Targeted Therapy at the End of Life in Advanced Cancer Patients

Abstract

Objective:

We describe the use of systemic therapy in advanced cancer patients admitted to an acute care hospital, with a focus on targeted therapy. We aim to spotlight the utilization of targeted agents in the last months of life.

Methods:

Adult patients (N=252) with advanced solid tumors who died as inpatients in the National University Hospital, Singapore, were included in this retrospective study. Patients' demographic and clinical data were extracted from hospital records. Information on systemic therapy was extracted from the time of diagnosis and all other data limited to the last three months before death.

Results:

187 adult patients received palliative systemic therapy from the time of diagnosis, of which 125 (66.8%) received it within three months of death. Of patients receiving only nontargeted systemic treatment (n=106), 60 (56.6%) and 26 (24.5%) received it within three months and one month of death respectively. Comparatively, 81 patients received palliative targeted systemic therapy, of which 65 (80.3%) and 40 (49.4%) had treatment within three months and one month of death respectively (p=0.001 and p<0.001). Targeted therapy was first initiated in the last three months of life in 38 patients. Oral agents targeting epidermal growth factor receptor (lung cancer patients) and vascular endothelial growth factor receptor (non–lung cancer patients) pathways were commonly employed. Lung cancer patients were more likely to have targeted therapy as their last line of systemic therapy: 26/54 lung cancer patients compared with 29/133 non–lung cancer patients (48.1% versus 21.8%, p<0.001).

Conclusions:

Targeted therapy is used in more than half of patients who received systemic therapy within three months of death. The degree to which these agents are being utilized near the end of life suggests the need to reexamine the risk/benefit profile of targeted therapy for this population, and the decision-making process around their use.

Introduction

Cancer therapy is becoming increasingly complex, with targeted therapy being employed with greater frequency in a variety of cancers. Since the turn of the century there has been acceleration in the discovery of new monoclonal antibodies and small molecules. Cure rates are continuously being improved, for example, by rituximab in CD20-positive non-Hodgkin's lymphoma, and trastuzumab in Her-2-positive breast cancer.^1,2

Targeted therapy has added an exciting dimension to anticancer treatment: the premise of tumor-selective mechanism of action, with accompanying milder toxicity profiles and the possibility of oral treatment are some of the attractions at hand. With chemotherapy reportedly being utilized more towards the end of life, we aimed to describe the use of targeted treatment in this setting.³ In a previously published subset of this study we observed that anticancer treatment at the end of life of non–small cell lung cancer patients consisted predominantly of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).⁴ We hence sought to observe the use of palliative systemic therapy (i.e., systemic therapy with noncurative intent) at the end of life in our institution with a focus on the utilization of targeted therapy in advanced cancer patients. We also sought to compare the difference in types of targeted therapy in the last three months between lung and non-lung cancer as well as the timing of initiating targeted therapy in this interval.

Patients and Methods

Study design

We designed a retrospective cohort study comprised of adult patients diagnosed with incurable advanced solid tumors, who died as inpatients under the care of the Department of Hematology-Oncology, National University Hospital, National University Health System (NUHS), Singapore. The NUHS is a 900-bed tertiary-care hospital and is one of the two major public cancer treatment facilities in Singapore. The study was approved by the hospital's institutional review board.

Exclusion criteria

Patients with hematologic malignancies (e.g., leukemia, lymphoma, and myeloma) were excluded. If patients were diagnosed and treated for advanced cancer in other institutions but had passed away in our center, they were excluded from the analysis because treatment data were not available. These were not infrequent occurrences, due to the zoning regulations for emergency ambulance services. Patients who were discharged to inpatient hospices, or had been discharged to die at home, were not included, as the mortality audit had excluded such patients, and the exact dates of deaths were not available. Patients who were on clinical trials, in whom treatment were blinded, were also excluded. Finally, patients who were diagnosed with incurable cancer within one month of their death were excluded, as these patients may have been diagnosed in extremis, and thus not usually considered for systemic anticancer treatment.

