Download original articles - Oxford Academic

original articles
9. Paz-Ares LG, Biesma B, Heigener D et al. Phase III, randomized, double-blind,
placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the
first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin
Oncol 2012; 30(25): 3084–3092.
10. Reck M, von Pawel J, Zatloukal P et al. Phase III trial of cisplatin plus gemcitabine
with either placebo or bevacizumab as first-line therapy for nonsquamous nonsmall-cell lung cancer: AVAiL. J Clin Oncol 2009; 27(8): 1227–1234.
Annals of Oncology
11. Manegold C, van Zandwijk N, Szczesna A et al. A phase III randomized study of
gemcitabine and cisplatin with or without PF-3512676 (TLR9 agonist) as first-line
treatment of advanced non-small-cell lung cancer. Ann Oncol 2012; 23(1): 72–77.
12. Spigel DR, Kim ES, Lynch TS et al. Randomized phase III trial of gemcitabine (G)/
carboplatin (C) with or without iniparib (I) in patients ( pts) with previously untreated
stage IV squamous lung cancer. J Thor Oncol 2013; 8(Suppl 2): Abstract
#O15.06.
Annals of Oncology 25: 2162–2166, 2014
doi:10.1093/annonc/mdu442
Published online 5 September 2014
Adjuvant cisplatin-based chemotherapy in
nonsmall-cell lung cancer: new insights into the effect
on failure type via a multistate approach
F. Rotolo1*, A. Dunant1, T. Le Chevalier2, J. -P. Pignon1 & R. Arriagada3 on behalf of the IALT
Collaborative Group
Departments of 1Biostatistics and Epidemiology; 2Medical Oncology; 3Radiation Oncology, Gustave Roussy, Villejuif, France
Received 17 June 2014; revised 13 August 2014; accepted 20 August 2014
Background: Adjuvant cisplatin-based chemotherapy has become the standard therapy against resected nonsmall-cell
lung cancer (NSCLC). Because of variable results on its late effect, we reanalyze the long-term data of the International
Adjuvant Lung Cancer Trial (IALT) to describe in details the role of adjuvant chemotherapy.
Patients and methods: In the IALT, 1867 patients were randomized between adjuvant cisplatin-based chemotherapy
and control, who were followed up for a median of 7.5 years. Of these, 1687 patients were enrolled from 132 centers
accepting to report the times to cancer events. We used event history methodology to estimate the effects of adjuvant
chemotherapy on the risks of local relapse, distant metastasis, and death.
Results: Adjuvant chemotherapy was highly effective against local relapses [HR = 0.73; 95% confidence interval (CI) 0.60–
0.90; P = 0.003] and nonbrain metastases (HR = 0.79; 95% CI 0.66–0.94; P = 0.008) but not against brain metastases
(HR = 1.1; 95% CI 0.82–1.4; P = 0.61). The effect on noncancer mortality was nonsignificant during the first 5 years (HR = 1.1;
95% CI 0.81–1.5; P = 0.29), whereas the risk of noncancer mortality was subsequently higher with treatment (HR = 3.6; 95%
CI 2.2–5.9; P < 0.001). This harmful effect, however, potentially concerned only about 2% of the patients at 8 years.
Conclusion: Adjuvant cisplatin-based chemotherapy reduced the risk of local relapse and of nonbrain metastasis, thereby
improving survival. This treatment exerted no residual effect on mortality during the first 5 years, but a higher risk of noncancer
mortality was found thereafter. Detailed long-term follow-up is strongly recommended for all patients in randomized trials
evaluating adjuvant treatments in NSCLC.
Key words: cisplatin, nonsmall-cell lung cancer, adjuvant chemotherapy, randomized trial, multistate model, failure
pattern
introduction
During the last decade, adjuvant cisplatin-based chemotherapy
has been established as an effective treatment in resected nonsmall-cell lung cancer (NSCLC) and it has become the standard
therapy in this patient population [1, 2]. The International
Adjuvant Lung Cancer Trial (IALT) [3], the first and largest
*Correspondence to: Dr Federico Rotolo, Department of Biostatistics and Epidemiology,
Gustave Roussy, 114 Rue Edouard-Vaillant – 94805 Villejuif Cedex, France. Tel: +33-142-11-61-28; E-mail: [email protected]
randomized study on this issue, showed a significant overall survival advantage of 4.1% at 5 years in patients receiving adjuvant
chemotherapy compared with surgery alone. The joint (Lung
Adjuvant Cisplatin Evaluation [4]) LACE analysis included the
IALT and the four other largest randomized trials [5–8]. LACE
and, more recently, a worldwide individual patient-based metaanalysis [9] confirmed a survival benefit of about 5% at 5 years
obtained with adjuvant chemotherapy.
