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Analyzing Disease Flares: Impact of Discontinuing Targeted Therapy Unclear
对爆发性进展的分析：不清楚中断靶向治疗的影响
Maurie Markman, MD
Published Online: Wednesday, March 21, 2012
The concept that patients with cancer may experience relatively rapid progression of their disease process following the withdrawal of a particular antineoplastic agent is certainly not a new concept.1 Although it is always difficult to distinguish what may legitimately be considered disease flare from the more likely scenario of the events simply representing the natural history of the malignancy, reports of such experiences after the discontinuation of hormonal therapeutic strategies have been well documented. More recently, disconcerting events have been described following the stopping of bevacizumab treatment in patients with malignant brain tumors.
癌症患者在停止一种特定的抗肿瘤药物之后可能出现疾病的快速进展已经不是一种新的概念了。虽然很难从那些更可能体现了恶性肿瘤自然病程的事件场景中合理地区分出什么是爆发性进展，但在停止激素治疗之后所表现出的类似状况的报告已经被充分地记录在册了。最近，（有文献）描述了在对恶性颅内肿瘤患者停止贝伐单抗的治疗后出现的令人不安的事件。
In the case of targeted antineoplastic drug therapy, a very solid theoretical rationale can be advanced to explain how discontinuation of therapy, either because of excessive toxicity or the documented failure of the regimen to favorably impact the course of the disease, might quite realistically result in far more rapid progression of the malignant process than predicted by observations of the cancer’s natural history in an individual patient.
在靶向抗肿瘤药物治疗的情况下，一个非常坚实的理论根据能够解释如何来停止治疗，由于过度的毒性或是已被证明失败的疗程，都会影响疾病的进程，实际上这可能极大地导致了很多肿瘤进程的快速进展，超过了由在患者个体中所观察到的癌症的自然病程所得到的预期。
It has long been appreciated that the secretion of greater local and circulating concentrations of growth factors that can overcome the inhibitory effects of a particular antineoplastic agent is one prominent mechanism of cancer resistance. Assuming that a targeted therapy has been effective in blocking access of an essential growth factor to a clinically relevant target, release of that blockade (following withdrawal of the therapy) may expose these active receptors to a local environment composed of far greater concentrations of the growth stimulatory substances.
（我们）已经充分认识到，生长因子在局部和循环浓度中更大量的分泌能够克服一种特定抗肿瘤药物的抑制效果，这是一种癌症耐药的显著的机制。假定靶向治疗有效的阻断了必要的生长因子到临床相关靶点的通路，撤出封锁(停止治疗)可能使这些活跃的受体暴露于由更高浓度的生长刺激物质所组成的局部环境中。
As a result, while disease progression may have unequivocally already occurred in a relatively small proportion of the malignant cells, it is theoretically reasonable to propose that the subsequent complete release from receptor blockage (due to discontinuation of the targeted antineoplastic) will result in acceleration of biological activity in a much larger percentage of the malignant cell population.
结果就是，一部分相对数量较少的肿瘤细胞可能已经明确产生了疾病的进展，（因此）从理论上能够合理地得出：随后完全释放对受体的阻断（因为中止了靶向抗肿瘤药物的治疗）将会导致在更大比例的肿瘤细胞群中产生加速的生理活性。
To address this clinically relevant question in the setting of treatment with tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR), investigators retrospectively examined the outcome of a group of patients who developed resistance to either gefitinib or erlotinib and were subsequently scheduled to participate in trials exploring novel strategies to overcome such resistance.3 As a component of the study designs, a prospectively defined “washout” period was included in which patients had the tyrosine kinase inhibitor discontinued before the new treatment was initiated. In this experience, disease flare, defined as death or required hospitalization prior to the initiation of the new therapy, was observed in 14 of 61 patients (23%). The median time to this event was only 8 days (range, 3-21 days), with the observed onset of significant symptoms, rapid increases in the extent of cancer, and short survival.
为了解决在采用EGFR TKI治疗情况下的这个临床相关的问题，研究者回顾性地检视了来自于一组对吉非替尼或厄洛替尼耐药的患者的研究结果，这些患者在耐药之后随即被安排加入新的克服耐药策略的临床试验中。作为研究设计的一个组成部分，一个预先定义的“洗脱期”被计为从患者停止使用TKI之后到开始接受新治疗之前的一段时间。在这个临床中，爆发性进展被定义为在接受新治疗之前患者的死亡或者需要住院接受治疗，这在61位患者中的14位中观察到了(23%)。至该事件出现的中位时间仅为8天(范围，3至21天)，以及观察到的带有显著症状的发病、肿瘤范围快速的增长、和缩短的生存时间。
While this single report cannot be considered definitive with regard either to defining the percentage of patients at risk or to the magnitude of symptomatic progression if disease flare occurs, the experience strongly suggests that lung cancer patients who are receiving EGFR tyrosine kinase inhibitors require careful monitoring if such therapy is discontinued secondary to disease progression, unacceptable toxicity, or patient choice.
该份单独的报告未能明确地定义处于危险中的患者的比例，也未能确定当爆发性进展时出现的症状的严重程度，其强烈建议接受EGFR TKI的肺癌患者当由于出现继发性疾病进展、不可耐受的毒性或者患者意愿而停止用药时，需要仔细地监控病情。
Finally, it will be important for the clinical oncology research community to continue to investigate the issue of disease flare in this setting as targeted antineoplastic therapy becomes an integral component of care in an increasing number of clinical settings.
最后，这对于临床肿瘤研究团体调查爆发性进展的问题来说是重要的，特别是在靶向抗肿瘤治疗已经成为增多的临床场景的一部分时。
这篇评述仍然在说明停止TKI后出现爆发性进展的一些相关信息，所谈到的内容之前都有涉及，这里就不用多说了
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