Data collection

Study subjects were identified from weekly mortality lists of the department from July 2007 to April 2009. Data was collected from hospital electronic records, including the computerized patient support system (CPSS) and the computerized pharmacy record system (iPharm). Demographic data such as race, age, gender, and primary tumor subtype were recorded. We looked retrospectively at the various health resources utilized in the last three months of life, especially specific systemic anticancer treatments such as conventional chemotherapy, hormone therapy, and targeted therapy. Information regarding systemic therapy use was obtained from the time of diagnosis. Statistical analyses were made using the Pearson's χ² test or Fisher's exact test for comparison of proportions between two groups, and the Mann Whitney U test for comparison of medians between two groups.

Definitions

Systemic treatment included not only the use of chemotherapy, but also targeted treatment or the use of hormonal therapy. Chemotherapy is considered to be any cytotoxic agents that were cytotoxic, i.e., antineoplastic therapy intended to kill tumor cells in the absence of a specific molecular target. Targeted therapy is defined as any agent that is given either alone or in combination with chemotherapy directed towards specific cellular or molecular pathways or targets of oncogenesis. These included small molecule TKIs such as gefitinib, as well as large ligand monoclonal antibodies such as cetuximab.⁵

Results

A total of 413 patients who died from July 2007 to April 2009 were identified, and 252 patients who fulfilled the criteria for inclusion were analyzed (see Table 1). The patients were mainly of Chinese race (81%) and males comprised 56%. The median age of the patients was 62 years (range 19–92).

Table 1.

Patient and Treatment Profile

	n (%)
Total patient cohort^a	252 (100)
Sex
Male	141 (56)
Female	111 (44)
Race
Chinese	204 (81)
Malay	34 (13.5)
Indian	10 (4.0)
Others	4 (1.6)
Median overall survival (months)	13.0^b

Treatment profile
Patients who had received palliative systemic treatment since diagnosis	187 (100)
Average duration between last systemic treatment and death (months)	3.7
Median number of lines of systemic treatment	2^c
Patients receiving systemic treatment within 3 months of death	125 (66.8)
Patients receiving systemic treatment within 1 month of death	66 (35.3)
Patients receiving systemic treatment within 2 weeks of death	36 (19.3)

Median age 62 years; range 19–92.

Range 1–354.

Range 1–10.

Receiving palliative systemic therapy since the diagnosis of incurable cancer were 187 patients, with 65 patients receiving only best supportive care after diagnosis (i.e., treatment with intent to maximize quality of life but without specific antineoplastic therapy) (see Fig. 1). Among the patients who had received palliative systemic treatment, 125 (66.8%) patients received at least some treatment in their last three months of life, including 66 patients (35.3%) in their last month of life and 36 patients (19.3%) within two weeks to their death. The median overall survival of the entire cohort (from the time of diagnosis) was 13.0 months. The median survival for patients who received systemic treatment up to the last three months of life was 30.0 months, while those without was 11.6 months. No further statistical analyses were performed for survival, as this was purely a retrospective observational study.

Fig. 1.

Study sample.

There were 106 patients who had only nontargeted systemic treatment since their diagnosis. Of these, 60 patients (56.6%) received at least some treatment within three months of death; and of these, 26 patients (24.5%) were still receiving treatment within one month of death. Comparatively, 81 patients received palliative targeted systemic therapy in the course of their systemic anticancer treatment. Of these, 65 patients (80.3%) received at least some targeted therapy within three months of death, with a subset of 40 patients (49.4%) receiving it within one month of death. These differences between the two groups within three months and within one month of death were significant (p=0.001 and p<0.001, respectively). A total of 38 (46.9%) patients had initiated a new line of targeted therapy within three months of death, and 19 (23.5%) had done so within one month of death.

The most common primary malignancy was lung cancer, followed by colorectal and breast cancer. These three malignancies accounted for 60% of all patients, as well as 60% of patients that had some form of palliative systemic therapy since the diagnosis of incurable cancer (see Table 2). In most malignancies, targeted therapy made up a significant part of palliative systemic treatment at the end of life. The proportion of patients who had targeted therapy (out of those receiving any systemic therapy) in the last three months of life was the highest for lung cancer, hepatocellular carcinoma, cholangiocarcinoma, sarcomas, as well as urinary tract malignancies. However, the individual non–lung cancer malignancies had small absolute numbers.