Even though this improvement was observed at the classic
milestone of 5 years, long-term results should also be explored
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected].
Annals of Oncology
to ensure that late toxicities do not compromise the initial
benefits. Unfortunately, the long-term results of adjuvant
studies are rarely known, mainly for logistical reasons. An
updated analysis of IALT with a follow-up of 7.5 years [10]
confirmed a benefit within the first 5 years, but showed a 1.5
mortality relative risk thereafter in the treatment arm [95%
confidence interval (CI) 1.0–2.1, P = 0.04]. Is the effect of adjuvant chemotherapy partially counterbalanced in the long term
by late deleterious effects or late exacerbation of comorbidities?
Two other smaller trials with a median follow-up of 9.3 [11]
and 6.2 years [12], however, showed no evidence of a differential
effect of chemotherapy over time. One of them used carboplatin
[12]. LACE [4] (median follow-up: 5.2 years) could not evaluate
the late effects of chemotherapy because long-term data were unavailable for three trials [5–7].
The aim of the present study was to undertake detailed analyses using more sophisticated statistical methodologies, including competing risk and multistate approaches, to better describe
the early and late effects of cisplatin-based adjuvant chemotherapy in resected NSCLC.
materials and methods
IALT enrolled 1867 patients with resected NSCLC between February 1995
and January 2001, randomized to cisplatin-based adjuvant chemotherapy or
a control arm [3]. They were followed up for a median period of 7.5 years.
The participating centers were invited to optionally report, in addition to the
time to death, some patient outcomes, including the time to the first local
and distant relapse, and to second tumors. Such information can be used to
explore the effects of chemotherapy on mortality more thoroughly by separating its antineoplastic effect—changes in the risks of recurrence—from its
residual effect, if any. This potential residual effect could also result from a
change in second cancer hazards. We did not consider these events because
previous results did not show such an effect [10, 13]. An analysis of the incidence of cancer-related events, based on shorter-term follow-up data, was
published earlier [13]. We limited all our analyses to the 1687 patients enrolled from the 132 centers which accepted to report cancer-related events and
therefore excluded the 180 patients from the remaining 17 centers (supplementary Figure S1, available at Annals of Oncology online). Supplementary
Table S1, available at Annals of Oncology online, presents a description of the
1687 patients included.
We used proportional hazard competing risks and multistate models [14]
to estimate the effects of adjuvant chemotherapy on the risks of local relapse,
metastasis, and death. We assumed that chemotherapy had a possible effect
exclusively during the free-from-any-event period, and not after the occurrence of any cancer-related event. Following previous analyses [13], we
assumed different effects of chemotherapy on brain and nonbrain metastases. We estimated separately the effect of chemotherapy on mortality before
and after 5 years. Nonetheless, as few cancer-related events occurred after 5
years, we estimated both the effect of chemotherapy on them and their
influence on the overall risk of death for the entire observation period. For
full details of the statistical methods, see the supplementary Material, available at Annals of Oncology online.
results
In total, 1687 patients were followed up for intermediate events.
One or more recurrences were reported for 895 patients and none
for 792 patients. The database contained information on 401
local relapses and 689 metastases. In total, 1064 patients died
Volume 25 | No. 11 | November 2014
original articles
during the study, 236 without cancer events, 641 with either a
local relapse or metastasis, and 187 patients with both. Figure 1
and supplementary Figures S2 and S3, available at Annals of
Oncology online, show the frequencies of each event sequence.
Supplementary Table S2, available at Annals of Oncology online,
describes the causes of death by arm, for the whole study and by
period. Supplementary Figures S4–S6, available at Annals of
Oncology online, show the evolution along time of the probabilities of being in each clinical state.
Local relapses occurred mostly during the first 5 years: 28% at
5 years and 32% at 10 years. Twenty-six of the 401 local relapses
occurred after a metastasis, but only 15 occurred more than
4 months later. The risk of local relapse was lower in the chemotherapy arm (HR = 0.73; 95% CI 0.60–0.90; P = 0.003). The risk
of local relapse was lower after metastasis (HR = 0.56; 95% CI
0.33–0.96; P = 0.034; supplementary Table S3, available at Annals
of Oncology online). The risk of death was highly increased after
local relapses (HR = 26; 95% CI 20–34; P < 0.001).
