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■i
SMALL CELL CANCER OF THE LUNG:
AN INITIAL EVALUATION OF THE YALE TREATMENT PROTOCOL
A Thesis Submitted to the Yale University
School of Medicine in Partial Fulfillment
of the Requirements for the Degree of
Doctor of Medicine
by
David Jonathan Birnkrant
h\(^c\ 1 1 L
ABSTRACT
SMALL CELL CANCER OF THE LUNG:
AN INITIAL EVALUATION OF THE YALE TREATMENT PROTOCOL
David Jonathan Birnkrant
1985
A review of small cell cancer of the lung (SCCL) is presented,
followed by initial results from the Yale University treatment
protocol for SCCL.
The review includes selected topics on the epidemiology,
etiology, cytogenetics, cytomorphology , cells of origin, cell
products, clinical diagnosis, staging, prognosis, and treatment of
SCCL. The tumor emerges as one of diverse clinical behavior and
cellular character; it remains poorly understood. Despite
intermediate or slow doubling time, dissemination of the
tumor — microscopic or gross — is the rule at diagnosis. Modest success
has been achieved in treatment, allowing a small group of patients to
go on to long-term survival (4 or 5 years), but most patients relapse
after initial response to therapy and second-line therapy is rarely
effective. Special attention is paid to treatment design, including
the role of prophylactic cranial irradiation (PCI), adjuvant radiation
therapy, and the concept of local tumor control.
Results from the Yale University treatment protocol are
presented. T-hirty-nine evaluable patients were prospectively
randomized to therapy with cyclophosphamide, Adriamycin, and
vincristine (CAV) every 21 days or CAV alternating with Etoposide
(VP-16-213). All limited disease (LD) patients underwent thoracic
irradiation; complete responders received PCI. Eighty percent of LD
patients achieved complete response as did 12% of extensive disease
(ED) patients. Projected median survival ranged from 198 days for ED
non-responders to 560 days for LD complete responders. It is too
early to report on long-term survival. Addition of Etoposide (E)
afforded no significant survival advantage over the CAV regimen.
Etoposide added no significant additional toxicity; in fact, the
percentage of patients experiencing infections requiring
hospitalization was lower in the CAV/E group (6% vs. 33%). This may
be the result of a smaller proportion of patients on CAV/E
experiencing leukopenia (44% vs. 76%).
ACKNOWLEDGEMENTS
Dr. Carol Portlock was the perfect thesis advisor (_g^<.0001). Her
scholarship was complemented by a commitment to scientific
open-mindedness — which is to say: She came to the rescue when I was
up to my elbows in it, but never imposed her point of view. Thus I
had the happy experience of learning through discovery. Her gracious
good humor was infectious and her tolerance of my eccentric work
habits wonderful. Thanks to her, this thesis was transformed from a
requirement for graduation into a rewarding scientific project.
Dr. Diana Fischer was my Virgil through the inferno of
statistics. Because she never discussed this study except in the
broader context of statistical concepts, I’ve gained a sense of the
fundamentals of experimental design. Dr. Fischer shared her time,
knowledge, and enthusiasm with a generosity for which I am very
grateful .
Mrs. Terry O'Connor did the most extraordinary things with a
computer and she did them better and faster than I had thought
possible. No deadline was so pressing as to disturb her reassuring
calm. I am lucky to have enjoyed the benefit of her expertise and
good-naturedness.
Mrs. Rosemary Slattery was always ready with all manner of
encouraging words and warm smiles. When things got rough, she would
regale me with her classic answer to my desperate "Rosemary, will Dr.
Portlock be around next week?": "Well, I've worked with her for eight
years, and she hasn't taken a vacation yet...."
r
A large "thank you" to the physicians who made me welcome in
their offices, made it possible for me to review patients charts, and
made time to answer my questions: Drs. Fischer and Wiggans; Dr. M.E.
Katz; Drs. Levy, Farber, Bobrow, and Lundberg; Dr. J.E. Brown; Dr.
G.T. Kenneally; and Dr. I.S. Lowenthal.
Dr. J. Bernard Gee read this thesis for the Department of
Internal Medicine. His criticisms and comments were uniformly
helpful. At his suggestion, I was in contact with...
Dr. Raymond Yesner, who very kindly took the time to meet with me
on an "emergency" basis. Dr. Yesner ’s summary of the conclusions
reached at the September, 1984 meeting of the pathology panel of the
International Association for the Study of Lung Cancer made it
possible for me to include mention of an exciting new approach to the
histological classification of small cell lung cancer in this paper.
Thank you, Mrs. Fran DeGrenier, for typing strange words at
strange hours and meeting every deadline.
Finally, if a dedication were appropriate for so modest a piece
of work, it would be to my parents, with love.
TABLE OF CONTENTS
PART I: THE BASICS 1
Introduction 1
Epidemiology and Etiology 2
Cytogenetics, Cytomorphology , Cells of Origin and
Cell Products 5
Clinical Diagnosis 16
Staging and Prognosis 21
PART II: TREATMENT 30
Overview 30
Treatment of Limited-Stage Disease and Treatment-
Related Toxicities 36
Extensive-Stage Disease and Experimental Therapies 45
Closing Comments 49
PART III: THE STUDY 53
Methods 53
Patients and Results 57
Discussion 67
REFERENCES 71
TABLES
Table 1: Age Standardized Percentage Distribution of
SCCL by Cigarette Smoking Habit 85
Table 2: Distribution of Excess (Presumably Radiation-
Induced) Bronchogenic Cancers by Radiation
Exposure Group 86
Table 3: Symptoms of SCCL 87
Table 4: Percent Distribution of Metastases at
Presentation and at Autopsy in Two
Studies 88
Table 5: Recommendations for Restaging 89
Table 6: Prognostic Factors in SCCL
90
I
Table
7:
Treatment Results in SCCL: Selected Studies
91
Table
8;
Long-Term Survival (>_5 years) in SCCL
92
Table
9:
Treatment Protocol for Limited Disease
93
Table
10:
Treatment Protocol for Extensive Disease
94
Table
11:
Patient Characteristics by Treatment Arm
95
Table
12:
Metastatic Sites at Diagnosis in Extensive
Disease (ED) Patients by Treatment Arm
96
Table
13:
Sites of Relapse
97
Table
14:
Treatment Results: Response and Time to
Relapse
98
Table
15:
Survival
99
FIGURES
Figure
1:
Time to Relapse for Responders (CR + PR)
Disease Extent
by
100
Figure
2:
Time to Relapse for Extensive Disease
Patients by Response Group
101
Figure
3:
Time to Relapse for Limited Disease
Patients by Treatment Group
102
Figure
4:
Time to Relapse for Extensive Disease
Patients by Treatment Group
103
Figure
5:
Overall Survival
104
Figure
6:
Survival for Responders (CR + PR) by
Disease Extent
105
Figure
7:
Survival for Extensive Disease Patients
Response Group
by
106
Figure
8:
Survival for Limited Disease Patients by
Treatment Group
107
Figure
9:
Survival for Extensive Disease Patients
Treatment Group
by
108
List of Abbreviations
A
ACTH
ADH
APUD
BN
C
CBC
CEA
CK-BB
CNS
CR
CT
DDC
DNA
E
ECOG
ED
EKG
HCG
INH
LD
LDH
LI
M
MoAb
NCI
NR
NSE
P
PCI
PPD
PR
PS
PTH
RT
SIADH
SVC
TNM
V
VA
WHO
Adriamycin (doxorubicin)
adrenocorticotropic hormone
antidiuretic hormone
Amine Precursor Uptake and Decarboxylation
bombesin
cyclophosphamide
complete blood count
carcinoembryonic antigen
BB isoenzyme of creatine kinase
central nervous system
complete response
computerized tomography
dopa decarboxylase
deoxyribonucleic acid
Etoposide (VP-16-213)
Eastern Cooperative Oncology Group
extensive-stage disease
electrocardiogram
human chorionic gonadotropin
isoniazid
limited-stage disease
lactic dehydrogenase
labeling index
methotrexate
monoclonal antibody
National Cancer Institute
non-response
neuron specific enolase
cis-platin
prophylactic cranial irradiation
purified protein derivative
partial response
performance status
parathyroid hormone
radiation therapy
syndrome of inappropriate secretion of antidiuretic hormone
superior vena cava
tumor -nodes-me t as tases
vincristine
Veterans Administration
World Health Organization
1
SMALL CELL CANCER OF THE LUNG:
AN INITIAL EVALUATION OF THE YALE TREATMENT PROTOCOL
PART ONE: THE BASICS
Introduction
Small cell cancer of the lung (SCCL) is a disease whose
significant incidence and poor prognosis make it of major concern.
This is especially true in a society like ours, with its increasing
emphasis on preventive medicine and the containment of health care
costs. The etiologic factors in the disease — tobacco smoking,
ionizing radiation, asbestos and chemicals — make SCCL somewhat
preventable. Treatment for SCCL is often initially effective, but
relapse is the rule and the disease then proves resistant to second-
line therapies. In light of the relatively poor results achieved with
today’s state-of-the-art therapy, it would be wise to direct concerted
efforts toward prevention of SCCL.^ Unfortunately, the medical
profession has made no successful attempt to wrest responsibility for
such a goal from businessmen and politicians. As long as tobacco
remains an important, heavily subsidized cash crop and images from
Madison Avenue dictate our behavior, the individual medical
practitioner-haranguing his patients about smoking — will remain at
best a nagger, at worst a bore.
This paper will emphasize the diversity in data on SCCL. Even
the most basic aspects of the disease are poorly understood and the
lack of an effective treatment strategy reflects that ignorance. The
first part of the paper takes the form of a review; the second part
presents initial data from the Yale University treatment protocol for
SCCL.
