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Real-world predictors of survival
in patients with extensive-stage
small-cell lung cancer in
Manitoba, Canada: a
retrospective cohort study
David E. Dawe
1,2,3
*, Rebekah Rittberg
1,2
, Iqra Syed
4
,
Mary Kate Shanahan
4
, Daniel Moldaver
4
, Oliver Bucher
5
,
Katie Galloway
5
, Kayla Reynolds
6
, James T. Paul
1,2
,
Craig Harlos
1,2
, Julian O. Kim
7,8
and Shantanu Banerji
1,2,3
1
Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada,
2
Department of
Hematology and Medical Oncology, CancerCare Manitoba, Winnipeg, MB, Canada,
3
CancerCare
Manitoba Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada,
4
AstraZeneca Canada,
Mississauga, ON, Canada,
5
Department of Epidemiology and Cancer Registry, CancerCare Manitoba,
Winnipeg, MB, Canada,
6
Department of Cellular & Physiological Sciences, University of British
Columbia, Vancouver, BC, Canada,
7
Department of Radiology, University of Manitoba, Winnipeg,
MB, Canada,
8
Department of Radiation Oncology, CancerCare Manitoba, Winnipeg, MB, Canada
Background: Extensive-stage small-cell lung cancer (ES-SCLC) is an incurable
cancer with poor prognosis in which characteristics predictive of long-term
survival are debated. The utility of agents such as immune checkpoint inhibitors
highlights the importance of identifying key characteristics and treatment
strategies that contribute to long-term survival and could help guide
therapeutic decisions.
Objective: This real-world analysis examines the characteristics, treatment
patterns, and clinical outcomes of patients receiving chemotherapy without
immunotherapy for ES-SCLC in Manitoba, Canada.
Methods: A retrospective cohort study assessed patient characteristics,
treatment, and survival duration (short: <6 months; medium: 6–24 months;
long: >24 months) using the Manitoba Cancer Registry and CancerCare
Manitoba records. Eligible patients were aged >18 years with cytologically
confirmed ES-SCLC diagnosed between January 1, 2004, and December 31,
2018, and received cytotoxic chemotherapy (CT). The one-, two-, and five-year
probabilities of overall survival (OS) were assessed relative to patient, disease, and
treatment characteristics using Kaplan-Meier methods and Cox proportional
hazards models.
Results: This analysis included 537 patients. Cisplatin was used in 56.1% of
patients, 45.6% received thoracic radiotherapy (RT), and few received
prophylactic cranial irradiation (PCI). In the overall cohort, one-, two- and five-
year OS rates were 26%, 8%, and 3%, respectively. For patients with Eastern
Cooperative Oncology Group Performance Status (ECOG PS) 0, OS rates at one,
two, and five years were 43%, 17%, and 10%, respectively, vs. 27%, 8%, and 2% for
Frontiers in Oncology frontiersin.org01
OPEN ACCESS
EDITED BY
Yu Yao,
The First Affiliated Hospital of Xi’an
Jiaotong University, China
REVIEWED BY
Christoph Pöttgen,
University of Duisburg-Essen, Germany
Michael Shafique,
Moffitt Cancer Center, United States
*CORRESPONDENCE
David E. Dawe
ddawe@cancercare.mb.ca
RECEIVED 22 March 2023
ACCEPTED 07 August 2023
PUBLISHED 18 September 2023
CITATION
Dawe DE, Rittberg R, Syed I, Shanahan MK,
Moldaver D, Bucher O, Galloway K,
Reynolds K, Paul JT, Harlos C, Kim JO and
Banerji S (2023) Real-world predictors of
survival in patients with extensive-stage
small-cell lung cancer in Manitoba,
Canada: a retrospective cohort study.
Front. Oncol. 13:1191855.
doi: 10.3389/fonc.2023.1191855
COPYRIGHT
© 2023 Dawe, Rittberg, Syed, Shanahan,
Moldaver, Bucher, Galloway, Reynolds, Paul,
Harlos, Kim and Banerji. This is an open-
access article distributed under the terms o f
the Creative Commons Attribution License
(CC BY). The use, distribution or
reproduction in other forums is permitted,
provided the original author(s) and the
copyright owner(s) are credited and that
the original publication in this journal is
cited, in accordance with accepted
academic practice. No use, distribution or
reproduction is permitted which does not
comply with these terms.
TYPE Original Research
PUBLISHED 18 September 2023
DOI 10.3389/fonc.2023.1191855
those with ECOG PS 1–2, and 16%, 3%, and 3% for those with ECOG PS 3–4. In
long-term survivors, ECOG PS scores were lower and abnormal laboratory test
results were less frequent. Overall, 74.4% of long-term survivors received
thoracic RT and 53.5% received PCI. Known poor prognostic factors –
including brain/liver metastases, high lactate dehydrogenase (LDH), abnormal
sodium, and low hemoglobin levels –were less common but still seen in long-
term survivors.
