Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer
Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer
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DOI：
10.1093/jnci/dji114
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发表时间：
2005-05-04
影响因子：
10.3
通讯作者：
Thatcher, N
中科院分区：
文献类型：
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作者：
Lorigan, P;Woll, PJ;Thatcher, N
背景。最近对小细胞肺癌（SCLC）的剂量强度研究得出了相互矛盾的结果。我们对预后较好的SCLC患者（即预后评分为0-1）进行了一项III期随机试验，以研究非格昔汀和血祖细胞支持的异环磷酰胺、卡铂和依托泊苷（ICE）化疗的剂量密度加倍是否能改善生存，与标准ICE化疗相比。方法：我们研究了318例经病理证实的SCLC患者，他们被随机分配接受6个周期的ICE化疗，周期间隔为4周（标准组）或2周（剂量密集组）。剂量密集组的患者在第4至14天每天皮下注射非格昔汀，并在第2至6周期前采血，并在治疗后24小时返回。毒性，包括血液学毒性和中性粒细胞减少性败血症的发生率，进行监测。生存率采用Kaplan-Meier法计算。所有统计检验均为双侧检验。结果：标准组的中位剂量强度为99%（四分位数范围为96% ~ 100%），剂量密集组的中位剂量强度为182%（四分位数范围为163% ~ 196%）。中位随访14个月后，标准组148例可评估患者中有118例（80%）对治疗有总体反应，剂量密集组147例可评估患者中有129例（88%）对治疗有总体反应，差异无统计学意义。标准组的中位总生存期为13.9个月（95%可信区间[CI] = 12.9 ~ 15.8个月），剂量密集组的中位总生存期为14.4个月（95% CI = 12.7 ~ 16.0）， 2年生存率分别为22% （95% CI = 16% ~ 29%）和19% (95% CI = 14% ~ 27%)，差异均无统计学意义。标准组的中位治疗空闲时间为286天（95% CI = 229 ~ 343天），剂量密集组的中位治疗空闲时间为367天（95% CI = 321 ~ 413天）（差异= 81天；P = 0.109）。剂量密集组报告的血液学毒性显著高于标准组，但标准组合并中性粒细胞减少性脓毒症的周期数显著高于剂量密集组（分别为15.3%和11.6%；差异= 3.7%,95% CI = -4.1%至11.5%;P = 0.03）。结论：与标准ICE相比，剂量密集ICE化疗可缩短SCLC的治疗时间和减少中性粒细胞减少性败血症，但并未提高总生存率。
Background. Recent dose-intensity studies of small-cell lung cancer (SCLC) have yielded conflicting results. We carried out a phase III randomized trial in patients with better-prognosis SCLC (i.e., prognostic score of 0-1) to investigate whether doubling the dose density of ifosfamide, carboplatin, and etoposide (ICE) chemotherapy with filgrastim and blood-progenitor-cell support improves survival, compared with standard ICE chemotherapy. Methods: We studied 318 patients with pathologically proven SCLC who were randomly assigned to receive six cycles of ICE chemotherapy with a 4-week (standard arm) or 2-week (dose-dense arm) interval between cycles. Patients in the dose-dense arm received filgrastim subcutaneously daily on days 4 through 14 and had autologous blood collected before cycles 2 through 6, which was returned 24 hours after treatment. Toxicities, including hematologic toxicity and incidence of neutropenic sepsis, were monitored. Survival was calculated by the Kaplan-Meier method. All statistical tests were two-sided. Results: The delivered median dose intensity was 99% (interquartile range = 96%-100%) for the standard arm and 182% (interquartile range = 163%-196%) for the dose-dense arm. After a median follow-up of 14 months, overall response to treatment was observed in 118 (80%) of the 148 evaluable patients in the standard arm and in 129 (88%) of the 147 evaluable patients in the dose-dense arm, a statistically nonsignificant difference. Median overall survival was 13.9 months (95% confidence interval [CI] = 12.9 to 15.8 months) in the standard arm and 14.4 months (95% CI = 12.7 to 16.0) in the dose-dense arm, and the 2-year survival was 22% (95% CI = 16% to 29%) and 19% (95% CI = 14% to 27%), respectively - neither difference being statistically significant. The median treatment free time was 286 days (95% CI = 229 to 343 days) for the standard arm and 367 days (95% CI = 321 to 413 days) for the dose-dense arm (difference = 81 days; P =.109).Statistically significantly more hematologic toxicity was reported in the dose-dense arm than in the standard arm, but the number of cycles complicated by neutropenic sepsis was statistically significantly higher in the standard arm than in the dose-dense arm (15.3% versus 11.6%, respectively; difference = 3.7%, 95% CI = -4.1% to 11.5%; P =.03). Conclusions: Dose-dense ICE chemotherapy for SCLC led to shorter treatment duration and less neutropenic sepsis than did standard ICE but did not improve overall survival.