2
Epidemiology and Etiology
Lung cancer death rates have been increasing at a spectacular
2
rate when compared to that of other cancers. After World War II,
lung cancer death rates for men began rising at a faster rate than
straightline projections would have predicted. The rate curve for
1 2
women has followed suit for the last twenty years. ’ Projections for
1984 show that lung cancer will be the most common cause of cancer
deaths for men and the second most common cause of cancer deaths for
2
women .
3
Weiss has reviewed numerous studies on the incidence of SCCL.
He reports W.E. Morton's unpublished data on SCCL rates in Portland,
Oregon for the period 1968-1972. The disease was more frequent in men
than women. Mean annual rates per 100,000 population were 13 for
4
males, 4 for females. In contrast, Annegers et al. reported a rate
of 6/100,000 among males in rural Olmstead County, Minnesota for the
period 1965-1974. This lower rate is consistent with the notion that
SCCL is less common in rural areas. ^
The median age at diagnosis in most series is about 60 years. ^
The Philadelphia Pulmonary Research Project studied the natural
history of lung cancer in men 45 years of age and older, each of whom
was followed for ten years. Unpublished data from the study, quoted
3
3
by Weiss, show the highest incidence of disease among men 55-64 years
of age. The study reported the highest rate of lung cancers in
general, irrespective of subtype, in the 60- to 64-year-old age
4
group. In contrast, Annegers et al. found their highest incidence
rate among men 75 years or older for the period 1965-1974.
SCCL is generally quoted as accounting for 20-25% of all lung
cancers.^ When the data are examined, however, the frequency of small
cell as a percentage of all typed cancers varies widely. In Weiss's
3
review, SCCL accounts for 13.7% - 39.6% of all typed lung cancers
among men and 9.4% - 31.3% of lung cancers among women, depending on
the study consulted. Perhaps these ranges represent differences in
histological interpretation, or differences in incidence related to
the population observed (the highest relative incidence figures come
8 9
from a study done in Iceland ). Kyriakos and Webber, reporting on
lung cancer in young adults, have found a rate of 13% SCCL among
patients of all ages with lung cancer at Barnes Hospital, St. Louis.
Their review of the literature revealed that SCCL accounted for 2-38%
of lung cancers in several large series. Interestingly, these authors
found a slightly higher relative incidence of SCCL (24%) among younger
patients (45 years of age or less). Kennedy^^ found a remarkably high
proportion of small cell tumors (65%) in his series of 40 lung cancers
occurring in patients under the age of 40 in England. In contrast,
Putnam^ ^ at Walter Reed Army Medical Center found 17% small cell
tumors among 24 patients with lung cancer under the age of 40.
4
The male: female ratio of SCCL is generally thought to be higher
than for other types of lung cancer, with a ratio of 3 males:! female
3
reported by Morton.
Etiological factors in SCCL include exposure to tobacco smoking,
ionizing radiation, asbestos, chemicals, metals, and possibly air
pollution. Pathogenesis of the disease is not well understood; the
tumors are usually central in location and are presumed to arise, like
squamous cell carcinoma, through chronic irritation, mucosal
12
denudement, and absorption of carcinogens. The cells of origin of
the tumor are of great interest and will be discussed later on.
There is probably a dose-response relationship between cigarette
consumption and the development of SCCL. The Philadelphia Pulmonary
13
Neoplasm Research Project's data supported this notion. Auerbach et
14
al. found that small cell as a percentage of all lung cancers rose
from 14.5% for ex-smokers progressively to 31.1% for those patients
smoking more than two packs a day. (See Table 1.) This rise was not
seen in other histological subtypes. Of note is the possibility that
cessation of smoking is associated with longer survival in SCCL, even
when patients stop at the time of diagnosis.
The link between exposure to ionizing radiation and SCCL is a
1 6
strong one. Archer et al. compared rates of lung cancer and its
subtypes among uranium miners to the rates expected for a matched
group without radiation exposure. The authors expected to find 14.06
respiratory cancers in their study group. Instead, 107 cases were
recorded among the miners, 66 of which were SCCL (62%). In the
5
matched control group, SCCL should have accounted for 14.05% of the
lung cancers. There was, in addition, a dose-response relationship
found for SCCL with increasing radiation exposure. These data appear
in Table 2. Unlike smoking, then, radiation exposure may produce a
predominance of small cell cancers in the lung. Agreement on this
point is not universal, however.^
Asbestos and chemicals have been implicated in the etiology of
lung cancers in general. Although data on subtypes is limited, SCCL
appears to be associated with exposure to these agents. The role of
smoking in the carcinogenicity of asbestos is still not clear; is
asbestos a carcinogen or a synergistic agent which promotes cancer in
smokers? The chemicals for which there is evidence of carcinogenicity
in humans include: "polycyclic aromatic hydrocarbons, certain metals
3
or their compounds, and certain simple organic chemicals." The list
of possible carcinogens grows longer every day, but the strict
scientific criteria needed to show causality make such proof a task
that is pain-staking, if not impossible.
Cytogenetics, Cytomorphology , Cells of Origin,
and Cell Products
The basis of understanding the small cell tumor lies in an
understanding of its component cells. One approach to these cells is
through cytogenetic studies. Do the chromosomes of the tumor have
identifiable characteristics?
6
Wurster-Hill and Maurer studied the chromosomes of patients'
SCCL tumors using direct bone marrow preparations and trypsin-Giemsa
banding. Chromosome number and structural aberrations (markers) were
frequent and highly variable. Chromosome number (ploidy, DNA index)
in untreated patients ranged from hypodiploid to polyploid with the
latter most common (the chromosome count was typically in the
80's). A structural abnormality of chromosome #1 was found in 14 of
the 18 patients with karyotypic abnormalities (total patients = 26).
But very few markers were common to two or more patients and the
consistency of given markers among the cells from one patient was
usually poor. The presence of cells with different abnormalities of
chromosome number in the same patient (e.g., diploid and polyploid)
18
was discovered. Vindelov et al. found that ploidy in their SCCL
tumor cells could be grouped into near-diploid, near-triploid , and
near-tetraploid values. Each of five patients was found to have two
clones with different chromosome number in a single metastasis (17% of
the total patients). The authors view this as evidence that SCCL, at
least for some patients, is not monoclonal. That is: new cell lines
evolve from the original tumor. These cell lines may have
characteristics (clinical, biochemical) that are entirely different
from those of the original tumor. The heterogeneity of the SCCL
tumor — a concept emphasized in this paper — may lie in the evolution of
more than one cell line from the original tumor.
19
Whang-Peng et al. found two distinct stem lines in 2 of their
12 cell lines cultured from human small cell lung cancer tissue.
7
These authors describe a consistent, acquired chromosomal
abnormality — a deletion in the short arm of chromosome #3 — present
both in SCCL cell lines and in fresh clinical specimens cultured for 2
days in a serum-free medium. Chromosome studies of other types of
neoplasms have not shown a specific abnormality of chromosome #3. The
data of Wurster-Hill and Maurer (abnormality of chromosome #1) do not
fit easily into the scheme of Whang-Peng et al.; an explanation of the
discrepancies awaits elucidation. Whang-Peng et al . appear to have
found a specific, acquired somatic cell defect (deletion 3p, 14-23)
associated with continued replication of SCCL tumor cells. If this
holds true, the diagnosis and treatment of SCCL will be
aided — especially if the function of the genes present in the region
of chromosome #3 where the deletion was found can be understood.
Another approach to the cells of the tumor is to ask: where does
SCCL arise from? That is, which cells in the lung first acquire the
chromosomal abnormalities, due to exposure to carcinogens, which lead
to the growth of a tumor?
20
Hattori et al. studied 24 cases of oat-cell (small cell)
carcinoma of the lung and four cases of bronchial carcinoid tumor both
under the electron microscope and biochemically. They found that SCCL
tumor cells were characterized by the presence of neurosecretory-type
granules (NSGs) of 800-2000 Angstroms, almost identical to but
somewhat smaller than the NSGs found in 4 samples of bronchial
carcinoid tumor . NSGs were not found in 139 samples of other types of
lung tumors studied. Serum serotonin level was elevated in 13 of 20
8
small cell cases and the degree of elevation seemed to correlate with
the number of NSGs present in the tumor cells. Serotonin level in
tumor tissue was elevated in 7 of 12 cases of SCCL but in only 1 of 4
cases of bronchial carcinoid tumor. In 5 of 7 cases of SCCL, both
serotonin and ACTH were elevated in tumor tissue samples. Other types
of lung cancer, which lacked NSGs, showed no elevation of serotonin
activity with the exception of one case of squamous cell carcinoma
(and one case of pleurisy due to collagen vascular disease). The
authors noted that the NSGs they found in bronchial carcinoid and SCCL
were identical to those which had been previously described by Bensch
21
et al . in the Kulchitsky-type cells in bronchial mucus glands.
Hattori et al. thus concluded that "oat-cell carcinoma is a special
type of lung tumor producing neurosecretory-type granules and a highly
malignant variant of bronchial carcinoid tumor which is originated
from neurosecretory-type cell (Kulchitsky-type cell) found in
20
bronchial glands." This is a remarkable statement, for the authors
have found an association between electron microscopic characteristics
of the tumor (NSGs) and tumor products (serotonin, ACTH) known to have
22
clinical significance as ectopic hormone products of SCCL tumors.