Conclusion: Although rare, patients with ES-SCLC may experience long-term
survival with CT ± thoracic RT ± PCI. Factors predicting long-term survival
include traditional prognostic factors such as ECOG PS, LDH level, and receipt of
thoracic RT or PCI. These findings support current treatment algorithms for ES-
SCLC and provide baseline survival estimates to assess the real-world impact of
adding immune checkpoint inhibitors in the future.
KEYWORDS
radiotherapy (RT), small cell lung cancer (SCLC), extensive stage (ES), performance
status (ECOG-PS), real world, long-term survival, overall survival (OS)
1 Introduction
Small-cell lung cancer (SCLC) is an aggressive malignancy
characterized by rapid growth and early development of
locoregional and distant metastasis (1,2). SCLC represents an
estimated 12% of all lung cancers in Canada (3). It is classified
according to disease extent and ability to safely deliver a radical dose
of radiotherapy (RT) as either limited stage (LS) or extensive stage
(ES). LS-SCLC comprises most patients with 8
th
edition tumor,
node, metastasis (TNM) stage I-IIIB and some with stage IIIC,
while ES-SCLC includes the balance of patients with stage IIIC and
all patients with stage IV disease (4). Between 60% and 70% of
patients with SCLC are diagnosed with ES-SCLC (3,5,6), and
approximately 95% of ES-SCLC cases are classified as TNM stage IV
(7). Prognosis for ES-SCLC has remained poor over the past 20
years (8–10), with a median survival interval of 7–12 months, two-
year survival rate of <5%, and five-year survival rate of 1%-2% (2,6,
11,12); however, higher survival rates have been observed in some
cohorts. Factors associated with poor prognosis of ES-SCLC include
poor Eastern Cooperative Oncology Group Performance Status
(ECOG PS), multiple metastatic sites,advancedage,elevated
lactate dehydrogenase (LDH) level, abnormal serum sodium level,
low hemoglobin level, weight loss, poor response to initial
treatment, and early relapse (2,13–18). Conversely, younger age,
female sex, good ECOG PS, normal creatinine and LDH levels, and
a single metastatic site are favorable prognostic factors in patients
with ES-SCLC (14,16). Patient characteristics and prognostic
factors influence patient eligibility for some treatments (1). For
example, older patients with ES-SCLC are less likely to receive
systemic treatment (1,19). Some older patients and those with
multiple comorbidities may only be considered eligible for best
supportive care, which is associated with a worse prognosis (8).
Standard of care in ES-SCLC has traditionally consisted of
platinum-based chemotherapy (CT) (cisplatin or carboplatin)
plus etoposide; in some populations, etoposide may be replaced
with irinotecan (20,21). Other components of therapy include
prophylactic cranial irradiation (PCI) and thoracic RT (8,9), which
may be provided to patients with ES-SCLC who show a tumor
response after initial systemic treatment to control local disease and
improve overall survival (OS) (10). Platinum-based CT was first
demonstrated to be effective in patients with SCLC in 1985 (21,22)
and is associated with better median survival than non-platinum
alkylating agents (23,24). Despite high response rates to first-line
CT, almost all patients relapse, require further treatment, and die of
progressive disease (2,25). Relapsed ES-SCLC is associated with low
response rates to subsequent therapy and extremely poor
prognosis (11).
With CT as the longstanding standard of care for ES-SCLC in
Canada, little improvement in prognosis has been observed over
decades (26). The recent emergence of immunotherapeutic options
has expanded therapy options in this patient population. Immune-
checkpoint agents that inhibit programmed death-1 (PD-1) or
programmed death ligand 1 (PD-L1) have demonstrated
statistically significant improvements in OS in combination with
CT vs. CT alone in patients with ES-SCLC (27–29). Health Canada,
the United States Food and Drug Administration, and the European
Medicines Agency have approved durvalumab (in combination
with etoposide and carboplatin or cisplatin) and atezolizumab (in
combination with etoposide and carboplatin) as first-line therapy
for ES-SCLC (30–35).
With the arrival of new therapeutic strategies, there is an unmet
need to understand how baseline patient characteristics influence
choice of treatment and clinical outcomes. To date, few real-world
studies have comprehensively examined treatment patterns and
Dawe et al. 10.3389/fonc.2023.1191855
Frontiers in Oncology frontiersin.org02
long-term survival among patients with ES-SCLC in Canada (8,36,
37). Our group previously evaluated the effect of cisplatin vs.
carboplatin on clinical outcomes of a cohort of patients diagnosed
with ES-SCLC and LS-SCLC from 2004 to 2013 in Manitoba (37).
More patients receiving carboplatin (26.2% of the cohort) had poor
ECOG PS, elevated LDH, and ES-SCLC than those receiving
cisplatin. Median OS (unadjusted) was 224 vs. 322 days in the
carboplatin and cisplatin groups, respectively. We previously
performed a separate analysis assessing the impact of hospital
admission at the start of CT on outcomes (13). Inpatients had a
greater disease burden and poorer ECOG PS than outpatients.
ECOG PS was identified on multivariable analysis as an
independent predictor of survival.
