Current Topics in Lung Cancer

86 Pages·1991·15.526 MB·English

by  Paul A. Bunn Jr. (auth.), Paul A. Bunn Jr. M. D. (eds.)

Monographs
Series Editor: U.Veronesi
P. A. Bunn, Jr. (Ed.)
Current Topics
in Lung Cancer
With 1 Figure and 24 Tables
Springer-Verlag
Berlin Heidelberg New York
London Paris Tokyo
Hong Kong Barcelona
Budapest
PAUL A. BUNN, JR., M. D.
Professor of Medicine and Director
University of Colorado Cancer Center
4200 East Ninth Avenue
Denver, CO 80262, USA
The European School of Oncology gratefully acknowledges the support from Bristol-Myers
Squibb Pharmaceuticals for this Task Force
library of Congress Cataloglng-in-Publicatlon Data
Current topics In lung cancer 1 P. A Bunn, Jr. (ed ), p. cm -(Monographs 1 European School of Oncology)
ISBN-13: 978-3-642-76786-9 e-ISBN-13: 978-3-642-76784-5
DOl: 10.1007/978-3-642-76784-5
1 Lungs-Cancer. I. Bunn, Paul A II. Series· Mono
graphs (European School of Oncology) [DNLM· 1. Lung Neoplasms-therapy. WF 658 C976] RC280.L8C86 1991
616.99'42406-dc20 DNLM/DLC
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Foreword
The European School of Oncology came into existence to respond to a need for informa
tion, education and training in the field of the diagnosis and treatment of cancer. There are
two main reasons why such an initiative was considered necessary. Firstly, the teaching of
oncology requires a rigorously multidisciplinary approach which is difficult for the Univer
sities to put into practice since their system is mainly disciplinary orientated. Secondly, the
rate of technological development that impinges on the diagnosis and treatment of cancer
has been so rapid that it is not an easy task for medical faculties to adapt their curricula
flexibly.
With its residential courses for organ pathologies and the seminars on new techniques
(laser, monoclonal antibodies, imaging techniques etc.) or on the principal therapeutic
controversies (conservative or mutilating surgery, primary or adjuvant chemotherapy,
radiotherapy alone or integrated), it is the ambition of the European School of Oncology
to fill a cultural and scientific gap and, thereby, create a bridge between the University and
Industry and between these two and daily medical practice.
One of the more recent initiatives of ESO has been the institution of permanent study
groups, also called task forces, where a limited number of leading experts are invited to
meet once a year with the aim of defining the state of the art and possibly reaching a
consensus on future developments in specific fields of oncology.
The ESO Monograph series was designed with the specific purpose of disseminating the
results of these study group meetings, and providing concise and updated reviews of the
topic discussed.
It was decided to keep the layout relatively simple, in order to restrict the costs and make
the monographs available in the shortest possible time, thus overcoming a common
problem in medical literature: that of the material being outdated even before publication.
UMBERTO VERONESI
Chairman Scientific Committee
European School of Oncology
Contents
Introduction
P. A. BUNN, JR. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1
The Biology of Lung Cancer
D. N. CARNEY • • • • . • • • • . ......... 3
Staging and Surgical Treatment for Non-Small Cell Lung Cancer
R. J. GINSBERG • . . • • • • • . • • • . . • • • • • • • . • • • . . • • • . . . . • . • 15
Radiotherapy for Non-Small Cell Lung Cancer
A. T. TURRISI, III . . . . . . . . . . . . . . . . . .. ...... 25
The Role.of Systemic Chemotherapy in Non-Small Cell Lung Cancer
P.A. BUNN, JR ••.•.••••...•..•••....•..•.••••••.•••• 33
Sta.£Jing and Treatment for Small Cell Lung Cancer
RE. POSTMUS .••. : .•.•..•••.••.•.•••.•••.•.••.•.•. 47
Surgery for Small Cell Lung Cancer
R. J. GINSBERG • • • . . • • . . . . • .......... 61
Combined Modality Therapy for Limited Small Cell Lung Cancer
A. T. TURRISI, III ..................................... 63
Cranial Irradiation
A. T. TURRISI, III ... . .................. 67
Future Directions in the Therapy of Lung Cancer
J. F. BISHOP •...••••..•..•••..••.•.•....•...••...• 71
Introduction
Paul A. Bunn, Jr.
Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado Health Sciences Center,
4200 East 9th Avenue, Denver, Colorado 80262, USA
Lung cancer is the most common and lethal malignancy in many countries in the world.
For example, in the United States lung cancer accounts for 16% of all new cancers and
28% of cancer deaths. The majority of patients present with metastatic disease, and the
overall cure rate is extremely low (about 13%). The incidence of lung cancer parallels
that of cigarette consumption, as about 85% of cases are due to tobacco use. Over the
past decade great strides were made in our understanding of the biology of lung cancer
and are summarised in this monograph by Dr. Desmond Carney. We have learned that
there are many genetic defects in lung cancer, including the loss of suppressor genes
and the overexpression of oncogenes. Growth factors and cell surface antigens are
described which are leading to new strategies for prevention and treatment.
Patients presenting with signs or symptoms suggestive of lung cancer must first have
biopsy confirmation and staging performed. Dr. Robert Ginsberg describes the current
strategies for lung cancer staging. Patients with non-small cell lung cancer (NCSLC) in
stage I-IliA undergo surgical resection. Previous attempts to improve surgical results with
adjuvant radiation or chemotherapy are discussed by Drs. Ginsberg, Turrisi and Bunn.
For NSCLC patients with advanced regional disease (stages lilA and IIIB), chest
radiotherapy has been the most commonly used therapy. Dr. Turrisi describes the
current state-of-the-art for chest irradiation. Recent studies suggest that combined
radiotherapy and chemotherapy should replace radiotherapy as the standard treatment
approach for these patients. In addition, neoadjuvant approaches with chemotherapy (±
chest radiotherapy) prior to surgery showed promising results. These trials are discussed
by Drs. Ginsberg, Turrisi and Bunn. For patients with metastatic NSCLC, cisplatin- and
carboplatin-based chemotherapy provided prolonged survival in several randomised
trials described by Dr. Bunn. Current investigations are designed to improve this small
but significant advance.
In small cell lung cancer (SCLC), chemotherapy has become the cornerstone of therapy.
Dr. Pieter Postmus describes the current chemotherapeutic approaches for SCLC. In
addition, Drs. Ginsberg and Turrisi describe the roles of surgery and radiotherapy in
SCLC. Finally, Dr. James Bishop describes recent and future approaches for improving
the therapeutic results in SCLC, including the use of colony stimulating factors.
The Biology of Lung Cancer
Desmond N. Carney
Department of Medical Oncology, Mater Misericordiae Hospital, Eccles Street, Dublin 7, Ireland
The incidence of lung cancer continues to biological properties of lung cancer cells. This
rise worldwide, such that in 1991 there will be has come about from studies of established
approximately 162,000 new cases in the and well characterised cell lines of both
United States and almost 142,000 deaths. SCLC and NSCLC. Studies of these cell
Among women the mortality from lung cancer lines have clearly demonstrated the hetero
exceeds that from breast carcinoma. In geneity that exists within any given tumour
Europe, among the European Community subtype, e.g., SCLC. It is likely, therefore, that
(EC) countries, cancer of the lung remains the this heterogeneity demonstrated in cell lines
leading cancer site in men with approximately may account for the heterogeneity observed
135,000 cases per year and 117,125 deaths. among patients in response to cytotoxic ther
An additional 23,000 cases are observed in apy. The biological properties within tumour
women. Lung cancer in the EC accounts for cells which may be of prognostic importance
29% of all cancer deaths-, and 21 % of all include the expression of drug- or irradiation
cancers among men. The trend in mortality of resistant genes, oncogenes coding for a more
lung cancer in the EC states indicates a 10- malignant behaviour, or biochemical or neu
15% increase among men every 5 years, with roendocrine properties. In this chapter, re
the exception of the United Kingdom. Of the 4 cently recognised biological properties of
major subtypes of lung cancer, namely, lung cancer cells will be discussed particu
squamous cell carcinoma, adenocarcinoma larly in relation to their clinical relevance.
and large cell carcinoma (collectively referred
to as non-small cell lung cancer - NSCLC)
and small cell carcinoma (SCLC), the only Genetic Factors In Lung Cancer [1-6]
hope for a meaningful survival for patients
with NSCLC is the resectability of the tumour.