Moreover, the ultrastructure of the tumor cells has provided a clue to
cell origin: the Kulchitsky-type cells of bronchial glands. The
latter can produce serotonin from tryptophan and 5-hydroxy-tryptophan,
which means they fit into Pearse’s conception of an APUD (Amine
23
Precursor Uptake and Decarboxylation) cell. APUD origin would, in
turn, imply a way of attacking the embryological lineage of SCCL ' s
9
cells of origin and relate SCCL to other cells of APUD origin in the
body. In fact, the above associations reach beyond our ability to
24
apply them. Indeed, Hattori et al. examined the cytomorphology of
SCCL tumors in relation to response to therapy in an article published
five years after the one already discussed. Surprisingly, although
almost all SCCL tumor cells were found to contain NSGs, the cells from
tumors which did not respond to combination chemotherapy showed few or
no NSGs. Some of the tissue specimens used in the study were obtained
from autopsy material, and it is possible that chemotherapy affected
the cell structure. Alternatively, a cell line without NSGs could
have arisen from the original tumor. Still, the lack of NSGs in the
non-responder group shakes the foundation of attempts to characterize
SCCL at an ultrastructural level in a way that is consistent with the
presumed cells of origin.
25
Tischler notes that the APUD concept has been elucidated and
revised since its initial introduction. APUD cells are now known to
occur in two distributions in the lung: as scattered Kulchitsky-like
cells and as organized groups of cells called neuroepithelial bodies.
Both occur in close proximity to nerve endings. The secretory
products and physiological role of APUD cells in the lung are
obscure. While the APUD concept may explain the source of some of the
hormones SCCL tumors produce, cytogenetic abnormalities — "derepression
of the genome" — might also account for production of ectopic
26
hormones.
10
Still, APUD has been used as a window to the study of SCCL’s
ectopic hormones. A wide variety of such hormones have been
identified and include ACTH, ADH, calcitonin, glucagon, HCG,
18 22 27
serotonin, PTH, and estradiol. ’ ’ The frequency of ectopic
hormone production by small cell tumors is not known; it is clear,
however, that clinically apparent syndromes that can be traced to
these hormones are much rarer than production of the hormones
themselves. Thus, while more than 50% of patients may have abnormally
high levels of hormones such as ACTH, ADH and calcitonin, clinical
syndromes such as SIADH or Cushing's syndrome appear to occur in less
28
than 10% of patients. Richardson et al . point out that the identity
of these tumor-produced "ectopic hormones" is not really known; they
may or may not be identical to "normal" hormones and radioimmunoassays
r 28
of these substances may be neither truly sensitive nor specific.
29
Despite these caveats. Science marches on. Baylin and Gazdar
have measured biochemical indices in SCCL with established
relationships to APUD cells outside the lung. These include L-dopa
decarboxylase (central to the APUD concept — it converts precursor
amino acids into their corresponding amines); and calcitonin (produced
by the APUD tumor medullary thyroid carcinoma). They also measured
histaminase and beta-endorphin, neither of which is specific to APUD
cell activity; still, both substances are thought to be involved in
hormone production by cancers. The authors found that the biochemical
parameters studied were not specific to SCCL and that there was great
heterogeneity of findings between different patients with SCCL, among
11
different lesion sites (primary vs. metastatic) in the same patient
with SCCL, and even within individual SCCL lesions. These data are
viewed as a reflection of heterogeneous cell populations all of which
are grouped together under the clinical term "small cell lung
cancer." The authors noted that quantitatively, however, their
endocrine parameters tended to group more with SCCL than with other
lung tumors.
An attempt has been made to find tumor products which will prove
to be specific markers of SCCL, whose concentrations are proportional
to tumor burden, and which are present in enough patients to make
measurement worthwhile. Three such newly described products are
bombesin, the BB isoenzyme of creatine kinase (CK-BB), and
neuron-specific enolase (NSE). I will describe a study of NSE as an
example .
30
Carney et al . studied serum NSE levels at diagnosis in 94
patients with SCCL. The levels were repeated during and after
therapy. Sixty-nine percent of all patients had a serum NSE level
more than 3 S.D. above control, including 87% of the patients with
extensive-stage disease (ED). Mean serum NSE was significantly higher
in patients with ED than in those with limited-stage disease. In 20
of 21 patients, all of whom had elevated NSE levels at diagnosis,
serum NSE fell significantly as the patients responded to
chemotherapy. In the one patient whose level remained unchanged, no
response to therapy was achieved and the disease progressed. The NSE
level dropped into the normal range for all patients achieving a
12
complete response.
Serial NSE measurements showed a good correlation between
clinical condition and the level of the marker. For example, in 9
patients with raised NSE levels on diagnosis the levels fell to near
normal range with therapy then rose again when the patients relapsed.
NSE has been identified in all cell lines of SCCL tested; it has not
been found in substantial amounts outside central and peripheral
nervous system tissue, findings consonant with the fact that APUD
cells and neurons tend to express much of the same genetic
25
information — they are ’’neuro-endocrine programmed.'* NSE thus has
the potential to be a useful marker for SCCL; iramunohistochemical
staining of lung tissue for NSE might someday help in making
pathological diagnoses.
A recent cytomorphological finding deserves mention. SCCL cells
from biopsies and derived cell lines were shown to contain
31
neurofilament-type intermediate filaments. Since the expression of
these filaments is tissue type specific and thought to be unchanged
after malignant transformation, another line of approach to the APUD
origin and diagnosis of SCCL may have been uncovered.
Despite the uncertainties described, a picture begins to emerge
of the cells that make up SCCL tumors. At a cytogenetic level, they
are characterized by variable numbers of chromosomes (ploidy) and a
specific acquired deletion of the short arm of chromosome #3 — 3p
(14-23). The cells contain neurosecretory granules and appear to be
of APUD origin. Although SCCL cells express a variety of biochemical
13
products, including certain hormones which account for clinical
syndromes associated with the disease, truly useful biochemical
markers for SCCL, which combine sensitivity and specificity, may
include neuron-specific enolase (NSE); bombesin (BN); and the BB
isoenzyme of creatine kinase (CK-BB). Finally, the idea that SCCL is a
collection of multiple cell lines, both in individual tumors and
between patients, is supported by the variety of tumor products and
their levels expressed by cells from single tumor sites; by cells
taken from primary vs. metastatic sites; and by cells from tumors
found in different patients. The notion of multiple cell lines is
further supported by the variable number of chromosomes (ploidy) found
18
by Vindelov et al . in some tumor samples from a single metastatic
24
site and by Hattori et al.'s finding of decreased or absent
neurosecretory granules in the cells of tumors unresponsive to
chemotherapy. The characteristics of SCCL have been further
elucidated by recent studies which build on the picture above.
Tumor cell chromosome number was recently examined in relation to
32
treatment response by a group at M.D. Anderson Hospital. They found
a DNA index of 0.70 to 2.09 ( 1 . 0=diploid) among 126 pre-treatment
specimens. Six percent of the cases had bi-clonal stem lines.
Hypodiploid tumors had decreased percent S-phase cells (reflecting
lesser proliferative activity). These tumors showed slower drug
response, but the response was more prolonged with resultant better
survival when compared to hyperdiploid tetraploid tumors characterized
by high % S-phase cells. Percent survival at more than 60 weeks could
14
be stratified by DNA index in a significant way, raising the
possibility that chromosome number and proliferative activity analysis
may one day be used as prognostic criteria. The presence of more than
one cell line in some tumors was again confirmed.
The use of monoclonal antibodies (MoAbs) may prove to be a useful
method whereby antigenic expression — and thus, indirectly, the tumor
genome — can be studied. Implications for future treatment design are
numerous and include the attachment of anti-tumor drugs to MoAbs,
creating a highly specific tumoricidal agent.
Groups at the NCI have published numerous abstracts in the last
two years reporting on studies in which MoAbs have been applied.
Considerable antigenic heterogeneity has been found within individual
SCCL tumors, between tumor lines, and, to a more limited degree,
33
between clonally related lines. SCCL is thus proving to be
heterogeneous in a way that challenges our understanding of cellular
behavior at the level of molecular genetics. Relative homogeneity has
been found in cell lines from different metastatic sites in the same
patient. This homogeneity was especially evident when numerous
characteristics of the cells were examined simultaneously: the
biomarkers dopa decarboxylase (DDC) and bombesin (BN), DNA index, and
34
three forms of antigenic expression (using MoAbs). Still, the
heterogeneity of antigen expression in tumor tissue and the poor
specificity of "tumor" antigens — i.e., their diverse distribution in
normal tissue — may cause considerable difficulty in the clinical
35
application of MoAbs.
15
A finding which may prove to be specific is that of HLA-A,B,C,
and beta-2 microglobulin deficiencies on the cell surfaces of human
SCCL lines, detected by MoAbs. Thusfar, non-SCCL lines have been
strongly positive for these structural markers.
36,37
38 39
Two exceptionally interesting reports from the NCI ’ have
appeared recently which illustrate our ability to study SCCL at a
cellular level through the use of biochemical markers, continuous cell
lines, and measurements of radiosensitivity and tumorogenicit y . The
authors report two major subgroups of SCCL: a classic form, which
expresses DDC, BN, NSE and CK-BB; and a variant form, which has a
faster doubling time and shorter latent period to tumor induction in
nude mice than the classic form. The variant form is radioresistant,
nor does it produce DDC or BN in appreciable quantities. It has
metabolic features which distinguish it from the classic form:
despite the presence of CK-BB, the product whose formation that enzyme
catalyzes ( phosphocreatine) is not present in classic cell lines.
Phosphocreatine isn't present in non-SCCL lines, but is present in the
variant cell lines.
