Advanced Lung Cancer—Reaching a Survival Ceiling with Chemotherapy, the Nibs, and the Mabs

doi:10.4236/jct.2011.22018

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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.

Email: [email protected]

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.

REFERENCES

[1] G. D’Addario, D. Rauch, R. Stupp, M. Pless, R. Stahel, N.

Mach, L. Jost, L. Widmer, C. Tapia, M. Bihl, M. Mayer,

K. Ribi, S. Lerch, L. Bubendorf and D. C. Betticher,

“Multicenter Phase II Trial of Gefitinib First-Line Ther-

apy Followed by Chemotherapy in Advanced Non-

Small-Cell Lung Cancer (NSCLC): SAKK Protocol

19/03,” Annals of Oncology, Vol. 19, No. 4, 2008, pp.

739-745. doi:10.1093/annonc/mdm564

[2] S. Huq, I. Maghfoor and M. Perry, “Lung Cancer,

Non-Small Cell,” Medscape.com, 2009.

http://emedicine. medscape.com/article/279960-print.)

[3] S. Reinberg, “More Dollars Don’T Boost Lung Cancer

Survival,” 2007.

http://health.usnews.com/usnews/health/healtday/071023/

more-dollars-dont-boost-lung-cancer-survival.htm.)

[4] D. Morgensztern, S. Waqar, J. Subramanian, F. Gao and

R. Govindan, “Improving Survival for Stage IV

Non-Small Cell Lung Cancer: A Surveillance, Epidemi-

ology, and End Results Survey from 1990 to 2005,”

Journal of Thoracic Oncology, Vol. 4, No. 12, 2009, pp.

1524-1529. doi:10.1097/JTO.0b013e3181ba3634

[5] K. L. Reckamp, B. K. Gardner, R. A. Figlin, D. Elashoff,

K. Krysan, M. Dohadwala, J. Mao, S. Sharma, L. Inge, A.

Rajasekaran and S. M. Dubinett, “Tumor Response to

Combination Celecoxib and Erlotinib Therapy in Non-

Small Cell Lung Cancer is Associated with a Low Base-

line Matrix Metalloproteinase-9 and a Decline in Se-

rum-Soluble E-cadherin,” Journal of Thoracic Oncology,

Vol. 3, No. 2, 2008, pp. 117-124.

doi:10.1097/JTO.0b013e3181622bef

[6] E. A. Kotteas, A. G. Charpidou and K. N. Syrigos, “Tar-

geted Therapy for Nonsmall Cell Lung Cancer: Focusing

on Angiogenesis, the Epidermal Growth Factor Receptor

and Multikinase Inhibitors,” Anticancer Drugs, Vol. 21,

No. 2, 2010, pp. 151-168.

doi:10.1097/CAD.0b013e328334da02

[7] C. G. Azzoli, S. Baker Jr., S. Temin, W. Pao, T. Aliff, J.

Brahmer, D. H. Johnson, J. L. Laskin, G. Masters, D.

Milton, L. Nordquist, D. G. Pfister, S. Piantadosi, J. H.

Schiller, R. Smith, T. J. Smith, J. R. Strawn, D. Trent and

G. Giaccone, “American Society of Clinical Oncology

Clinical Practice Guideline Update on Chemotherapy for

Stage IV Non-Small-Cell Lung Cancer,” Journal of

Clinical Oncology, Vol. 27, No. 36, 2009, pp. 6251-6266.

doi:10.1200/JCO.2009.23.5622

[8] G. V. Scagliotti, P. Parikh, J. von Pawel, B. Biesma, J.

Vansteenkiste, C. Manegold, P. Serwatowski, U. Gatze-

meier, R. Digumarti, M. Zukin, J. S. Lee, A. Mellem-

gaard, K. Park, S. Patil, J. Rolski, T. Goksel, F. de Mari-

nis, L. Simms, K. P. Sugarman and D. Gandara, “Phase

III Study Comparing Cisplatin Plus Gemcitabine with

Cisplatin Plus Pemetrexed in Chemotherapy-Naive Pa-

tients with Advanced-Stage Non-Small-Cell Lung Can-

cer,” Journal of Clinical Oncology, Vol. 26, No. 21, 2008,

pp. 3543-3551. doi:10.1200/JCO.2007.15.0375

[9] A. Sandler, “Bevacizumab in Non Small Cell Lung Can-

cer,” Clinical Cancer Research, Vol. 13, No. 15, 2007, pp.

s4613-4616. doi:10.1158/1078-0432.CCR-07-0647

[10] T. Fojo and C. Grady, “How Much is Life Worth:

Cetuximab, Non-Small Cell Lung Cancer, and the $440

Billion Question,” Journal of the National Cancer Insti-

tute, Vol. 101, No. 15, 2009, pp. 1044-1048.

doi:10.1093/jnci/djp177

[11] H. A. Burris, “Shortcomings of Current Therapies for

Non-Small-Cell Lung Cancer: Unmet Medical Needs,”

Oncogene, Vol. 28, No. 1 (Supplement), 2009, pp. S4-13.

doi:10.1038/onc.2009.196

[12] T. Fong, D. Morgensztern and R. Govindan, “EGFR In-

hibitors as First-Line Therapy in Advanced Non-Small

Cell Lung Cancer,” Journal of Thoracic Oncology, Vol. 3,

No. 3, 2008, pp. 303-310.

doi:10.1097/JTO.0b013e3181645477

[13] L. Horn and A. Sandler, “Epidermal Growth Factor Re-

ceptor Inhibitors and Antiangiogenic Agents for the

Treatment of Non-Small Cell Lung Cancer,” Clinical

Cancer Research, Vol. 15, No. 16, 2009, pp. 5040-5048.

doi:10.1158/1078-0432.CCR-09-0520

[14] National Institute for Health and Clinical Excellence,

“NICE Technology Appraisal Guidance 162, Erlotinib for

the Treatment of Non-Small-Cell Lung Cancer,” 2010.

http://www.nice.org.uk/TA162.

