The treatment of elderly cancer patients is complicated by many factors. We sought to assess the uptake and tolerance of chemotherapy among patients 75 years and older diagnosed with small cell lung cancer (SCLC) in years 2004–2008 in Alberta, Canada, and assess their survival. All patients who met the above criteria and had an oncologist-consult were included. Data were obtained from the Alberta Cancer Registry and chart review. A total of 171 patients were included in the study, 117 (68%) of whom began chemotherapy. Of those, 52% completed all cycles, 66% did not have any dose reductions, and 31% completed all cycles at the recommended dose. The risk of death for patients who did not complete all cycles of chemotherapy was 2.72 (95% CI: 1.52–4.87) and for those who completed all cycles but with a reduced dose was 1.02 (95% CI: 0.57–1.82) relative to those who completed chemotherapy at full dose after adjusting for several demographic/clinical factors. Our results suggest that a significant proportion of elderly patients are able to tolerate chemotherapy and receive a survival benefit from it while those who experience toxicity may receive a survival benefit from a reduction in chemotherapy dose as opposed to stopping treatment.
Lung cancer is the leading cause of cancer-related death in developed nations [
SCLC is characterized generally by a rapid growth rate, initial sensitivity to chemotherapy and radiation, and early metastasis to regional lymph nodes and/or distant sites [
The standard of care for patients with SCLC combined concurrent chemoradiotherapy for those with limited disease and chemotherapy alone for those with extensive disease [
Evidence-based care for the elderly lung cancer population is lacking due to the underrepresentation of this population in clinical trials [
The care of elderly patients is, however, often complicated by comorbidities, frailty, and decreased organ function. The purpose of this study was to describe the receipt of chemotherapy provided to elderly patients with SCLC in Alberta, Canada, and assess their chemotherapy tolerance and survival. We also sought to identify the reasons for not recommending chemotherapy and for dose reductions and assess the relationship of patient age in these decisions. In the absence of clear evidence from clinical trials, the analysis of the elderly SCLC population through retrospective population-based studies such as this one helps assess and quantify the value of treating elderly cancer patients with chemotherapy.
A retrospective, population-based study was conducted on all residents of Alberta, Canada, diagnosed with SCLC at the age of 75 years or older in years 2004–2008 who had an oncologist-consult. Selection of 75 years was chosen because the median patient age for SCLC in Alberta is about 70 years, and we wanted to focus on the “significant minority” of elderly patients. Furthermore, on basis of our clinical experience, we felt that patients who are 75 years and older are the ones for whom ideal treatment is the least clear; we, therefore, selected 75 years as the age cut-off. The province of Alberta consists of an area of 660,000 km2 and has a population of 3.7 million. Approximately 80% resides in urban areas [
The healthcare system in Alberta is funded and administered publically, as it is throughout all of Canada; standard cancer care such as consultations with specialists and chemotherapy is free to residents. Cancer care is organized and coordinated provincially. Consultations with oncologists, nonsurgical cancer treatment, and other services are provided at cancer care facilities. Prior to receiving chemotherapy, a patient must be referred to one of six cancer facilities in the province to have a consultation with an oncologist with whom treatment options are discussed. Two of these cancer facilities are located in the major cities of Edmonton and Calgary; the remaining four are located in smaller cities. Chemotherapy can be provided through any one of the 17 provincial cancer care facilities.
The Alberta Cancer Registry was used to identify patients 75 years of age or older diagnosed with SCLC (International Classification of Diseases for Oncology (ICD-O-3) [
A chart review was conducted on all potentially eligible patients identified from the cancer registry to identify those who had an oncologist-consult and to obtain details of the chemotherapy received. All patients who had an oncologist-consult were included in the study. The following data were extracted from patient charts: cancer stage; presence and type of comorbidities; Eastern Cooperative Oncology Group (ECOG) performance status; whether or not chemotherapy was recommended by the oncologist; reasons for not recommending chemotherapy; whether chemotherapy was administered or patient refused reasons patient refused chemotherapy; chemotherapy start date; treatment regimen received; whether the patient received all chemotherapy cycles; number of cycles received if less than the complete amount; reasons for incomplete chemotherapy cycles; whether dose reduction occurred; reasons for dose reduction and changes to the initially recommended chemotherapy regimen. A complete course of chemotherapy was defined as receiving any of the regimens once every three weeks for 4 cycles. Dose reduction was defined as any reduction in the dose of chemotherapy administered to the patient, compared to the recommended dose; dose reduction that occurred at any time during chemotherapy treatment, including the first cycle, was included. Information about other treatments received, such as radiation or second-course treatment, were not collected; however, it is likely that most, if not all, patients with limited stage disease who received chemotherapy also received radiation. Patients with extensive stage disease, however, would only have received radiation to relieve symptoms; such treatment is palliative and would not impact survival.
