Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement.

BACKGROUND: Uncontrolled studies suggest that high-dose chemotherapy is beneficial in patients with breast cancer and multiple metastases to the axillary lymph nodes. Many physicians accept this treatment as standard care. We aimed to assess adjuvant high-dose chemotherapy in breast cancer in a phase II randomised trial. METHODS: 97 women aged younger than 60 years, who had breast cancer with extensive axillary-node metastases (confirmed by a tumour-positive infraclavicular lymph-node biopsy), received three courses of up-front chemotherapy (FE120C). This regimen consisted of cyclophosphamide 500 mg/m2, epirubicin 120 mg/m2, and 5-fluorouracil 500 mg/m2 once weekly for 3 weeks. After surgery, stable patients or those who responded to chemotherapy were randomly assigned conventional therapy (fourth course of FE120C, followed by radiation therapy and 2 years of tamoxifen [40 patients]) or high-dose therapy (identical treatment but an additional high-dose regimen and peripheral-blood progenitor-cell [PBPC] support after the fourth FE120C course [41 patients]). This high-dose regimen comprised cyclophosphamide 6 g/m2, thiotepa 480 mg/m2, and carboplatin 1600 mg/m2. The primary endpoint was overall and disease-free survival. All analyses were by intention to treat. FINDINGS: No patients died from toxic effects of chemotherapy. With a median follow-up of 49 (range 21-76) months, the 4-year overall and relapse-free survivals for all 97 patients were 75% and 54%, respectively. There was no significant difference in survival between the patients on conventional therapy and those on high-dose therapy. INTERPRETATION: High-dose therapy is associated with substantial cost and acute toxic effects, but also has potentially irreversible long-term effects. Until the benefit of this therapy is substantiated by large-scale phase III trials, high-dose chemotherapy should not be used in the adjuvant treatment of breast cancer, apart from in randomised studies.

Dose and volume effects on fibrosis after breast conservation therapy.

PURPOSE: To analyze factors involved in the development of fibrosis in the boost area after breast conservation therapy (BCT) in patients treated with continuous low dose rate iridium implants following 50 Gy whole breast irradiation. METHODS AND MATERIALS: Fibrosis was estimated by palpation in 404 patients by four physicians. The median follow-up (FUP) duration was 70 months (range 30-133 months). Original implant data were used for reconstruction and dose-volume calculations. The total dose of the external whole breast irradiation and iridium implants was expressed in Normalized Total Dose (NTD): the total dose given in fractions of 2 Gy, which is biologically equivalent to the actual dose given according to the linear-quadratic model, using an alpha/beta value of 2 Gy, and 1.5 h for the recovery half-life of sublethal damage repair. To identify predictors of fibrosis we used a proportional odds model in a polychotomous logistic regression analysis. RESULTS: Seven independent factors were identified that were related to the severity of fibrosis: age, duration of FUP, clinical T-size, photon beam energy, NTD level, implant volume, and adjuvant chemotherapy. From the proportional odds model, a volume exponent could be estimated (0.16 +/- 0.04) that enabled us to determine dose-effect relations for different volumes. A 10-fold higher risk of fibrosis was seen when the total dose was above 79 Gy as compared with doses lower than 70 Gy. A fourfold increase in risk of fibrosis was seen for each 100 cm3 increase in irradiated boost volume. The use of adjuvant chemotherapy resulted in a twofold increase in the risk of fibrosis (dose modifying factor approximately 1.08). The application of Co-60 beams had a similar effect. The relative odds for the other factors were smaller (1.4 for each 10 years of older age, and 1.2 for clinical T-size over 20 mm). The FUP-period had a nonlinear effect: relative odds 2.2 at 6 years, 3.6 at 7-8 years, and 2.8 at 9-11 years. The dose rate (mean 0.57, range 0.26-0.89 Gy/h) had no influence on the development of fibrosis and there was no correlation between dose rate and irradiated volume. CONCLUSIONS: To optimize cosmetic results after BCT, both the total dose and the irradiated volume should be kept as low as possible. Minimum effective dose levels still have to be established. The boost volume can be minimized by more conformal brachytherapy techniques and optimal localization. It may be worthwhile to take adjuvant chemotherapy into account in decisions on boost dose levels.

Conservative breast cancer treatment: analysis of cosmetic results and the role of concomitant adjuvant chemotherapy.

Fifty-eight patients conservatively treated for T1 breast cancers are analyzed for cosmetic outcome; 17 had concomitant adjuvant combination chemotherapy (cyclophosphamide, adriamycin, 5 fluorouracil). The results are evaluated by clinical criteria and a quantitative measurement by use of light field projection at 33 months median follow-up. Surgery consisted of lumpectomy and axillary dissection; radiotherapy was given to the breast only except for additional internal mammary irradiation in central and medial lesions. (50 Gy whole breast, 64 Gy electron/photon boost). Questionnaires are used for inquiry on patient experience: 88% of the patients experienced a good to excellent cosmetic outcome. According to the panel only 64% show a good to excellent cosmesis. Panel-scores on asymmetry are compared with quantitative measurements. More esophagitis and probably a higher degree of fibrosis in the boost area is found in the chemotherapy group. No differences in cosmetic outcome, complication rates, and patient experiences are seen. Results are compared with published data.