Table 2.

Systemic Anticancer Treatment by Tumor Subtype

Primary tumor	Total number of patients	Number of patients who received palliative systemic therapy since diagnosis	Number of patients who received systemic therapy in last 3 months of life	Number of patients who received targeted therapy in last 3 months of life (%^a)
Lung	82	54	32	27 (84.3)
Colorectal	35	28	15	9 (60.0)
Breast	34	31	24	5 (20.8)
Gynecological	14	13	8	1 (12.5)
Stomach and esophagus	13	7	5	0 (0)
Hepatocellular carcinoma	12	8	5	5 (100)
Pancreas	12	9	7	4 (57.1)
Nasopharyngeal carcinoma	10	10	7	3 (42.9)
Sarcoma, including GIST	7	5	4	3 (75.0)
Cholangiocarcinoma	6	3	3	3 (100)
Prostate	5	5	5	0 (0)
Unknown origin	5	2	2	1 (50.0)
Urinary tract^b	5	4	3	2 (66.7)
Others^c	12	8	5	2 (40.0)
Total	252	187	125	65 (52.0)

GIST, gastrointestinal stromal tumor.

% of the patients who received systemic treatment in the last 3 months of life.

Renal cell carcinoma and bladder carcinoma.

Includes central nervous system tumors, hemangiopericytoma, thymoma, adrenocortical carcinoma.

We further subanalyzed the categories of lung and non–lung cancer patients, given the numbers of patients in the different tumor subtypes in our study and the broad biologic bases for targeted therapy in both groups. Both lung and non–lung cancer patients included significant numbers who received palliative targeted therapy since their diagnosis, with many continuing it into the last three months of life. Among 32 lung cancer patients who had palliative systemic therapy in the last three months of life, 27 patients (84.3%) received targeted therapy in this period. Among 93 non–lung cancer patients who had palliative systemic therapy in the last three months, 38 patients (40.8%) received targeted therapy in this period (p<0.001).

The wide repertoire of targeted agents employed at the end of life is displayed in Table 3. Epidermal growth factor receptor (EGFR) TKIs were the targeted therapy of choice in patients with lung cancer, with 22 out of 27 patients (81.5%) receiving them. In the non–lung cancer group, anti-VEGF (vascular endothelial growth factor) therapy was more commonly used, being especially popular in colorectal cancer and hepatocellular carcinoma, with 29 out of 38 patients (76.3%) in the non–lung cancer group receiving anti-VEGF treatment. A total of 25 out of the 65 lung and non–lung cancer patients (38.5%), 8 lung cancer and 17 non–lung cancer patients, had received targeted therapy in the last three months of life as part of a clinical trial. The use of oral agents was overall more common than intravenous agents largely due to the use of oral EGFR TKIs in the lung cancer group. This was also true of the use of anti-VEGF agents in non–lung cancer patients, with almost twice as many patients receiving oral anti-VEGF TKIs compared to bevacizumab.

Table 3.

Types of Targeted Therapy in the Last 3 Months of Life

	Lung cancer n (%)	Non-lung cancer n (%)	Total n (%)	P
Patients who received palliative targeted therapy in the last 3 months^a	27 (100)	38 (100)	65	-

Oral
Small molecule tyrosine kinase inhibitors
Anti-EGFR
Erlotinib	7 (25.9)	3 (7.8)	10 (15.4)	0.079
Gefitinib	17 (62.9)	0	17 (26.1)	<0.001
Anti-VEGF
Sunitinib	0	6 (15.7)	6 (9.2)	0.037
Sorafenib	1 (3.7)	5 (13.2)	6 (9.2)	0.388
Axitinib	0	2 (5.3)	2 (3.1)	0.507
Linifanib	4 (14.8)	3 (7.9)	7 (10.8)	0.437
Pazopanib	1 (3.7)	3 (7.9)	4 (6.2)	0.636
Others
Imatinib	0	1 (2.6)	1 (1.5)	1.000
MTOR inihibitors
Sirolimus	1 (3.7)	0	1 (1.5)	1.000
HDAC inhibitors
Belinostat	0	1 (2.6)	1 (1.5)	1.000
SB939	0	3 (7.9)	3 (4.6)	0.260
Cyclin-dependent kinase inhibitors
Seliciclib	1 (3.7)	2 (5.3)	3 (4.6)	1.000

Intravenous
Monoclonal antibodies
Anti-EGFR
Cetuximab	0	3 (7.9)	3 (4.6)	0.260
Anti-VEGF
Bevacizumab	0	10 (26.3)	10 (15.4)	0.004

Four lung cancer and 4 non-lung cancer patients received more than one type of targeted therapy.

EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; MTOR, mammalian target of rapamycin; HDAC, histone deacetylase.

There were 14 lung cancer and 24 non–lung cancer patients who had a new line of targeted therapy initiated within three months of death, including three lung cancer patients who had two lines of targeted therapy initiated (see Table 4). The new line of treatment was used predominantly in the first- and second-line setting for patients with lung cancer, but half the non–lung cancer patients had targeted therapy initiated in the last three months beyond the second-line setting.

Table 4.

Timing of Targeted Therapy in the Last 3 Months of Life

	Lung n (%)	Non-lung n (%)	P
Patients who received palliative targeted therapy in the last 3 months	27 (100)	38 (100)	-
At least one line of targeted therapy initiated within last 3 months	14 (51.9)	24 (63.2)	0.446
Targeted therapy initiated as^a
First-line therapy	5 (18.5)	8 (21.1)	1.000
Second-line therapy	7 (25.9)	4 (10.5)	0.067
Third-line therapy	0 (0)	4 (10.5)	0.276
Beyond third-line therapy	5 (18.5)	8 (21.1)	1.000
Median time from last prescription/administration of targeted agent to death, days [range]	19 [0–89]	27 [7–80]	0.800

Three lung cancer patients had more than one line of targeted therapy initiated within three months of dying.

Targeted therapy was the last line of treatment before death in significant numbers of both lung and non–lung cancer patients. Among all 187 patients who had received palliative systemic therapy, patients with lung cancer were more likely to have targeted therapy as their last line of systemic therapy: 26 out of 54 lung cancer patients compared with 29 out of 133 non–lung cancer patients received targeted therapy as their last line of treatment (48.1% versus 21.8%, p<0.001).

Discussion

To our knowledge, this is the first report examining the use of systemic treatment near the end of life with a focus on the emerging use of targeted therapeutic agents. The patient demographics in Table 1 are similar to the national demographics and statistics for cancer mortality in the most recent update.⁶ An analysis of the national registry for cancer deaths shows that the majority of patients die in the hospital.⁷

A significant proportion of the patients received systemic treatment even up to within two weeks of death (19.3%). This is consistent with previously reported statewide and nationwide studies in Canada and Sweden and single-institution studies in Portugal and Korea.^8–11

With the emergence of targeted treatment over the past decade, its utilization at the end of life is substantial. Indeed, patients whose treatment included targeted therapy were more likely to be still receiving targeted therapy in the last months of life, compared to the receipt of nontargeted therapy in the last months of life in the group whose treatment only includes conventional agents. Similarly, a larger proportion of patients in the targeted therapy group were started on a new line of targeted therapy in the last months of life compared to the corresponding proportion in the nontargeted therapy group, although this difference did not reach statistical significance. The anticipation of an increasing trend of utilization of targeted therapy towards the end of life can be founded on modern molecular concepts such as individualized biomarker profiling and oncogene addiction.¹² That some tumors rely predominantly on one molecular signalling pathway for replication means that blocking that specific pathway will cause regression of the tumor. Continued and recurrent blockade can lead to sustained, durable, and even repeated responses to targeted therapy. For example, the importance of maintaining EGFR pressure was demonstrated by response rates that can be seen even after interval retreatment with the same TKI on some patients. This is especially so in Asian female nonsmokers, phenotypes that have a higher chance of harboring sensitizing EGFR mutations.^13–15

About 40% of patients receiving palliative systemic therapy since diagnosis had targeted therapy, of which 80% received some targeted therapy within the last three months of life. We had previously reported on the aggressiveness of the use of EGFR TKIs in Asian non–small cell lung cancer patients and continue to show that trend here.⁴ While there were smaller numbers of patients in each non–lung cancer subtype, collectively we saw a tendency for the use of targeted antiangiogenic agents in this group. Anti-EGFR therapy was not seen commonly at the end of life in the non–lung cancer group: Erlotinib was used in patients with pancreatic carcinoma, and cetuximab in colorectal cancer.^{16, 17} We did not see the use of anti-HER2 therapy in the last three months of life.

