End-of-Life Care in Patients with Metastatic Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations

Introduction

Metastatic lung cancer is the leading cause of cancer-related death in the United States, with 158,040 deaths estimated in 2015. ¹ Treatment of metastatic nonsmall cell lung cancer (NSCLC) has been transformed by the discovery and subsequent therapeutic targeting of oncogenic driver mutations such as epidermal growth factor receptor (EGFR) (17% of lung adenocarcinoma) and anaplastic lymphoma kinase (ALK) (8% of lung adenocarcinomas) in the subset of patients whose tumors harbor these mutations.^2–4 Patients harboring these mutations who are treated with these targeted therapies experience improvements in both survival and quality of life.^3–5 Although there are now multiple available targeted therapies for patients with these driver mutations, the currently available treatments are not curative and patients ultimately die from progressive disease. Thus, providing optimal end-of-life (EOL) care for this unique population of patients with more effective treatment options than other patients with metastatic disease remains an important issue.

In recent years, many studies have described the prevalence of suboptimal EOL care outcomes in patients with advanced cancer.^6–8 In patients being treated with chemotherapy for metastatic disease, delivery of intensive medical care in the last weeks of life is common, including administration of chemotherapy, visits to the emergency department, hospitalizations, and intensive care unit stays. In addition, there is evidence that patients with advanced cancer who receive chemotherapy closer to the time of death have later hospice referrals and are less likely to die in their preferred place.^6,7

Given the improved cancer outcomes due to the new and increased number of treatment options for patients with metastatic lung cancer harboring an EGFR mutation, we sought to examine that these improvements may impact the delivery of EOL care in this population. Specifically, we assessed the rates of chemotherapy administration and hospitalizations near death as well as hospice utilization in patients with EGFR mutations.

Methods

This was a retrospective chart review of medical records of patients receiving care at Massachusetts General Hospital Cancer Center (MGH CC). Patients who were diagnosed with metastatic EGFR-mutant NSCLC from January 2009 to December 2012 were identified through thoracic patient databases. Only patients with activating EGFR mutations were included in the analysis. Patients with EGFR exon 20 insertions were excluded from the analysis as this mutation is generally resistant to EGFR-targeted therapy. We included patients who received all their cancer care at MGH CC, regardless of the number of treatments. For those who sought second opinions at MGH CC, they were excluded unless they had at least one line of treatment at MGH CC. This review was limited to patients who died by January 2015 to capture EOL care.

Descriptive statistics, including frequencies, mean, median, and range, were calculated using Microsoft Excel.

Results

We identified 61 patients with metastatic NSCLC and an activating EGFR mutation who fulfilled our inclusion criteria. Patient demographics are depicted in Table 1. The majority of the patients were female (68%), white or Asian (97%), and never or minimal smokers (76%).

Discussion

We found that patients with EGFR mutations frequently received cancer treatment and were admitted to the hospital near the EOL. Previous reports have shown 6–24% of patients with advanced cancer receive chemotherapy within 14 days of death.^6,9,10 In our cohort, 38% of the patients received chemotherapy within 14 days of death. The majority of patients (72%) received chemotherapy within 30 days of death, the highest reported in the literature. The most common chemotherapy used at the EOL was an EGFR-targeted therapy. Although many patients saw palliative care during their disease course, many of these visits were not until near the end of life. In addition, compared to other cancer populations, our cohort had lower rates of hospice enrollment and a shorter length of stay on hospice, with many patients dying in the hospital.^6,9 These data suggest that the continued use of chemotherapy near the EOL may have had a downstream effect of increased hospital admissions and lower hospice utilization.

There are many reasons why oncologists administer chemotherapy near the EOL in this population. First, patients with EGFR mutations can be very ill with progressive cancer, yet still respond to a new treatment. Oral and IV chemotherapy can be effective even in the third and fourth line setting as these patients can have prolonged responses to both targeted and standard chemotherapy, making prognostic assessment particularly challenging. In addition, some patients with EGFR mutations will have a “flare” with rapid cancer growth and symptom deterioration when EGFR-directed therapy is discontinued. To prevent this flare, oncologists may continue to recommend oral EGFR-directed therapy, even with a patient's worsening health status. Finally, oral targeted chemotherapy also may have fewer side effects compared to traditional chemotherapy, allowing for easier continuation at the EOL. Thus, it is often quite reasonable to recommend additional chemotherapy as a patient with an EGFR mutation's health status worsens. However, a consequence of this practice may be the inability to provide high-quality EOL care, such as less time in the hospital and more time in hospice care.

Several studies have described the factors that are important to patients and their families at the EOL. Patients and families report that pain and symptom management, making decisions about treatment preferences, preparing for death, strengthening important relationships, being treated as a “whole person,” and achieving a sense of completion and control are all important at the EOL.^11,12 Traditionally, hospice services help patients and their families achieve many of these goals. ¹³ Patients with metastatic cancer who received home hospice services at the EOL are more likely to be treated for psychological distress and pain, to report open communication, and to have deaths in their preferred place.^13,14 In contrast, more unmet needs are reported when hospice is not involved. ¹³ Thus, the lower rates of hospice utilization for the patients in our population raise concern that important aspects of EOL care may not have been addressed. However, the traditional hospice model is intrinsically flawed because patients must generally forgo cancer treatment upon enrollment. Although some hospices now allow patients to continue chemotherapy upon enrollment, so called “open access hospices,” many are not. ¹⁵ Given this barrier to hospice utilization, we need to investigate alternative care models to support patients with EGFR mutations at the EOL.

Limitations to our study include that our study population was from a single, tertiary care hospital, which may limit its generalizability. In addition, this was a retrospective study that included a historical cohort with no matched control. Despite these limitations, the data suggest an important difference in care patterns for this population and further research is warranted to assess EOL care in this population.

Cancer treatments for patients with EGFR mutations represent one of the most remarkable successes in oncology in the last decades. Notably, the identification of EGFR mutations and EGFR-directed therapies was the first of the now many discoveries, including ALK translocations and immunotherapy, to substantially improve outcomes for patients with lung cancer. However, as cancer therapies improve and patients live longer with their illness, we will need to restructure our healthcare delivery models for patients at the EOL. We will not be able to rely on the current hospice model for provision of high-quality EOL care for patient populations who may continue to receive chemotherapy closer to death. Possible models could include increased availability of open access hospices or greater integration of palliative care services earlier in the disease course, which would allow patients to remain on cancer treatments while receiving the benefits of a multidisciplinary team with expertise in providing the supportive care needed for patients at the EOL and their families. Continued research and innovation are therefore critical to establish comprehensive care models that address high-quality care for patients' entire trajectory of disease, from diagnosis to death.