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Original Article
Variables affecting survival after second primary lung cancer: A population-based study of 187 Hodgkin's lymphoma patients
1Department of Radiation Oncology and Rubin Center for Cancer Survivorship, University of Rochester School of Medicine, Rochester, NY 14642, USA; 2Division of Biostatistics, Department of Environmental Medicine, New York University School of Medicine, New York, NY, 10016, USA
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Abstract
Background: Patients successfully treated for Hodgkin's lymphoma (HL) are at known risk for subsequent malignancies, the most common of which is lung cancer. To date, no population-based study has analyzed prognostic variables for overall survival (OS) among HL survivors who developed non-small cell lung cancer (NSCLC).
Methods: For 187 HL patients who developed NSCLC (among 22,648 HL survivors), we examined the impact of the following variables on OS after NSCLC diagnosis: gender, race, sociodemographic status (based upon county of residence), calendar year and age at NSCLC diagnosis, NSCLC histology and grade, HL stage and subtype, radiation for HL and latency between HL and NSCLC. Patients were grouped by NSCLC stage as follows: localized, regional or distant. All patients were reported to the population-based Surveillance, Epidemiology, and End Results program. For those variables significant on univariate analyses, hazard ratios (HR) were derived from Cox proportional hazards model. Results: Sociodemogaphic status, gender and latency between NSCLC and HL did not significantly affect OS of any NSCLC stage group. For patients with localized NSCLC, a history of mixed celluarlity HL was associated with a 3-fold improved OS (P=0.006). For patients with regional NSCLC, prior radiotherapy for HL was associated with a 2-fold worse OS (P=0.025). Conclusions: A history of mixed cellularity HL subtype and a history of no radiotherapy for HL are favorable prognostic factors among patients who develop NSCLC. Further research into clinicopathologic and treatment-associated variables potentially affecting OS after second primary NSCLC among HL survivors is warranted. Key words
Non-small cell lung cancer; Hodgkin's lymphoma; population-based; cancer survivorship
J Thorac Dis 2012;4:22-29. DOI: 10.3978/j.issn.2072-1439.2011.12.02
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Introduction
Hodgkin's lymphoma (HL) remains a largely curable disease (1), though the excellent life expectancy is offset by adverse late effects of treatment, including second malignancies (2-7). The 3- to 20-fold relative risks of lung cancer after HL (2,4,6-11) accounts for the largest absolute risk of second cancer (2,12), with lung cancer being the greatest contributor to overall mortality from second cancers. Beyond 15-30 years after therapy for HL, the cumulative mortality from all second primary cancers exceeds deaths due to HL (3,13-15). While HL treatment with radiotherapy (10,16-18) and/or alkylating-agent chemotherapy (10,18-19) both increase lung cancer risks in dose-dependent manner, smoking is implicated as the most important etiologic factor (10,17-18,20). We (21), and others (8,22-24), have analyzed survival after lung cancer diagnosis in HL survivors. In our recent U.S. population-based analysis (21), we compared the survival of 187 HL survivors who developed NSCLC versus 178,431 patients with first primary NSCLC, simultaneously accounting for demographic, clinicopathologic, and treatment-associated variables. We demonstrated a significantly inferior OS among HL survivors who develop NSCLC, compared to patients with de novo NSCLC (21), which we hypothesized may be attributable to host factors inherent to the development of HL, more aggressive tumor biology of therapy-associated cancers, or a limitation in treatment options for NSCLC after HL.
We now investigate the impact of specific demographic,
clinicopathologic, and treatment-associated variables on survival
of HL survivors who developed NSCLC. We hypothesized that
radiotherapy for HL and lower sociodemographic status would
adversely affect survival after NSCLC. Within a cohort of 22,648
patients with a first primary HL reported to the populationbased
cancer registries of the Surveillance, Epidemiology,
and End Results (SEER) program (http://seer.cancer.gov/),
we identified all patients who developed NSCLC as a second
primary cancer (HL-NSCLC). This cohort represents the same
patient group for whom we previously compared their survival
to patients with de novo NSCLC (21).