Distant metastases—202 brain and 487 nonbrain lesions—
were even more frequent, with an incidence of 33% at 5 years
and of 38% at 10 years. Overall, 63 metastases were observed
after local relapses, but only 32 metastases occurred more than 4
months later. Chemotherapy was highly effective in reducing
nonbrain metastases (HR = 0.79; 95% CI 0.66–0.94; P = 0.008)
but not brain metastases (HR = 1.1; 95% CI 0.82–1.4; P = 0.61).
The risk of metastasis was significantly higher after local relapse
(HR = 1.7; 95% CI 1.2–2.5; P = 0.003), estimated without distinguishing brain and nonbrain metastases due to the small
number of events. The risk of death was highly increased after
brain metastasis (HR = 38; 95% CI 29–50; P < 0.001) and nonbrain metastasis (HR = 40; 95% CI 31–51; P < 0.001).
We estimated that 53% of the controls developed a local relapse
or a nonbrain metastasis at 8 years. Consequently, more than half
of the patients could potentially benefit from the chemotherapy.
Once this benefit was taken into account, its residual effect
(i.e. on noncancer mortality) was nonsignificant during the first
5 years (HR = 1.1; 95% CI 0.81–1.5; P = 0.29), meaning that all
the activity of chemotherapy consisted in the prevention of recurrences (excepted brain metastases). In contrast, after 5 years,
the risk of noncancer death was higher in the treatment arm
(HR = 3.6; 95% CI 2.2–5.9; P < 0.001), even though the antineoplastic benefit was still present. Of note, only 36% of the controls
were alive and free of cancer at 5 years and only 6% of them (2%
of all the controls) died of other causes during the next 3 years.
Figure 2 and supplementary Table S3, available at Annals of
Oncology online, summarize the main results and supplementary Table S4, available at Annals of Oncology online, presents
the effects of the adjustment variables. As expected, the risks of
all events, including death, increased with advanced tumor and
nodal stage. The risk of death was higher for advanced stages irrespective of whether cancer events had occurred or not (not
shown). Patients who had undergone a lobectomy or a segmentectomy, when compared with pneumonectomy, had a higher
risk of local relapse (HR = 1.3; 95% CI 1.1–1.5; P = 0.003), brain
metastasis (HR = 1.4; 95% CI 0.98–1.9; P = 0.065), and nonbrain
metastasis (HR = 1.2; 95% CI 0.97–1.5; P = 0.088). A lower risk
of death in lobectomy/segmentectomy patients (HR = 0.87; 95%
CI 0.78–0.96; P = 0.001) was observed, after taking into account
the effect of cancer-related events.
doi:10.1093/annonc/mdu442 | 
original articles
Annals of Oncology
Randomization
Both
arms
792
patients
without
recurrence
1687 patients with follow-up of recurrences
94*
269
343
895
patients
with
recurrence
bDM
202
c = 556
12*
177
7
c = 15
LR
+
bDM
32
13
c=1
LR
401
50
c = 28
LR
+
nbDM
163
19
c=7
nbDM
487
c = 16
623
censored
patients
236
155
31
178
156
308
1064
deaths
Deceased
Figure 1. Number of events and event sequences in the IALT study—both arms. For example: a total of 202 bDM were observed, 177 as first event, 12 concomitantly with LR, and 13 after LR; among the 177 patients with bDM only, 7 had LR later, 155 died, and 15 were censored; among the 32 patients with both
bDM and LR, 31 died and 1 was censored. DM, distant metastasis; LR, local relapse. The numbers in the gray boxes are the number of patients whose follow-up
data were censored (c=). Note that only the time to the first metastasis, either brain or nonbrain, was available for each patient. Events on the arrows to intersections of event sets (for instance those 12 patients from randomization to LR + bDM) denote simultaneous events; other events occurred sequentially, like those
7 patients having LR after bDM.