The possibility that there are two major subgroups of SCCL — one
clinically aggressive, resistant to treatment, and lacking the
characteristic APUD enzyme (DDC) — is reminiscent of the findings of
2 A
Hattori et al. Recall that those authors reported on the lack of
neurosecretory granules (NSGs) in a group of tumors resistant to
chemotherapy. Are Hattori 's resistant tumors composed of cells from
the NCI's variant subgroup? The absence of DDC in a tumor one would
16
expect to be clinically aggressive (the SCCL variant) is like the
absence of NSGs in tumors proven to be therapy-resistant; basic APUD
characteristics are lacking. The usefulness of APUD characteristics
in understanding SCCL is not clear. The APUD origin of some cell
lines becomes questionable. Perhaps tumor cells lacking NSCs and cell
lines with characteristics of the variant subgroup are highly
aggressive subpopulations of cells which have evolved from the
original, more indolent APUD-derived tumor. The concept of classic
and variant cell lines and the presence of more than one cell line in
32
a tumor also brings to mind the report from M.D. Anderson which
stratified tumor aggressivity by chromosome ploidy and proliferative
activity.
Cytogenetic study of the classic and variant cell lines —
evaluating chromosome number and seeking the deletion in chromosome #3
19
associated with SCCL — as well as cytomorphological study, with a
special interest in neurosecretory granules, may prove fruitful.
Clearly, researchers are only beginning to explore the cellular basis
of SCCL's clinical behaviors.
Clinical Diagnosis
Cohen and Matthews, Matthews and Hirsch^^ and Matthews^^ have
reviewed the radiographic, clinical, and pathological presentations of
SCCL.
On X-ray, SCCL usually appears as a central mass. Because the
tumor metastasizes early, hilar node involvement is common, with or
17
without mediastinal widening on presentation (64%). Post¬
obstructive pneumonitis, atelectasis, and pleural effusion (due to
lymphatic blockage) may be present. Less commonly, a peripheral tumor
mass is seen on presentation (19%). Very rarely, the patient presents
with a central tumor mass and no obvious nodes (3%). The lesion must
be distinguished from epidermoid (squamous cell) carcinoma, which also
presents as a central lesion. But epidermoid lesions are rarely
associated with mediastinal adenopathy or widening as evident as that
in SCCL. Moreover, SCCL tumors demonstrate central cavitation less
frequently than squamous cell lesions.
While the pathogenesis of SCCL and epidermoid cancer is probably
similar, there are numerous differences in gross pathology.
Epidermoid tumors are often bulky, polypoid, obstructive intraluminal
growths, with a friable consistency, with or without central
cavitation and liquefaction necrosis. SCCL, in contrast, tends to
form submucosal plaques that spread to involve central
structures: the trachea, mainstem bronchi, and the bronchial, hilar,
and mediastinal lymph nodes. If the superior vena cava is invaded, it
can be thrombosed, causing SVC syndrome. (SVC syndrome may also arise
secondary to compression.) SCCL tumors have a glossy grey-white cut
surface that is frequently hemorrhagic and necrotic — but central
cavitation is rare.
Pathological classification of SCCL is based on light
microscopy. In 1977, the World Health Organization revised their
classification system based on a decade of study. The subtypes now
18
used include lymphocyte-like or oat cell (#21); intermediate forms
(fusiform, polygonal, "other” — #22); and combined (oat cell with a
definite component of squamous cell or adenocarcinoma).
The nuclear detail of small cell — its fine or coarse stippled
pattern of nuclear chromatin and small, indistinct nucleoli — is highly
characteristic. Cytoplasm is usually scanty or may appear to be
absent. Cells are arranged in a loosely cohesive but clustered
pattern, forming cords, sheets, or pseudorosettes (cuffing around
blood vessels).
There are numerous problems that arise in diagnosing SCCL, as
40
reviewed by Matthews and Hirsch. These include inadequacy of biopsy
material (biopsy samples that are too small, bronchial washings or
sputa of equivocal cytology); crushing of tissues, resulting in
overinterpretation of malignancy; and improper tissue processing, with
resultant artifacts. The authors contributed to two interobserver
studies designed to identify problems and assess reliability in SCCL
42 43
diagnosis. ’ They found unanimity or "near unanimity" (7 of 8
pathologists) in the diagnosis of SCCL in over 90% of the tumors
studied. The consistency of subtyping of SCCL tumors according to the
1977 WHO criteria was assessed in one of the studies. Unanimity among
3 pathologists was achieved in only 54% of the cases. This is a
remarkable figure, for it raises doubts about all studies designed to
characterize SCCL subtypes (e.g., the response of different subtypes
to therapy — a topic to be discussed later).
19
The great majority of patients with SCCL are symptomatic at
presentation. Cough is a common symptom, referable to the primary
tumor. Chest pain, dyspnea, symptoms of pneumonitis (due to
obstruction or compression), wheeze and hemoptysis may occur. (See
12 44
Table 3.) ’ Mediastinal extension of the tumor results in
hoarseness or SVC syndrome, the former secondary to involvement of the
recurrent laryngeal nerve (usually on the left, where its course is
longer). SVC syndrome tends to be associated with right lung tumors,
since the superior vena cava passes through the chest on the right.
Early, widespread metastases are the hallmark of SCCL and
45
contribute to its symptomatology. Livingston et al., in their
series of 375 patients, found liver to be the metastatic site most
often involved in extensive-disease patients, followed closely by
bone; then, bone marrow, brain, skin/soft tissue/nodes, and pleural
45
effusion. (See Table 4.) Thirty-seven percent of these patients
had involvement of more than one metastatic site, in contrast to 49%
46
in a study of 106 patients at the NCI. The significant metastatic
sites, in terms of symptomatology, are bone and brain, causing pain
and neurological complaints, respectively. Although cardiac
involvement is rarely mentioned in clinical series, 20-25% of SCCL
patients have been reported to have cardiac metastases at
12, 14
autopsy. ’ (See Table 4.) Such involvement can result in signs and
symptoms of heart failure, EKG changes, even tamponade. Adriamycin,
commonly used in treatment protocols for SCCL, has cardiotoxic side
effects; thus, ejection fractions are routinely computed at the start
I
20
of therapy. Still, one wonders what implications subclinical cardiac
involvement might have with respect to treatment complications.
The existence of clinical syndromes related to ectopic hormone
production by SCCL tumors has already been mentioned. All are rare.
SIADH, reported in 5-10% of most series, seems to occur most
frequently in association with SCCL when the cause of SIADH is
22
neoplastic. CNS manifestations predominate in symptomatic patients
and may include seizures, disorders of consciousness, and
extrapyramidal signs. The patient is unable to excrete a maximally
dilute urine when presented with a water load and such testing can
uncover many subclinical cases. Fluid restriction helps correct the
hyponatremia, but chemotherapy is the definitive approach.
Ectopic ACTH production is clinically significant in 3-7% of
22
patients with SCCL. Nmnerous tumors thought to be of APUD origin
make the hormone. Symptomatic patients rarely present with the
classic features of Cushing's syndrome — instead, weight loss, severe
weakness, glucose intolerance, edema and/or hypertension are more
likely presentations of their hypercortisolism. The metabolic
complications of symptomatic ACTH overproduction can be severe and
22
management is difficult, although Greco et al. report early evidence
that combination chemotherapy can be effective.
Paraneoplastic syndromes other than ectopic hormone production
have been found to be associated with SCCL. Possible etiologies of
these syndromes include viral agents, autoimmune phenomena, and
humoral substances elaborated by the tumor.
21
Eaton-Lambert syndrome is associated with SCCL more often than
22
with other diseases. It is an unusual clinical entity,
characterized by the dichotomous findings of proximal muscle weakness
with difficulty walking coupled with facilitation of muscular
potentials on repeated stimulation. Thus, the patient's grip may
become stronger and stronger during testing. The syndrome tends to
occur among male patients over 40 years of age and seems to respond to
cytotoxic therapy. Should chemotherapy fail, guanidine may be
22
effective by causing increased release of anticholinesterases. The
electromyogram is diagnostic.
A final syndrome requiring mention is paraneoplastic
22
encephalopathy. This is thought to be the cause of death in two
patients in the present study. Clinically, the syndrome may involve
the cerebrum, brainstem, optic nerves, and cerebellum. Pathologic
lesions are generally found in all these regions, although involvement
of one area may dominate the clinical picture. Dementia is the most
common manifestation of cerebral involvement. Radiologic studies are
normal; the CSF may show an elevated protein level; the E<EG is often
slow and diffuse.
Staging and Prognosis
There is a TI#1 ( tumor-nodes-metastases) staging system for SCCL
but its use, until recently, had fallen out of favor. The TNM system
is surgically-oriented and poor therapeutic results have been achieved
using surgery alone. TNM was viewed as prognostically useless. More
22
recently, however, interest in surgery as an adjuvant therapy (part of
a multimodal therapeutic approach) has been revived and the TNM system
may yet take its place as a standard method of staging. (See the
section on treatment.) Still, the system of the Veterans
Administration Lung Cancer Study Group remains the one employed in
almost all current studies. It divides patients into limited-stage
(LD) and extensive-stage (ED) disease groups. LD is defined as tumor
confined to one hemithorax with or without mediastinal
lymphadenopathy , with or without ipsilateral supraclavicular node
involvement. The tumor must fit within a single radiation therapy
portal. Tumor beyond these confines is defined as extensive
disease.
In general, two-thirds of all patients present with ED; one-third
5 48 49 48
with LD. ’ ’ Ihde and Hansen have pointed out that, with very
thorough diagnostic work-ups, more patients with metastatic disease
not easily detectable are placed in the ED group. When this is done,
survival data for the individual ED and LD groups may appear improved,
since a group of relatively "healthy” ED patients is created by
removing a group of relatively "sick" LD patients. Overall survival
(ED + LD) does not change. The truth of this observation must be
supplemented by the observation that, despite the sophistication of
the technology available to the physician determined to uncover the
most retiring metastasis, test results are often equivocal. It is not
clear whether or not to include certain patients in the ED group and
they may be given the "benefit of the doubt" — identified as patients
A
23
with limited disease so that they might enter the LD treatment group.
