Recent Advances in
Perioperative Chemotherapy of Locally Advanced Breast Cancer
A. Heiss, F. Kober, M. Hermann and R.
In the past local advanced breast cancer had a 5-year survival rate of 0 % and a relapse rate of 50 % (5) with surgical intervention only. The 5-year survival rate had increased to 13 % by 1965 as a result of the instruction of postoperative radiation therapy. In recent years it has been increasingly recommended to treat local advanced breast cancer with perioperative chemotherapy. The first such treatment was tested by Brock on a rat tumor in 1959. Rosen et al. used preoperative chemotherapy for the first time on an osteosarcoma. According to different published studies, an improvement of the survival rate to more than 30 % was achieved with patients who were treated with preoperative chemotherapy in comparison with 20 % of patients treated only with adjuvant chemotherapy. All previous studies have shown that the response rate to preoperative chemotherapy is more than 50 %. The better prognosis of responders than nonresponders is significant. However, it is still unclear exactly when the operation should be performed and the methods of examination by which this can be determined.
Patients and chemotherapy. Since 1987 a prospective study on 29 patients with local advanced breast cancer has been carried out in the Kaiserin-Elisabeth-Hospital, and 26 patients have so far been fully evaluated. The average age of the patients was 67 years (range, 33 to 84 years), and the median survival time was 32,8 months (minimum, 7 months; maximum, 67 months). Inclusion criteria were as follows: (i) primary breast cancer; (ii) tumor stage T3 to T4, Nx, Mx, T2, Npos, Mx; (iii) no previous chemotherapy treatment; (iv) no contraindication to chemotherapy; and (v) patient`s consent. Of the 26 patients evaluated, 19 were in the T4 stage, 2 were in T3, and 5 were in T2. Eight patients had distant metastases when they were first seen. Furthermore, 11 patients had ulceration of the skin, 3 had an inflammatory carcinoma, 5 had multilocular carcinoma, and 15 patients had tumors fixed on the chest wall. Eighteen patients were inoperable according to Haagensen`s criteria. (5)
Before proceeding with preoperative chemotherapy, we verified the diagnosis by mammography, sonography, and fine-needle biopsy. Chest radiography, liver sonography, and a bone scan were carried out as staging examinations. The preoperative chemotherapy followed the following schema: day 1, 500 mg of cyclophosphamide per m2 of body surface area (BSA), 14 mg of mitroxantrone per m2 of BSA, and 500 mg of 5-fluorouracil per m2 of BSA; day 2, 500 mg of 5- fluorouracil per m2 of BSA, days 2 to 5, 200 mg of cyclophosphamide orally, from day 1, 20 mg of tamoxifen. The interval between cycles (two to four preoperative cycles) was 3 weeks, and there was a total of six or seven cycles. Twenty-four patients completed the total treatment (two patients refused postoperative chemotherapy).
However, we are faced with the dilemma of how to accurately monitor the response of the tumor to preoperative chemotherapy, thus determining the best time to operate. In our study tumor development was observed not only by clinical methods but also by breast sonography and mammography, thereby providing a correlation between clinical and pathological results. The responses to preoperative chemotherapy were as follows: 4 patients had complete remission. 18 had partial remission, and 4 had minimal response or no change. The most important criteria for the time of operation were the reduction of the tumor size and its movement. In most cases the operation took place 3 to 4 weeks after the third preoperative chemotherapy.
Type of operation. In our study, 2 patients had a radical mastectomy, 17 had a modified mastectomy, 7 had a partial mastectomy or lumpectomy plus axillary lymph node dissection, 2 agreed only to palliative lumpectomy and 1 refused to be operated on (she had a inflammatory carcinoma, and after six cycles of chemotherapy there was a considerable reduction of inflammation and the tumor was reduced by more than 75 %, verified by mammography and sonography).
Results. In our prospective study we could clearly divide the patients into two groups. In the first group, containing 16 patients (61,5 %), the response rate was more than 50 % and the median survival time was 36,3 months. In the second group, containing 10 patients (38,5 %), the response rate was less than 50 % and the median survival time was 27,2 months. In agreement with other studies, our study also showed a higher median survival time for the responders than for the nonresponders: 4 patients had a complete remission (15,3 %), 18 had partial remission (69,6 %), and 4 had minimal or no change (15,3 %); therefore, a total of 85 % had complete or partial remission. Eight patients died, three postoperatively, two from myocardical infarction, and one from pulmonary infarction (n=29). Four patients with stage T4 N1 M1 cancer died as a result of distant metastases 43, 33, 17, and 12 months after onset of therapy. One patient developed distant metastases and died 1 year later. Four patients had a local recurrence, and one had a scar recurrence. Eighteen patients were still tumor free by May 1993.
Discussion. In recent years neoadjuvant chemotherapy has become generally recommended for advanced inoperable primary breast carcinoma. Response rates of about 75 % and histologically confirmed complete remissions up to 20 % have been reported in the literature. In or group of patients we had a response rate of 85 % (complete response plus partial response) and a median observation time of 32,8 months. The relapse rate was 19,2 %. Hormonal therapy (tamoxifen, 20 mg) was used from the beginning of and in combination with the neoadjuvant chemotherapy (according to various reports in the literature, the response rate to tamoxifen among receptor-negative women was 13 %). In our study the hormonal therapy was continued for 2 years postoperatively or until tumor progression. A standard regimen has not yet been established. Usually, polychemotherapy including anthracycline is used. In our prospective study cyclophosphamide, 5-fluorouracil, and mitoxantrone were used. One patient developed grade 4 leukopenia (World Health Organization classification). Twenty-four patients (n=26) completed perioperative chemotherapy; 2 received postoperative radiotherapy.
On the basis of our study we believe that perioperative chemotherapy is also indicated even in older patients with locally advanced breast cancer.