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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

Phase 3
18 Years
Open (Enrolling)
Advanced Breast Cancer

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Trial Information

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

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 [16]. 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.

Inclusion Criteria

Inclusion Criteria

- Histologically Confirmed Metastatic, or Recurrent Breast Cancer

- Age over 18 Years

- ECOG Performance Status 0-2

- Premenopausal or Postmenopausal Breast Cancer Patients With Measurable or
Non-Measurable Lesions, Who Are Candidates for Chemotherapy

- Life Expectancy ≥ 3 Months

- Patients May Have Received Prior Neoadjuvant or Adjuvant Taxane Regimen as Long as it
Has Been 12 Months Since Completion of Regimen.

- Patients Either May or May Not Have a Prior Anthracycline Containing Regimen.

- Prior Hormonal Therapy as a Treatment of Metastatic Disease is Allowed. But
Antitumoral Hormonal Therapy Must be Terminated Prior to Enrollment(up to the Date of

- Prior Radiation Therapy Allowed as Long as < 25% of the Bone Marrow Has Been
Treated,and the Patients Must Have Recovered From the Acute Toxic Effects of the
Treatment Prior to Study Enrollment.Prior Radiation to the Whole Pelvis is Not
Allowed. Prior Radiotherapy Must be Completed 4 Weeks Before Study Entry.

- Adequate Bone Marrow Function (≥ ANC 1,500/ul, ≥ Platelet 100,000/ul, ≥ Hemoglobin
9.0 g/dl)

- Adequate Renal Function (≤ Serum Creatinine 1.5 mg/dl or CCr ≥ 50 ml/Min)

- Adequate Liver Function (≤ Serum Bilirubin 1.5 mg/dl, ≤ AST/ALT x 3 Upper Normal

- No Prior History of Chemotherapy for Metastatic, Recurrent Breast Cancer

- Written Informed consent.

Exclusion Criteria

- Serious Uncontrolled Intercurrent Infections

- Serious Intercurrent Medical or Psychiatric Illness, Including Active Cardiac Disease

- Pregnancy or Breast Feeding

- Second Primary Malignancy(Except Cancer of Cervix or Skin or Other Malignancy Treated
at Least 5 Years Previously With no Evidence of Recurrence)

- Documented Parenchymal or Leptomeningeal Brain Metastasis

- Peripheral Neuropathy ≥ Grade 2

- Prior Treatment With Gemcitabine Will Not be Allowed.

- HER-2 Overexpressing Breast Cancer and Concomitant Trastuzumab Treatment is Not

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression free survival

Outcome Time Frame:

approximately 4 years

Safety Issue:


Principal Investigator

Young-Hyuck Im, M.D., Ph.D

Investigator Role:

Principal Investigator

Investigator Affiliation:

Samsung Medical Center


South Korea: Institutional Review Board

Study ID:




Start Date:

May 2007

Completion Date:

December 2011

Related Keywords:

  • Advanced Breast Cancer
  • maintenance chemotherapy
  • metastatic or recurrent breast cancer
  • gemcitabine
  • paclitaxel(GP)
  • Breast Neoplasms