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.