Journal of Cancer Therapy, 2011, 2, 157-160
doi:10.4236/jct.2011.22018 Published Online June 2011 (http://www.SciRP.org/journal/jct)
157
Advanced Lung Cancer—Reaching a Survival
Ceiling with Chemotherapy, the Nibs, and the
Mabs
Riccardo Lencioni1, James Chen2, Gordon Downie3, Llew Keltner2
1Department of Surgery, Pisa University School of Medicine, Pisa, Italy; 2Light Sciences Oncology, Inc., Bellevue, USA; 3Titus Re-
gional Medical Center, Mount Pleasant, USA.
Received February 8th, 2011; revised March 29th, 2011; accepted April 7th, 2011.
ABSTRACT
Lung cancer is the leading cause of cancer-related death worldwide. Despite intensive research conducted during the
past years, little improvement in overall survival has been ach ieved for patients with advanc ed disease. Chemotherapy
and radiation continue to be the mainstays of treatment for unresectable patients, and targeted agents seem to have
added little improvement to overa ll survival while dramatically increasing co sts and producing significant clin ical side
effects. In contrast to the immunosuppression which occurs as a result of the use of chemothera py and pa thway blockers,
novel therapies are emerg ing which either stimulate tumor specific immun e responses due to apoptotic fo cal tumor de-
struction or attack tumor-induced regulatory T-cell immunosuppression. Such new approaches should be fully explored,
as they have potentia l to offer very different outcomes for advanced lung cancer patients.
Keywords: Lung Cancer, Chemotherapy, Targeted Therapy
1. Introduction
Lung cancer is the leading cause of cancer-related deaths
in the United States and worldwide [1,2]. Intensive re-
search and many clinical trials have yielded little im-
provement in overall survival (OS), according to the
American Cancer Society [3]. A recent study using the
SEER database demonstrated that, between the years
1990 and 2005, one-year OS increased from 13.2 to
19.4%, and two-year OS only increased from 4.5 to 7.8%
[4]. For non-small cell lung cancer, the most prevalent
type, the one-year survival rate for all stages combined
has remained unchanged for many years at approxi-
mately 15% [2,5]. The 5-year survival for patients diag-
nosed with stage IV disease is only 1% [6]. Chemother-
apy and radiation continue to be the mainstays of treat-
ment for patients with advanced disease, and targeted
agents (biologics) seem to have added little improvement
to OS while dramatically increasing costs and producing
significant clinical side effects.
2. Chemotherapy
Guidelines for treatment of stage IV disease (the most
advanced patients) have very recently been updated by
the American Society of Clinical Oncology [7]. Patients
with good performance status are best treated with a
platinum-based, two-drug combination, and patients with
poor performance status are treated with a single cyto-
toxic drug. The doublet combinations of platinum com-
pounds include cisplatin or carbop latin with gemcitabin e,
vinorelbine, pemetrexed, or taxanes [8].
3. Targeted Drug Therapy
3.1. Bevacizumab
Bevacizumab is an antiangiogenic agent that has un-
dergone three randomized controlled trials (RCT) in
combination with chemotherapy. One RCT of car-
bop latin /pacl itaxel with or without bevacizumab showed
a very modest improvement in OS of 2 months (from
10.3 to 12.3 months) at the expense of increased toxicity
(grade 4 and 5) involving hematologic and nonhema-
tologic systems [7,9]. In elderly patients, no improve-
ment in survival has been demonstrated. The combina-
tion of bevacizumab with other cytotoxic regimens has
not improved OS and is not recommended [7]. A Phase 3
controlled, double-blinded study of bevacizumab and
erlotinib versus erlotinib in a second-line role did not

Advanced Lung Cancer—Reaching a Survival Ceiling with Chemotherapy, the Nibs, and the Mabs
158
demonstrate any enhanced survival (9.3 vs 9.2 months)
[6]. The approximate cost of addition of bevacizumab to
a chemotherapy regimen is $ 90 K [10]. Based on this
added cost and small incremental OS advantage, some
opinion leaders have questioned the cost effectiveness of
bevacizumab [10].
3.2. Cetuximab
Cetuximab is an antibody that binds the epidermal
growth factor receptor (EGFR) [2]. Four RCTs have ex-
plored chemotherapy with or without cetuximab. One
study demonstrated an improvement of 1.2 months in OS
(11.3 vs 10.1 months) with the addition of cetuximab
along with increased gastrointestinal and dermatologic
toxicity [7]. Cetuximab also increases the rate of grade
3/4 febrile neutropenia [11]. The approximate cost of
addition of cetuximab to a chemotherapy regimen is
$80K [10]. Based on this added cost and small incre-
mental OS advantage, some opinion leaders have ques-
tioned the cost effectiveness of cetuximab [10].