The current study represents an expansion of this earlier real-
world retrospective cohort, with additional data from patients
diagnosed up to the year 2018. Immunotherapy first became
available for ES SCLC patients in Canada in 2020. The primary
objectives were to describe patient characteristics and treatment
regimens of patients who received CT for ES-SCLC and to estimate
the probability of OS for this cohort to five years from diagnosis.
Secondary objectives were to characterize the population of patients
with ES-SCLC in Manitoba, to assess the impact of baseline patient
and ES-SCLC characteristics and treatment regimens on OS, and to
describe the characteristics and treatment regimens of short- (<6
months), medium- (6-24 months), and long-term survivors (>24
months). This study will provide a more complete perspective of the
ES-SCLC landscape in Canada.
2 Materials and methods
2.1 Study design
This is a retrospective, population-based, cohort study of ES-
SCLC patients who received CT in the Canadian province of
Manitoba, which has a catchment population of approximately 1.4
million universally insured persons with a sole-source, provincially
administered, cancer treatment agency (CancerCare Manitoba
[CCMB]). This study was approved by the University of Manitoba
Health Research Ethics Board (HREB H2015:154 [HS18575]).
2.2 Study cohort
Eligible patients 1) were aged >18 years, 2) had cytologically
confirmed ES-SCLC (International Classification of Diseases for
Oncology [ICD-O] morphology codes 80413, 80423, 80443, 80453),
and 3) received cytotoxic CT. Patients who did not receive CT or
had non-SCLC or LS-SCLC were excluded from the analysis.
2.3 Data source
Data were collected from a previously described study cohort
from the Manitoba Cancer Registry (MCR) (13), which is among
the oldest cancer registries in North America and is operated by
CCMB to collect, classify, and maintain detailed information on all
cancer cases in Manitoba. An existing cohort of patients diagnosed
between January 1, 2004, and December 31, 2013, was expanded to
include patients diagnosed between January 1, 2014, and December
31, 2018. Additional case details for all patients were obtained
through a manual review of CCMB electronic medical records.
Follow-up data were available until September 30, 2021.
2.4 Outcome measures
For the primary and secondary objectives, outcome measures
were descriptive of the patient cohort and the treatment regimens
they received. Patient characteristics included demographic and
clinical information at the time of diagnosis: age, sex, smoking
status, stage of disease, laboratory test results, ECOG PS, and
location of metastases. Measuresofparticularintereston
laboratory testing included levels of LDH, sodium, and
hemoglobin, previously identified as prognostic markers in ES-
SCLC (14–17). Our database did not include data on nutritional or
inflammatory markers that have shown prognostic value in some
studies (38). ECOG PS was obtained based on the description of
patient functional status in the initial history and physical
examination for patients whenever it was not explicitly stated.
Treatment information included regimen received, such as CT
(cisplatin or carboplatin) and etoposide, any RT, thoracic RT to
lung primary and/or mediastinum (concurrent, consolidative, or
palliative),orbrainRT(PCI,palliative whole-brain RT).
Concurrent RT was given while the patient was receiving CT
(planned dose ≥40 Gy). Consolidative RT was given shortly after
completion of CT with no evidence of progression and was
identified in the physician’s notes as consolidative. Thoracic RT
that did not fit into either the concurrent or consolidative categories
was categorized as palliative.
Clinical outcomes included treatment response and OS; OS was
defined as the time interval (months) from the date of first CT
treatment to death, censoring from loss to follow-up, or end of the
follow-up period (September 30, 2021). Response to treatment was
classified from the clinical records as complete (total resolution of
tumor burden), partial (evidence of a decrease in tumor burden
without total resolution), stable (no change in tumor burden),
progression (increase in tumor burden), or unknown. Patients
were classified by survival time: short term (<6 months), medium
term (6-24 months), and long term (>24 months). Proportions of
patient characteristics, treatment regimens, and patient responses
were tabulated and compared by short-, medium-, and long-
term survival.
2.5 Statistical analysis
Descriptive statistics were used for patient, disease, and
treatment characteristics. Frequency (n and %) was determined
for each categorical variable of interest, and the median and range
were determined for continuous variables. Comparisons were
performed using Pearson Chi-square and Fisher exact tests for
Dawe et al. 10.3389/fonc.2023.1191855
Frontiers in Oncology frontiersin.org03
categorical variables and Kruskal-Wallis tests for continuous and
non-normally distributed variables. OS probabilities were estimated
for one, two, and five years and were stratified by treatment
regimen, age, sex, ECOG PS, smoking status, location of
metastases, disease stage at diagnosis, and RT use. Log-rank
testing was used to check for statistical significance, with P-values
≤0.05 indicative of statistical significance.
Univariable followed by multivariable hazard regression
analysis was performed to assess patient, disease, and treatment
characteristics associated with OS. The univariable hazard
regression associations with P-values ≤0.2 were entered into the
multivariable hazard regression model. To account for the
immortality bias associated with having lived long enough to
receive lung or brain RT, landmarked survival curves were
generated that included only patients who survived ≥6 months.
