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Phase II Study of Neoadjuvant Chemotherapy of Breast Cancer

Phase 2
19 Years
Open (Enrolling)
Breast Cancer

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Trial Information

Phase II Study of Neoadjuvant Chemotherapy of Breast Cancer

Neoadjuvant chemotherapy has been used for years to treat patients with breast cancer whose
primary tumors are too large to allow for breast conservation surgery [1]. Reduction in size
of the primary tumor with neoadjuvant chemotherapy has made possible the use of lumpectomies
instead of mastectomies in a large fraction of these cases. In the past this was the major
objective of neoadjuvant chemotherapy for breast cancer, but more recently the focus has
changed and the goals have expanded [2]to include: 1- determination of the chemosensitivity
of the tumor so that subsequent chemotherapy can be modified accordingly. 2- to prolong
disease free survival . 3- to prolong survival.

So far there has been no consistent improvement in survival using this approach, although
two recent studies suggest that a survival benefit might actually occur[3, 4]. However,
there is consensus that patients who receive neoadjuvant chemotherapy and who achieve a
"pathological CR", meaning that no tumor is found at time of definitive tumor resection,
have experienced longer survival[5-8]. Perhaps with a more active neoadjuvant combination a
significantly higher pathological CR rate can be obtained, and thus longer survival

Most neoadjuvant regimens that have been used in the past have only included induction with
3-4 courses of an anthracycline based regimen without a Taxane, followed by surgery and
further chemotherapy subsequently. However, the incorporation of docetaxel after an
anthracycline-based regimen (Aberdeen and NSABP-B27 protocols) [4, 9]led to better clinical
response, subsequently to better breast conservation and more important, an increase in the
pathological complete response rate. In the NSABP-B-27 study, 2,411 patients with operable
primary breast cancer were randomly assigned to one of three treatment arms: a) four cycles
of preoperative AC followed by surgery. b) four cycles of preoperative AC followed by four
cycles of preoperative docetaxel (100 mg/m2 IV every 3 weeks), or c) four cycles of AC
followed by surgery and subsequently four cycles of postoperative docetaxel. Compared to
preoperative AC alone, preoperative AC followed by preoperative docetaxel increased the
clinical complete response rate (40.1% v 63.6%; P < .001), the overall clinical response
rate (85.5% v 90.7%; P < .001), the pathologic complete response rate (13.7% v 26.1%; P <
.001), and the proportion of patients with negative nodes (50.8% v 58.2%; P < .001).

Improvement of relapse free survival has also been observed in the NSABP-B-27 and Aberdeen
trials. In the latter trial, improvement in overall survival has also been reported.. A
statistically significant improvement in overall survival has not been observed yet in the
NSABP-B-27 trial but a longer follow-up of this study is required to better evaluate the
impact of including Taxotere (Docetaxel) as part of the neoadjuvant strategy on overall
survival of breast cancer. One subgroup of patients in the NSABP-B-27 trial was found in a
retrospective analysis to benefit the most. This was the group who achieved a clinical
partial response after the first four courses of AC and who received four additional courses
of Docetaxel. They benefited from a longer disease free survival.

In another neoadjuvant trial performed at MD Anderson Cancer Center, patients with a
pathologic response but with residual tumors >1 cm were randomized to receive postoperative
chemotherapy based on their response to preoperative chemotherapy. Those patients who had a
change in their chemotherapy experienced a longer survival.

A review of neoadjuvant trials shows that those with the higher number of preop chemotherapy
courses have the best results. We feel that the next step should be the development of a
preoperative combination chemotherapeutic regimen which provides the highest pathological
complete response rate and the highest lymph node negative status.

In our study we propose to: 1- incorporate Docetaxel as part of the induction neoadjuvant
regimen in all patients. 2- tailor the neoadjuvant chemotherapy regimen according to the
preoperative response as judged by MRI so that patients whose maximum response after the
first four courses of an anthracycline-docetaxel based combination, is a partial remission
or less, will receive four courses of a non-cross resistant regimen. 3- prolong the
duration of neoadjuvant preoperative chemotherapy to a total of eight courses. 4- complete
the neoadjuvant chemotherapy before surgery so that the chances for a pathological CR are
increased. 5- include Trastuzumab (Herceptin) as part of the neoadjuvant treatment in
patients who are Her-2 positive.

A combination derived from the established TAC (Taxotere, Adriamycin, Cyclophosphamide)
regimen but which uses Epirubicin, a less cardiotoxic analogue of Doxorubicin (Adriamycin),
will be tested. Those Her-2 negative patients whose response to the first 4 courses of
induction TEC is less than a complete remission, will have their treatment changed to a
second line regimen, Navelbine-Avastin-Xeloda ("NAX"), with the intention of capturing a
better response prior to surgery. Those who are Her-2 positive will initially also receive
TEC but subsequent therapy will include Trastuzumab (Herceptin) whether they respond well or
not to TEC.

Inclusion Criteria:

- Previously untreated (no chemotherapy or hormonal therapy or radiation therapy)
invasive breast cancer.

- Diagnosis of invasive ductal or lobular breast cancer plus or minus DCIS.
Inflammatory carcinomas will also be eligible.

- Age > 18 years

- Tumor > 1.0 cm by MRI and/or sonographic or clinical exam measurements.Although only
tumors > 2 cm are considered measurable by RECIST criteria, we will nevertheless
include tumors > 1 cm since the primary endpoint is pathological CR rate.

- Performance Status ECOG <2 or Karnofsky >50%

- Peripheral neuropathy < grade 1

- Hematologic (minimal values):

- Absolute neutrophil count > 1,500/mm3

- Hemoglobin > 8.0 g/dl

- Platelet count > 100,000/mm3

- Hepatic

- Total Bilirubin normal

- AST and ALT and Alkaline Phosphatase do not have to be within the range. In
determining eligibility the more abnormal of the two values (AST or ALT) should be
used as shown below.

Exclusion Criteria:

- Pregnant or breast feeding patients are excluded.

- Patients with second malignancies with expected survival < 5 years.

- Previous chemotherapy with either Taxanes, Anthracyclines or Cyclophosphamide.

- Patients with history of severe hypersensitivity reaction to Taxotere (Docetaxel) or
other drugs formulated with polysorbate 80.

- Pure DCIS diagnoses are not eligible.

- Special histologies with favorable prognosis such as mucinous, tubular are not

- Patients with reduced ejection fraction <50% are not eligible.

- Patients with tumors < 1.0 cm

- Cardiac thrombotic events in the past 12 months

- Stroke or transient ischemic attacks (TIA) within 12 months

- Poorly controlled hypertension defined as persistent blood pressure elevation >150
systolic and/or 100 diastolic not responsive to medications

- GI condition that increases risk of perforation within 6 months of study

- Any serious non-healing wound, ulcer, or bone fracture

- No minor surgical procedure within 7 day of study entry or major surgery within 28
days of study entry or anticipation of need for major surgical procedure during the
course of the study

- Significant vascular disease such as symptomatic peripheral vascular disease

- Any evidence of bleeding diathesis or coagulopathy

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate the pathological CR rate in breast and lymph nodes of a novel neoadjuvant regimen for invasive breast carcinoma

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Fernando Cabanillas, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Auxilio Mutuo Cancer Center


United States: Institutional Review Board

Study ID:

CCAM 07-03



Start Date:

July 2008

Completion Date:

December 2012

Related Keywords:

  • Breast Cancer
  • neoadjuvant chemotherapy breast cancer
  • Breast cancer patients with tumors over one cm
  • Breast Neoplasms