[15] T. S. Mok and S. S. Ramalingam, “Maintenance Therapy

in Nonsmall-Cell Lung Cancer: A New Treatment Para-

digm,” Cancer, Vol. 115, No. 22, 2009, pp. 5143-5154.

Advanced Lung Cancer—Reaching a Survival Ceiling with Chemotherapy, the Nibs, and the Mabs

160

doi:10.1002/cncr.24563

[16] M. S. Reif and M. P. Rivera, “Evidence-Based Outcomes

for Patients with Advanced Non-Small Cell Lung Can-

cer,” Seminars in Respiratory and Critical Care Medicine,

Vol. 21, No. 1, 2000, pp. 443-449.

doi:10.1055/s-2000-9405

[17] K. Suda, K. Tomizawa and T. Mitsudomi, “Biological

and Clinical Significance of KRAS Mutations in Lung

Cancer: An Oncogenic Driver that Contrasts with EGFR

Mutation,” Cancer and Metastasis Reviews, Vol. 29, No.

1, 2010, pp. 49-60. doi:10.1007/s10555-010-9209-4

[18] B. Boughton, “Two Clinical Trials on Gefitinib Show

Benefits for Asian Lung Cancer Patients,” Medscape.com,

2009.http://www.medscape.com/viewarticle/707751_prin

t.)

[19] S. M. Gadgeel, “Targeted Therapy in Lung Cancer: The

Good, the Bad, and the Ugly,” Clinical Lung Cancer, Vol.

10, No. 1, 2009, pp. 10-12. doi:10.3816/CLC.2009.n.002

[20] E. D. Pleasance, P. J. Stephens, S. O’Meara, D. J.

McBride, A. Meynert, D. Jones, M. L. Lin, D. Beare, K.

W. Lau, C. Greenman, I. Varela, S. Nik-Zainal, H. R.

Davies, G. R. Ordonez, L. J. Mudie, C. Latimer, S. Ed-

kins, L. Stebbings, L. Chen, M. Jia, C. Leroy, J. Marshall,

A. Menzies, A. Butler, J. W. Teague, J. Mangion, Y. A.

Sun, S. F. McLaughlin, H. E. Peckham, E. F. Tsung, G. L.

Costa, C. C. Lee, J. D. Minna, A. Gazdar, E. Birney, M.

D. Rhodes, K. J. McKernan, M. R. Stratton, P. A. Futreal

and P. J. Campbell, “A Small-Cell Lung Cancer Genome

with Complex Signatures of Tobacco Exposure,” Nature,

Vol. 463, No. 7228, 2010, pp. 184-190.

doi:10.1038/nature08629

[21] C. Gridelli, P. Maione, A. Rossi, G. Palazzolo, G. Colan-

tuoni and E. Rossi, “Management of Unfit Older Patients

with Advanced NSCLC,” Cancer Treatment Reviews,

Vol. 35, No. 6, 2009, pp. 517-521.

doi:10.1016/j.ctrv.2009.04.011

[22] L. A. Emens, J. P. Machiels, R. T. Reilly and E. M. Jaffe e,

“Chemotherapy: Friend or Foe to Cancer Vaccines?”

Current Opinion in Molecular Therapeutics, Vol. 3, No.

1, 2001, pp. 77-84.

[23] M. Krusch, J. Salih, M. Schlicke, T. Baessler, K. M.

Kampa, F. Mayer and H. R. Salih, “The Kinase Inhibitors

Sunitinib and Sorafenib Differentially Affect NK Cell

Antitumor Reactivity in Vitro,” The Journal of Immunol-

ogy, Vol. 183, No. 12, 2009, pp. 8286-8294.

doi:10.4049/jimmunol.0902404

[24] K. R. Molhoek, C. C. McSkimming, W. C. Olson, D. L.

Brautigan and C. L. Slingluff Jr., “Apoptosis of CD4(+)

CD25(high) T Cells in Response to Sirolimus Requires

Activation of T Cell Receptor and is Modulated by IL-2,”

Cancer Immunology Immunotherapy, Vol. 58, No. 6,

2009, pp. 867-876. doi:10.1007/s00262-008-0602-6

[25] E. Bromley, B. Owczarczak, L. Keltner, S. Wang and S.

O. Gollnick, “Characterization of an Anti-Tumor Immune

Response after Light-Activated Drug Therapy Using Ta-

laporfin Sodium in a Spontaneously Metastasizing

Mammary Tumor Model,” Journal of Clinical Oncology,

Vol. 27, No. 15s, 2009, p. 3052.

[26] J. D. Wolchok, B. Neyns, G. Linette, S. Negrier, J.

Lutzky, L. Thomas, W. Waterfield, D. Schadendorf, M.

Smylie, T. Jr. Guthrie, J. J. Grob, J. Chesney, K. Chin, K.

Chen, A. Hoos, S. J. O’Day and C. Lebbe, “Ipilimumab

Monotherapy in Patients with Pretreated Advanced

Melanoma: A Randomised, Double-Blind, Multicentre,

Phase 2, Dose-Ranging Study,” The Lancet Oncology,

Vol. 11, No. 2, 2010, pp. 155-164.

doi:10.1016/S1470-2045(09)70334-1