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Potential Pitfalls of Crossover and Thoughts on Iniparib in Triple-Negative Breast Cancer

机译:在三阴性乳腺癌中交叉的潜在误区和对依那普利的思考

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摘要

As recruitment for oncology clinical trials has become more difficult, there appears to have been an increase in the number of studies that allow patients in the control arm to “crossover” and receive the experimental therapy after disease progression. Although some researchers worry that allowing such crossover may abolish gains in progression-free survival in the experimental arm, the possibility that crossover might inadvertently benefit the experimental arm has not been addressed. In clinical trials in which the experimental agent has little or no intrinsic activity and is used to modulate an active combination, such crossover might negatively affect the overall survival of the control arm. Because resistance to the active combination—manifested as disease progression—has occurred, the likelihood of benefit from adding the experimental drug is reduced. Consequently, patients who were randomly assigned to the control arm continue to receive the now inactive combination after crossover, whereas patients in the experimental arm who discontinue study participation may seek out potentially effective salvage regimens. This difference in subsequent therapies may confer an advantage to the experimental arm that is manifested as gains beyond those achieved in progression-free survival, gains that occur not because the experimental therapy induced a change in tumor biology that persists beyond treatment discontinuation but because the control arm suffers by continuing to receive a therapy on which their tumor is progressing. Such an outcome may explain the recently reported trial results for iniparib in triple-negative breast cancer. Given that allowing patients in the control arm to receive the experimental agent may confound interpretation of overall survival, such crossover should not be used indiscriminately, especially if the experimental agent has little or no intrinsic activity.
机译:随着肿瘤临床试验的招募变得越来越困难,研究的数量似乎增加了,从而使对照组的患者能够“交叉”并在疾病进展后接受实验性治疗。尽管一些研究人员担心允许进行这种交叉操作可能会消除实验组无进展生存的收益,但尚未解决交叉可能无意中使实验组受益的可能性。在临床试验中,实验药物几乎没有或没有内在活性,并用于调节活性组合,这种交叉可能会对控制臂的总体存活产生负面影响。因为已经出现了对活性组合的抗药性(表现为疾病进展),所以降低了添加实验药物的获益可能性。因此,随机分配到对照组的患者在交叉后仍继续接受现在无效的联合治疗,而实验组中中断研究的患者可能会寻求潜在的有效挽救方案。后续疗法中的这种差异可能会给实验组带来优势,表现为超越无进展生存期所获得的收益,这种收益之所以出现,并不是因为实验疗法引起了肿瘤生物学的改变,而这种改变持续到治疗终止后才继续存在,而是因为控制手臂因继续接受其肿瘤进展的治疗而受苦。这样的结果可能解释了最近报道的三倍阴性乳腺癌中伊尼帕利的试验结果。考虑到允许对照组的患者接受实验药物可能会混淆总体生存率的解释,因此不应随意使用这种交叉方法,尤其是在实验药物的内在活性很小或没有内在活性的情况下。

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