An early toxic effect of chemotherapy during the first 12 months
for noncancer deaths (HR = 1.7; 95% CI 1.0–2.8; P = 0.044) was
observed, consistent with previous findings during the first
6 months [4]. Moreover, we compared the incidence of noncancer deaths among patient free from cancer at 5 years in the treatment arm, between patients with planned total cisplatin total
doses of 300, 320, 360, and 400 mg/m2. The noncancer mortalities were very similar (log-rank test P = 0.57) with an 8-year incidence of 13%, 11%, 13%, and 6%, respectively. Likewise, no
link was found between the cisplatin-associated regimen and the
late increase in mortality: among 5-year survivors, the 8-year
survival was 0.86 (etoposide) versus 0.87 (vinca alkaloids), with
a nonsignificant difference between their subsequent survival
(log-rank test P = 0.73).
discussion
The benefit yielded by cisplatin-based adjuvant chemotherapy
in the IALT was a reduction in the risk of both local relapses
and nonbrain metastases. It had no effect on the risk of brain
metastases, probably due to the blood–brain barrier [15].
 | Rotolo et al.
Besides this antineoplastic activity, cisplatin-based adjuvant
chemotherapy had no additional effect on mortality during the
first 5 years. In contrast, although cancer events declined after
the first 5 years, the risk of noncancer deaths increased in the
treatment arm compared with the control arm. This long-term
increased risk for treated patients was relatively high (threefold), but only 2% of the controls died of noncancer causes
between 5 and 8 years whereas the benefit (a 25% reduction in
the risk) concerned cancer events which affected more than 50%
of the controls at 8 years.
As only 5% of cancer events occurred after 5 years, we
assumed that adjuvant chemotherapy exerted a similar effect on
them throughout the study. A complementary analysis with separate estimated effects on the two periods did not show any significant difference in the effect of chemotherapy on cancer events
over time (data not shown).
The risk of each type of relapse changed significantly after the
occurrence of other cancer-related events. The risk of metastases
increased by 70% after a local relapse. This result was probably due
at least to two different phenomena. First, after a local relapse, the
physician prescribed additional examinations to detect metastases,
Volume 25 | No. 11 | November 2014
original articles
Annals of Oncology
<5 years
s ctr
CT v
CT
Chemotherapy
(CT)
vs
l:
ctr
l: 1.1
**
.73
0
CT vs ctrl: 1.1
CT
vs
CT v
ctr
l: 0
s ctr
.79
l: 3.6
**
***
Local relapse
DM vs
not
0.56*
LR
vs
Brain
distant metastasis
no
t: 2
LR vs
not
1.7**
6*
bDM vs not: 38***
Distant metastasis
Non-brain
distant metastasis
**
DM
vs
t:
no
40
Death
***
nb
£ 5 years
Figure 2. Summary of results (hazard ratios) regarding the chemotherapy (CT) effect when compared with control (Ctrl) and the effect of events on each
other, from the three multistate models: (A) the model for death with intermediate recurrences (solid arrows), which also estimated the residual (=remaining
after taking into account the effect of chemotherapy on recurrences) effect of chemotherapy on death, before and after 5 years. (B) The model for local relapse
(LR), with nonsimultaneous intermediate distant metastases (DM, dotted arrows). (C) The model for brain and nonbrain metastasis (bDM, nbDM), with nonsimultaneous intermediate local relapse (dashed arrows). Gray-colored HRs are not significantly different from 1 at a 95% level. Black HRs are significantly
lower/higher than 1. Significance codes: ***P < 0.001, **0.001 ≤ P < 0.01, *0.01 ≤ P < 0.05.
which were therefore diagnosed earlier and more frequently than
in patients without a local relapse. Second, a local relapse could
itself give rise to new metastases unrelated to the primary cancer.
Conversely, the risk of local relapse decreased by 44% after a
metastasis. A sensible explanation for this risk reduction is that
metastases are so life threatening that physicians focused on immediate patient survival rather than local relapse detection.
An increased incidence of second malignancies has been
observed in testicular cancer patients treated with cisplatin [16–19],
but not in IALT [10]. Therefore, we decided to exclude them from
the current analyses. As expected, the risk of death was strongly
increased after a cancer-related event. The huge hazard ratios (26,
38, and 40) could have been overestimated because the exact time
to death is known, whereas cancer events are diagnosed and
recorded later than their onset. Thus, shorter relapse-to-death gaps
could lead to an overestimation of the risk of death after relapse.
Finally, we observed a lower risk of all recurrences in patients
who had undergone a pneumonectomy than those submitted to
lobectomy or segmentectomy, but a higher risk of death once
the effects on the relapses were taken into account. This suggests
that excision of the whole lung reduces the risk of relapse but
increases mortality due to other causes, which is consistent with
clinical knowledge [20, 21].