Multivariable Cox regression was performed to determine patient
and disease characteristics and treatment regimens associated with
prognosis, and P-values < 0.05 were considered statistically
significant. Splines were used for continuous predictors if they
demonstrated a non-linear relationship with the outcome (39).
Data analyses were performed in SAS version 9.4 (SAS Institute
Inc., Cary, NC, USA) and STATA version 17.0 (StataCorp, College
Station, TX, USA).
3 Results
3.1 Patient demographics
Number of eligible cases at each inclusion step are outlined in
Figure 1. Patient demographics and disease characteristics for the
537 patients included in the study are summarized by survival
subgroup in Table 1. The median age of this cohort was 66 (range
38-87) years, with an equal proportion of males and females (49.5%
males). The majority of patients (75.6%) had ECOG PS 0-2, and
83.2% of patients had stage IV disease. Long-term survivors were
less likely than medium- or short-term survivors to have ECOG PS
3-4, any abnormal laboratory results (LDH, sodium, or hemoglobin
levels), or metastases to brain, bone, or liver. Median follow-up time
for the entire cohort was 7.7 months. By survivor duration groups,
median follow-up times were 3.0 months, 9.8 months, and 40.8
months for short-, medium-, and long-term survivors, respectively.
Treatment response outcomes and pattern of treatment
regimens are presented by survival subgroup in Table 2.
Complete/partial response was experienced by 61.3% of patients.
More patients received cisplatin than carboplatin (56.1% vs. 43.2%)
as first-line therapy, 71.1% of patients underwent RT, and < 15%
received PCI. At least four cycles of CT were completed by 97.7% of
long-term survivors, 92.6% of medium-term survivors, and 35.2%
of short-term survivors, although delayed courses were more
frequent (81.4%) with long-term survivors than with medium- or
short-term survivors (71.8% and 35.7%, respectively). Thoracic RT
was administered to 74.4% of long-term survivors, 53.7% of
medium-term survivors, and approximately one-quarter of short-
term survivors, respectively. PCI was administered to 53.5% of
long-term survivors, 13.8% of medium-term survivors, and a
minimal number of short-term survivors.
3.2 Survival analysis
Kaplan-Meier analysis for survival within the entire cohort
demonstrated OS estimates at one, two, and five years of 26%,
8%, and 3%, respectively (Figure 2A). Females were more likely than
males to survive to two years (10% vs. 5%) and five years (4% vs. 2%;
log-rank P= 0.05; Figure 2B). For patients with ECOG PS 0, the
one-, two-, and five-year survival rates were 43%, 17%, and 10%,
respectively, vs. 27%, 8%, and 2%, for patients with ECOG PS 1-2,
and 16%, 3%, and 3%, for patients with ECOG PS 3-4. Patients with
an initial ECOG PS of 0 were significantly more likely to survive to
one, two, and five years than patients with an initial ECOG PS ≥1
(log-rank P< 0.01; Figure 2C). Patients with normal LDH and
sodium levels at diagnosis had significantly higher survival rates
than those with elevated LDH (log-rank P< 0.01; Figure 2D) and
abnormal sodium (log-rank P= 0.01; Figure 2E), respectively. The
survival probability was not significantly different for normal vs.
low hemoglobin level (log-rank P= 0.53; Figure 2F). Median OS
and interquartile range (IQR) for concurrent, consolidative, and
palliative thoracic RT were 1.9 (IQR 0.8-upper bound missing), 1.1
FIGURE 1
Flowchart of number of eligible cases at each inclusion/exclusion step.
Dawe et al. 10.3389/fonc.2023.1191855
Frontiers in Oncology frontiersin.org04
(IQR 0.9-1.4), and 0.7 (IQR 0.6-0.8) years, respectively.
Landmarked OS analysis performed in patients who survived for
six months or longer showed a significant difference in OS by type
of RT (P< 0.01) (Figure 3A). Median OS was 1.3 years among
patients treated with PCI, and survival rates were higher among PCI
recipients than those who did not receive PCI. Landmarked OS
analysis at six months supported longer median OS with PCI use (P
< 0.01; Figure 3B).
On univariable analysis, survival was significantly associated with
ECOG PS, CT completion, age at diagnosis, LDH level, PCI, and
thoracic RT (Supplementary Table 1). On multivariable analysis, use
of PCI and lung RT (none, concurrent, consolidative, palliative) as
well as completion of CT were independent predictors of improved
OS, while poor ECOG PS and increased LDH level was an
independent predictor of reduced OS (Table 3). A landmarked
multivariable Cox analysis examining only patients surviving for six
TABLE 1 Baseline patient and disease characteristics.
