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.

Sex

Female

Minimum age

18 Years

Maximum age

50 Years

Inclusion criteria:

1. Modified radical mastectomy (or breast conserving surgery) and axillary clearance, histologically confirmed stage IIA, IIB or IIIA adenocarcinoma (excluding supraclavicular lymph nodes) of the breast, with 4 or more involved axillary lymph nodes. Presence of tumor cells near or in the resection margins at microscopic examination is acceptable
2. The primary tumor must be immunohistochemically negative for HER-2/neu expression. An immunohistochemistry score of 1+ is also acceptable. A score of 3+ is not acceptable. A score of 2+ is only acceptable if a FISH analysis (or equivalent) has clearly shown that there is no HER-2/neu gene-amplification
3. No prior chemotherapy or radiotherapy
4. No evidence of distant metastases
5. Age \< 50 years
6. Performance status (ECOG-ZUBROD) 0 or 1;
7. Normal bone marrow function, WBC \> 4.0 x 109/l, platelets \> 100 x 109/l;
8. Adequate renal function (creatinine clearance \> 60 ml/min.);
9. Adequate hepatic function (serum bilirubin \< 25 umol/l);
10. Study treatment must begin within 6 weeks of surgery;
11. No other malignancy except adequately treated in situ carcinoma of the cervix or basal cell carcinoma of the skin;
12. No significant prior or concomitant disorder that might interfere with adherence to the intensive treatment regimen, including but not limited to a history of angina, myocardial infarction or heart failure, severe lung function impairment, peptic ulcer disease, etc.;
13. Availability for follow-up.

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• BACKGROUNDBergh J, Wiklund T, Erikstein B, Lidbrink E, Lindman H, Malmstrom P, Kellokumpu-Lehtinen P, Bengtsson NO, Soderlund G, Anker G, Wist E, Ottosson S, Salminen E, Ljungman P, Holte H, Nilsson J, Blomqvist C, Wilking N. Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study. Lancet. 2000 Oct 21;356(9239):1384-91. doi: 10.1016/s0140-6736(00)02841-5. PMID 11052580
• BACKGROUNDTallman MS, Gray R, Robert NJ, LeMaistre CF, Osborne CK, Vaughan WP, Gradishar WJ, Pisansky TM, Fetting J, Paietta E, Lazarus HM. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med. 2003 Jul 3;349(1):17-26. doi: 10.1056/NEJMoa030684. PMID 12840088
• BACKGROUNDNitz UA, Frick M, Mohrmann S. Lindemann H, Jackisch C, Werner C, Souchon R, Metzner B, Rufert U, Bender HG. Tandem high dose chemotherapy versus dose-dense conventional chemotherapy for patients with high risk breast cancer: Interim results from a multicenter phase III trial. Proc Am Soc Clin Oncol 22: 2003 (abstract 3344).
• BACKGROUNDBonneterre J, Roche H, Kerbrat P, Bremond A, Fumoleau P, Namer M, Goudier MJ, Schraub S, Fargeot P, Chapelle-Marcillac I. Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol. 2005 Apr 20;23(12):2686-93. doi: 10.1200/JCO.2005.05.059. PMID 15837983
• BACKGROUNDRodenhuis S, Bontenbal M, Beex LV, Wagstaff J, Richel DJ, Nooij MA, Voest EE, Hupperets P, van Tinteren H, Peterse HL, TenVergert EM, de Vries EG; Netherlands Working Party on Autologous Transplantation in Solid Tumors. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med. 2003 Jul 3;349(1):7-16. doi: 10.1056/NEJMoa022794.