High-Risk Breast Cancer Clinical Trial
Official title:
A Prospective Randomized Feasibility and Phase II Adjuvant Breast Cancer Study of the Netherlands Working Party for Autotransplantation in Solid Tumors.
Objectives of the study:
This randomized multicenter phase II study compares the tolerability, toxicity and quality
of life between two high-dose chemotherapy regimens based on cyclophosphamide, thiotepa and
carboplatin.
Regimen A: full dose CTC. Regimen B: two courses of CTC (tCTC) with 33% dose reduction.
Primary endpoints are:
- Maximum degree of non-hematological toxicity.
Secondary endpoint:
- Total number of hospital days.
- Quality of life evaluations during and following high-dose chemotherapy (up to 1 year).
- Effect of therapeutic dose monitoring of CTC or tCTC.
Trial design:
This investigation is a multicenter prospective randomized phase II study. Patients eligible
for the study will be identified after mastectomy or wide tumor excision with axillary
clearance. Following randomization, all patients will receive four courses of
cyclophosphamide, epirubicin and fluorouracil (FEC). Patients with early progressive disease
at any time will be taken off study. The first chemotherapy course must be given as soon as
possible after the surgical procedure, preferably within 3 weeks, but not later than 6 weeks
since primary surgery. After the third or fourth FEC course G-CSF is administered and
peripheral stem cells will be harvested. All radiation therapy (including radiation therapy
administered as part of a breast conserving strategy) must be postponed until all
chemotherapy has been concluded.
Questionnaires, comprising the Rotterdam Symptom Checklist (RSCL) and the Short-Form General
Health Survey (SF-36) will be sent by mail before randomization, after chemotherapy, 3
months thereafter, further on every l/2 yr till at least 1 year follow-up as performed
earlier. [6, 28, 29].
All patients will be randomized before the initiation of chemotherapy.
- The 'standard' treatment arm will include 4 courses of FEC followed by high-dose
chemotherapy with a single course of full dose CTC followed by peripheral stem cell
reinfusion. Subsequently, conventional external beam radiotherapy to the breast or
chest wall and to the regional lymph node areas including the axilla and the
parasternal area will be administered following guidelines of the individual center.
Patients with hormone receptor positive disease will go on to receive 5 years of
tamoxifen. Patients with receptor positive disease who have not entered menopause will
be advised to undergo ovarian ablation as well.
- The 'experimental' treatment arm will be identical to the 'standard' one, except that
the single course of CTC will be replaced by 2 courses of tCTC each followed by
peripheral stem cell reinfusion.
High-dose chemotherapy with the alkylating agent combination CTC appears to add significantly to the efficacy of conventional dose chemotherapy in patients with high-risk breast cancer, provided that the HER-2/neu gene is not amplified in the tumor. As a high-dose chemotherapy regimen, CTC is associated with significant toxicity [31,32]. Although high-dose alkylating therapy seems to be effective, there is virtually nothing known about the dose-response curve for this combination (for a detailed discussion see the classical paper by E. Frei III [32]. If one assumes that the efficacy increase levels off with increasing dose, the efficacy of tCTC might be almost as great as that of CTC, but with considerably less toxicity. In addition, two closely spaced courses of tCTC might further increase the efficacy of the regimen. There are some suggestions that a double transplant may be more effective than a single one, in multiple myeloma and in Ewing sarcoma. A similar suggestion has also been made for breast cancer (study of Nitz et al ref 4, table 1). ;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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