The present analysis is the first to employ cutting-edge statistical
methods to study the role of adjuvant cisplatin-based chemotherapy in resected NSCLC. Its main results are in accordance with
those published earlier [10]. However, the use of multistate models
allowed distinguishing the effects of cisplatin, neatly separating its
antineoplastic role from the late increase in noncancer mortality.
In addition, this methodology enabled us to estimate the impact of
cancer events on the risk of subsequent events including death.
Our major finding is that adjuvant chemotherapy is effective
against local relapses and nonbrain metastases but that it leads
to increased noncancer mortality after 5 years. It is well
Volume 25 | No. 11 | November 2014
established that patients with resected NSCLC experience excess
long-term mortality compared with the general population, probably because of co-morbidities [22]. Nevertheless, this would not
explain differential long-term noncancer mortality between
treated and control NSCLC patients. In our study, this late overmortality could be an artifact due to the low number of patients
in some transitions in the multistate model. However, the results
are consistent with previous analyses with simpler methods.
Regarding the potential role of postoperative radiotherapy, it was
a center choice and then stratified in the randomizing procedure.
In addition, we did not find a late deleterious effect related to
radiotherapy [10]. Our findings concur with the increased risk of
potentially lethal late effects of platinum-based chemotherapy evidenced in large databases on testicular cancer [16–18, 23–24]. A
potential toxic effect of cisplatin-based chemotherapy on noncancer deaths was recently evaluated by a literature-based meta-analysis including 6430 NSCLC patients from 16 randomized trials
including IALT [25]. Over the whole follow-up period, there was
a significant increase (30%) in noncancer mortality in the cisplatin
arm but the time of occurrence of the deleterious effect was not
studied. When the IALT is excluded, the increased relative risk (RR)
remains borderline significant (RR = 1.2; 95% CI 0.99–1.48,
P = 0.06) over a median follow-up of 5.4–9.6 years for the three
larger studies.
Even if this late overmortality only concerns a small percentage of the patients, it will be higher with future potent antineoplastic adjuvant, unless this improvement also includes a
decrease in late toxic effects. The optimal situation would be to
find tumor markers able to select chemosensitive tumors, and
thus better target the subpopulations that are likely to benefit,
but until now this research has remained inconclusive [26, 27].
The most plausible explanation for the late overmortality is
a long-term toxic effect of cisplatin suggested by published
results in NSCLC and other cancers. Nevertheless, the current
doi:10.1093/annonc/mdu442 | 
original articles
results are based on a small number of noncancer deaths
after 5 years and long-term follow-up in this category of randomized trials is scarce nowadays. Longer and detailed
follow-up should therefore be strongly recommended in the
ongoing randomized phase III trials evaluating adjuvant
NSCLC treatments.
acknowledgements
The authors are grateful to Lorna Saint Ange for editing. They
thank the Steering Committee and all the IALT Collaborators
for providing the IALT dataset (supplementary Appendix 1,
available at Annals of Oncology online).
disclosure
The authors have declared no conflicts of interest.
references
1. Pisters KMW, Evans WK, Azzoli CG et al. CCO and the ASCO guideline for adjuvant
chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non-small
cell lung cancer. J Clin Oncol 2007; 25: 5506–5518.
2. National Comprehensive Cancer Network. NCCN guidelines version 1.2013, nonsmall cell lung cancer—NCCN guidelines for patients. http://www.nccn.org/
patients/guidelines/nscl/index.html (18 September 2014, date last accessed).
3. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based
adjuvant chemotherapy in patients with completely resected non-small-cell lung
cancer. N Engl J Med 2004; 350: 351–360.
4. Pignon JP, Tribodet H, Scagliotti GV et al. Lung adjuvant cisplatin evaluation: a
pooled analysis by LACE collaborative group. J Clin Oncol 2008; 26: 3552–3558.
5. Douillard JY, Rosell R, De Lena M et al. Adjuvant vinorelbine plus cisplatin versus
observation in patients with completely resected stage IB–IIIA non-small-cell lung
cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a
randomised controlled trial. Lancet Oncol 2006; 7: 719–727.
6. Scagliotti GV, Fossati R, Torri V et al. Randomized study of adjuvant chemotherapy
for completely resected stage I, II or IIIa non-small cell lung cancer. J Natl Cancer
Inst 2003; 95: 1453–1461.
7. Waller D, Peake MD, Stephens RJ et al. Chemotherapy for patients with non-small
cell lung cancer: the surgical setting of the Big Lung Trial. Eur J Cardiothorac Surg
2004; 26: 173–182.
