Service de Gériatrie, Centre Hospitaliser Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France.
Laboratoire CarMeN, Inserm U1060, INRA U1397, Université Claude Bernard Lyon, Lyon, France.
J Am Geriatr Soc. 2023 Jul;71(7):2297-2307. doi: 10.1111/jgs.18350. Epub 2023 Apr 10.
Age is a major risk factor for the acute and chronic complications of cancer chemotherapy. The current approach to the prevention of these complications is reactive and involves the reduction of the doses and the delay of treatment which may compromise the outcome. There is a limited number of antidotes to chemotherapy toxicity and these have complications of their own. Oldest old and frail patients are mostly excluded from life saving cancer treatment due to the risk of severe and even lethal complications.
molecular biology has revealed that different checkpoints control the proliferative cycle of normal and neoplastic cells. Two new drugs, Trilaciclib and ALRN-6924 may cause a temporary cell cycle arrest (CCA) of normal cells without blocking the proliferation of the neoplastic ones and render the normal cells temporarily invulnerable to the toxicity of chemotherapy. We reviewed the publications related to these drugs on the Medline, the published drug information and the presentations to major medical conferences.
In three randomized controlled phase II trials Trilaciclib proved effective in preventing neutropenia, thrombocytopenia and anemia in patients with non small cell lung cancer with non proficient RB1 gene. Forty-five percent of patients were 65 and older and age did not prevent the effectiveness of the drug. Trilaciclib was approved by the FDA for the management of these patients. ALRN-6924 appeared promising in preventing myelotoxicity in patients whose cancer had deleted or mutated TP53, but failed to show any significant activity in a randomized controlled study. The development of this drug is now on hold CONCLUSIONS: CCA is a novel proactive approach to the toxicity of chemotherapy of special interest to older patients. At the very least it may prevent all forms of myelotoxicity with a single agent, obviating the risk and cost of polypharmacy. It allows to avoid the complications of myelopoietic growth factors which include severe pain, stem cell competition, bone marrow exhaustion, and hematological malignancies. It may allow the treatment of frail patients with full chemotherapy doses. It is also reasonable to expect that may complications other common and sometimes lethal complications of chemotherapy such as stomatitis, esophagitis, diarrhea and dehydration.
年龄是癌症化疗急性和慢性并发症的主要危险因素。目前预防这些并发症的方法是被动的，包括减少剂量和延迟治疗，这可能会影响治疗效果。对抗化疗毒性的解毒剂数量有限，而且它们本身也有并发症。由于严重甚至致命并发症的风险，最年长和虚弱的患者大多被排除在挽救生命的癌症治疗之外。
分子生物学揭示了不同的检查点控制正常和肿瘤细胞的增殖周期。两种新药物，Trilaciclib 和 ALRN-6924 可以引起正常细胞的暂时细胞周期停滞（CCA），而不会阻止肿瘤细胞的增殖，并使正常细胞暂时对化疗毒性具有不易感性。我们在 Medline 上查阅了与这些药物相关的出版物、已发表的药物信息以及主要医学会议的报告。
在三项随机对照的 II 期临床试验中，Trilaciclib 被证明可有效预防非小细胞肺癌中 RB1 基因非功能不全的患者中性粒细胞减少症、血小板减少症和贫血。45%的患者年龄在 65 岁及以上，但年龄并未阻止药物的有效性。Trilaciclib 已获得 FDA 批准用于这些患者的治疗。ALRN-6924 在预防癌症中 TP53 缺失或突变的患者的骨髓毒性方面显示出有希望的结果，但在一项随机对照研究中未能显示出任何显著的活性。该药物的开发现已暂停。
CCA 是一种针对化疗毒性的新型主动方法，特别适用于老年患者。至少，它可以用单一药物预防所有形式的骨髓毒性，避免多药治疗的风险和成本。它允许用全剂量化疗治疗虚弱的患者。也有理由期望它可以预防其他常见且有时致命的化疗并发症，如口腔炎、食管炎、腹泻和脱水。