When this happens, the survival of the ED group presumably goes up and
that of the LD group goes down. Again, overall survival remains
unchanged .
Involvement of certain metastatic sites has been found to have
prognostic significance. More fundamentally, extent of disease has
strong prognostic implications. Staging procedures in SCCL must be
designed with these facts in mind. Diagnostic modalities must be
selected for their combination of sensitivity and specificity.
Chest X-ray remains the basic method by which intrathoracic
disease is evaluated. However, fiberoptic bronchoscopy is a very
useful tool — it allows diagnosis by biopsy or bronchial washings and
can detect small lesions. The bronchoscope is used routinely at some
centers to document complete response to therapy.
CT scans of the chest are less widely used, although they provide
a better sense of tumor volume. Some note that the CT scan's
sensitivity is not matched by its specificity in detecting malignant
pulmonary nodules when compared to conventional linear
tomography . Others point to the relative inaccuracy of CT scans in
diagnosing disease in the middle mediastinum when compared to staging
mediastinoscopy or thoracotomy.^^ Still, CT provides useful
51 52
information not obtained with conventional radiography. ’
Both mediastinosocopy and CT of the chest may take on a more
important role in initial staging in the future. The reason for this
is the resurgence of interest in TNM staging to evaluate adjuvant
24
surgery for early control of intrathoracic tumor mass. Surgery aside,
data is accumulating that would indicate a survival advantage for
patients with smaller presenting tumors in the chest. A group in
53
England found a higher incidence of complete response and a survival
advantage for patients with intrathoracic tumors whose total
2 54
cross-sectional was area less than 30 cm on CT. A Toronto group
reported a significant survival advantage for limited disease patients
without superior mediastinal node involvement as diagnosed by
mediastinoscopy or roentgenographic appearance — i.e., patients with
so-called "very limited" disease, which is potentially resectable.
These two studies illustrate the potential use of CT and/or
mediastinoscopy in evaluation of chest tumor extent. Such information
could be useful for treatment and/or prognosis.
Bone and bone marrow are common sites of metastatic spread. It
seems important to perform both bone marrow biopsy and aspiration^^ as
56
well as bone scan if extent of disease is to be assessed, for the
procedures complement each other to some extent. The prognostic
57
significance of these sites of involvement is unclear, however. Two
recent studies found bone marrow involvement to be a negative
58 59
prognostic factor; ’ a third report found no prognostic
significance.^^ A study from the Finsen Institute^^ identified a
group with an especially poor prognosis: patients with bone marrow
metastases and thrombocytopenia. In any case, bone scan and bone
marrow biopsy and aspiration remain standard procedures in staging
48
SCCL. Ihde and Hansen have reported worsening of the bone scan
25
during overall disease remission in a minority of patients.
Liver metastases appear to be a negative prognostic factor.
46 61 59
Groups at the NCI ’ and Toronto have found liver involvement to
bode ill and the level of interest in accurate diagnosis of liver
metastases supports the wide acceptance of this notion.
A variety of techniques may be used to evaluate the liver,
including liver function tests, radionuclide scanning, CT,
peritoneoscopy with biopsy, percutaneous biopsy, and ultrasonography
with fine needle aspiration. Liver-spleen radionuclide scan remains
the mainstay of current staging. Although this modality has been
maligned, it remains a reliable, available, relatively inexpensive,
62
non-invasive diagnostic tool in SCCL. At the NCI, peritoneoscopy
with liver biopsy was found to be the most sensitive diagnostic
method, but an algorithm combining radionuclide scan with liver
function tests was highly accurate while remaining non-invasive.^^ A
63
recent study from the Finsen Institute reported ultrasonography with
fine needle aspiration to be more accurate than peritoneoscopy. The
ultrasound technique was also ’’less invasive" — but the number of
patients studied was small.
Whether or not prophylactic irradiation should be employed to
avoid CNS metastases in patients with SCCL is a controversial topic.
Less controversial is the prognostic significance of CNS involvement
and how to diagnose it.
Brain metastases are present in approximately 10% of patients
48
with SCCL at diagnosis and in 30-65% of patients at autopsy.
As
26
therapy improves and patients with SCCL live longer, they accumulate
greater risk for developing this complication.
Both the NCl'^^ and Toronto^^ groups found brain metastases to be
a negative prognostic factor, but this result has not been
invariable. Diagnosis can be made by radionuclide scan or CT of the
head. CT scans are thought to be superior, uncovering lesions
64
before they become symptomatic and allowing accurate staging.
A current set of recommendations for restaging of patients
thought to have achieved clinical response is presented in Table
5.^^ The argument that restaging should be effected with as much care
as initial staging is a good one since any metastasis large enough to
be clinically detectable is of great significance. Perhaps someday
biomarkers already described (e.g., bombesin, neuron-specific enolase)
will become standard indicators of subtler disease.
What factors can be said to have prognostic significance in SCCL?
Performance status — a numerical estimate of a patient's ability to go
about his daily routine with or without symptoms — and stage of disease
(limited vs. extensive), predominate in most studies of significant
48 59
prognostic factors. ’ In fact, the International Association for
the Study of Lung Cancer feels it is no longer necessary to
demonstrate the superior survival of patients with LD in current
chemotherapy treatment reports. Still, significantly improved
AG
survival for LD patients is not a universal finding. Data already
mentioned indicate that small intrathoracic tumor area and a finding
of "very limited" (i.e., potentially resectable) disease may confer a
27
53 54
prognostic advantage. ’ Patients who have failed a previous
chemotherapeutic protocol invariably have a bad prognosis on
48
second-line therapy.
The following are of less certain significance. Weight loss on
presentation (0-10%) has been found to be associated with
66
significantly decreased median survival, as has multiple metastatic
46
sites (one vs. two vs. three or more). Age of 55 years of more has
been associated with decreased response rates and shorter survival in
patients not achieving complete response.
Numerous laboratory parameters may be useful as prognostic
indicators; carcinoembryonic antigen (CEA) has been reported to be an
independent prognostic factor, as has The feasibility of
using an objective prognostic index based on laboratory parameters at
diagnosis to replace subjective performance status assessment is under
study. At the NCI,^^ albumin and hemoglobin were found to be the most
influential prognostic factors in survival.
The fact that, of the various metastatic sites, CNS and liver are
the most likely to have prognostic significance has already been
discussed.
Finally, the prognostic significance of the various subtypes of
SCCL remains unclear. The VA Lung Group^^ reported better survival
for patients with lymphocyte-like (classic, oat-cell)
vs. intermediate-type disease. This held true for patients within the
extensive disease group, but not the limited disease group, when
72
analyzed separately. In contrast, a large NCI study found no
■5
J
28
clinically significant differences among the subtypes. A recent
community hospital study indicates that lymphocyte-like SCCL may be
73a
associated with better 2 year survival.
The pathology panel of the International Association for the
Study of Lung Cancer is in the process of proposing a revision of the
73b
current WHO histological classification system for SCCL. The
"combined" subgroup would remain; however, "oat cell" and
"intermediate" subtypes would be classified together in the new
"classic small cell" subgroup. Another new subgroup would be
created: "small cell-large cell," in which there is an admixture of
classic small cells with large cells having open nuclei and prominent
eosinophilic nucleoli.
73b
Dr. Raymond Yesner has reported, in a personal communication,
that the new classification system is based on the belief that
polygonal and fusiform cell types — currently grouped in the
intermediate subtype — show no significant clinical, biological, or
ultrastructural differences from classic oat cells. The VA Lung Group
study, as reported earlier in this paper, found a survival advantage
for oat cell over intermediate-type disease. It turns out that this
group, unlike investigators who found no such survival advantage,
included in the intermediate subtype only tumors with a mixture of
classic small cells and large cells — not tumors of polygonal and
fusiform cells, which they grouped with classic oat cell tumors. The
proposed classification system is based on the belief that tumors of
the small cell-large cell subgroup carry a graver prognosis than those
29
of the classic small cell subgroup.
Finally, the new small cell-large cell subgroup is thought to be
identical to the vitro "variant" cell line described earlier in
38 39
this paper based on reports from the NCI. ’ The variant cell line
is relatively resistant to radiation and chemotherapy and has a large
cell appearance, but produces some characteristic SCCL biomarkers.
Similarly, the classic small cell subgroup is felt to have its in
vitro equivalent in the NCI’s "classic" subclass.
Table 6 presents a summary of prognostic factors.
PART TWO: TREATMENT
Overview
A better theoretical grasp of cancer in general now permits
clinicians to treat SCCL with a modest degree of success. As the
characteristics of the tumor become better understood, the limitations
of current therapy become painfully clear. Will the treatment
breakthrough come from the slow evolution of rational therapeutic
design or through a fortuitous discovery? It is unlikely that
stepwise investigation will cure SCCL in the near future; and, given
the cost-conscious environment of present-day cancer research, the
prospect of a serendipitous discovery is better thought of as a
fantasy than a hope.
In order to treat SCCL and to evaluate properly its response to
treatment, the growth characteristics of the tumor need to be known.
Two basic approaches exist: measures of clinical doubling time made
by estimating tumor volume changes on chest radiographs over time; and
in vitro studies of tumor cells. Tritiated thymidine uptake by SCCL
cells allows calculation of the labeling index (LI) — the fraction of
labeled tumor cells among all cells counted. LI reflects the rate of
cell production by the tumor — it measures the fraction of cells
actively synthesizing DNA.
SCCL responds well — initially — to treatment with radiation
73c
therapy (which acts on dividing cells) and to treatment with agents
such as methotrexate (which is S-phase specific) and cyclophosphamide
31
74
(which is probably cycle-dependent). Intuitively, one would
therefore expect SCCL to be a rapidly dividing tumor — one with a high
LI and short doubling time as measured in clinical studies.