It is clear that not all targeted treatments produce the same result. The traditionally chemo-resistant gastrointestinal stromal tumor was the first solid tumor that showed exquisite responsiveness to targeted therapy with imatinib.¹⁸ Lung adenocarcinomas, by far a more common solid malignancy, were later shown to respond so remarkably to EGFR TKIs that even patients on the brink of death can be rescued. Sixty-eight percent of patients with metastatic lung cancer had improved from a performance status of 3 or more at baseline to a performance status of 0 to 1 after being treated with gefitinib.^19,20 Survival for many Asian lung cancer patients, in whom sensitizing EGFR mutations are found, has been significantly prolonged.^21,22 While the antiangiogenic strategy has shown good “class effect” in renal cell carcinoma, its efficacy in other settings, such as in hepatocellular carcinoma, is more tenuous and at best modest.^23,24 The marketing approval for bevacizumab in metastatic breast cancer was recently withdrawn by the FDA following disappointing results from newer trials, contradicting prior expectations.^25–27 The additive benefit of anti-EGFR therapy in metastatic colorectal cancer and head and neck cancer is also moderate.^17,28 We report a variety of agents used at the end of life in non–lung cancer patients, surmising that the attempts at a clinical benefit may have been overly optimistic, especially in those in which therapy was initiated beyond the second-line setting.

The rationale behind increased chemotherapy utilization at the end of life has been comprehensively discussed.²⁹ These reasons may be heightened in the era of targeted therapy with its accompanying attractions. The preference for oral antiangiogenic agents, often as monotherapy, in non–lung cancer patients could signify a convenient and harmless endeavor to prolong life after conventional treatment has failed. This raises several looming questions. Will end of life care be compromised as a result? Should patients in hospices be allowed to take oral targeted therapy? Will the use of targeted therapy delay or prevent access to palliative/hospice services near the end of life?

While the discovery of predictive biomarkers of treatment response continues to breach new frontiers, the challenge remains for oncologists to recognize when “blind” attempts may yield more disappointments than success.^30–32 The enormous cost of targeted therapies is an obvious factor in the equation, though we observed the inclusion of patients in clinical trials at the end of life, where the cost element would have been defrayed.³³ We are aware of the potential influence of publication biases in both the medical and lay media in reporting cancer treatment and outcomes.^34–36 Others have argued that that many patients do not have sufficient information regarding true prognosis and outcomes in making end of life decisions.^29,37

We acknowledge the limitations of this study. Our institution is one of two that provide tertiary medical oncology services. Other public hospitals in the country may concentrate more on best supportive care. Our study also does not capture the 30% of patients that die at home, nor the 10% that die in inpatient hospice.⁷ These patients may have had a less aggressive approach to the end of life, but as yet no local data has been presented. We included a variety of different primary tumors in the arbitrarily defined non–lung cancer subgroup. This heterogeneity would caution against applying the results to each cancer subtype. However, we feel that the subtypes reflect to some extent the general patient population in the wards, and the observed prescribing pattern mirrors the overall day-to-day practice. While it remains a challenge to demonstrate the effect of aggressive chemotherapy on patients' survival,^38,39 retrospective studies of decedents remain a convenient, effective, and reliable method in profiling and understanding end of life care.⁴⁰

The complex interplay of factors surrounding the experience of chemotherapy at the end of life will be an area of ongoing study,^29,41 more so now in the epoch of molecular medicine. With the emerging variety of novel targeted agents in the pipeline, the communicative process between oncologist and patient has to seek clarity and prudence in navigating through the treatment options. We highlight the previously undescribed phenomenon of targeted therapy at the end of life in our institution and foresee more research in this area.

Footnotes

Author Disclosure Statement

No conflicting financial interests exist.

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