Lizzy Driessen

The objective of this thesis was to investigate patterns of treatment and outcomes among older patients with non-small cell lung cancer (NSCLC) in daily clinical practice. Clinical evidence for different treatment options, treatment tolerance, and survival are accumulating and promising for patients with NSCLC in general. However, evidence from clinical trials is predominantly based on the selected group of younger and fit patients without or with only few comorbid conditions. Older patients with NSCLC are heterogeneous and greatly differ from younger patients regarding performance status, comorbidity, and patient wishes. Guidelines for older patients specifically are highly needed and should include evidence regarding treatment options and outcomes with high external validity. Also, only limited evidence regarding the potential beneficial effects of geriatric assessment and therapeutic training before, during, and after medical treatment (prehabilitation and rehabilitation) is available for this population. In chapter 1, we presented an elaborate overview of evidence regarding treatment options, outcomes, and potentially beneficial additions to standard care for patients with NSCLC in general, as well as the lack of evidence for the older population specifically.

Part 1 Population-based data regarding treatment and survival
In chapter 2, we demonstrated that almost half of all patients diagnosed with NSCLC in the Netherlands between 1990 and 2014 was aged ≥70 years. Although this group received standard treatment options more often over time, relative survival (a proxy for lung cancer specific survival) was significantly lower compared to younger patients. Furthermore, disparities in relative survival between patients aged <70 years and those aged ≥70 years were narrowing for stage I NSCLC, remained similar for stage II, and were widening for stage III and IV NSCLC at the expense of older patients. For patients with stage I specifically, chapter 3 indicated that the proportion undergoing surgical resection remained similar in 2004-2008 and 2009-2013, whereas the proportion receiving radiotherapy increased over time. For elderly, surgery was superior compared to radiotherapy in terms of long-term overall survival. Chapter 4 elaborated on patients aged ≥65 years with stage I and II NSCLC, and demonstrated that although short-term survival was similar between surgery and stereotactic radiotherapy (SBRT), long-term survival was superior for those undergoing surgery. Furthermore, patients aged ≥75 years underwent surgery less often and had poorer overall survival compared to those aged 65-74 years, even after adjustment for other prognostic factors. In Chapter 5, we found that patients with stage III NSCLC aged ≥75 years received chemoradiotherapy less often and overall survival was poorer compared to those aged 65-74 years. However, survival rates were similar between age groups within treatment options. The oldest old patients with stage I-IV NSCLC aged ≥85 years were investigated in chapter 6. It appeared that only one in three patients ≥85 years received standard treatment. In the selected group that did receive standard treatment, similar survival outcomes were achieved as in patients aged ≤85 years. • Among older patients with NSCLC in the Netherlands, increases in standard treatment and survival have been seen over time. However, the oldest patients do not always benefit to the same extent as those aged <75 years in terms of standard treatment and survival. • Older patients often present with high-risk characteristics. Therefore, confounding by indication is an important explanation for differences in standard treatment and survival, and only relatively fit (older) patients are considered candidates for standard treatment. Part 2 Patient characteristics for treatment tolerance and survival In chapter 7, we elaborated on patients with stage III NSCLC aged ≥70 years in the south-eastern part of the Netherlands by exploring treatment choice, reasons for omission of standard treatment, treatment tolerance, and overall survival. The main reasons for omission of concurrent chemoradiotherapy were poorer performance status, comorbidity, a combination of both, or refusal by patients or family. It appeared that overall survival was comparable between concurrent and sequential chemoradiotherapy in this older population, although relatively fit and younger elderly received concurrent chemoradiotherapy more often. Furthermore, treatment tolerance was significantly poorer for those receiving concurrent compared to those receiving sequential chemoradiotherapy. However, the proportion of patients not completing intended treatment was comparable between these treatment options. Although relatively young and fit older patients with stage III NSCLC received concurrent chemoradiotherapy, survival outcomes are similar compared to those receiving sequential chemoradiotherapy while treatment tolerance is worse. Part 3 Optimizing treatment selection and outcomes In chapter 8, we evaluated current clinical practice of geriatric assessment for older patients with NSCLC by sending pulmonologists and radiotherapists involved in this field a survey. It appeared that the implementation of geriatric assessment varied widely across the country, regarding involvement of geriatricians, geriatric domains, and the use of geriatric tools. Although the additive value of geriatric assessment for treatment decision-making in vulnerable and frail subgroups for both physicians and patients were uniformly recognized, a lack of evidence of the benefits as well as logistic problems within the hospital were main barriers for the inclusion of geriatric assessment in standard diagnostic work-up. We examined systematic evidence regarding prehabilitation and rehabilitation including a home-based component in chapter 9. We found that physical fitness was improved significantly or clinically relevant among patients with NSCLC undergoing curative treatment. Furthermore, combining (home-based) resistance and endurance training, as well as supervision and personalization, seem necessary to optimize physical fitness, adherence, treatment tolerance, and recovery. • Age alone should not be decisive for treatment decision-making. Therefore, outcomes of a geriatric assessment can contribute to tailored treatment choices, including the needs, interests, and values of older patients including quality of life. Some form of geriatric assessment should be included as part of standard diagnostic work-up, leading to multidisciplinary and shared treatment-decision making. • Patients with NSCLC could benefit from supervised and personalized prehabilitation and rehabilitation in order to improve physical fitness, treatment tolerance, and adherence. Moreover, vulnerable and high-risk patients are expected to benefit most. Finally, in chapter 10, the findings of this thesis were thoroughly discussed in relation to current literature, strengths and opportunities for improvement, and future perspectives for research with regard to older patients with NSCLC. The results of this PhD thesis indicated that treatment and outcomes among the older population are improving, although elderly remain disadvantaged as compared to younger patients in terms of survival. The effects of geriatric assessment for treatment decision-making are recognized by physicians in clinical practice, and effects of prehabilitation and rehabilitation on physical activity, treatment tolerance, and quality of life are promising. Altogether, some extra personal care during the poignant time of diagnosis and treatment could contribute to improved short-term and long-term outcomes which could ameliorate the balance between survival and quality of life for each individual within the heterogeneous population of elderly with NSCLC in daily clinical practice.