This study was reviewed and approved by the Alberta Cancer Research Ethics Committee.
Descriptive statistics were calculated to describe the utilization and tolerance of chemotherapy in the SCLC patients who had an oncologist-consult. Exploratory data analyses were performed to determine cut-off values for continuous variables and to assess the relationships of these variables with commencing chemotherapy, dose reductions, and not completing all chemotherapy cycles. Chi-square test or Fisher’s exact test (if the expected value of a cell was less than 5) were performed to assess the statistical significance of these associations.
Kaplan-Meier (K-M) curves were generated to compare patient survival by age (<80 versus ≥80) and treatment completeness status. In order to ensure chemotherapy, completeness status was known at the beginning of the time period; the start time (T0) was defined as 12 weeks after the oncologist-consult; all patients were followed to the earlier of their death date or December 31, 2010. The log-rank test and the Wilcoxon test were used to determine statistical differences between the curves. The statistical software R was used to generate the K-M graphs.
Cox proportional hazard models were used to estimate the effect of treatment status on patient survival, adjusting for ECOG score, disease stage, age at diagnosis, number of comorbidities, and chemotherapy regimen used. As in the K-M graphs, the start time (T0) was defined as 12 weeks after the oncologist-consult date in order to categorize patients properly for chemotherapy completion and dose reduction statuses. The Wald Chi-square test was used to calculate
There were 238 patients aged 75 years or older diagnosed with SCLC in Alberta, Canada, in years 2004 to 2008. Of these, 11 were excluded for the following reasons: 2 were not residents of Alberta; 7 had a diagnosis of combined non-small cell and small cell lung cancer; and 2 had another cancer diagnosis for which they were receiving treatment. Of the remaining 227 potentially eligible patients, 171 (75%) had an oncologist-consult to discuss treatment options and were included in this study. There were 56 patients (25% of those potentially eligible for this study) who did not have an oncologist-consult. Relative to the patients who had an oncologist-consult, those who did not tend to be older (46% were older than 80 years compared to 35%). Additionally, almost half of them (46%) died within two weeks of their diagnosis.
Figure
Flow chart of the number of patients included in the study, had a consult, were recommended chemotherapy, received it, and completed it.
The relationship between the demographic and clinical characteristics of the patients included in the study and age is shown in Table
Association of demographic/clinical characteristics and age of patients diagnosed with SCLC who had an oncologist-consult.
Age at diagnosis | Age at diagnosis 80 | ||
---|---|---|---|
75–79 years |
years and older |
||
Total | 111 | 60 | |
| |||
Sex |
|
||
Male | 61 (55) | 36 (60) | |
Female | 50 (45) | 24 (40) | |
| |||
Stage |
|
||
Extensive | 85 (77) | 46 (77) | |
Limited | 25 (23) | 13 (22) | |
Unknown | 1 (1) | 1 (2) | |
| |||
ECOG |
|
||
0, 1, and 2 | 51 (46) | 19 (32) | |
3 and 4 | 43 (39) | 28 (47) | |
Missing | 17 (15) | 13 (22) | |
| |||
Number of |
|
||
0 | 13 (12) | 3 (5) | |
1 | 44 (40) | 20 (33) | |
2 | 26 (23) | 24 (40) | |
≥3 | 28 (25) | 13 (22) |
Table
Association of demographic/clinical characteristics and receipt/tolerance of chemotherapy of patients diagnosed with SCLC aging 75 years and older who had an oncologist-consult.
Consult with an oncologist | Began chemotherapy | Dose reduction | Incomplete chemotherapy cycles | |
---|---|---|---|---|
|
|
|
|
|
Total | 171 (100) | 117 (68) | 40 (34) | 56 (48) |
| ||||
Sex |
|
|
|
|
Male | 97 (57) | 66 (68) | 25 (38) | 35 (53) |
Female | 74 (43) | 51 (69) | 15 (29) | 21 (41) |
| ||||
Age at diagnosis |
|
|
|
|
75–79 | 111 (65) | 82 (74) | 24 (29) | 40 (49) |
≥80 | 60 (35) | 35 (58) | 16 (46) | 16 (46) |
| ||||
Year of diagnosis |
|
|
|
|
2004 | 32 (19) | 17 (53) | 6 (35) | 3 (18) |
2005 | 35 (20) | 28 (80) | 8 (29) | 17 (61) |
2006 | 36 (21) | 24 (67) | 9 (38) | 13 (54) |
2007 | 36 (21) | 23 (64) | 7 (30) | 11 (48) |
2008 | 32 (19) | 25 (78) | 10 (40) | 12 (48) |
| ||||
Stage |
|
|
|
|
Extensive | 131 (77) | 83 (63) | 28 (33) | 43 (52) |
Limited | 38 (22) | 33 (87) | 12 (36) | 12 (36) |
Unknown | 2 (1) | 1 (50) | 0 (0) | 1 (100) |
| ||||
ECOG |
|
|
|
|
0, 1 and 2 | 70 (40) | 59 (84) | 24 (41) | 22 (37) |
3 and 4 | 71 (42) | 40 (56) | 11 (28) | 26 (65) |
Missing | 30 (18) | 18 (60) | 5 (28) | 8 (44) |
| ||||
Number of |
|
|
|
|
0 | 16 (9) | 13 (81) | 5 (38) | 7 (54) |
1 | 64 (38) | 41 (64) | 16 (39) | 18 (44) |
2 | 50 (29) | 30 (60) | 8 (27) | 16 (53) |
≥3 | 41 (24) | 33 (80) | 11 (33) | 15 (45) |
2Row percentage: denominator is the number who had a consult in corresponding row.
