2012 Research Highlights

www.thelancet.com/respiratory Vol 1 March 2013 e13

Published Online
January 14, 2013
http://dx.doi.org/10.1016/
S2213-2600(13)70008-0
Non-small-cell lung cancer: promising advances in treatment
Non-small-cell lung cancer (NSCLC) is a leading
worldwide cause of cancer-related mortality.
1
Here, we
focus on important publications relating to advances in
the care and treatment of NSCLC in 2012.
NSCLC is traditionally thought to be a disease of elderly
people, but a paucity of validated data exist regarding
adjuvant chemotherapy for early stage NSCLC in an elderly
population. Cue and colleagues,
2
did a population-
based retrospective cohort study in which they identied
6304 patients with non-metastatic NSCLC, 2763 (44%)
of whom were elderly (aged 70 years), and receipt of and
outcome from adjuvant chemotherapy was reviewed and
stratied by age group.
Within this elderly cohort, there was a male
preponderance and there was also an associated increase
in medical comorbidities and lengthy postoperative
admissions to hospital compared with younger patients
(<70 years). The major histological subtype was
adenocarcinoma, which was less common in elderly
patients than it was in the individuals younger than
70 years. Patients were subdivided according to the
preadjuvant and postadjuvant chemotherapy watershed
(ie, 20012003 and 20042006, respectively). This
analysis showed that since adjuvant chemotherapy for
NSCLC became the standard of care, use of this approach
increased from 33% to 162%, resulting in an increase in
4-year survival from 471% to 499% (p=001) in those
older than 70 years. This increase in use, however, remains
substantially lower than in the non-elderly population.
Treatment was generally well tolerated and not associated
with more morbidity when the elderly population was
compared with those younger than 70 years.
Although surgery is regarded as standard care in the
management of early stage NSCLC, stereotactic body
radiotherapy (SBRT) is an increasingly used alternative
treatment approach for patients who are deemed
medically inoperable because of age, frailty, or medical
comorbidities. SBRT uses highly precise radiotherapy
beams, which are tightly conformed to the target and
thus avoid damaging surrounding tissue. Not only
is treatment conveniently available in an outpatient
setting, delivered using 35 fractions of high-dose
radiotherapy typically over a 2-week period, but SBRT
has also been shown to have a survival advantage
when compared with conventionally fractionated
radiotherapy, which is less conformal, needs larger
treatment volumes, and is delivered over a period of
roughly 65 weeks.
Grills and colleagues reported treatment outcomes
on the largest dataset to date of 505 patients treated
with SBRT, from ve institutions between 1998 and
2010.
3
96% had stage IAB disease, 87% were deemed
medically inoperable, and 64% were biopsy proven.
Median prescribed dose was 54 Gy (range 2064) in
three fractions (range 115). Very promising local control
rates of 94%, similar to those of surgery, were seen with
a median follow-up of 16 years (range 0173). Regional
control rates were 89% and distant control rates were
80%, with most treatment failures being distant. Overall
survival was 60% (78% if operable, 58% if inoperable).
Grade 2 or higher radiation pneumonitis was seen in
7% of patients. This large study adds greatly to the
growing body of evidence that lends support to the role
of SBRT in the management of primary lung cancer,
especially in patients who cannot undergo surgery
because of medical comorbidities.
Further insight into the molecular diversity of NSCLC
was given by Bergethon and colleagues,
4
who did
a multicentre retrospective analysis in which they
identied 1073 patients with NSCLC. They detected the
ROS1 translocation in 18 (2%) patients using uorescence
in situ hybridizationthese mutations were mutually
exclusive of epidermal growth factor receptor (EGFR)
mutations and anaplastic lymphoma kinase (ALK)
rearrangements. Clinicopathological data, smoking
history, and survival information were collected.
