高风险乳腺癌术后大剂量化疗长期结局

　　对于未经筛选的乳腺癌患者，术后大剂量化疗研究未能显示生存获益，不过缺乏长期随访结果。

　　2020年1月30日，《美国医学会杂志》肿瘤学分册在线发表荷兰癌症研究所、列文虎克医院、阿姆斯特丹大学、阿姆斯特丹癌症中心、格罗宁根大学、鹿特丹大学、奈梅亨大学、莱顿大学、特文特大学、马斯特里赫特大学、乌得勒支大学的研究报告，比较了大剂量化疗与传统剂量化疗对三期乳腺癌术后患者的20年有效性和安全性结局。

NCT03087409: High-dose Chemotherapy With Hematopoietic Stem-cell Rescue for High-risk Breast Cancer: Long-term Follow-up of a Randomized Phase III Study

　　该多中心随机对照三期临床研究于1993年8月1日～1999年7月31日从荷兰10家医院入组年龄<56岁（平均年龄44.5±6.6岁）乳腺癌腋窝淋巴结转移≥4枚女性885例，按1∶1的比例随机分为两组进行术后化疗：

• 常规剂量化疗443例：5个周期氟尿嘧啶500mg/m²＋表柔比星90mg/m²＋环磷酰胺500mg/m²

• 大剂量化疗442例：4个周期常规剂量化疗，第5个周期环磷酰胺6000mg/m²＋噻替哌480mg/m²＋卡铂1600mg/m²＋造血干细胞移植

　　2016年6月1日～2017年12月31日，通过医疗记录、全科医师、荷兰国家统计局、全国癌症登记中心收集随访数据。2018年2月1日～2019年10月14日，根据意向治疗进行统计学分析。主要终点为总生存、安全性、第二恶性肿瘤或心血管事件的累计发生风险。

　　结果，中位随访20.4年（四分位：19.2～22.0年），大剂量化疗与常规剂量化疗相比：

• 总生存率（全部患者）：45.3%比41.5%（风险比：0.89，95%置信区间：0.75～1.06，P=0.19）

• 总生存率（腋窝淋巴结转移≥10枚患者）：44.5%比29.9%（风险比：0.72，95%置信区间：0.54～0.95，P=0.02）

• 总生存率（三阴性乳腺癌患者）：52.9%比37.5%（风险比：0.67，95%置信区间：0.42～1.05，P=0.08）

• 第二恶性肿瘤累计发生风险：12.1%比16.2%（P=0.10）

• 高血压累计发生风险：21.7%比14.3%（P=0.02）

• 高胆固醇累计发生风险：15.7%比10.6%（P=0.04）

• 心律失常累计发生风险：8.6%比4.6%（P=0.005）

• 其他重要心血管事件累计发生风险相似

　　因此，该研究结果表明，大剂量化疗对未经筛选的三期乳腺癌患者未提供长期生存获益，不过对于腋窝淋巴结转移≥10枚的高风险患者可以提供长期生存获益，对二次恶性肿瘤或重要心血管事件的长期风险影响不大。

JAMA Oncol. 2020 Jan 30. [Epub ahead of print]

High-Dose Chemotherapy With Hematopoietic Stem Cell Transplant in Patients With High-Risk Breast Cancer and 4 or More Involved Axillary Lymph Nodes: 20-Year Follow-up of a Phase 3 Randomized Clinical Trial.

Steenbruggen TG, Steggink LC, Seynaeve CM, van der Hoeven JJM, Hooning MJ, Jager A, Konings IR, Kroep JR, Smit WM, Tjan-Heijnen VCG, van der Wall E, Bins AD, Linn SC, Schaapveld M, Jacobse JN, van Leeuwen FE, Schroder CP, van Tinteren H, de Vries EGE, Sonke GS, Gietema JA.

Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, the Netherlands; Amsterdam UMC, Cancer Center Amsterdam, Amsterdam, the Netherlands; University Medical Center Groningen, Groningen, the Netherlands; Erasmus MC University Medical Center, Rotterdam, the Netherlands; Radboud University Medical Center, Nijmegen, the Netherlands; Leiden University Medical Center, Leiden, the Netherlands; Medisch Spectrum Twente, Enschede, the Netherlands; Maastricht University Medical Center, Maastricht, the Netherlands; University Medical Center Utrecht, Utrecht, the Netherlands.