Initial results were consistent with this view.^^ For a while,
researchers took a value of about one month as the doubling time of
small cell tumors. Based on this assumption, the period of risk — the
amount of time for regrowth from a single cell to clinical
recurrence — was thought to be about two years.
Two years became a magical interval, synonymous with long-term
survival^^ ’ and, perhaps, cure. This view was consistent with
clinical impression, doubling time data, and the finding that SCCL had
a higher median LI than other solid tumors (except Burkitt’s
78
lymphoma). Although it has since become clear that two year
survival is of limited value, it remains, for many, an important
criterion. A review article from 1982 states that "many patients who
survive alive and disease-free for 2 years, remain
79
disease-free." The reference given, from 1979, was employed
K 77
above .
In 1978, a group at the NCI reported a median doubling time of
77 days (range: 25-160 days) among their 12 cases of SCCL. Most
tumors were felt to have demonstrated relatively intermediate or long
doubling times. Assuming that the range of 1x10^ to 1x10^ cells is
clinically significant, the authors used the median doubling time of
77 days to project that therapy leaving a tumor burden of 1x10 cells
would not present as a clinical relapse for at least two years;
32
therapy destroying all but one cell would produce an interval of risk
lasting 4-5 years.
The above projections may not be entirely accurate. First, the
range of tumor doubling times must be taken into account. Second,
treatment may change the cell kinetic characteristics of SCCL
78
tumors; there is good evidence to support biochemical and
81 82
histological changes in tumors after therapy. ’ Still, 4 or 5 year
survival is probably more accurately synonymous with long-term
survival if cure is implied. Clinical evidence has accumulated to
support this notion in the form of late relapses.
Such evidence has been available for a number of years. The
83
NCI-International Association for the Study of Lung Cancer report
which appeared in 1980 studied patients who survived more than 2.5
years. Recurrent disease was noted in 21 of 96 patients: 8 patients
died 30-33 months after diagnosis; one was alive, with disease, at 34
months; recurrence was detected in 10 other patients after 36-51
months; and two patients treated by surgery alone succumbed to
recurrent disease at 8 and 9 years, respectively.
Recently, data from cooperative and single institutions have been
84
gathered on late relapses. The NCI reported that 8 of 28 patients
who had been disease-free at 30 months relapsed with SCCL (median: 54
months from diagnosis; range: 31-74 months) after follow-up of 5-10
years. The group at M.D. Anderson Hospital reviewed patients
surviving 3 years or more. Eleven of 43 such patients relapsed
systemically . Seven of the 11 relapses were at more than 3
33
85 86
years. Livingston, reporting for the Southwest Oncology Group,
looked at 17 patients who survived 5 years or more in a single study
(13% of those entered). Five late deaths were due to recurrent tumor
(onset: 33-73 months from treatment).
87
As early as 1978, Greco et al. published a paper in which the
notion that 2 year survival might not represent cure was clearly
expressed. The existence of "late recurrences" was recognized.
Before discussing treatment modalities: What is the natural
history of SCCL? The median length of survival of untreated patients
with SCCL is generally quoted as 2-3 months, depending on extent of
disease at presentation.^ One widely quoted study is that of the VA
47
Lung Study Group, in which 38 SCCL patients with limited disease
achieved a median survival of 11.7 weeks and 108 patients with
extensive disease achieved a median survival of 5.0 weeks on placebo.
88
In a cooperative VA study reported by Roswit et al.,
placebo-treated SCCL patients with limited disease had a median
survival of more than 16 weeks.
Surgery was one of the first modalities used to treat SCCL. The
results were not good. Even apparently resectable lesions were
frequently found to have seeded distant sites; relapse was the rule.
A study of pathology material from the tumors of 19 patients who died
within 30 days of apparently successful surgical resection found
persistent disease in 13 of 19 patients, 12 of whom had distant
89
metastases. Radiation therapy (RT) alone proved better than surgery
90
in a British Medical Research Council trial. The patients had
limited disease thought to be resectable and were fit enough for
surgery or radical RT. At 10 year follow-up, the surgery group had a
mean survival of 199 days, the RT group 300 days. Three patients in
the RT group who survived five years remained alive and disease-free
at 10 years. Four RT patients died between 2 and 5 years. The sole 5
year survivor in the surgery group in fact underwent no surgical
treatment due to breathlessness and received RT instead.
88
In contrast, in a cooperative VA study already mentioned, there
was no significant increase in survival for a group with limited
disease receiving 4-5,000 rads of RT compared to a placebo group.
Median survival for the RT group was a bit over 16 weeks.
74
Selawry, in a 1973 report, reviewed the response of SCCL to
single agent chemotherapy. Small cell was found to be the most
responsive to single agents of all lung cancer subtypes.
Therapeutic design moved quickly once the efficacy of
chemotherapy had been shown. Radiation therapy was combined with
91
chemotherapy, creating a multi-modal approach; multiple
87 92
chemotherapeutic agents were employed. ’ It became clear that
patients who achieved complete response lived longer than those
achieving partial response or no response (in complete responders, the
disease had been made clinically undetectable); and partial responders
93
seemed to live longer than non-responders.
Chemotherapy has become the backbone of therapeutic approaches to
SCCL. Basic principles of chemotherapy design have been applied to
the disease. Attempts have been made to: combine drugs which have
35
therapeutic efficacy as single agents; choose combinations of drugs
with different modes of action; treat with apparently non-cross-
resistant sequential combinations of drugs; find combinations of drugs
with synergistic anti-tumor effects; and use drug dosages high enough
to maximize dose-response advantages while minimizing the inherent
trade-off of dose-related toxicity.
Disease extent is a major prognostic factor in SCCL and treatment
results reflect this fact. It is wise to discuss therapy of limited
disease and extensive disease separately. In general, limited disease
treatment has changed little in the past five years and is dominated
by controversies over the use of radiation therapy to the chest and
prophylactic cranial irradiation as adjuvants to combination
chemotherapy. An exception to this statement is the renewed interest
in surgery as an adjuvant therapy in resectable lesions. The more
creative approaches to therapy — new drugs, larger doses,
non-cross-resistant sequential combinations — have been confined
largely to treatment of extensive disease or patients who have
relapsed. The reason for this is that current conservative
therapeutic designs produce a predictable, although small, number of
long-term survivors in the limited disease group; the extensive
93
disease group has fewer responders and shorter survival. Clinicians
are reluctant to give up ’’acceptable" survival and known toxicity
risks for experimental therapies.
65
Aisner et al., reporting for the International Association for
the Study of Lung Cancer have summarized current expectations in
36
trials employing aggressive therapy against SCCL. Combination
chemotherapy should produce complete response in more than 50% of
patients with limited disease (LD) and more than 20% of patients with
extensive disease (ED). With adequate staging, median survival of at
least 14 months in LD and 7 months in ED may be expected. Finally,
15-20% of LD patients should achieve disease-free survival of 3 years
or more although such survivors remain rare among ED patients.
Table 7 presents a summary of selected treatment protocols for
SCCL. It is intended to show the evolution of therapy and variability
of treatment results. It does not present highly experimental
approaches of the kind usually reserved for extensive disease patients
or patients who have relapsed from first-line therapy. Unless drawn
from the same paper, the studies are not comparable.
Table 8 presents information on long-term survivors from studies
using various treatment modalities.
Treatment of Limited-Stage Disease and
Treatment-Related Toxicities
Two controversial aspects of therapy design are especially
relevant to limited disease, since their goal is prophylaxis or rapid,
effective local control: the use of prophylactic cranial irradiation
(PCI); and intrathoracic irradiation for local tumor control, both as
adjuvants to combination chemotherapy.
Neither non-randomized nor randomized trials of PCI have
99, 103
demonstrated any clear advantage in survival.
.1
37
99
Baglan and Marks thus argued that the nominal purpose of PCI
was to prevent neurological signs and symptoms, since their review of
the literature uncovered an incidence of brain metastases averaging
23% for patients not receiving PCI versus 5% for the PCI group. The
authors were able to treat 64% of 39 patients with brain metastases
(all but 4 of whom were symptomatic) successfully enough to eradicate
symptoms for the rest of the patients' lives. The authors predicted
that, based on their results treating symptomatic patients and on
previous treatment results with PCI, of 100 prophylactically
irradiated and 100 symptomatically irradiated patients, 77 extra
patients would have to receive PCI so that 3 patients might be spared
CNS symptoms. They considered the potential benefit of PCI to be
insignificant .
Baglan and Marks's argument hinges on effective treatment of CNS
metastases. Agreement on this point is not uniform; still, a
recent NCI study indicated that brain metastases can be treated
effectively enough so that such patients die of other causes in most
102
cases.
A large retrospective NCI study^^*^ examined PCI with a special
interest in: PCI timing; PCI's effect on long-term survival; and
selection of any subgroups of patients for whom PCI would be most
helpful. The results were of great interest: there was significant
improvement in overall survival for the group receiving PCI. However,
the group which received no PCI also had the least intensive
chemotherapy. With that caveat in mind, the authors felt that PCI had
38
its greatest positive effect in the complete responders (with limited
or extensive disease). Among patients achieving complete response who
had received no PCI, 17% relapsed in a CNS site alone. Isolated CNS
relapse was seen in no complete responders who had received PCI. Two
and three year survival was improved in the PCI groups, but not
significantly so. With respect to the timing of PCI: there were no
CNS relapses in the first four months in any group and no striking
treatment result differences between a group receiving PCI on day 1 of
the protocol and a group receiving PCI at week 12 or 24, contingent on
a complete or partial therapy response.