3Row percentage: denominator is the number who began chemotherapy in corresponding row.
4
Of those who had an oncologist-consult, 28 patients (16%) were not recommended chemotherapy, and 27 patients (19%) for whom chemotherapy was recommended refused it. Oncologists’ reasons for not recommending chemotherapy and patients’ reasons for refusing it are listed in Table
Oncologists’ reasons for not recommending chemotherapy and patients’ reasons for refusing chemotherapy.
Reasons for not recommending chemotherapy1 | Reasons for patients’ refusal of chemotherapy1 | |
---|---|---|
|
|
|
Total | 28 (100) | 27 (100) |
| ||
Performance status | 22 (79) | 3 (11) |
Co-morbidities | 16 (57) | 4 (15) |
Toxicity | 0 (—) | 20 (74) |
Lack of social network or support | 1 (4) | 2 (7) |
Wound healing problems | 1 (4) | 0 (—) |
Age | 0 (—) | 2 (7) |
Transportation issues | 0 (—) | 1 (4) |
Other reasons | 0 (—) | 4 (15) |
Unclear | 4 (14) | 4 (15) |
2Column percentage.
Of those who began chemotherapy, 33% had a dose reduction, and 48% did not complete all treatment cycles. The most common reason for dose reduction was hematological toxicity (30 of 40 patients), while 10 of 40 patients had a dose reduction due to frailty and performance status (Table
Reasons for dose reduction and not completing chemotherapy.
Reasons for dose reduction1 | Reasons for incomplete chemotherapy cycles1 | |
---|---|---|
|
|
|
Total | 40 (100) | 56 (100) |
| ||
Hematological toxicity | 30 (75) | 32 (56) |
Nonhematological toxicity | 3 (8) | 19 (34) |
Frailty/performance status | 10 (25) | 25 (44) |
Other medical reason | 5 (13) | 13 (25) |
Patients’ decision | 0 (—) | 2 (4) |
Unclear | 6 (15) | 8 (14) |
2Column percentage.
Table
Drug regimen received and number of cycles completed by treatment status.
Began chemotherapy |
Dose reduction |
Incomplete chemotherapy cycles |
|
---|---|---|---|
Total | 117 (100) | 40 (34) | 56 (48) |
| |||
Drug regimen |
|
|
|
Carboplatin/etoposide | 55 (47) | 24 (44) |
27 (49) |
Cisplatin/etoposide | 36 (31) | 11 (31) | 12 (33) |
oposide | 25 (21) | 5 (20) | 16 (64) |
CAV | 1 (1) | 0 (0) | 1 (100) |
| |||
Numbers of cycles completed | |||
1 | 30 (26) | 6 (20) | |
2 | 12 (10) | 4 (33) | |
3 | 14 (12) | 5 (36) | |
4+4 | 61 (52) | 25 (41) |
2Row percentage: denominator is the number who began chemotherapy in corresponding row.
3
4Defined as completed chemotherapy cycles.
All but four patients died by the end of the follow-up period, December 31, 2010. Lung cancer was the recorded cause of death for all patients with the exception of 14; 13 patients died of a noncancer related cause, and one patient died of prostate cancer. Figure
Kaplan-Meier survival curves of all SCLC patients who had an oncologist-consult by chemotherapy completion status, where T0 is 12 weeks after consult.
Table
Adjusted1 hazard ratio of death of patients 75 years or older diagnosed with SCLC in 2004–2008 in Alberta, Canada, who had an oncologist-consult2.