3.3. Erlotinib and Gefitinib
Erlotinib and gefitinib are reversible EGFR tyrosine
kinase inhibitors (TKIs) used primarily as second- or
third-line treatment. After prior chemotherapy treatment,
erlotinib was shown to be superior to placebo and in-
creased OS by 2 months (6.7 vs 4.7 months) [12]. Gefit-
inib failed to demonstrate a survival advantage in previ-
ously treated patients in another Phase 3 trial [12]. The
EGFR TKIs combined with chemotherapy have failed to
show any benefit compared with chemotherapy alone in
four large RCTs [12]. Another limitation is increased
toxicity in elderly patients [11]. However, certain patient
characteristics—namely, Asian race, female gender,
never smoker status, and adenocarcinoma histology—
may confer a survival advantage with EGFR TKIs [12,
13]. The approximate cost of addition of erlotinib to a
chemotherapy regimen is $16,200 [10]. Based on the
added cost and small incremental OS advantage, the Na-
tional Institute for Clinical Excellence (NICE) in Great
Britain has recommended that erlotinib be used in Na-
tional Health Service patients as an alternative to do-
cetaxel in second-line treatment for lung cancer “only on
the basis that it is provided by the manufacturer at an
overall treatment cost (including administration, adverse
events and monitoring costs) equal to that of docetaxel”
[14]. NICE does not recommend erlotinib “as second-
line treatment of locally advanced or metastatic NSCLC
in patients for whom docetaxel is unsuitable (that is,
where there is intolerance of or contraindications to do-
cetaxel) or for third-line treatment after docetaxel ther-
apy.” Other payers may follow NICE’s guidance for er-
lotinib.
3.4. Other Platinum-Based Combinations and
Maintenance Therapy
A large randomized Phase 3 study has been conducted
comparing cisplatin/g emcitabine to cisplatin/p emetrexed;
overall survival was 10.3 months in both groups [8]. Due
to the perceived efficacy plateau in the first-line setting
for advanced disease, the concept and practice of main-
tenance therapy has been promulgated as a means of en-
hancing survival [15]. The initiation of maintenance
therapy presupposes lack of progressive disease with
front-line therapy. Currently, pemetrexed has been dem-
onstrated to afford patients significantly longer progres-
sion free survival versus placebo in a maintenance role
after platinum-based first-line chemotherapy. Improve-
ment in median OS has yet to be shown [15].
4. Discussion
Multiple clinical trials have demonstrated that most of
the survival benefit of systemic agents accrues with dou-
blet chemotherapy, which can afford a median OS on the
order of 7 to 10 months with significant associated toxic-
ity [11,12]. The median survival with palliative measures
alone ranges from 2 to 5 months [16]. One third of pa-
tients with non-small cell lung cancer do not receive fur-
ther therapy past the first-line, for a number of reasons
[15].
Targeted agents have been largely disappointing in the
majority of patients, with the exception of perceived im-
proved survival seen in a small subset of never-smoking,
Asian females. However, in a recent Japanese phase III
trial NEJ002, and the Iressa Pan-Asia Study (IPASS), no
change in overall survival was noted comparing gefitinib
to platinum-doublet chemotherapy [17,18].
Despite stagnant survival rate improvements, costs for
oncology drugs continue to rise. NICE requires that
drugs cost less than £ 30 K (~$ 43 K currently) per qual-
ity adjusted life year in order to be reimbursed. Published
studies of targeted agents in NSCLC would seem to fall
far short of this goal. For example, a 12-week regimen of
bevacizumab, with a 1.2-month increase in survival can
be extrapolated to cost $800K to prolong a patient’s life
by one year [10]. Despite the best efforts of the biotech
and pharmaceutical industry, and despite rapidly in-
creasing prices of oncology drugs, survival rates have
largely reached a plateau.
Targeted agents in the first and subsequent lines have
added significantly to toxicity as well [19]. Due to the
tremendous genetic diversity of lung cancer, which confer s
tumor resistance, development of more “nibs,” “mabs,”
combinations thereof, and other narrow pathway blockers
will likely continue to yield little in improved OS while
driving treatment costs up significantly [13,20]. The ma-

Advanced Lung Cancer—Reaching a Survival Ceiling with Chemotherapy, the Nibs, and the Mabs159
jority of patients are primarily resistant (initially refrac-
tory) or acquire resistance (experience loss of response)
to EGFR TKIs and will likely be resistant to other similar
agents in development [11]. Moreover, most advanced
lung cancer patients are older and many are unfit for the
optimal chemotherapy regimens; therefore, other alterna-
tive, truly innovativ e ap pro ach es to adv anced lung cancer
are desperately needed for the disease, which continues
to increase in overall incidence worldwide [21].
In contrast to the immunosuppression which occurs as
a result of the use of chemotherapies and pathway block-
ers, [22-24] novel therapies are emerging which either
stimulate tumor specific immune responses due to apop-
totic focal tumor destruction[25 ] or attack tumor-induced
regulatory T-cell immunosuppression [26].
New approaches should be funded and explored, in-
cluding ablative and non-ablative focal therapy which
may offer very different outcomes for advanced lung
cancer patients with potential for fewer side effects.
5. Acknowledgements
The authors take full responsibility for the scope, direc-
tion and content of the manuscript. They would like to
thank Res earch Analysis Library for the assistance in the
literature review and in the preparation of the draft
manuscript. Editorial assistance was supported by Light
Science Oncology, Inc.
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