Improving delivery of chemotherapy for older patients

改善老年患者的化疗实施

• 批准号: 7701354
• 负责人: MARTINE EXTERMANN
• 金额: $ 6.85万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7701354
• 关键词: Accounting; Adverse effects; Affect; Age; American; Cancer Patient; Cardiovascular Diseases; Cause of Death; Characteristics; Clinical; Clinical Trials Design; Common Terminology Criteria for Adverse Events; Data; Disease; Dose; Effectiveness; Elderly; Event; Future; Grant; Guidelines; Institutes; Lead; Maintenance; Malignant Neoplasms; Methodology; Modeling; Modification; National Cancer Institute; Odds Ratio; Oncologist; Outcome; Patients; Protocols documentation; Quality of life; Randomized Controlled Clinical Trials; Recurrence; Research; Risk; Risk Factors; Scheme; Severities; Subgroup; Terminology; Testing; Time; Toxic effect; Treatment Protocols; Treatment outcome; Work; aged; base; cancer therapy; chemotherapy; clinical practice; clinically significant; cohort; cost; cost effectiveness; design; evidence base; experience; functional status; improved; older patient; public health relevance; response; treatment planning

DESCRIPTION (provided by applicant): Cancer is a disease of the elderly (60% occur beyond the age of 65). It is also the second cause of death in older Americans, after cardiovascular diseases. Chemotherapy is a mainstay of its treatment, and being able to deliver it safely while minimizing dose reductions is essential to its effectiveness. Typically, in cancer trials, dose reductions are made for grade 3-4 non-hematologic toxicity or grade 4 hematologic toxicities (hereafter "severe toxicity"). Our research, notably the CRASH project (grant ACS RSG-03-151-01-CCE), has demonstrated that 2/3 of older chemotherapy-treated patients have a severe toxicity. Yet, this toxicity appears to have only a low impact on their functional status (Chen et al. 2003) and the dose-intensity of their treatment in clinical practice (Extermann et al. 2002). It also appears to generate a variable response by oncologists. Our recent data show that only 57% of patients undergo a change in their regimen after a severe toxicity, whereas 43% do not (O'Leary 2008). Counter-intuitively, the 1st group had a 37% recurrence of severe toxicity, whereas the 2nd only had a 17% recurrence rate (Odds ratio 2.85, p = 0.0075). This suggests that oncologists, somehow, are able to identify differential risk factors for toxicity recurrence. Baseline parameters and toxicity types were not correlated with this outcome. Our data imply that standard dose reduction schemes are not well adapted to older patients, with a potential for undertreating them. Given the 2 to 3-fold difference in risk of recurrence of severe toxicity between the two subgroups, there is a clear clinical need to understand the factors underlying this, and an opportunity for meaningful improvement. This R03 is aimed at designing an improved dose modification scheme for older patients that will be compared to standard dose-modification schemes in a randomized trial. We hypothesize that taking into account the duration of toxicity and its impact on the patient's function would lead to better treatment adaptations. I.e., for a same CTC grade, severe short, rapidly reversed toxicities with low impact on the patient's function would not lead to changes in treatment and have low risk of recurrence, whereas protracted toxicities would be more likely to recur, and might also highlight a decreased patient functional reserve. The present project will be derived from the methodology of the CRASH trial, with the focus shifted from understanding pretreatment risk factors for toxicity to the assessing the first period of severe toxicity, and its risk of recurrence. We will accrue a cohort of 200 patients aged 65 and older undergoing chemotherapy. Predictors associated with dose maintenance and recurrence of severe toxicity will be identified, and a dose-modification scheme optimizing dose maintenance without recurrence of severe toxicity will be designed, using cost-effectiveness type modeling. The research and clinical significance of this project is potentially large. Present protocols have dose reduction guidelines based strictly on CTC severity criteria. A better model might contribute to an improved treatment and outcomes for a third of older cancer patients on chemotherapy. It might also lead to more elderly-inclusive clinical trial designs. PUBLIC HEALTH RELEVANCE: The current rules to modify chemotherapy after a severe side effect do not appear well adapted to older patients. They might lead to too little treatment in some and a recurrence of severe side effects in others. The Aim of this study is to design a better scheme for dose modification.

描述（由申请人提供）：癌症是老年人的疾病（60％以上是65岁）。这也是年龄较大的美国人的第二个死亡原因，仅次于心血管疾病。化学疗法是其治疗方法的中流疗法，并且能够安全地提供降低剂量，这对于其有效性至关重要。通常，在癌症试验中，降低剂量是针对3-4级非血液学毒性或4级血液学毒性（以下“严重毒性”）进行的。我们的研究，尤其是崩溃项目（Grant ACS RSG-03-151-01-CCE），已经证明2/3较旧的化学疗法治疗患者具有严重的毒性。然而，这种毒性似乎对其功能状态的影响很小（Chen等，2003）和在临床实践中治疗的剂量强度（Extermann等，2002）。它似乎也产生了肿瘤学家的可变响应。我们最近的数据表明，严重毒性后只有57％的患者发生了改变治疗方案，而43％的患者则不会发生变化（O'Leary 2008）。违反直觉，第一组的严重毒性复发37％，而第二组仅具有17％的复发率（优势比2.85，p = 0.0075）。这表明肿瘤学家以某种方式能够识别毒性复发的差异风险因素。基线参数和毒性类型与此结果无关。我们的数据表明，标准剂量减少方案不能很好地适应老年患者，并有可能无法治疗它们。鉴于两个亚组之间严重毒性的复发风险的2至3倍差异，明显的临床需要了解这一点的因素以及有意义的改善的机会。该R03旨在为老年患者设计改进的剂量修饰方案，并将其与随机试验中的标准剂量修饰方案进行比较。我们假设考虑到毒性的持续时间及其对患者功能的影响将导致更好的治疗适应。即，对于相同的CTC级，严重的短而迅速逆转的毒性对患者的功能影响低，不会导致治疗变化，并且复发的风险较低，而持久的毒性更可能重复出现，并且可能会突出患者功能储备的降低。本项目将源自崩溃试验的方法，重点从理解毒性的预处理风险因素转变为评估严重毒性的第一阶段及其复发风险。我们将累积200名65岁及65岁以上化疗的患者的队列。将使用成本效益类型的建模设计，将设计与剂量维持和严重毒性复发相关的预测因素，并将设计剂量调整方案优化剂量维持而无需复发严重毒性。该项目的研究和临床意义可能很大。目前的方案具有严格基于CTC严重性标准的剂量减少指南。更好的模型可能会导致改善治疗方法的治疗方法，并在化学疗法中对年龄较大的癌症患者的治疗结果有所改善。这也可能导致更多包括老年人的临床试验设计。公共卫生相关性：严重的副作用后，修改化学疗法的当前规则似乎不适用于老年患者。它们可能导致某些人的治疗太少，而另一些人则复发。这项研究的目的是设计一个更好的剂量修饰方案。