Neoadjuvant chemotherapy with combined infusional 5-fluorouracil, adriamycin and cyclophosphamide in locally advanced breast cancer

Abstract

[한글]

목적: 국소 진행성 유방암에서 술전 항암화학요법 (neoadjuvant chemotherapy)의 목적은 병기감소이다. 저자는 국소 진행성 유방암 환자 82례에서 연속 정주 5-fluorouracil, adriamycin, cyclophosphamide 병합약제 (iFAC)를 이용한 술전 항암화학요법의 효능과 안전성를 평가하고자 하였다.

방법: 국소 진행성 유방암 환자 82명에서 iFAC으로 술전 항암화학요법을 시행하였다. iFAC regimen 은 5-fluorouracil 은 체표면적당 1000mg을 제 1일부터 제 3일까지 연속 정주, adriamycin은 체표면적당 40mg을 제 1일에 정주, clophosphamide는 체표면적당 600mg을 제 1일에 정주하는 방법이며 3주마다 반복하였다. 종양 반응이 최대에 이르렀을 때 수술을 시행하였고 수술 후 iFAC로 보조 항암요법 (adjuvant chemotherapy)과 방사선 치료를 시행하였다. 호르몬 수용체가 양성이거나 폐경 상태인 환자들은 호르몬 치료도 시행하였다. 29명의 수술 조직에서 c-erbB-2 상태를 immunohistochemistry (IHC)와 fluorescence in situ hybridization (FISH) 방법으로 조사하였다.

결과: 82명중 병기감소는 71명 (86.6%)에서 있었으나 그 중 4명은 액와 림프절 크기 증가, 유방에 새로운 병변 발생, 액와 림프절 고정의 불변 등으로 인해 절제불가능하였다. 반면에 병기감소가 없는 11명중에서 5명은 유방 종양의 크기 감소로 인해 절제가능하여, 결과적으로 총 72명이 절제가능한 상태였다 (절제가능율, 87.8%). 임상적 반응율은 84.2% (완전반응, 17.1%; 부분반응, 67.1%), 그리고 병리학적 완전 반응율은 7.8%였다. 임상적 반응을 보인 69 명중 조기 반응율 (iFAC 3주기내에 최대반응을 나타낸 경우)은 73.9%였고 지연 반응율 (iFAC 3주기 이후에 최대 반응을 나타낸 경우)은 26.1%였다. 총 891 주기의 iFAC 항암치료 동안 WHO 등급 3/4의 혈액학적 독성은 백혈구 감소증 36.0%, 빈혈 36.0%, 혈소판 감소증 0.5%였다. 1명은 폐렴으로 인한 패혈성 쇼크가 발생하였으며 3명은 울혈성 심부전증을 나타내었으나, 항암치료와 연관되어 사망한 경우는 없었다. 중앙 추적관찰 기간 51개월 동안, 82명의 중앙 총 생존기간은 66개월, 수술을 시행한 64명의 중앙 무병 생존기간은 45개월, 중앙 총 생존기간은 89개월이었다. IHC와 FISH에 의한 c-erbB-2의 양성률은 각각 31.0%, 37.9% 였고, 두 방법의 일치도는 93.1% (27/29)였으며, IHC 음성인 경우에 무병 생존기간 및 총 생존기간이 연장되는 경향을 나타내었다. iFAC 항암치료에 대한 조기 반응이 국소 재발 억제, 원격 재발 억제, 무병 생존 및 총 생존률에 대해서 공통적으로 좋은 예후 인자였으며, 유방 종괴의 크기가 10cm 이하인 경우가 조기 반응에 대한 좋은 예측 인자였다 (hazard ratio=0.1, p=0.003).

결론: 국소 진행성 유방암에서 술전 iFAC 항암화학요법은 FAC 정주법과 비슷한 반응율을 보이며 독성도 수용가능하였다. iFAC 술전 항암화학요법에 대한 조기 반응은 좋은 예후 인자였으며, 치료 초기 종양의 크기가 조기 반응 여부에 대해 유일한 예측 인자였다.

[영문]Purpose: The goal of neoadjuvant chemotherapy is the downstaging of locally advanced breast cancer (LABC). The author evaluated the efficacy and safety of neoadjuvant chemotherapy with an infusional 5-FU, adriamycin and cyclophosphamide (iFAC) regimen in LABC patients.

Methods: 82 LABC patients were treated with iFAC chemotherapy, which was composed of infusional 5-FU (1000mg/m2, continuous intravenous infusion, day 1-3), adriamycin (40mg/m2, intravenous bolus, day 1), and cyclophosphamide (600mg

m2, intravenous bolus, day 1) every 3 weeks. Surgery was performed when tumor response was at a maximum. Adjuvant chemotherapy with iFAC and radiotherapy were performed after surgery. Patients with positive hormonal receptor status or in a post-menopausal state were also treated with hormonal therapy. c-erbB-2 status was determined by both immunohistochemisty (IHC) and fluorescence in situ hybridization (FISH) in surgical specimens of 29 patients.

Results: Of the 82 patients, downstaging occurred in 71 patients (86.6%). However, four of them were still unresectable because of increased axillary node size in 1 patient, newly developed breast lesion in 2, and unchanged fixed axillary node in 1, respectively. Five of 11 patients without downstaging became resectable due to decreased breast tumor size. As a result, 72 patients (67 patients with downstaging plus 5 patients without downstaging) were resectable (resectability rate, 87.8%). The clinical response rate was 84.2% (CR, 17.1%; PR, 67.1%) and the pathologic complete response rate was 7.8%. Of the clinical responders (69 patients), 51 (73.9%) were early responders who showed a maximum clinical response at ≤ 3 cycles of iFAC, while 18 (26.1%) were late responders who showed a maximum response at > 3 cycles of iFAC. During 891 cycles of chemotherapy, grade 3/4 hematological toxicities were leukopenia (36.0%), anemia (0.8%), and thrombocytopenia (0.5%). One patient experienced septic shock resulting from pneumonia, and 3 patients showed congestive heart failure. However, there were no treatment-related deaths. The median follow-up period of the 82 patients was 51 months and the median overall survival duration was 66 months. The median disease-free and overall survival durations for 64 resected patients were 45 and 89 months, respectively. c-erbB-2 positivity was 31.0% by FISH and 37.9% by IHC with the concordance rate of 93.1% (27/29). A trend was noted that disease-free and overall survivals were prolonged in patients without expression of c-erbB-2 by IHC. An early response to chemotherapy was identified as a favorable prognostic factor of locoregional recurrence-free, distant recurrence-free, disease-free, and overall survivals. A smaller breast tumor size (<10cm) was a favorable predictor of an early response (hazard ratio=0.1, p=0.003).

Conclusion: Neoadjuvant chemotherapy with iFAC was found to have a comparable response rate with that of bolus FAC and acceptable toxicity in LABC. Moreover, an early response to neoadjuvant iFAC chemotherapy was a favorable prognostic factor, and initial tumor size was the only significant predictor of the early response.