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Methods
Patients
From the U.S. population-based SEER 13 (1973-2006) database,
patients were identified who developed NSCLC as a first
primary cancer after HL diagnosis (HL-NSCLC group). Of
22,648 patients registered with a first primary HL in the SEER-
13 program, 238 developed a second primary NSCLC, with a
minimum latency of 2 months, which is the standard adopted
by the SEER program to exclude synchronous primary cancers.
Because we made no a priori assumptions about NSCLC
etiology (i.e. tobacco use, HL therapy, host susceptibility), we
did not otherwise require a specific latency period between HL
and NSCLC.
Patients were grouped into localized, regional or distant stage
NSCLC, as described in SEER Staging Manuals (http://seer.
cancer.gov/tools/codingmanuals/historical.html). Generally,
localized NSCLC is confined to the ipsilateral lung or bronchus
(≥2 cm from the carina), and/or with atelectasis that does not
involve the entirety of the lung, regional NSCLC involves hilar or
mediastinal nodes and/or direct extension to regional structures,
and distant NSCLC implies metastatic spread beyond regional
nodes or structures.
Because SEER did not record lung cancer stage before 1988,
analyses grouped by stage are restricted to those reported from
1988 forward. One-hundred eighty-seven of 238 HL-NSCLC
patients were assigned a NSCLC stage. The histologic types of
NSCLC that were included are listed in our prior publication
(21) and in Table 1.
HL stage and presence or absence of B symptoms were
obtained from the SEER database extent of disease (EOD) fields.
For 13 patients, the EOD data resulted in two possible HL stage
assignments; the variable of HL stage was analyzed separately
using both of these assignments as described previously (21).
The SEER database records sociodemographic parameters
of the population residing in each patient's county of residence, determined from U.S. census data. As a surrogate
for sociodemographic status, the proportion of adults residing
within the patient's county who were age ≥25 years with less than
a high-school education was used (21).
Statistical analysis
Actuarial OS was calculated using the Kaplan-Meier method.
Survival times were measured from date of NSCLC diagnosis
until date of death or last follow-up. All survival analyses were
conducted using SAS 9.1.3 software (SAS Institute Inc). Kaplan–
Meier curves were prepared using R 2.7.0. For univariate analysis,
the log-rank test was used to test the significance of discrete
variables, and Cox regression was used to test the significance of
continuous variables.
For the multivariate analyses, Cox proportional hazards
regression analyses were used; the initial Cox model included
year of NSCLC diagnosis, age at NSCLC diagnosis and all
variables with P values <0.2 in the univariate analyses. Year of
NSCLC diagnosis and age at NSCLC diagnosis were excluded
from the final Cox analysis (described in the results) if not
significant with univariate and initial multivariate analyses.
All P values are two-sided, with P<0.05 defined as statistically
significant.
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Results
Patient and tumor characteristics
Among 238 HL survivors who developed NSCLC, the lung
cancer stage was available for 187. Table 1 outlines the previously
described (21) demographic and clinicopathologic characteristics
of these 187 patients at the time of HL and NSCLC diagnoses
(grouped by NSCLC stage), as well as the latency between these
diagnoses. The stage distribution of NSCLC after HL (20%
localized, 29% regional, and 51% distant) was not appreciably
different between the eras of 1988-1999 and 2000-2006 (P=0.92).
The pertinent differences in demographic and clinicopathologic
characteristics between NSCLC stage groups was also described
previously (21). Eight of 38 (21%) of patients with localized
NSCLC received radiation alone for NSCLC, 28 received surgical
resection alone and 2 received no surgery or radiation. Twenty of
54 (37%) of those with regional NSCLC received radiation for
NSCLC (of whom 6 also underwent surgical resection); twentythree
underwent surgical resection without radiation and 11
received no surgery or radiation.
