Clinical decision-making and health-related quality of life during first-line and maintenance therapy in patients with advanced non-small cell lung cancer (NSCLC): findings from a real-world setting

Non-small cell lung cancer (NSCLC) accounts for 85% of all cases of lung cancer and causes the most cancer deaths worldwide [ 1, 2]. More than 50% of NSCLC patients present with advanced disease at diagnosis, for which four to six cycles of platinum-based doublet chemotherapy is the standard first-line treatment [ 3]. Patients responding to first-line therapy with stable disease or a partial/complete response after cycle 4 are considered for subsequent maintenance therapy (MT), either with a new agent (i.e. switch MT) such as pemetrexed or erlotinib or with one of the first-line agents (i.e. continuation MT) such as pemetrexed or bevacizumab [ 4, 5].

In clinical phase III trials, MT with pemetrexed has been shown to improve overall and progression-free survival of patients suffering from non-squamous NSCLC [ 6– 8]. However, MT commits patients to continuous cytotoxic chemotherapy in a disease setting where the overall survival benefit remains modest [ 3, 9]. Hence, in line with European Society for Medical Oncology guidelines, decision-making about MT must take into account persisting toxicity after first-line chemotherapy, performance status and patients’ choices concerning treatment options [ 10]. In addition to physician ratings, toxicity can be comprehensively evaluated through patient-reported outcome measures (PROMs) such as the assessment of health-related quality of life (HRQOL).

Studies evaluating HRQOL in NSCLC clinical trials showed no substantial impairment of patients’ HRQOL following MT with pemetrexed [ 11– 14]. Similar results have been reported for erlotinib [ 15, 16]. However, results on HRQOL from clinical trials should be interpreted with caution because of an inherent selection bias whereby patients with low income level or poor health status are less likely to participate in clinical trials, leading to the risk of overestimating HRQOL [ 17, 18].

To enable patients to make an informed decision on whether or not to undergo MT, both patients and physicians require comprehensive data on symptom burden and HRQOL under real-life conditions in this treatment setting [ 5]. Therefore, further investigation of HRQOL impairments related to pemetrexed MT has been encouraged [ 19, 20], especially in observational studies in a setting which considers the patient’s perspective. Therefore, the aim of this study was to assess HRQOL during first-line chemotherapy and subsequent MT, and determine patients’ and physicians’ reasons leading to clinical decisions in the treatment of advanced NSCLC.

This study aimed at assessing clinical decision-making for MT with either pemetrexed or erlotinib as well as HRQOL in patients with advanced NSCLC in a real-world setting. Compared with first-line therapy, we found that the HRQOL and symptom burden improved in MT for symptoms such as nausea and vomiting, sleep disturbances, constipation and appetite loss. While this may be partly explained by the discontinuation of platin-based chemotherapy, the reported increase in alopecia and taste alterations might possibly indicate late first-line treatment toxicity.

Our findings are comparable to those of studies reporting on HRQOL in maintenance pemetrexed [ 11– 13] showing that HRQOL seems to be at least maintained during long-term MT for certain symptoms while further impairing others. When compared with patients receiving placebo, patients undergoing MT with both pemetrexed [ 13] and erlotinib [ 15] reported similar HRQOL using the self-administered Functional Assessment of Cancer Therapy-Lung (FACT-L), with the exception of a larger degree of appetite loss under MT as well a significantly prolonged time to worsening of pain and analgesic use.

In the landmark PARAMOUNT trial [ 14], pemetrexed was associated with significantly more low-grade nausea, anaemia, oedema, and neutropenia than placebo, while the incidence of low-grade fatigue, anaemia, and neutropenia decreased with longer treatment exposure. Though HRQOL impairments in the course of long-term pemetrexed maintenance as measured by the EQ-5D were not substantial, even low-grade toxicities were reported to have been potentially burdensome for patients.

In our study, treatment toxicity and side effects as well as physical and emotional exhaustion were the most common reasons for patients to decline MT in the first place. The reported incidence of reasons, however, might imply that clinicians underestimate the effects of patient-reported toxicity and treatment sequelae. Treatment toxicity and side effects of first-line chemotherapy were indicated twice as often by patients than by physicians to be the reason for not considering MT, despite stable disease. Patients further reported physical or emotional exhaustion in 10 cases. This finding is consistent with other treatment preference studies [ 26] where the extent and severity of current treatment-related side effects played a large role in patients’ attitudes to continued treatment. While patients attach high value to delaying the worsening of symptoms [ 27], progression-free survival benefits are viewed as most beneficial when disease symptoms are mild but as detrimental when disease symptoms are severe [ 28].

This discrepancy in patients’ and physicians’ perceptions of treatment burden and reasoning for and against MT reflects the notion that information reported by the physician cannot substitute direct patient reporting [ 29]. In this study, the physician voiced the decision to opt for or discontinue MT in the majority of cases. This emphasises the need for closer integration of PROMs such as the assessment of HRQOL and patient choice of treatment into the process of clinical decision-making on MT. Systematic collection of patient-reported outcome data in the real-world clinical setting has proven feasible and can contribute to clinical management on different levels [ 30– 32]. Group-level data on HRQOL during MT provide patients and clinicians with information to substantiate possible treatment-related functional and HRQOL consequences, thereby promoting shared and informed decision-making. On the individual patient level, continuous PROM monitoring supports personalised clinical management, enhancing patient–physician communication and continuity of care [ 33, 34].

The interpretation of our results is limited by the fact that while addressing first-line chemotherapy and MT, the study excluded second-line treatment as well as patients who did not receive MT after first-line chemotherapy. The latter, in particular, would have represented an interesting comparator group but were not assessable for logistical reasons. Because of the study sample size, particularly during MT, statistical power allowed only limited analyses of change over time. Belani et al. [ 13] reported similar problems regarding compliance with questionnaire completion in the PARAMOUNT trial. Despite the study limitations, however, the comprehensive assessment of HRQOL and symptom burden using the EORTC QLQ-C30, its lung cancer-specific modules QLQ-LC13, and additional items on taste alterations and skin toxicity are strengths of this study.

Our results indicate that HRQOL and symptom burden during MT stabilise over time in some aspects, while remaining debilitating in others. Treatment burden dominates patients’ perspectives on therapy and affects their treatment decisions. Comprehensive data on symptom burden and HRQOL impact of MT systematically assessed under real-life conditions can contribute to optimised clinical care. As the use of MT is increasingly considered in other advanced cancers [ 35, 36], the integration of PROMs generated in clinical trials as well as on the individual patient level is required to enable shared decision-making and personalised health care based on a mutual understanding of treatment objectives and expectations.