In this preliminary group, patients whose NSCLC
tumours were ROS1positive, were young (median age
of 498 years, range 3279), never-smokers, and had an
adenocarcinoma histological subtype. This phenotype
is similar to that associated with ALK-positive patients,
which might explain why an ALK inhibitor can have
activity in this molecular subset. No agents specically
targeting ROS1 are available, but there is promising
preclinical and early clinical activity seen with the new
ALK inhibitor crizotinib, thus dening a new subset of
patients with NSCLC who have drug-targetable tumours.
The reversible EGFR inhibitors, erlotinib and getinib,
have been established as rst-line treatments for patients
with advanced NSCLC who harbour the activating EGFR
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2012 Research Highlights
e14 www.thelancet.com/respiratory Vol 1 March 2013
mutation. However, resistance and ultimate progression
is inevitable and the option for further treatment was
previously restricted to standard chemotherapyuntil,
that is, a new agent afatinib, an irreversible Erb-B family
antagonist, became available in the USA in September,
2012. Miller and colleagues,
5
designed a randomised,
double-blind, multicentre phase 2b/3 trial (LUX-Lung1)
examining use of afatinib compared with placebo. In this
study, 697 patients were enrolled and 585 (84%) were
allocated to receive treatment, 390 (67%) with afatinib
and 195 (33%) with placebo. The investigators detected
no benet in terms of median overall survival, although
there was a statistically signicant median progression-
free survival that favoured afatinib versus placebo
(33 months vs 11 month, respectively; p<0001).
Most of the molecularly targeted therapeutic advances
in NSCLC have been shown in subsets of patients with
adenocarcinoma, with advances in the treatment of
squamous cell carcinoma not as forthcoming. Lynch
and colleagues undertook a randomised, double-blind,
international, multicentre phase 2 study in 204 patients
with previously untreated advanced NSCLC,
6
in which
they tested the biological activity of the anti-cytotoxic
T-cell lymphocyte-4 monoclonal antibody ipilimumab.
Lynch and colleagues study showed an improved
overall survival, with median overall survival of
122 months in the ipilimumab cohort (six cycles of
chemotherapy, with ipilimumab being introduced at
cycle three). This treatment strategy was design to
enhance activation of T cells by pretreating patients
with a cytotoxic agent. Subgroup analysis on this small
cohort has also shown that squamous cell carcinomas
had a better clinical outcome than non-squamous
cell carcinoma. Further studies testing immunological
agents are underway in a squamous cell subset of NSCLC.
Keith Ian Quintyne, Lorraine Walsh, *Linda Coate
Mid-Western Regional Hospital, Limerick, Ireland (KIQ, LW, LC),
and Graduate Entry Medical School, University of Limerick,
Limerick, Ireland (KIQ)
lindae.coate@hse.ie
We declare that we have no conicts of interest.
1 Jemal A, Bray A, Centre MM, et al. Global cancer statistics. CA Cancer J Clin
2011; 61: 6990.
2 Cue S, Booth CM, Peng Y, et al. Adjuvant chemotherapy for non-small-cell
lung cancer in the elderly: a population-based study in Ontario, Canada.
J Clin Oncol 2012; 30: 181321.
3 Grills IS, Hope AJ, Guckenberger M, et al. A collaborative analysis of
stereotactic lung radiotherapy outcomes for early-stage non-small-cell
lung cancer using daily con-beam computed tomography image-guided
radiotherapy. J Thorac Oncol 2012; 7: 138293.
4 Bergethon K, Shaw AT, Ou S-HI, et al. ROS1 rearrangements dene a unique
molecular class of lung cancers. J Clin Oncol 2012; 30: 86370.
5 Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with
advanced, metastatic non-small-cell lung cancer after failure of erlotinib,
getinib, or both, and one or two lines of chemotherapy (LUX-Lung1):
a phase 2b/3 randomised trial. Lancet Oncol 2012; 13: 52838.
6 Lynch TJ, Bondarenko I, Luft A et al. Ipilimumab in combination with
paclitaxel and carboplatin as rst-line treatment in stage IIIB/IV non-small
cell lung cancer: results from a randomized, double-blind, multicenter
phase II study. J Clin Oncol 2012; 30: 204654.