Prognostic factors among HL survivors with NSCLC
NSCLC stage was highly significant (P<0.001) for OS for all
stage comparisons (i.e. localized vs. regional, regional vs. distant and localized vs. distant), and thus all analyses were performed
wth patients grouped by NSCLC stager. The actuarial survival,
by NSCLC stage was described previously (21). Table 2 shows
results from univariate analyses assessing the influence of various
prognostic factors on OS of HL-NSCLC patients, grouped by
NSCLC stage. For 13 (7%) patients, 2 different possible HL
stages were assigned (see Methods); therefore separate univariate
analyses were performed allowing for each stage assignment to
be analyzed. HL stage (I-II or III-IV) was not significant for any
NSCLC stage group. For regional NSCLC patients, P values for
HL stage ranged from 0.11-0.16, though no HL stage grouping
was consistently adverse or favorable among the separate
analyses.
For patients with localized NSCLC, mixed cellularity HL
subtype (P=0.035) was a significantly favorable prognostic factor,
while older age at HL diagnosis (P=0.012), older age at NSCLC
diagnosis (P=0.006) and radiotherapy for NSCLC (P=0.004)
were significantly adverse prognostic factors. Radiotherapy for
HL was an adverse (P=0.068) factor for patients with regional
NSCLC; additionally, non-white race proved to be a significantly
associated with worse OS. For distant NSCLC, no prognostic
variable proved to be significant for OS.
Table 3 summarizes the multivariate analyses of potential
prognostic variables affecting OS. For HL-NSCLC patients
with localized NSCLC, increasing age at NSCLC diagnosis
was associated with a non-significantly (P=0.15) increased risk
of death, while HL subtype other than mixed cellularity was
associated with a significantly greater risk of death (HR=3.45;
P=0.006). For patients with regional NSCLC, prior radiation
for HL (HR=2.08, P=0.025), non-white race (HR=3.70,
P=0.019) and earlier calendar year of NSCLC diagnosis
(HR=1.08, P=0.021) were adverse predictors of OS. The median survival of HL-NSCLC patients with regional disease
who received radiation for HL versus those who did not receive
radiation for HL was 6 vs. 14 months, and the corresponding
1-year OS was 27% vs. 55%. Of note, the percentage of HLNSCLC
patients undergoing radiation for regional NSCLC
was similar (P=0.48) for patients previously irradiated for HL
(22 of 33, 67%) versus patients who did not undergo radiation
for HL (12 of 21, 55%).
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Discussion
Important new findings in our study, based on 187 HLNSCLC
patients include a 3-fold improved OS among
localized NSCLC patients with a history of mixed celluarlity
HL (versus other subtypes), and a 2-fold worse OS among
regional NSCLC patients treated with radiation (versus no
radiation) for HL.
We are not aware of other investigations that analyze
demographic, clinicopathologic, and treatment-associated
prognostic factors for survival after NSCLC among HL
survivors. Moreover, our study was conducted within the
large, population-based registries that comprise the U.S. SEER
Program.
Overall survival
We previously showed that overall, only 4% of all HL-NSCLC
patients died of HL; for regional and distant NSCLC, 85%
percent of deaths were from NSCLC, versus 48% for localized
NSCLC (21). For localized NSCLC, deaths from heart disease
occurred in 20% and deaths from other cancers (not HL or
NSCLC) occurred in 16%, causes of mortality known to be
increased among HL survivors (3,13,14).
Variables affecting survival of HL-NSCLC patients
Among HL-NSCLC patients, variables significantly affecting
OS, based on multivariate analyses, included HL subtype,
radiotherapy for HL, calendar year of NSCLC diagnosis and
race. Older age was a non-significant adverse factor among
those with localized NSCLC (Table 3), though we previously
showed that the discrepancy in median survival between older
and younger HL-NSCLC patients with localized disease was less
pronounced compared to the de novo NSCLC population (21),
partially attributable to increased deaths from other-cancers.
In the current study, mixed cellularity HL subtype was
associated with a significantly (P=0.006) >3-fold reduced mortality after localized NSCLC. Possible reasons for this
association are unknown, but perhaps somehow relate to
an increased likelihood of these patients having received
chemotherapy for HL (25,26). We also previously showed that
the distribution of HL subtypes among patients who developed
NSCLC was significantly different between stage groups
(P=0.005), with patients who developed localized NSCLC more
likely to have had mixed cellularity HL, and less likely to have
had nodular sclerosis HL (21).