8. Winton T, Livingston R, Johnson D et al. Vinorelbine plus cisplatin vs. observation
in resected non-small cell lung cancer. N Engl J Med 2005; 352: 2589–2597.
9. NSCLC Meta-analyses Collaborative Group. Adjuvant chemotherapy, with or
without postoperative radiotherapy, in operable non-small cell lung cancer: two
meta-analyses of individual patient data. Lancet 2010; 375: 1267–1277.
10. Arriagada R, Dunant A, Pignon JP et al. Long-term results of the international
adjuvant lung trial evaluating adjuvant Cisplatin-based adjuvant chemotherapy in
resected lung cancer. J Clin Oncol 2010; 28: 35–42.
 | Rotolo et al.
Annals of Oncology
11. Butts CA, Ding K, Seymour L et al. Randomized phase III trial of vinorelbine plus
cisplatin compared with observation in completely resected stage IB and II non-smallcell lung cancer: updated survival analysis of JBR-10. J Clin Oncol 2010; 28:
29–34.
12. Strauss GM, Herndon JE, Maddaus MA et al. Adjuvant paclitaxel plus carboplatin
compared with observation in stage IB non-small-cell lung cancer: CALGB 9633
with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and
North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008; 26:
5043–5051.
13. Dunant A, Pignon JP, Le Chevalier T. Adjuvant chemotherapy of non-small cell
lung cancer: contribution of the International Adjuvant Lung Trial. Clin Cancer Res
2005; 11: 5017s–5021s.
14. Putter H, Fiocco M, Geskus RB. Tutorial in biostatistics: competing risks and
multistate models. Stat Med 2007; 26: 2389–2430.
15. Hansen HH. Should initial treatment of small cell carcinoma include
systemic chemotherapy and brain irradiation? Cancer Chemother Rep 1973; 4:
239–241.
16. van den Belt-Dusebout AW, de Wit R, Gietema JA et al. Treatment-specific risks of
second malignancies and cardiovascular disease in 5-year survivors of testicular
cancer. J Clin Oncol 2007; 25: 4370–4378.
17. Travis LB, Fosså SD, Schonfeld SJ et al. Second cancers among 40,576 testicular
cancer patients: focus on long-term survivors. J Natl Cancer Inst 2005; 97:
1354–1365.
18. Haugnes HS, Bosl GJ, Boer H et al. Long-term and late effects of germ cell
testicular cancer treatment and implications for follow-up. J Clin Oncol 2012; 30:
3752–3763.
19. Travis LB, Andersson M, Gospodarowicz M et al. Treatment-associated leukemia
following testicular cancer. J Natl Cancer Inst 2000; 92: 1165–1171.
20. Okada M, Yamagishi H, Satake S et al. Survival related to lymph node involvement
in lung cancer after sleeve lobectomy compared with pneumonectomy. J Thorac
Cardiovasc Surg 2000; 119: 814–819.
21. Deslauriers J, Grégoire J, Jacques LF et al. Sleeve lobectomy versus
pneumonectomy for lung cancer: a comparative analysis of survival and sites or
recurrences. Ann Thorac Surg 2004; 77: 1152–1156.
22. Janssen-Heijnen ML, van Steenbergen LN, Steyerberg E et al. Long-term excess
mortality for survivors of non-small cell lung cancer in the Netherlands. J Thorac
Oncol 2012; 7: 496–502.
23. Meinardi MT, Gietema JA, van der Graaf WT et al. Cardiovascular morbidity in
long-term survivors of metastatic testicular cancer. J Clin Oncol 2000; 18:
1725–1732.
24. Fosså SD, Gilbert E, Dores GM et al. Noncancer causes of death in survivors of
testicular cancer. J Natl Cancer Inst 2007; 99: 533–544.
25. Petrelli F, Barni S. Non-cancer-related mortality after cisplatin-based adjuvant
chemotherapy for non-small cell lung cancer a study-level meta-analysis of 16
randomized trials. Med Oncol 2013; 30: 641.
26. Olaussen KA, Dunant A, Fouret P et al. DNA repair by ERCC1 in non–small-cell
lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006; 355
(10): 983–91.
27. Friboulet L, Olaussen KA, Pignon JP et al. ERCC1 Isoform Expression and DNA
Repair in Non–Small-Cell Lung Cancer. N Engl J Med 2013; 368(12):
1101–1110.
Volume 25 | No. 11 | November 2014