The NCI group thus suggested that PCI may be most effectively
employed at 2-4 months, after documented complete response has been
achieved. Patients achieving less than complete response could be
treated symptomatically since the study found no apparent advantage
103
using PCI in that group. A recent study from Toronto found no
increased survival but significantly decreased brain relapse at 2
years for complete responders receiving PCI (21% vs. 52%).
Data is accumulating to support selective use of PCI — the data is
on toxicities associated with PCI. Numerous groups have reported
neurological toxicities among long-term survivors which may be due to
PCI or the combination of PCI and chemotherapy (nitrosureas, in
84,104,105 , ^ . . 106 .
particular). A group at Indiana University found
neurologic problems in 9 of 11 long-term disease free patients (>3
years) who had received PCI + nitrosureas, and in 6 of 8 patients who
had received PCI and chemotherapy without nitrosureas. Onset of
39
neurological symptoms was usually 1-3 years after completion of
therapy. Problems encountered included memory loss, dementia,
confusion, ataxia, psychomotor retardation, dysphonia and optic
atrophy. Two patients required institutionalization; 6 others have
had great impairment of their daily lives. Only 4 of 18 patients have
had no neurologic impairment after therapy. Recently, a prospective
evaluation revealed an '’extraordinary high frequency of CCT
(computerized cranial tomography) abnormalities in patients with SCCL
after treatment with chemotherapy and cranial irradiation.
The role of PCI in the treatment of SCCL remains unclear. It
appears that PCI may offer a relapse protection advantage in patients
achieving a complete response that is worth the risk of possible
long-term neurological side effects. Much may depend on the side
effects clinicians are willing to tolerate to protect the subgroup of
complete responders who, without PCI, would experience isolated CNS
relapse. Neurological side effects need to be further studied so that
especially toxic PCI-chemotherapy combinations can be avoided. More
data are needed on survival, relapse, and toxicity through randomized
trials of PCI in complete responders.
The controversy surrounding the use of radiation therapy to the
chest to complement multi-agent chemotherapy is a complex one.
Multi-modal therapy, referring to combined radiation and
chemotherapy, is of two main types: sequential and concurrent. In
sequential therapy, there is a temporal pause between the two
modalities; in concurrent therapy, they are given simultaneously.
I
'■ii
40
1 Oft
Catane et al. , found a trend favoring concurrent therapy over
sequential therapy for increased two year survival. The difference
was not statistically significant, however. The concurrent therapy
group achieved better complete therapy response with local tumor
control and, of patients achieving complete response, fewer patients
receiving concurrent therapy relapsed in the radiation therapy
portal .
The toxicity enhancement effects of concurrent therapy are
critical in evaluation of protocol design. In Catane' s study, 7 of 14
patients receiving maximal concurrent radiation and chemotherapy (9
weeks) died of treatment toxicity. Yet, 4 of the 7 treatment
survivors achieved 2 year survival — the highest proportion of any
group in the study. The authors concluded that 3 weeks of concurrent
radiation therapy (RT) and chemotherapy (CT) produced the optimal
combination of high 2 year survival and acceptable toxicity.
109
Cox et al., found that tumor control probability, assessed by
serial chest radiographs, increased with increasing biological dose in
patients treated with RT alone. But in RT + CT patients, local
control was achieved at lower RT doses than would have been expected.
RT was generally begun during the last week or immediately after
completion of chemotherapy.
The point is that RT and CT appear to act synergistically : they
enhance each other's treatment effects but they also enhance
toxicities. Acute toxicity enhancement effects include myocardial,
pulmonary, skin and esophageal damage with Adriamycin;
chronic
■fiki)
i
i
41
toxicities will be discussed shortly. However, delay of one week
between modalities is thought to be protective.
We enter the RT + CT vs. CT alone controversy with this
perspective: the timing of combined modality treatment is important
for toxicity and anti-tumor effects; RT seems to act synergistically
with CT on tumor cells. To date, the critical parameters of RT-CT
combination therapy — timing and dosage — have not been adequately
j 111
studied.
The main argument for combined modality treatment is local tumor
112
control. Byhardt and Cox argue that failure of chemotherapy alone
to prevent relapses in the chest is the reason to add adjuvant RT.
Combined modality therapy reduces relapses in the radiation portal
and, with this local tumor control, allows better long-term survival
for limited disease patients.
113
Cohen notes that the true test of adjuvant RT is whether or
not it increases the number of long-term survivors — i.e., patients
living at least three years — in randomized trials comparing RT + CT to
CT alone.
The use of adjuvant RT in extensive disease is not as
controversial a topic. Most investigators seem to agree that survival
is not increased by RT to the primary tumor. The data supporting this
114
notion are relatively scanty, but meticulous local control
apparently strikes most investigators as less essential when the tumor
has already spread beyond one hemithorax. What can be said about
local control and its relationship to long-term survival?
42
Peschel et in a retrospective review of 12 patients
achieving survival of more than 2 years, stressed the need for local
tumor control — surgery or high dose (>4800 rads) lung irradiation — to
avoid local relapse. Three of 5 patients who had received
chemotherapy alone or low dose irradiation (<3500 rads) had late local
83
relapses. Similarly, Matthews et al. reported on the treatment
received by patients in their long term (>2.5 year) survival
registry. The two largest groups represented were patients who had
received RT + CT and those who had received surgery alone. (The role
of adjuvant surgery in current treatment protocols will be discussed
later. )
Several controlled, randomized studies have compared CT + RT to
116
CT alone. Hansen et al. reported shorter median survival in the RT
+ CT group compared to the CT group. In contrast, Bunn et al.^^^ and
1 18
Perez et al. reported better median survival and complete response
rate with thoracic irradiation. The Perez study also reported an
initial, significant superiority in actuarial 3 year survival for the
group receiving RT (20% vs. 5%). Toxicity was greater in the RT + CT
group. There were 2 induction deaths in the RT + CT group vs. none in
119
the CT group in Bunn's study. Mira et al. have added RT to CT at
day 85 of their protocol and found that, in about 1/3 of responders
who did not achieve complete response after initial CT, RT increased
complete response rate and median survival.
Radiation therapy to the chest has a logical place in the care of
patients with limited-stage disease. Local control is an extremely
43
useful concept in designing treatment protocols for long-term
survival. Still, the trade-off is increased toxicity.
This is a good point to review treatment toxicities briefly, with
a special interest in toxicities associated with combined modality
120 12X3.
therapy. ’ Most chemotherapy regimens used for treating SCCL
produce some degree of myelosuppression . Addition of radiation
affects the bone marrow and in a healthy adult, ribs, sternum, and
121b
scapula comprise 15-20% of functioning bone marrow. With most
standard CT protocols the duration of granulocytopenia is relatively
short; febrile episodes are reported in about 30% of patients,
documented infections in 5%, fatal infections in 2%. When adjuvant RT
is added, infections have been reported to rise to 11.7%, fatal
120
infections to 2.7%. Infection can be documented in about 40% of
febrile, neutropenic patients; 50% of these have bacteremia. A total
of 60% of febrile, neutropenic patients are thought to be infected on
120
the basis of cultures or clinical signs or symptoms. Thus,
antimicrobial therapy is empirically employed in all such patients.
Radiation therapy alone — but especially in combination with
chemotherapy — contributes to two major acute toxicities: esophagitis
and pneumonitis.
As has been mentioned, Adriamycin enhances radiation induced
esophagitis. Chronic esophageal stricture is a hazard avoided through
careful planning of the portals and timing of RT and of the dose and
type of cytotoxic therapy.
1
44
CT adds to the problem of radiation pneumonitis; also, chronic
pulmonary fibrosis has emerged as a major concern in long-term
survivors after multi-modal therapy.
Cardiac toxicity is a potential complication of SCCL treatment.
Pericarditis, aggravation of coronary artery disease, and
cardiomyopathies especially associated with Adriamycin are all
potential toxicities.
Peripheral neuropathy is a toxicity associated with vincristine.
The long-term neurological sequelae of CT + RT have already been
discussed in the context of prophylactic cranial irradiation.
Finally, second malignancies are arising as toxic complications.
Four cases of acute leukemia — all arising 2-1/2 to 3 years after
120
diagnosis of SCCL — have been reviewed by Abeloff et al. All four
patients had achieved complete responses; 3 of the 4 had received
multi-modal CT + RT therapy.
Adjuvant surgery is a final topic to discuss in the treatment of
limited-stage SCCL. Two studies have been mentioned which examined
83 115
the characteristics of long-term survivors with SCCL; ’ in each
study, patients who had received surgery as initial or only treatment
formed a significant subgroup.
122
The role of adjuvant surgery remains unclear. Comis et al.
contributed a relatively early study, which they have recently
123
updated. TNM staging was used for the surgical procedure; the
authors found that patients with superior mediastinal (N2) disease did
124
not seem to benefit from adjuvant surgery. Foster et al.
found
45
that — due to extent of disease or such factors as poor medical
condition and inadequate pulmonary function — only 10 of 37 eligible
125
limited disease patients were surgical candidates. Friess et al.,
in a retrospective review, found that the 15 patients with limited
disease who had entered one of their combined modality protocols after
surgical resection had significantly better median and 2 year survival
than patients without initial surgery. The best median survival was
in patients with the smallest lesions (<5 cm) who had undergone
surgery before starting the protocol.
