Chemotherapy of Breast Cancer

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1 Japan - Taiwan Joint Symposium on Medical Oncology Session 7 Breast cancer journal homepage: Chemotherapy of Breast Cancer Mei-Ching Liu Department of Medicine, Koo Foundation Sun Yat-Sen Cancer Center Abstract. The incidence of female breast cancer increased from year of 1979 gradually in Taiwan. In year of 2003, Breast cancer is the top leading cancer incidence. Although the mortality also increased, the slope was not paralled with increase of incidence. This fact indicated the early diagnosis and improvement of treatment of breast cancer. The role of adjuvant chemotherapy is the major cause of improvement. KF-SYSCC started the multidisplinary treatment of breast cancer since set up of hospital. Breast cancer team formally formed in Then we have chemotherapy guideline. According to this guideline, from 1990 to 1999, the result of 1357 patients showed:the 5-year DFS for stage 0 was 93%, for stage I: 83%, for stage II: 77%, for stage III: 50%, and for these patients who received induction chemotherapy: 38%. Later on, further modified adjuvant C/T of CAF to TAC. ACMF to dose dense ATC showed a very mild side effect and improved survival of TAC to FAC is proved by BCIRG001. The ATC versus ACMF showed improved DFS and OS for patients of breast cancer with 10 or more Lymph node involvement. Keywords : KF-SYSCC, Induction chemotherapy, adjuvant chemotherapy, dose dense chemotherapy INTRODUCTION In Taiwan, the incidence of female breast cancer increased from year of 1979 gradually, there was a dramatic increase in 1994 then reached to peak in year of According to cancer registration in year of 2003, the female breast cancer is the top leading cause of cancer incidence (Figure 1) as ranked by incidence rate of 4802/10 5 populations. Although there was also a tendency of increase of mortality of female breast cancer, the slope of this increase is not parallel as that *Corresponding author: Dr. Mei-Ching Liu Tel: ext.1684 Fax: chiayu@mail.kfcc.org.tw of the increase of incidence. This fact indicated the progress of early detection and the treatment of breast cancer, especially the development of new chemotherapy of breast cancer and the progress of supportive treatment. The age of breast cancer patients increased gradually from y/o and reached to peak at y/o, it then deceased gradually from y/o to more than 80 y/o. This tendency was in contrast to the age incidence of other cancers which had the tendency of increasing incidence according to the increase of age. Koo Foundation Sun Yat-Sen Cancer Center (KF-SYSCC) is the first cancer center in Taiwan. It was set up in year of 1982 at the temporary location in Taipei and moved to permanent center in Taipei County at year of 1997.

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78 M. C. Liu / Proc JTJS (2007) 76-84 THE EXPERIENCES OF TREATMENT OF BREAST CANCER IN TAIWAN The treatment of the cancer in KF-SYSCC was via multi displinary teamwork.

3 78 M. C. Liu / Proc JTJS (2007) THE EXPERIENCES OF TREATMENT OF BREAST CANCER IN TAIWAN The treatment of the cancer in KF-SYSCC was via multi displinary teamwork. In the breast team, it included: 1.) The physicians of surgical department, medical oncology, diagnostic radiology, pathology, radiation oncology, rehabilitation, plastic surgery, psychiatrist. 2.) The supportive group: nursing department, dietitian and social worker. 3.) Monitor group: care manager, biostatistian of clinical protocol office. The whole group holds the breast conference on morning of Monday and Wednesday every week. The patients operated last week were discussed and the treatment planning was decided. PATIENT S MATERIALS From 1999 to Dec a total of 2137 patients of breast disease were registered, among them, 4 were breast lymphoma, 19 were breast sarcoma and 757 patients has received prior treatment for breast cancer at other hospital, so 1357 patients were diagnosed as primary breast cancer and included in this series of report. The pathological stage of these operated breast cancers was as followings: 176 (13.6%) stage 0, 357 (26.5%) stage I, 403 (29.8%) stage II, 231 (17.1%) stage III, and 94 (7.0%) stage IV, 94 patients (6.7%) received preoperative induction chemotherapy followed by surgery. GUIDELINE FOR POSTOPERATIVE ADJUVANT CHEMOTHERAPY In the past years we have gradually evolved the guideline for adjuvant chemotherapy. As seen in Table 1, for node negative breast cancer with tumor more or equal to 1cm, patients were treated with either follow up or CMF or CAF followed by Tamoxifen according

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5 80 M. C. Liu / Proc JTJS (2007) 76-84

M. C. Liu / Proc JTJS (2007) 76-84 81 to the hormone status. The regimen of chemotherapy was performed according to the risk factors. For node positive breast cancer: 1.