Characteristic Short-
term survival
Medium-
term survival
Long-
term survival P-value
a
Patients, n (%)
b
196 (36.5) 298 (55.5) 43 (8.0)
Age, years, median (range) 66 (38-87) 66 (38-87) 61 (47-80) 0.126
c
Sex, n (%) 0.122
d
Male 102 (52.0) 149 (50.0) 15 (34.9)
Female 94 (48.0) 149 (50.0) 28 (65.1)
ECOG PS, n (%) <0.001
07 (3.6) 40 (13.4) −
e
1-2 117 (59.7) 203 (68.1) 28 (65.1)
3-4 69 (35.2) 54 (18.1) −
e
Brain metastases, n (%) 0.116
Yes 27 (13.8) 25 (8.4) −
e
Liver metastases, n (%) <0.001
Yes 61 (31.1) 61 (20.5) −
e
Bone metastases, n (%) 0.001
Yes 46 (23.5) 37 (12.4) −
e
Collaborative stage, n (%) 0.237
III 21 (10.7) 52 (17.5) 10 (23.3)
IV 173 (88.3) 241 (80.9) 33 (76.7)
Smoking status, n (%) 0.732
Never/ex-smoker/unknown 133 (67.9) 193 (64.8) 24 (55.8)
Current 63 (32.1) 105 (35.2) 19 (44.2)
LDH,
f
n (%) <0.001
Normal 39 (19.9) 113 (37.9) 28 (65.1)
Elevated 135 (68.9) 171 (57.4) 12 (27.9)
Sodium,
g
n (%) 0.014
Abnormal 61 (31.1) 76 (25.5) 7 (16.3)
Hemoglobin,
h
n (%) 0.038
Low 101 (51.5) 149 (50.0) 18 (41.9)
a
Fisher exact test P-value.
b
unknown data comprise the differences in characteristic subtotals and the group totals.
c
Kruskall Wallis test P-value.
d
Chi-square P-value.
e
patient numbers ≤5 are censored based on requirements from Manitoba Health.
f
elevated LDH: >230 U/L.
g
abnormal sodium: <135 or >147 mEq/L.
h
low hemoglobin: males <140 g/L, females <120 g/L. ECOG PS, Eastern Cooperative Oncology Group Performance Status; LDH, lactate dehydrogenase.
Dawe et al. 10.3389/fonc.2023.1191855
Frontiers in Oncology frontiersin.org05
months or longer was performed to account for immortality bias, and
it showed a similar pattern of significant associations (Table 4).
Interaction between LDH and ECOG PS was also found to be
significant in this landmarked model (Figure 4).
4 Discussion
This real-world population-based study describes patient and
disease characteristics, patterns of clinical practice prior to availability
of immunotherapy, and treatment outcomes in patients with ES-SCLC
who received CT as part of their treatment. To our knowledge, this is
the most up-to-date population-based study to comprehensively
examine treatment patterns and clinical outcomes in ES-SCLC in
Canada. Our results are consistent with other studies of long-term
survivors with ES-SCLC, indicating that good ECOG PS, good
response to CT, and use of thoracic RT and PCI are associated with
longer survival in patients with ES-SCLC (2,11,40,41). In particular,
ouranalysisprovidesadditionalevidence to the existing literature that
ECOG PS is a strong independent predictor of survival in patients with
SCLC treated with CT (1,13). Patients with ECOG PS 0 had a
significantly higher median survival (0.82 years) and five-year
survival probability (10%) than those with ECOG PS 1-2 (0.67 years;
2%) or 3-4 (0.46 years; 3%). These findings align with the five-year OS
in our earlier study using data from part of the current cohort of
patients diagnosed prior to December 31, 2013 (ECOG PS 0: 10.7%; 1-
2: 3.1%; 3-4: 2.8%) (13). A real-world analysis of 988 patients in China
with SCLC showed a significantly longer median OS among patients
with ES-SCLC (n = 507) and ECOG PS 0-1 vs. 2-3 (12.0 [95%
confidence interval (CI): 11.0-13.0] vs. 9.0 [95% CI 6.9-11.1]
months) (42). Another real-world study based in China of 358
patients with ES-SCLC found no significant difference in the median
OS between ECOG PS 0-1 and 2-4 (14.5 vs. 9.3 months; hazard ratio
[HR] 1.37; P= 0.095); however, only 9.8% of their cohort (N = 358) had
ECOG PS ≥2(14).
Associations were also identified between long-term survival
and other factors, such as LDH, serum sodium, and hemoglobin
levels. Outcomes did not differ based on the type of CT received, but
TABLE 2 Treatment characteristics by survival.
Characteristic Short-
term survival
Medium-
term survival
Long-
term survival P-value
a
Patients, n (%)
b
196 (36.5) 298 (55.5) 43 (8.0)
Response, n (%) <0.001
Complete or partial 49 (25.0) 242 (81.2) 38 (88.4)
Stable 7 (3.6) 18 (6.0) −
c
Progression 34 (17.4) 28 (9.4) −
c
Unknown 106 (54.1) 10 (3.4) −
c
Chemotherapy, n (%) 0.006
Cisplatin 94 (48.0) 180 (60.4) 27 (62.8)
Carboplatin 99 (50.5) 118 (39.6) 15 (34.9)
1st chemotherapy setting,
n (%)
<0.001
Inpatient 57 (29.1) 42 (14.1) 7 (16.3)
Outpatient 139 (70.9) 256 (85.9) 36 (83.7)
Course of therapy, n (%)
Completed chemotherapy 69 (35.2) 276 (92.6) 42 (97.7) <0.001
Dose reduction 50 (25.5) 84 (28.2) 12 (27.9) 0.801
Course delayed 70 (35.7) 214 (71.8) 35 (81.4) <0.001
Lung RT delivery, n (%) <0.001
None 143 (73.0) 138 (46.3) 11 (25.6)
Concurrent/consolidative −
c
49 (16.4) 20 (46.5)
Palliative 47 (24.0) 111 (37.3) 12 (27.9)
PCI received, n (%) <0.001
Yes −
c
41 (13.8) 23 (53.5)
a
Fisher exact test P-value;
b
unknown data comprise the differences in characteristic subtotals and the group totals;
c
patient numbers ≤5 are censored based on requirements from Manitoba Health. PCI, prophylactic cranial irradiation; RT, radiotherapy.