In contrast, for SCLC patients the sensitivity of The majority of cases of lung cancer will de
this tumour type to cytotoxic therapy including velop in heavy cigarette smokers although it
radiation therapy and chemotherapy offers has long been recognised that only a minority
the only chance for long-term meaningful of such smokers will develop lung cancer.
survival. Despite major advances in under Other factors which increase the susceptibility
standing the disease stage and prognostic to lung cancer development in addition to ci
factors of patients with lung cancer, there has garette smoking include occupations such as
been no significant improvement in the over mining, ship building and petroleum refining.
all survival of patients with this disease in the In addition, it has recently been suggested
past 2 decades. For patients with inoperable that genetic factors may play an important
NSCLC, which accounts for the majority of role in the pathogenesis and development of
cases with this subtype of lung cancer, the lung cancer [1]. Several studies have
median survival ranges from 6 to 9 months. demonstrated an increased risk of lung
For patients with SCLC who are treated with cancer mortality in siblings of lung cancer
systemic chemotherapy, the median survival probands while others have reported on fa
is approximately 11 months. milial aggregations of lung cancer and other
Since the early 1980s there has been a dra cancers. In a recent study by Sellers et aI., of
matic advance in our understanding of the 337 families, each ascertained through a lung
4 D.N. Carney
cancer proband, the results indicated compat floating aggregates of tightly-to-Ioosely
ibility of the data with Mendelian condominant packed cells. Once established as permanent
inheritance of a rare major autosomal gene cultures, which may take up to 6 months,
that produces an earlier age of onset of the these cells can be maintained indefinitely in
cancer [5]. These authors demonstrated that either serum-free or serum-supplemented
in patients at the age of 50, 27% of lung medium, will form colonies in soft agarose,
cancers are attributable to the Mendelian tumours in athymic nude mice and can be
gene alone, 42% to the joint effect of the gene successfully cryopreserved. In general, these
and smoking, 27% to smoking alone and 4% cell lines retain both the morphology, cytology
to neither the alleged gene nor smoking. and histological appearances very similar to
However, in patients at the age of 70, only 9% the original biopsy specimens from which the
of their lung cancers could be attributed to the cell lines are cultured. Stability in culture is
alleged gene. This alleged Mendelian gene usually noted for these cell lines over pro
has yet to be determined. longed periods.
Other studies have shown that smokers who In contrast, NSCLC cell lines usually
are extensive metabolisers of the anti-hyper demonstrate substrate adherence unlike
tensive drug debrisoquine are at a signifi SCLC cells. Once established as permanent
cantly higher risk of developing lung cancer cell cultures, these cells retain the morphol
compared with poor metabolisers [2,4]. This ogy of the original tumour type, will form tu
increased risk was noted among individuals, mours in athymic nude mice and colonies in
both black and white, and was noted not only soft agarose. Cell lines of SCLC and NSCLC
between patients with lung cancer and control established from different sites including pri
subjects, but also among those with lung mary and metastatic sites demonstrate no
cancer and cancers other than lung cancer. significant heterogeneity in a range of biolog
Debrisoquine is metabolis~ed by a P-450 en ical and biochemical markers.
