Abstract：
BACKGROUND: The multi-centre two-stage SCALOP-2 trial (ISRCTN50083238) assessed whether dose escalation of consolidative chemoradiotherapy (CRT) or concurrent sensitization using the protease inhibitor nelfinavir improve outcomes in locally advanced pancreatic cancer (LAPC) following four cycles of gemcitabine/nab-paclitaxel.
METHODS: In stage 1, the maximum tolerated dose (MTD) of nelfinavir concurrent with standard-dose CRT (50.4 Gy in 28 fractions) was identified from a cohort of 27 patients. In stage 2, 159 patients were enrolled in an open-label randomized controlled comparison of standard versus high dose (60 Gy in 30 fractions) CRT, with or without nelfinavir at MTD. Primary outcomes following dose escalation and nelfinavir use were respectively overall survival (OS) and progression free survival (PFS). Secondary endpoints included health-related quality of life (HRQoL).
RESULTS: High dose CRT did not improve OS (16.9 (60 % confidence interval, CI 16.2-17.7) vs. 15.6 (60 %CI 14.3-18.2) months; adjusted hazard ratio, HR 1.13 (60 %CI 0.91-1.40; p = 0.68)). Similarly, median PFS was not improved by nelfinavir (10.0 (60 %CI 9.9-10.2) vs. 11.1 (60 %CI 10.3-12.8) months; adjusted HR 1.71 (60 %CI 1.38-2.12; p = 0.98)). Local progression at 12 months was numerically lower with high-dose CRT than with standard dose CRT (n = 11/46 (23.9 %) vs. n = 15/45 (33.3 %)). Neither nelfinavir nor radiotherapy dose escalation impacted on treatment compliance or grade 3/4 adverse event rate. There were no sustained differences in HRQoL scores between treatment groups over 28 weeks post-treatment.
CONCLUSIONS: Dose-escalated CRT may improve local tumour control and is well tolerated when used as consolidative treatment in LAPC but does not impact OS. Nelfinavir use does not improve PFS.
METHODS: In stage 1, the maximum tolerated dose (MTD) of nelfinavir concurrent with standard-dose CRT (50.4 Gy in 28 fractions) was identified from a cohort of 27 patients. In stage 2, 159 patients were enrolled in an open-label randomized controlled comparison of standard versus high dose (60 Gy in 30 fractions) CRT, with or without nelfinavir at MTD. Primary outcomes following dose escalation and nelfinavir use were respectively overall survival (OS) and progression free survival (PFS). Secondary endpoints included health-related quality of life (HRQoL).
RESULTS: High dose CRT did not improve OS (16.9 (60 % confidence interval, CI 16.2-17.7) vs. 15.6 (60 %CI 14.3-18.2) months; adjusted hazard ratio, HR 1.13 (60 %CI 0.91-1.40; p = 0.68)). Similarly, median PFS was not improved by nelfinavir (10.0 (60 %CI 9.9-10.2) vs. 11.1 (60 %CI 10.3-12.8) months; adjusted HR 1.71 (60 %CI 1.38-2.12; p = 0.98)). Local progression at 12 months was numerically lower with high-dose CRT than with standard dose CRT (n = 11/46 (23.9 %) vs. n = 15/45 (33.3 %)). Neither nelfinavir nor radiotherapy dose escalation impacted on treatment compliance or grade 3/4 adverse event rate. There were no sustained differences in HRQoL scores between treatment groups over 28 weeks post-treatment.
CONCLUSIONS: Dose-escalated CRT may improve local tumour control and is well tolerated when used as consolidative treatment in LAPC but does not impact OS. Nelfinavir use does not improve PFS.
摘要：
背景：多中心两阶段SCALOP-2试验（ISRCTN50083238）评估了在吉西他滨/nab-紫杉醇四个周期后，合并放化疗（CRT）或使用蛋白酶抑制剂奈非那韦同时增敏是否可以改善局部晚期胰腺癌（LAPC）的预后。
方法：在第1阶段，从27名患者的队列中确定了纳非那韦与标准剂量CRT（28个部分的50.4Gy）同时使用的最大耐受剂量（MTD）。在第2阶段，159名患者被纳入标准剂量与高剂量（60Gy/30分）CRT的开放标签随机对照比较，在MTD有或没有奈非那韦。剂量递增和使用奈非那韦之后的主要结果分别是总生存期（OS）和无进展生存期（PFS）。次要终点包括健康相关生活质量(HRQoL)。
结果：高剂量CRT没有改善OS（16.9（60％置信区间，CI16.2-17.7）与15.6(60CI14.3-18.2)个月；调整后的危险比，HR1.13（60CI0.91-1.40；p=0.68）。同样，奈非那韦没有改善中位PFS（10.0（60CI9.9-10.2）与11.1（60CI10.3-12.8）个月；调整后HR1.71（60CI1.38-2.12；p=0.98））。高剂量CRT在12个月时的局部进展在数值上低于标准剂量CRT（n=11/46（23.9％）与n=15/45(33.3%))。奈非那韦和放疗剂量增加均不影响治疗依从性或3/4级不良事件发生率。在治疗后28周内，治疗组之间的HRQoL评分没有持续差异。
结论：剂量递增的CRT可以改善局部肿瘤控制，并且在LAPC中用作巩固治疗时具有良好的耐受性，但不影响OS。奈非那韦的使用不会改善PFS。
方法：在第1阶段，从27名患者的队列中确定了纳非那韦与标准剂量CRT（28个部分的50.4Gy）同时使用的最大耐受剂量（MTD）。在第2阶段，159名患者被纳入标准剂量与高剂量（60Gy/30分）CRT的开放标签随机对照比较，在MTD有或没有奈非那韦。剂量递增和使用奈非那韦之后的主要结果分别是总生存期（OS）和无进展生存期（PFS）。次要终点包括健康相关生活质量(HRQoL)。
结果：高剂量CRT没有改善OS（16.9（60％置信区间，CI16.2-17.7）与15.6(60CI14.3-18.2)个月；调整后的危险比，HR1.13（60CI0.91-1.40；p=0.68）。同样，奈非那韦没有改善中位PFS（10.0（60CI9.9-10.2）与11.1（60CI10.3-12.8）个月；调整后HR1.71（60CI1.38-2.12；p=0.98））。高剂量CRT在12个月时的局部进展在数值上低于标准剂量CRT（n=11/46（23.9％）与n=15/45(33.3%))。奈非那韦和放疗剂量增加均不影响治疗依从性或3/4级不良事件发生率。在治疗后28周内，治疗组之间的HRQoL评分没有持续差异。
结论：剂量递增的CRT可以改善局部肿瘤控制，并且在LAPC中用作巩固治疗时具有良好的耐受性，但不影响OS。奈非那韦的使用不会改善PFS。