This secondary analysis of a randomized clinical trial examines 20-year efficacy and safety outcomes of a large trial of adjuvant high-dose chemotherapy and hematopoietic stem cell transplant (HSCT) vs conventional-dose chemotherapy for patients with stage III breast cancer.

QUESTION: What are the 20-year efficacy and safety outcomes of adjuvant high-dose chemotherapy with hematopoietic stem cell transplant compared with conventional-dose chemotherapy for patients with stage III breast cancer?

FINDINGS: This 20-year follow-up of a multicenter randomized phase 3 trial of 885 patients with stage III breast cancer showed no overall improvement in long-term survival after high-dose chemotherapy compared with conventional chemotherapy but showed clinically important survival benefit for patients with 10 or more involved axillary lymph nodes.

MEANING: Adjuvant high-dose chemotherapy with stem cell support should not be used in unselected patients with stage III breast cancer, but the survival benefit in subgroups of patients suggests that further research is needed.

IMPORTANCE: Trials of adjuvant high-dose chemotherapy (HDCT) have failed to show a survival benefit in unselected patients with breast cancer, but long-term follow-up is lacking.

OBJECTIVE: To determine 20-year efficacy and safety outcomes of a large trial of adjuvant HDCT vs conventional-dose chemotherapy (CDCT) for patients with stage III breast cancer.

DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis used data from a randomized phase 3 multicenter clinical trial of 885 women younger than 56 years with breast cancer and 4 or more involved axillary lymph nodes conducted from August 1, 1993, to July 31, 1999. Additional follow-up data were collected between June 1, 2016, and December 31, 2017, from medical records, general practitioners, the Dutch national statistical office, and nationwide cancer registries. Analysis was performed on an intention-to-treat basis. Statistical analysis was performed from February 1, 2018, to October 14, 2019.

INTERVENTIONS: Participants were randomized 1:1 to receive 5 cycles of CDCT consisting of fluorouracil, 500 mg/m2, epirubicin, 90 mg/m2, and cyclophosphamide, 500 mg/m2, or HDCT in which the first 4 cycles were identical to CDCT and the fifth cycle was replaced by cyclophosphamide, 6000 mg/m2, thiotepa, 480 mg/m2, and carboplatin, 1600 mg/m2, followed by hematopoietic stem cell transplant.

MAIN OUTCOMES AND MEASURES: Main end points were overall survival and safety and cumulative incidence risk of a second malignant neoplasm or cardiovascular events.

RESULTS: Of the 885 women in the study (mean [SD] age, 44.5 [6.6] years), 442 were randomized to receive HDCT, and 443 were randomized to receive CDCT. With 20.4 years median follow-up (interquartile range, 19.2-22.0 years), the 20-year overall survival was 45.3% with HDCT and 41.5% with CDCT (hazard ratio, 0.89; 95% CI, 0.75-1.06). The absolute improvement in 20-year overall survival was 14.6% (hazard ratio, 0.72; 95% CI, 0.54-0.95) for patients with 10 or more invoved axillary lymph nodes and 15.4% (hazard ratio, 0.67; 95% CI, 0.42-1.05) for patients with triple-negative breast cancer. The cumulative incidence risk of a second malignant neoplasm at 20 years or major cardiovascular events was similar in both treatment groups (20-year cumulative incidence risk for second malignant neoplasm was 12.1% in the HDCT group vs 16.2% in the CDCT group, P=.10), although patients in the HDCT group more often had hypertension (21.7% vs 14.3%, P=.02), hypercholesterolemia (15.7% vs 10.6%, P=.04), and dysrhythmias (8.6% vs 4.6%, P=.005).

CONCLUSIONS AND RELEVANCE: High-dose chemotherapy provided no long-term survival benefit in unselected patients with stage III breast cancer but did provide improved overall survival in very high-risk patients (ie, with ≥10 involved axillary lymph nodes). High-dose chemotherapy did not affect long-term risk of a second malignant neoplasm or major cardiovascular events.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03087409

PMID: 31999296

DOI: 10.1001/jamaoncol.2019.6276