Targeted Therapy at the End of Life for Patients with Lung Cancer

Introduction

Targeted therapy has been the key phrase in cancer treatment since the start of the new millennium. Both monoclonal antibodies and small molecules are now employed in a variety of cancers. Cure rates have been improved, for example, by rituximab in CD20-positive non-Hodgkin lymphoma and trastuzumab in Her-2–positive early-stage breast cancer. However, at other times, more modest survival gains are obtained in an essentially palliative setting.

Lung cancer has not been spared the onslaught of the “nibs” and “mabs.” Targeted therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has become standard treatment in a variety of settings in advanced non–small cell lung cancer (NSCLC), including as first-line treatment, ¹ in pretreated patients, ² and even in selected patients with poor performance status. ³ It is known that Asian patients, in particular, have a higher proportion of response to and clinical benefit from EGFR TKIs. ⁴ This is likely due to the high incidence of peripheral adenocarcinomas, in which EGFR mutations are found in a high proportion of cases. ⁵

Lung cancer is the leading cause of cancer mortality in our country ⁶ and the majority of patients present with advanced disease. ⁷ Treatment for these patients is palliative in intent. Several studies have suggested trends to aggressiveness of care at the end of life in patients with advanced cancer.^8,9 More specifically, a recent study reported an increased use of chemotherapy in patients with advanced-staged NSCLC near the end of life. ¹⁰ We thought it interesting and relevant to characterize the use of targeted therapies in relation to the end of life in our patients with NSCLC.

Patients And Methods

Data for this brief report on patients with NSCLC were extracted from an institutional review board–approved single-institution retrospective study on “aggressiveness of care at the end of life.” In this study, all adult patients diagnosed with advanced solid tumors that were deemed incurable and who died as inpatients under the Department of Haematology Oncology in the National University Hospital (NUH) were included. The NUH is a 900-bed tertiary-care hospital and is one of two public cancer treatment facilities in Singapore. Study subjects were identified from weekly mortality lists of the department, and the study aimed to include 250 patients for analysis. For simplicity, all patients with hematologic malignancies (including leukemia, lymphoma, myeloma) were excluded. Also excluded were patients diagnosed and treated for advanced cancer in other institutions but had their final “terminal” admission in the NUH. This was not an infrequent occurrence due to the zoning regulations for emergency ambulance services. Finally, we arbitrarily excluded patients who were diagnosed with incurable cancer within 1 month of their demise, intentionally aiming to omit those who may have been diagnosed in extremis, and thus not usually in contention for a serious consideration of systemic anticancer treatment.

Data were collected retrospectively on the various health resources utilized in the last 3 months of life including the use of specific anticancer treatments such as chemotherapy and radiotherapy. Most of the data were gleaned from hospital electronic records, including the computerized patient support system (CPSS) and the computerized pharmacy record system (iPharm). For this paper we focused on the anticancer drug treatments utilized in patients with NSCLC near the end of life.

Results

The “aggressiveness of care at the end of life” study included patients who died from advanced cancer in hospital and met the inclusion criteria from July 2007 to September 2008. From this 250-patient database, there were 53 cases of NSCLC. Thirty-six of these 53 patients with NSCLC received systemic anticancer treatment after diagnosis of advanced, incurable cancer. The characteristics of these patients are shown in Table 1. The patients were mainly of Chinese race (86.1%) and men (66.7%). Adenocarcinoma was the predominant histological subtype (69.4%).

Of the 36 patients receiving systemic therapy, 22 patients (61.1%) received it in their last 3 months of life, 12 patients (33.3%) received it in the last month of life, and 9 patients (25.0%) received it in their last 2 weeks of life. Most of the treatment at the end of life consisted of targeted therapy. For example, within the last 3 months of life, 21 patients (58.3%) received targeted agents while only three patients (8.3%) received conventional chemotherapy. Results are summarized in Table 2.

Of the 21 patients receiving targeted agents in the last 3 months of life, 17 patients received one drug, three patients received two drugs, and one patient received three targeted drugs. Gefitinib was the commonest targeted agent prescribed, followed by erlotinib. Sequential therapy with different targeted agents was prescribed in some patients, as well as combinations of targeted agents. Investigational targeted agents on clinical trial protocol were prescribed in six patients (Table 3). Most of the patients receiving targeted agents had at least one line of targeted treatment initiated within the last 3 months of life, usually as first or second line systemic therapy (Table 4). Targeted therapy was usually the last line of systemic treatment before death, and the median time from the last prescription of targeted therapy to death was 21 days.

Discussion

The EGFR TKIs (gefitinib, erlotinib) are routinely used in the treatment of advanced NSCLC. The BR-21² and Iressa Survival Evaluation in Lung Cancer (ISEL) ⁴ studies showed benefit for the use of erlotinib and gefitinib respectively in pretreated patients, while the recently reported Iressa Pan-Asian Study (IPASS) study showed that gefitinib could be used in the first-line setting in a selected Asian population of never or light-smokers with adenocarcinoma histology. ¹ Inoue et al. ³ even gave gefitinib to poor performance status patients with NSCLC harboring EGFR mutations who would otherwise not qualify for chemotherapy and showed striking clinical responses and reversal of performance status in this scenario.

In this brief report, we show an aggressive pattern of use of these targeted therapies in patients with NSCLC in the last 3 months of their life. Gefitinib and erlotinib were frequently prescribed close to the end of life. We also observed targeted therapies used in sequence, combination targeted therapies, and investigational targeted therapies being prescribed at the end of life. The feasibility of sequential EGFR TKI treatment has previously been described by our group. ¹¹

We found that targeted therapy was frequently initiated close to death and continued to be prescribed to patients as close as 5 days before demise. Some patients received targeted agents beyond the fifth line of treatment. These observations could be indicators of oncologists attempting to achieve an equivalent of the “Lazarus Response” as recently elaborated in an editorial by Langer. ¹² Although EGFR mutation testing is not done routinely in our hospital, the rapid clinical improvement seen in EGFR TKI responders can itself be a guide to treatment decision. ¹³

Our rates of systemic anticancer therapy use at the end of life are comparable to those reported by other authors.^8–10 For example, in a single institution study, Braga et al. ⁹ reported that the proportion of patients who received chemotherapy in the last 3 months, last month, and last 2 weeks of life was 66%, 37%, and 21%, respectively. What is novel in our study was that targeted therapy was far more frequently used than conventional chemotherapy and hence could be assuming primacy in the aggressive treatment of NSCLC at the end of life. A survey of community oncologists in the United States earlier in the decade had found that the percentage of patients receiving gefitinib near the end of life was not higher than those receiving other chemotherapy. ¹⁰ In our single institution study EGFR TKIs were found to be the drugs of choice by far. Reasons for this may include their greater potential for benefit in the Asian context, patients' preference for oral treatment, and the drugs' favorable toxicity profile.

We acknowledge the limitations to this study, including the small sample size, the single institution experience, and the lack of a control group.

Conclusion

We report that targeted agents have replaced conventional chemotherapy in the treatment of NSCLC close to the end of life. The advantages and conveniences of oral EGFR TKI therapy have probably made this the treatment of choice in our oncologists' attempt to attain disease control at the last hour.