zyme, P-45011 06, which has been recently Studies of large panels of cell lines of SCLC
cloned, and the gene coding for this enzyme, have demonstrated that these can be subdi
CYP2D6, is located on chromosome 22 [4]. vided into 2 major categories, namely, classic
The characterisation ·of these genetic -factors and variant SCLC [7,9,10]. Classic cell lines
which increase the susceptibility to develop which account for 70% of all cells express el
ment of lung cancer offers the possibility of evated levels of range of neuroendocrine
applying molecular genetic techniques as markers including L-dopa decarboxylase
screening tool for the identification of patients (DOC), bombesin/gastrin-releasing peptide
at risk of development of lung. cancer. (GRP), neuron-specific enolase (NSE) and
creatine kinase-SS (CK-SB). In addition,
classic cell lines have a relatively long dou
Cell Lines of Lung Cancer bling time and a low cloning efficiency in vitro,
are radiosensitive, and have the typical mor
phological characteristics of the intermediate
The use of chemically defined, serum-free, cell type of SCLC [9,10,12]. Variant cell lines
hormone-supplemented medium has greatly have selective loss of some of these neu
improved our ability to establish permanent roendocrine markers including low or absent
cell lines of both SCLC and NSCLC lung levels of DOC and bombesin-GRP, and con
cancer [7-11]. These cell lines have been tinually express elevated levels of NSE and
established from a range of sites including CK-SS. Variant cell lines have a more ag
primary tumours, and metastatic sites such as gressive growth behaviour demonstrating a
bone marrow, lymph node aspirates and high cloning efficiency in soft agarose, a short
biopsies, malignant pleural effusions and doubling time in vitro and a short latent period
other surgically resected masses. Using a to tumour formation when inoculated into
chemically defined, serum-free medium, cell athymic nude mice. Variant cell lines are ra
lines can now be readily established from al dioresistant and morphologically more
most 75% of specimens of SCLC and be closely resemble large-cell undifferentiated
tween 20% and 30% of NSCLC specimens carcinoma. In addition, as will be noted, these
[8,11]. In general, SCLC cells usually grow as variant cell lines demonstrate significant DNA
The Biology of Lung Cancer 5
amplification of the c-myc gene and show in be of importance in predicting the establish
creased expression of the gene. ment of a cell line. There was no significant
Recently it has been demonstrated that up to association of in vitro tumour growth with
20% of NSCLC cell lines and primary biopsy survival of patients from whom a tumour
specimens, in particular those of adenocarci containing specimen could be obtained.
nomas, will express the entire range of neu However, the survival of patients from whom
roendocrine markers as noted above [13]. As a tumour specimen was obtained for culture
will be noted, neuroendocrine NSCLC tu (n = 51 patients) was significantly worse than
mours (NE-NSCLC) appear to be more for the 17 patients from whom no specimen
chemosensitive both in vitro and in vivo and was obtained. Among all 67 patients who
this may be of consideration in therapy selec were treated with a similar combination
tion of patients with NSCLC. chemotherapeutic schedule, no differences
were observed among the 3 groups of pa
tients studied, i.e., patients from whom no
The Prognostic Value of Cell Line specimen reached the laboratory, patients
Establishment [14-16] from whom a tumour-containing specimen
reached the laboratory but no cell line was
established, and those patients in whom a
Several recent studies have addressed the cell line was readily established in vitro. Thus
clinical relevance of the ability to establish a this study demonstrates that the response
permanent cell line in culture from fresh pa rates and survival probabilities of patients
tient biopsy specimens. In an earlier study of with extensive stage SCLC from whom cell
the clinical behaviour of SCLC patients from lines were permanently established was not
whom cell lines were established, it was statistically different from patients in whom in
demonstrated that the median survival of 19 vitro growth of tumour-containing specimens
newly diagnosed, previously untreated pa could not be accomplished. It must be noted,
tients from whom cell lines were established however, that most cell lines were estab
at diagnosis, was 14 weeks, in contrast to a lished from metastatic sites and it would be
median survival time of 48 weeks of 123 ex important to attempt to carry out such a study
tensive-stage patients from whom cell lines of patients with limited stage disease in whom
were not established at that time [16]. A more cell lines could be established from the pri
recent prospective study by Stevenson et a!. mary biopsy specimens.
has re-evaluated the relationship between In contrast to this study, the impact of tumour
the in vitro tumour cell growth and prognosis cell establishment in vitro from patients with
in patients with extensive stage SCLC [14]. Of newly diagnosed NSCLC has clearly
the 68 patients evaluated in this study, tu demonstrated that this is an independent
mour-containing specimens for culture were prognostic factor for survival in NSCLC pa
received from 51 patients. Each patient had tients [15]. In a study of 124 consecutive pa
an average of 2.8 pretreatment biopsies or tients with NSCLC from whom viable tumour
aspirates of which an average of 1.2 were specimens could be obtained, cell lines were
tumour-containing specimens. Bone marrow established from 25. Although lung tissue
aspirate specimens (134 of 187 specimens) was the most frequent source of the tumour
accounted for the majority of all specimens. In containing specimen, only 5 of 63 specimens
this study, a cell line was established in 23 of (8%) obtained from lung tissue were success
the 51 patients from whom a tumour-contain fully established as cell lines, while tumour
ing specimen was obtained (34% of all pa cell lines were established from lymph nodes
tients). When one considers all 187 speci in 8 of 19 specimens (42%). The median sur
mens obtained in the laboratory, the overall vival was 7 months among patients from
success rate of establishment of cell lines whom cell lines were established compared
was 13%. with 18 months in patients from whom cell
While a number of clinical prognostic factors lines were not established (P < 0.001). This
were analysed to determine their impact on prognostiC importance was clearly demon
the ability to establish cell lines, only a signifi strated among patients who were candidates
cant number of metastatic sites were noted to for curative resection. In the 61 patients with
6 D.N. Carney
potentially curable disease, 8 patients (13%) quential determination of serum NSE may be
had cell lines successfully established and a used as a sole predictor of clinical response
median survival of only 8 months compared to therapy and of relapse [21].