Dawe et al. 10.3389/fonc.2023.1191855
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survival was superior in patients who completed CT. While there
seems to be a global (including Canada) preference for carboplatin
over cisplatin (8), cisplatin was first-line therapy in a higher
proportion of our patients. Carboplatin- and cisplatin-containing
regimens have been found to be similarly efficacious, with no
significant differences in response rate, progression-free survival,
or OS (43,44). Nearly all (97.7%) of the long-term survivors in our
study completed their CT regimen, despite it including delays in
81.4% of cases. Survival of our cohort –26%, 8%, and 3% at one,
two, and five years, respectively –aligns with findings from other
A
B
DE F
C
FIGURE 2
Analysis of OS by patient characteristic: (A) Overall cohort (n = 537); (B) Sex (n = 537); (C) ECOG PS (n = 533); (D) LDH (n = 537); (E) Serum sodium
(n = 536); (F) Hemoglobin (n = 537). CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance Status; Hgb, hemoglobin;
LDH, lactate dehydrogenase; OS, overall survival.
A
B
FIGURE 3
Analysis of extensive-stage patient’s OS by treatment pattern landmarked at 6 months (n = 338): (A) Type of lung RT; (B) PCI. OS, overall survival;
PCI, prophylactic cranial irradiation; RT, radiotherapy.
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TABLE 3 Multivariable analysis of the full cohort (N = 492).
Variable Categories HR
Lower
95% CI
Upper
95% CI P-value
Overall
P-value
ECOG PS 0 Reference –––
1-2 1.63 1.21 2.21 0.001
3-4 1.97 1.39 2.80 <0.001 0.0003
LDH ‘
a
1.01 1.00 1.01 0.01
‘‘
a
0.89 0.73 1.07 0.22
‘‘‘
a
1.19 0.88 1.60 0.25 <0.0001
Lung RT (original) None Reference –––
Concurrent 0.15 0.06 0.42 <0.001
Consolidative 0.58 0.42 0.80 0.001
Palliative 0.75 0.61 0.92 0.005 <0.0001
PCI No Reference –––
Yes 0.39 0.28 0.55 <0.001 <0.0001
Treatment Cisplatin (I) Reference –––
Cisplatin (C) 0.46 0.32 0.66 <0.001
Carboplatin (I) 1.03 0.72 1.46 0.89
Carboplatin (C) 0.46 0.32 0.68 <0.001 <0.0001
a
Spline transformations according to knots at the 5
th
(143), 35
th
(220), 65
th
(351), and 95
th
(1474) percentiles. CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group
Performance Status; HR, hazard ratio; LDH, lactate dehydrogenase; PCI, prophylactic cranial irradiation; RT, radiotherapy; SE, standard error; I, incomplete course; C, complete course.
TABLE 4 Multivariable analysis of the landmarked cohort of patients with ES-SCLC who survived to 6 months (N = 322).
Variable Categories HR
Lower
95% CI
Upper
95% CI
P-value Overall
P-value
ECOG PS 0 Reference –––
1-2 6.10 1.33 27.93 0.02
3-4 9.30 1.58 54.88 0.01 0.05
LDH ‘
a
1.01 1.00 1.02 0.001
‘‘
a
0.98 0.97 1.00 0.008 <0.0001
Lung RT (original) None Reference –––
Concurrent 0.20 0.07 0.56 0.002
Consolidative 0.62 0.43 0.89 0.01
Palliative 0.85 0.65 1.10 0.21 0.002
PCI No Reference –––
Yes 0.46 0.33 0.64 <0.001 <0.0001
LDH x ECOG PS LDH’* ECOG 1-2 0.99 0.99 1.00 0.07
LDH’’ * ECOG 1-2 1.01 1.00 1.02 0.16
LDH’* ECOG 3-4 0.99 0.99 1.00 0.04
LDH’’ * ECOG 3-4 1.01 1.00 1.03 0.08 0.07
a
Spline transformations according to knots at the 10
th
(161), 50
th
(258), and 90
th
(744) percentiles. CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance Status;
HR, hazard ratio; LDH, lactate dehydrogenase; PCI, prophylactic cranial irradiation; RT, radiotherapy; SE, standard error.