6 M. C. Liu / Proc JTJS (2007) to the hormone status. The regimen of chemotherapy was performed according to the risk factors. For node positive breast cancer: 1.) For one to three axillary lymph node involvements, patients were treated by CAF, AC or CMF followed by Tamoxifen if the ER or PR was positive. 2.) For 4 or more axillary lymph nodes involvement, patients were treated by CAF or AC before year of 1996 and shifted to A CMF after year of 1996 followed by Tamoxifen if the ER or PR was positive. 3.) For the locally advanced breast cancer e.g. tumor more or equal to 5 cm or with skin invasion, patients will receive induction chemotherapy for 3 cycles of ECF followed by surgery then adjuvant chemotherapy. RESULTS 5 Years Survival Rate As seen in Figure 2, the 5-year disease free survival for these 1357 patients was 69% and overall survival of 77%. Disease Free Survival by Stage As shown in Figure 3, the 5-year DFS for stage 0 was 93%, for stage I: 83%, for stage II: 77%, for stage III: 50%, and for these patients who received induction chemotherapy: 38%. The DFS According to Number of Lymph Node Involvement As shown in Figure 4, for node (-) breast cancer, the 5-year DFS was 87%. For patients with one to three lymph nodes involvement the DFS was 71%. For patients with 4 to 9 lymph node involvement the DFS was 76%. For patients with 10 or more lymph nodes involvement the 5-year DFS was 36.5%. The reason of better 5-year DFS for patients with 4 to 9 nodes than one to three nodes was because all patients with 4 to 9 nodes received dose dense Adriamycin followed by CMF, and for patients with one to three

82 M. C. Liu / Proc JTJS (2007) 76-84 nodes they either received AC, CAF or CMF.

7 82 M. C. Liu / Proc JTJS (2007) nodes they either received AC, CAF or CMF. Better Survival for Patients with Age More Than 40y/o As shown in Figure 5, the 5-year DFS for stage I breast cancer was 90% for patient with age more than 40y/o, it decreased to 76% only for those who were equal or less then 40y/o. The P value of these two groups was 0.001, showed a significant difference between age above 40y/o and below and equal to 40 y/o. This conspicuous feature between different ages was also seen in stage II breast cancer. Modification of Guideline after Above Survival Outcome As seen in Figure 6, the 3-year DFS for patients with ten or more positive nodes was only 39.9% in contract to the 79.6% for patients with 4 to 9 nodes, this indicated a very poor prognosis of patients with ten or more positive nodes who were treated by traditional A CMF. Due to this poor prognosis, we started the sequential dose dense Doxorubicin (A), followed by Paclitaxel (T) followed by Cyclophosphamide (C) for patients of breast cancer with 10 or more positive node. The dose of Doxorubicin was 80 mg/m 2, and 200 mg/m 2 for Paclitaxel and 3000 mg/m 2 for Cyclophosphamide. Every cycle of chemotherapeutic agent was given every 2 weeks and re- peated for 3 cycles. Due to it s a dose dense regimen, prophyloctic G-CSF 2 mg/kg for 8 days was given prophylactically. After completion of adjuvant chemotherapy, chest wall radiation was preformed and followed by hormone treatment according to hormone status. From year of 1997 April to Sep. 2002, a total of 58 patients received the dose dense ATC as adjuvant chemotherapy for their breast cancer after operation. From year of 2003 to year of 2006, another 177 patients received this regimen. Until present, totally 52 patients were followed for more than 5 years. The side