with 32 months for those from whom no cell More recent studies have also evaluated the
lines were established. No major differences relevance of markers such as serum chromo
were observed among the 62 patients who gran in-A and CEA in patients with SCLC [19].
received palliative treatment from whom cell However, their widespread application in the
lines were or were not established. Thus this management of SCLC patients remains to be
study clearly demonstrates that the estab determined.
lishment of cell lines from patients with As noted, SCLC cell lines can be readily
NSCLC is an independent prognostic vari established into those which express
able, in particular among patients undergoing neuroendocrine properties (classic cell lines)
a curative resection. This factor should now and those which have selective loss of these
be taken into consideration in planning ther markers (variant cell lines). In one retrospec
apeutic strategies for patients with NSCLC, in tive study the importance of these neuroen
particular in the consideration of adjuvant docrine markers was suggested by the ob
chemotherapy for patients who undergo cu servation that the patients from whom variant
rative surgical resection and from whom a cell cell lines were established had a survival pe
line is permanently established. riod of 33 weeks compared with those pa
tients from whom cell lines were established
but did not have the variant phenotype (53
Neuroendocrine NSCLC and SCLC weeks) [16]. More recent studies of NSCLC
Tumours [17-27] tumours have also demonstrated that up to
20% of these specimens express a range of
neuroendocrine properties. The expression of
It has long been established that a range of similar endocrine markers by both SCLC and
paraneoplastic syndromes have been NSCLC is highly suggestive that these tu
demonstrated in patients with lung cancer mour types arise from a common stem cell. In
and in particular SCLC [17]. Studies'of per addition, it has been demonstrated both in
manently established cell lines have also vitro and in vivo that classic small cell tu
demonstrated that these tumours secrete a mours may evolve into a phenotype with se
range of peptide hormones. Many studies lective loss of neuroendocrine properties and
have evaluated the importance of these a morphological appearance more like that of
markers as a predictor for survival and prog NSCLC. Finally, Baylin and his colleagues
nosis of patients with SCLC [18-20]. have demonstrated that complementation
However, with few exceptions measurements events between myc genes and the Harvey
of these markers provide very little new data ras oncogene can actually promote direct
above that obtained by physical examination transition of SCLC to NSCLC phenotype, in
or routine staging procedures alone. Studies cluding the expression of NSCLC-associated
of serum NSE in SCLC patients have growth factors [23,24]. All of these data sug
demonstrated that it is elevated in approxi gest that a common stem cell exists for all cell
mately 70% of all patients with levels signifi types of lung cancer and will clearly explain
cantly higher among those patients with ex the presence of distinct neuroendocrine fea
tensive-stage disease. Like other tumour tures appearing in both SCLC and NSCLC
markers, serum NSE levels decrease with tumours. Several investigators have reported
clinical response to cytotoxic therapy and in on the prognostic significance of neuroen
crease again at time of tumour relapse and/or docrine differentiation in NSCLC [25,27].
progression. Data by Johnson et al. [20] and These studies suggest that neuroendocrine
others suggest that sequential measurements NSCLC tumours represent a distinct biologi
of serum NSE may be of value in the early cal subset of NSCLC including the following:
detection of relapse before its clinical detec 1. N E-NSCLC lack deletions of chromo
tion. Others have suggested that in the non some 3p, a distinctive feature of classic
protocol setting where detailed radiodiagnos SCLC.
tic investigations may be of limited value, se-