Adjusted1 hazard |
|
|
---|---|---|
ECOG Score |
|
|
0, 1, and 2 | 1 | |
3 and 4 | 2.01 (1.22, 3.31) | 0.007 |
Missing | 1.59 (0.88, 2.88) | 0.12 |
| ||
Stage |
|
|
Limited | 1 | |
Extensive | 1.24 (0.80, 1.92) | 0.33 |
| ||
Age at diagnosis |
|
|
75–79 | 1 | |
≥80 | 1.06 (0.66, 1.75) | 0.80 |
| ||
Co-morbidities |
|
|
0 or 1 | 1 | |
2 or more | 1.63 (1.00, 2.66) | 0.05 |
| ||
Drug regimen |
|
|
Cisplatin/etoposide | 1 | |
Carboplatin/etoposide | 1.15 (0.5, 2.65) | 0.56 |
Oral etoposide | 1.15 (0.71, 1.89) | 0.75 |
| ||
Treatment status |
|
|
Complete/full dose | 1 | |
Complete/reduced dose | 1.02 (0.57, 1.82) | 0.94 |
Not completed | 2.72 (1.52, 4.87) | 0.0007 |
No chemotherapy | 2.01 (0.97, 4.18) | 0.6 |
2Start time was 12 weeks after the date of the initial oncologist-consult.
The purpose of this study was to describe the uptake and tolerance of chemotherapy among elderly patients with SCLC and assess their survival. Thirty-five percent of our study population was aged 80 years and older. These elderly patients, compared to those 75–79 years of age, received less chemotherapy and were more likely to receive a dose reduction, but were equally likely to complete all chemotherapy cycles. Notably, the adjusted hazard ratio of death did not differ between the two age groups. Overall, 52% of patients who began chemotherapy completed all cycles, and 41% had reduced chemotherapy doses. These results are confirmation that a significant proportion of elderly patients are able to tolerate chemotherapy and receive a survival benefit from it even in the presence of dose reductions.
Our results also suggest that elderly patients who have their chemotherapy dose reduced but complete all chemotherapy cycles have a similar survival (HR 1.02, CI 0.57–1.82) to those who complete all chemotherapy cycles at the full dose, after adjusting for ECOG score, disease stage, age, co-morbidity count, and drug regimen. Several phase II clinical trials have tested the efficacy of lower dose combinations of concurrent carboplatin and etoposide regimens in elderly SCLC patients [
A larger study similar to ours which included a population-based group of elderly SCLC patients was conducted in The Netherlands [
Although a large proportion of elderly patients were able to tolerate and experience a survival benefit from chemotherapy, 48% of patients who began chemotherapy were not able to complete all treatment cycles and did not have a survival benefit. Clearly, all elderly patients are not good candidates for chemotherapy. The difficulty is identifying the ones who are; there is a need for a reliable means to identify elderly patients who would benefit from chemotherapy that does not base its conclusions on chronological age and rather aims to determine biological age by the measurement of objective standard measures [
A limitation to the study is the nature of all retrospective studies in that they cannot prove causality. Additionally, there is always selection bias in terms of which patients receive treatment in a real clinical situation as opposed to a clinical trial setting. On the other hand, an inherent strength of a population-level retrospective study such as this one is that the treatment and outcome can be described for every patient, as we have done so herein. The major limitations are in obtaining complete information on all the factors that might impact one of or both treatment and outcome in order to properly adjust for them in analyses. In our study we had limited information on the patients who did not have an oncologist-consult, representing 25% of the entire population of SCLC patients aged 75 years or older in Alberta. The data we do have, however, suggests that many of these patients would not have been candidates for any kind of treatment as they died very soon after being diagnosed. It is possible, however, that some of them could have benefited from chemotherapy but did not have the opportunity because they were not referred to an oncologist, were unable to obtain transportation to an oncologist, were not interested in receiving chemotherapy, or another reason. We were not able to identify reasons for not seeing an oncologist. Regarding the patients who did have an oncologist-consult, performance status was missing for 18% of patients, and we did not collect information on receipt of other treatment modalities which could have affected survival and the ability to tolerate chemotherapy. It is possible that there is also missing/incomplete information related to the specific reasons for dose reductions and incomplete cycles. A further limitation arises from the relatively small number of patients with limited disease, which prevented us from fully exploring the interrelationships between age, stage, chemotherapy uptake, tolerance, and survival. Further study in a larger patient population may provide interesting insights on these issues.
SCLC is a significant health issue of the elderly. We have shown that while an appreciable proportion of elderly patients diagnosed with SCLC do not begin chemotherapy treatment, those that do are able to tolerate the treatment and receive survival benefits from it. It is, therefore, vital that elderly patients as well as younger patients are considered for established treatment. Our results also suggest that elderly SCLC patients who complete chemotherapy at a reduced dose have a similar prognosis to those who receive the full dose. Future research should focus on better understanding the relationship between frailty and toxicity to ensure the careful selection of patients who will benefit from chemotherapy treatment.
S. Fisher and T. M. Al-Fayea contributed equally to this paper.
The authors thank John Fleming for creating the online data collection tool used for conducting the chart review and also for reviewing the analyses for accuracy. The authors also thank Angela Bella for assisting with formatting and references.