospital|
|Seoul, Korea, Republic of, 143-729|
|Ewha University Hospital|
|Seoul, Korea, Republic of, 911-1|
|Asan Medical Center|
|Seoul, Korea, Republic of|
|Soonchunhyang University Hospital|
|Seoul, Korea, Republic of|
|Ulsan University Hospital|
|Ulsan, Korea, Republic of, 682-714|
|Principal Investigator:||Young-Hyuck Im, M.D., Ph.D||Samsung Medical Center|