The increased risk of death (albeit non-significant in
multivariate analyses) among localized NSCLC patients treated
with radiation for NSCLC may reflect the fact that historically
radiation for early stage lung cancer was the preferred treatment
for patients with relatively poor performance status and/or
comorbidities that precluded surgical resection (27), though
was based upon a small number (8 of 38) receiving radiation
alone. The decreased risk of death among non-white HL patients
with regional NSCLC (n=6) was based upon sparse numbers,
and may represent a chance finding. The improved OS of HL
survivors with more recent NSCLC diagnosis (significant
for regional NSCLC) presumably reflects improved NSCLC
outcomes following chemotherapy and radiotherapy advances
over the past decades (28,29), a hypothesis confirmed by the
highly significant (P<0.0001) effect of calendar year on OS in the
general population (data not shown). However, improvements in
lung cancer survival over time have been modest(28-30).
In the current analysis, a history of radiotherapy for HL was
associated with a significantly (P=0.025) worse OS (HR=2.08) among regional stage NSCLC patients. One possible reason
accounting for the worse OS of regional NSCLC among those
irradiated for HL is the potential limitation in treatment options
for patients who were previously irradiated for HL. While our
analysis did not demonstrate a lower likelihood of receiving
radiation for regional NSCLC among patients who received
radiation for HL versus those who did not, it is plausible that
those with prior radiation did not receive full dose radiation
and/or were treated with fields that compromised tumor
coverage, though our analysis cannot address this hypothesis.
Another possible explanation is that prior radiotherapy for HL
may introduce radiation-induced genetic alterations potentially
affecting the biologic behavior of treatment-induced NSCLC and
its responsiveness to therapy. In an analytic population-based
study of lung cancer following radiation for HL (31), archived
paraffin-embedded tissues were evaluated for 15 patients who
developed NSCLC and compared with de novo NSCLC. NSCLC
after HL was characterized by a significant 5.9-fold increase
(P=0.0002) in microsatellite alterations (31). The authors
conclude that NSCLC developing in irradiated HL patients
demonstrates widespread genomic instability, as manifested
by increased numbers of microsatellite alterations. While the
impact of miscrosatellite instability on the treatment response
of NSCLC is speculative, the hypothesis of treatment-induced
genetic instability affecting outcomes of second malignancies is
compelling.
Comment
Strengths of the current study include the sizable number
of patients (n=187) which allowed for analyses of outcomes
by NSCLC stage, age, and other patient-related and tumorrelated
variables. Known limitations of SEER data include
lack of detailed information about radiotherapy doses and
fields, as well as the underreporting of radiotherapy use (32).
Also, SEER does not report whether chemotherapy was
administered, or information on tobacco use or tobacco history,
factors, along with thoracic radiotherapy, which are linked to
increased risks of NSCLC development, and which may also
affect outcomes after NSCLC diagnosis (10,16,18-20,33). The
SEER registries also do not collect data on known prognostic
factors associated with NSCLC survival, such as weight loss
and performance status (34-36). The SEER program also does
not record presenting symptoms at diagnosis, which has been
reported to be significant factor among patients who developed
thoracic malignances after HL (24). Lastly, SEER only records
the sociodemographic profile of the patient's county of
residence, and thus individual sociodemographic parameters
are not available. Nonetheless, we show that a history of mixed
cellularity HL and prior radiotherapy for HL appear to impact
survival after NSCLC.
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Acknowledgement
The authors would like to thank Laura Brumbaugh for editorial
assistance.
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References
Cite this article as: Milano MT, Li H, Constine LS, Travis LB. Variables
affecting survival after second primary lung cancer: A population-based
study of 187 Hodgkin's lymphoma patients J Thorac Dis 2012;4(1):22-29. doi:
10.3978/j.issn.2072-1439.2011.12.02
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