Dawe et al. 10.3389/fonc.2023.1191855
Frontiers in Oncology frontiersin.org08
population-based studies in Canada, contributing to the improved
generalizability of these data in the aggregate. A retrospective,
longitudinal, cohort study in Alberta, Canada used population-level
data to describe treatment patterns, demographic and clinical
characteristics, and OS of patients with ES-SCLC (2010–2018) (8).
Median OS among those receiving first-line CT (46.5% of the total
cohort; n = 903) was 7.8months (95% CI 7.5–8.2) and was 5.7 (95% CI
4.9–6.9) and 3.8 (95% CI 3.0–4.6) months when CT was used as
second- and third-linetreatment, respectively. Five-year OS was 2.9%
(95% CI 1.8–4.5) in the group that received first-line CT. Another real-
world study in Alberta included patients with LS-SCLC and ES-SCLC
managed at a tertiary cancer center(36). First-line CT was used in 90%
of ES-SCLC patients (53% CT alone, 17% with thoracic RT, and 20%
with immunotherapy, nonthoracic RT, or metastatic resection), and
20% received PCI. Median OS was 9 months with first-line CT and 13
months amongpatients treated witha combination of CT and thoracic
RT. As in our study, these investigators found PCI to be an
independent predictor of improved OS (HR 0.48; 95% CI 0.3-0.7; P
< 0.01); however, analysis of outcomes related to PCI are likely biased
by preferential administration to healthier patients.
OS rates in this study are also consistent with those of CT-only
control arms in recent randomized, controlled trials of immune
checkpoint inhibitors (ICIs) (27–29). The CASPIAN study of first-
line durvalumab plus CT (etoposide plus either carboplatin or
cisplatin) reported a one-year OS for the placebo plus CT-control
arm of 40% (27). The IMpower133 study of first-line atezolizumab
plus CT (carboplatin and etoposide) reported a one-year OS of 38%
in the CT-only control arm (28), and the KEYNOTE-604 study of
first-line pembrolizumab plus CT (etoposide plus either carboplatin
or cisplatin) determined one- and two-year OS in the CT-only
control arm of 40% and 11%, respectively (29). As may be expected
for a real-world population, our cohort was slightly older (median
66 years), had poorer ECOG PS status, and had a higher proportion
of patients with brain metastases than the control arms of the
clinical trials. Nevertheless, the subgroup of our cohort with ECOG
PS 0 had one-year OS of 43% and two-year OS of 17%.
The CASPIAN and IMpower133 trials through post hoc
analyses determined that long-term survival was higher among
patients receiving an ICI with standard CT as first-line therapy vs.
CT alone. In CASPIAN, OS at 18 months was 34% in the group that
received durvalumab with CT (cisplatin or carboplatin) plus
etoposide vs 25% for CT and etoposide alone (27). In
IMpower133, OS at 18 months was 34.0% for atezolizumab with
CT (carboplatin) plus etoposide vs 21.0% for CT and etoposide
alone (45). OS at 24 and 36 months in CASPIAN extensions were
22.2% and 17.4%, respectively, for the durvalumab plus CT-
etoposide group vs 14.4% and 5.8%, respectively, for CT-
etoposide alone (46,47). Similar to our findings, long-term
survivors in CASPIAN (i.e., those still alive after the data cutoff;
median follow-up 39.4 months) were more likely than short- or
medium-term survivors to have favorable prognostic characteristics
such as ECOG PS 0 and absence of brain or liver metastases (48). In the
long-termsurvivor subgroup of the IMpower133 trial (median follow-
up 22.9 months), a between-treatment differenceof > 5% was found for
characteristics including age ≥65 years, sex, ECOG PS 0, LDH level,
and presence of brain metastases (49). The control arms of these recent
trials highlight the continued poor prognosis of patients receiving CT
alone for ES-SCLC. Immunotherapy is changing the treatment
algorithm in ES-SCLC, suggesting that platinum-based doublet CT
combined with an ICI is becoming the new standard of care (50). The
advent of new therapeutic options in SCLC emphasizes the need to
target prognostic factors and individualize treatment decision-making
(2). The similarity of results seen between real world populations and
trial control arms suggests that the improved survival seen in trials of
CT plus immunotherapy could bear out in future real-world
assessments. Additional research is needed to elucidate factors that
influence the survival of patients with SCLC treated with CT in
combination with immunotherapy. Questions also remain regarding
the safetyand impact of consolidative thoracic RT in patients receiving
CT + ICI regimens, since the landmark trials of CT + ICI did not
include consolidative thoracic RT. Based on early phase and cohort
data, a recent Canadian guideline suggests considering some patients
receiving CT + ICI for consolidative thoracic RT (51). It remains
unclear whether the prognostic benefit we saw in our cohort with no
ICI will translate to patients who receive CT + ICI.