8 M. C. Liu / Proc JTJS (2007) Table 2. Side Effect of Chemotherapy of dose dense ATC Adriamycin Taxol Cyclophosphamide Nausea Gr.0 8(14%) 31(53%) 17(29%) Gr.I 10(17%) 16(28%) 16(28%) Gr.II 34(59%) 11(19%) 24(41%) Gr.III 6(10%) 0 1(2%) Vomiting Gr.0 24(48%) 46(79%) 32(55%) Gr.I 11(19%) 4(7%) 6(10%) Gr.II 11(19%) 7(12%) 19(33%) Gr.III 6(10%) 0 1(2%) Gr.IV 2(3%) 1(2%) 0 Diarrhea Gr.0 43(74%) 47(81%) 46(79%) Gr.I 10(17%) 5(9%) 6(10%) Gr.II 4(7%) 6(10%) 6(10%) Gr.III Gr.IV 1(2%) 0 0 Mucositis Gr.0 37(64%) 48(83%) 51(88%) Gr.I 10(17%) 6(10%) 4(7%) Gr.II 9(16%) 3(5%) 3(5%) Gr.III 2(3%) 1(2%) 0 Gr.IV effects including nausea, vomiting, diarrhea, mucositis were limited and manageable as summarized on Table 2. Since this is a dose dense regimen, the morrow sppression and hence, neutropenic fever were important. As shown in Table 3, as counted by cycle, there were 25% Gr.III granulocytopenia and 60% Gr. IV granulocytopenia. The patients were educated with adequate nutrition care. Among 522 cycles of chemotherapy, only 11 cycles of neutropenic fever developed. The rate of neutropenic fever was 2.1%. The Result of ATC vs ACMF The patient characteristic was summarize in Table 4. The age lymph node number was compatible as show in Figure 7. The 5 years discase survival improved from 50% of A CMF to 74% of ATC. P=0.02. The overall sarvival improved from 52% for A CMF to 86% for ATC chemotherapy. TAC, New Regimen for Adjuvant Chemotherapy for Node(+) Breast Cancer In the BCIRG001 study the replacement of 5FU by Docetaxel as adjuvant chemotherapy for node (+) breast cancer showed an improved DFS from 68% by FAC to 75% for TAC (P=0.001). The overall survival improved from 81% for FAC to 87% for TAC (P= 0.008). The hematological toxicity of Febrile neutropenia was 24.7% for TAC v.s. 2.5% for FAC but Gr.¾ infection was 3.9% for TAC 2.2% for TAC and no any septic death. So we adopted the TAC for node(+) breast cancer and from year of 2000 to year of 2005, a total of 39 evaluable patients revived TAC with prophylactic G-CSF and Ciproxin after chemotherapy. There was 11.8% Gr.III and 79.6% Gr.IV granulocytopenia but finally only 7 cycles of neutropenic fever developed the infection node was 6 / 210 =2.6%.

9 84 M. C. Liu / Proc JTJS (2007) Modification of Induction Chemotherapy As described in previous paragraphs, we treated the patients of LABC with induction chemotherapy. The regimen was ECF ( Epirubium 70 mg/m 2, cyclophosphamide 600 mg/m 2, 5FU 600 mg/m 2 ) for 3 cycles followed by re-staging to define no systemic metastasis, then patient received operation followed by adjuvant chemotherapy and radiation ± hormone treatment. The clinical response showed PCR=8% with 6% of DCIS, 51% of CCR. So the total response rate was 65%. After a median follow up of 5 year the disease free survival was according to the lymphnode number (Figure 8). Since 2002 the regimen was changed to Docetexel 60 mg/m 2 and Cisplatin 60 mg/m 2 for 4 cycles followed by surgery then esealated gradually to 75 mg/m 2 for both agents. The clinical response was PCR=10%, DCIS=8%, so PCR=18% with PRR=85% showed a better clinical response. The survival still waits for analysis. REFERENCES 1. Epidemiology DOH : Taiwan Cancer Registry Polychemotherapy for early breast cancer:an overview of the randomized trials. Lancet 352: P930-42, Moliterni A, Bonadonna G, Valagussa P, et al. Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive axillary nodes. J Clin Oncol (7): , Randomized tral of intense CEF chemo thepy compared with CMF in premenopausal nodepositive breast cancer. JCO 16: P , Buzzoni R, Bonadonna G, Valagussa P, et al. Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes. J Clin Oncol 9(12): , Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial J Clin Oncol 21 (8): , Liu MC, Chen CM, Yang PH, et al. Sequential Dose Dense Usage of Adriamycin, Taxol, High Dose Cyclophosphamide with G-CSF Support Improved the Survival of Breast Cancer with Ten or more Positive Lymphnodes than A-CMF Regimen. 4 th European Breast Cancer Conference March, Noronha V. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352: , Mei-Ching Liu Management of TAC in and Asia population. Chinese Breast Cancer Society. Aug Liu MC, Chen CM, Yu BL. The Induction Chemotherapy with Taxotere and Cisplatin for Locally Advanced Breast Cancer. 4 th European Breast Cancer Conference March, 2004.

Adjuvant chemotherapy of breast cancer

Journal of BUON 10: 175-180, 2005 2005 Zerbinis Medical Publications. Printed in Greece REVIEW ARTICLE Adjuvant chemotherapy of breast cancer S. Bešlija Department of Medical Oncology, Institute of Oncology,