4.1 Study limitations
While observational and retrospective studies are prone to
selection bias, our use of a population-based registry sample of all
eligible CT treated patients throughout Manitoba was intended to
minimize that risk. However, the study cohort was limited to
patients who received CT and, therefore, those who survived long
enough to receive treatment, which introduces selection bias. This is
a particular issue for treatments given almost exclusively after CT,
such as thoracic RT or PCI. To adjust for immortality bias,
landmarked analyses were performed. This being a retrospective
study, some of the data on ECOG PS were derived from patient
description in the medical chart instead of explicitly recorded values,
leading to a risk of misclassification. Of the patient records analyzed,
there were missing laboratory values (2%-7% of patients for the
FIGURE 4
Log of the hazard for the interaction between LDH and ECOG PS
Landmarked analysis at 6 months; multivariable models (n = 322).
ECOG PS, Eastern Cooperative Oncology Group Performance
Status; LDH, lactate dehydrogenase.
Dawe et al. 10.3389/fonc.2023.1191855
Frontiers in Oncology frontiersin.org09
laboratory measures of interest) and limited information on brain,
liver, and bone metastases for patients diagnosed prior to 2010. Our
cohort alsodoes not includeany patients who received chemotherapy
plus ICIs, since these regimens were not available in Manitoba during
the studied period. The absence of patients receiving these regimens
means that our results should not be extrapolated to patients receiving
chemotherapy plus an ICI.
5 Conclusions
Our study provides supporting evidence that long-term survival
with ES-SCLC occurs. Findings from this real-world data further
support the association between long-term survival and known
prognostic factors such as ECOG PS, laboratory values, and receipt of
RT in addition to CT. With the recent introduction of immunotherapy
into the routine clinical management of SCLC, future real-world
evidence can characterize the long-term responders to ICIs.
Data availability statement
The datasets presented in this article are not readily available
because the data used in this analysis are owned by the government
of Manitoba. The authors were given permission to use the data to
conduct the analysis. However, they do not have permission to
share the data. The authors did not have special access privileges
and interested researchers would be able to access the data in the
same manner as the authors. Requests to access the datasets should
be directed to the Provincial Health Research Privacy Committee,
Research Manitoba, A201 Chown Building, 753 McDermot
Avenue, Winnipeg MB, R3E 0T6 (email: phrpc@researchmb.ca)
and CancerCare Manitoba. Instructions can be found at: https://
www.rithim.ca/phrpc-submission-information and https://
www.cancercare.mb.ca/Research/research-impact-commitee.
Ethics statement
The studies involving humans were approved by University of
Manitoba Health Research Ethics Board. The studies were
conducted in accordance with the local legislation and
institutional requirements. The ethics committee/institutional
review board waived the requirement of written informed consent
for participation from the participants or the participants’legal
guardians/next of kin because almost all patients had died of their
disease and no identifiable data would be reported. This study used
cancer registry data and retrospective chart review.
Author contributions
DD: trial design, data curation, formal analysis, visualization,
writing –review and editing. RR: data acquisition, formal analysis,
visualization, writing –review and editing. IS: writing –review and
editing. MS: writing –review and editing. DM: writing –review and
editing. OB: data curation, formal analysis, writing –review and
editing. KG: data curation, formal analysis, writing –review and
editing. KR: data acquisition, writing –review and editing. JP: writing
–review and editing. CH: writing –review and editing. JK: writing –
review and editing. SB: writing –review and editing. All authors
contributed to the article and approved the submitted version.
Acknowledgments
The authors wish to acknowledge Jenny Cai and Jeff Alexander
(SNELL Medical Communication) for medical writing assistance.
DD would like to acknowledge the Manitoba Medical Services
Foundation, which awarded him a salary award to protect some
of his time for research.
Conflict of interest
IS and MS are employees and shareholders of AstraZeneca. DM
was an employee of AstraZeneca at the time of this study.
DD reports advisory board attendance for Merck Canada,
Novartis, Jazz Pharmaceuticals, Pfizer, and AstraZeneca, honoraria
for education content from Boehringer-Ingelheim and Bristol Myers
Squibb, grants from Canadian Institutes of Health Research,
CancerCare Manitoba Foundation, and Manitoba Medical Services
Foundation. RR reports grant funding received from AstraZeneca. SB
reports advisory board attendance for AstraZeneca, Bayer, Bristol
Myers Squibb, Jazz Pharmaceuticals, Merck Canada, Novartis
Janssen, Pfizer, and Roche, clinical trial funding from AstraZeneca,
Bayer, and Roche, grants from Canadian Institutes of HealthResearch,
grants from CancerCare Manitoba Foundation, and grants from
Genome Canada, outside the submitted work.
The remaining authors declare that the research was conducted
in the absence of any commercial or financial relationships that
could be construed as a potential conflict of interest.
The authors declare that this study received funding from
AstraZeneca Canada. The funder had the following involvement
with the study: study design, writing of this article, data
interpretation and decision to submit it for publication. The
funder was not involved in data analysis and did not have access
to patient data.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated organizations,
or those of the publisher, the editors and the reviewers. Any product
that may be evaluated in this article, or claim that may be made by its
manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online
at: https://www.frontiersin.org/articles/10.3389/fonc.2023.1191855/
full#supplementary-material
Dawe et al. 10.3389/fonc.2023.1191855
Frontiers in Oncology frontiersin.org10
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