Adjuvant surgery in SCCL may become an accepted treatment
122
modality. Comis et al. have some good initial results, but the
number of patients is very small. Basic questions remain. When is
adjuvant surgery most effective? (I.e., should it be employed before
or after initial chemotherapy?) Is adjuvant surgery only possible or
efficacious in a relatively small number of patients? Finally: are
the results of adjuvant surgery going to reflect better treatment or
simply the better prognosis of a subgroup of patients with "very
limited" stage disease?^^
Extensive-Stage Disease and Experimental Therapies
1 14
Comis, in his review of treatment for SCCL, considers
infrequent long-term survival to be the distinguishing characteristic
of extensive-stage disease. Intensive therapies (high dose, high
toxicity; multiple, novel combinations; new drugs) have achieved
better median survival. A glance at the registry of long-term
46
QO
survivors (>2.5 years) reported in 1980 reveals that, of 97
patients, only 8 presented with extensive-stage disease. Extent of
disease is a powerful prognostic indicator and survival data reflect
this fact.
114
Corais cites the following as the most prevalent new approaches
to extensive disease: increasing the intensity of chemotherapy; using
a sequence of drug combinations which are thought to be
non-cross-resistant; and incorporating Etoposide (VP-16-213) into the
initial combination of drugs.
Intensive chemotherapy seeks to take advantage of dose-response
relationships and of the intuitive notion that if "effective" is good
65
"intensive" is better. Aisner et al. point to the paucity of data
on dose schedule dependency. The determination of maximum doses
proceeds slowly, on a drug-by-drug basis. Maximum acceptable toxicity
appears to be the end-point. The results have not been encouraging
and toxicity risks are considerable. Late intensive combined modality
126
therapy with autologous bone marrow infusion and high-dose therapy
with protected environment-prophylactic antibiotic units to reduce
127
infectious morbidity have been reported to yield no long-term
survival advantage over more conventional therapy. Neutropenia and
infection are prominent risks. High dose regimens may be especially
beneficial in patients achieving complete response;^^’ however, the
generally low rate of complete response among extensive disease
patients limits their potential application.
47
Another novel approach to therapy is the use of
non-cross-resistant drug combinations in cycles. The results have not
114 129
been exciting; ’ still, the approach may hold some promise.
130
Evans et al. have pointed out that most alternating sequences of
drugs do not appear to be truly non-cross-resistant. They cite a
truly non-cross resistant sequence study in which response was
131
improved. Still, "truly non-cross-resistant" seems to mean that
potentially better response is achieved by achieving potentially
better response — a suspiciously circular chain of reasoning.
New drug development is, of course, a major focus of continuing
research. These drugs, for ethical reasons, are usually tested
initially in patients for whom first-line chemotherapy has failed.
Aisner et al.^^ note the hazards of this approach. It may be that
aggressive initial therapy alters the nature of the tumor so that it
becomes refractory to any subsequent treatment. (Evidence that
therapy changes biochemical and histological characteristics of SCCL
81 82
tumors has already been noted in this paper. ’ ) Aisner cites
Etoposide and vindesine as examples. Etoposide is probably the most
active single agent in untreated SCCL, with response rates averaging
130
over 40%. Yet, the drug has generally been found to produce
insignificant response rates in patients refractory to standard
130
therapy. Perhaps the problem is not pre-treatment, but simply that
tumors unresponsive to first-line therapy are refractory to most novel
therapies as well.
48
In any case, Etoposide (VP-16-213) has proved to be a promising
new agent in treating SCCL. It appears to show a dose-response
relationship; a study of high-dose Etoposide achieved an 80% response
132
rate in 10 patients with extensive disease. Etoposide is often
used in current multi-agent chemotherapy combinations.
133 13^ 133
VM-26 (related to vincristine), vindesine, ’ and,
136
"logically,” vindesine + Etoposide may have activity against
SCCL. The latter seems a good example of combining two drugs to see
if the combination proves to have some magical synergism. Sometimes
synergism is found. When Etoposide alone was compared to Etoposide +
cis-platin (EP) in patients refractory to cyclophosphamide-
130
Adriamycin — vincristine (CAV) therapy , the EP group experienced a
better response rate, higher median survival and increased
thrombocytopenia all thought to reflect the synergistic action of
Etoposide and cis-platin described in some animal tumor
137
systems. Since their patients had been refractory to CAV therapy,
the authors suggested they may have found a truly non-cross-resistant
sequence for further investigation (CAV-EP). The usefulness of EP as
consolidation therapy after initial CAV or "combined alkylators" has
been reported to show little promise.
Finally, mention should be made of two studies similar to the
Yale treatment protocol for SCCL whose results appear in the next
139
section of this paper. Zekan et al. found that CAVE afforded
significantly increased total treatment response over CAV (82%
vs. 66%). Etoposide was said to have added little toxicity although
49
3/57 CAVE patients suffered treatment-related deaths vs. 1/59 CAV
patients. Estimated median survival was not significantly different
for the two treatment groups in limited disease or extensive disease.
140
Messeih et al. reported a significantly increased overall
response rate (65% vs. 50%), and complete response rate (44% vs. 18%)
for their CAVE group and — strikingly — extensive disease patients
achieved a complete response rate of 35% on CAVE versus 0% on CAV.
Overall median survival for all responders and median survival for
complete responders was not significantly different for the two
treatment groups.
Closing Comments
Despite the tantalizing response of SCCL to initial radiation or
chemotherapy, relapse is the rule. Long-term survival (best defined
as longer than 4-5 years if any association with cure is to be
implied) is rare. Extensive disease patients have an especially
dismal prognosis but this may improve if more can achieve complete
response to therapy. Still, the disease remains one in which many
patients are treated to allow survival of a few. Severe treatment
toxicities can be avoided with rational dosage, timing, and selection
of therapeutic modalities. They should be avoided, for there is no
evidence that toxic therapies are the best therapies, and when cure is
rare treatment should be relatively palatable.
Limited-stage disease offers the most hope. Prophylactic cranial
irradiation (PCI) appears to have enough chronic neurological
50
toxicities that its use is best limited to complete responders, two to
four months after the start of therapy. Thus, PCI will be employed
mostly in limited-stage disease. PCI may fall out of favor entirely
if, for example, its chronic toxicities are found to outweigh its
protection of the subgroup of patients who would otherwise suffer
isolated CNS relapse. Nitrosureas appear to be especially associated
with the chronic toxicity of PCI. Patients with less than complete
responses can be treated for CNS metastases as they arise. Chest
irradiation makes a great deal of sense in limited disease; there is
enough clinical evidence and good theoretical speculation to support
the notion that local control of intrathoracic disease is essential
for long-term survival. Care must be taken to avoid acute toxicities
that accompany multi-modal therapy; chronic pulmonary toxicity is a
significant factor which requires further study.
The importance of local control makes adjuvant surgery a
potentially useful treatment modality. The apparently superior
survival of patients with small '*very limited" tumors highlights the
need for a biochemical marker or other method of early diagnosis
before SCCL becomes clinically apparent. If high risk populations
could be screened for the disease, survival in SCCL would certainly
improve, even with the limitations of current therapy.
Our understanding of SCCL is poor. The variability of treatment
results and the resistance of small cell tumors to second-line drugs
are but two reflections of our ignorance in the clinical setting. The
variability among pathologists in identifying tumor subtypes and the
51
lack of apparent prognostic significance of these subtypes make the
current system of histological classification questionable.
Heterogeneity is the hallmark of SCCL; tumor cells are variable
in chromosome number, proliferative activity, antigenic expression,
clonal origin, cytomorphology and biochemical behavior (including
expression of tumor products and biochemical markers). Tumor cells
with few or no neurosecretory granules, low dopa decarboxylase and
bombesin activity, high ploidy and active proliferative behavior have
all been identified as belonging to a clinically more aggressive
subclasss. The "variant" subclass of tumor cells may be both
radioresistant and more aggressive than the "classic" subclass. The
origin of aggressive tumor cells is obscure since dopa decarboxylase
and neurosecretory granules are distinguishing APUD characteristics.
Perhaps they evolve from cells in the original tumor (i.e., the tumor
formed by initial malignant transformation).
The reclassification of SCCL proposed by the pathology panel of
the International Association for the Study of Lung Cancer is of great
significance. It is thought that the NCI’s "variant" subclass tumor
cells are the iui vitro equivalent of the proposed small cell-large
cell subgroup, and that the NCI's "classic" cells are the in vitro
equivalent of the proposed classic small cell subgroup. If, for the
first time, a prognostically significant classification system has
been found, whose subtypes can be reliably identified by different
pathologists and studied with equivalent in vitro cell lines, then a
major step will have been taken in the struggle to link basic science
52
research on cellular characteristics with clinical practice. Until
then, information on the heterogeneity of SCCL tumor cells and the
cellular characteristics of clinically aggressive tumors goes beyond
our ability to use it: the information doesn't help in diagnosis, for
our diagnostic tools detect only gross disease; it doesn't clarify our
histological classification system, which is based on light
microscopy; it doesn't assist us in prognosis, which is based on gross
extent of disease and subjective evaluation of a patient's ability to
carry out his daily tasks; and it probably won't help us design better
therapy, since our therapeutic modalities are so very limited. But
only work on cells will characterize the SCCL tumor. Our methods of
diagnosis, classification, prognosis, and treatment will become more
refined as understanding of the tumor cells expands. New
modalities — hyperthermia, monoclonal antibodies, radiosensitizing
drugs^ — may prove useful by empirical trial. Today's dilemma is that
a hit-or-miss approach to SCCL is bound to fail and the information we
need for rational therapy is elusively basic.
1
'1
53
PART THREE: THE STUDY
This paper presents the initial results of a Yale University
treatment protocol for small cell cancer of the lung (SCCL). The data
are part of a continuing study; methods, patients, results, and
discussion are presented below.
Methods
During the period October, 1980 to April, 1983 all referred
patients with histologically confirmed SCCL (by cytology or biopsy of
metastatic sites) were entered in the study. Patients were accepted
regardless of stage of disease, performance status, or life
expectancy, provided they had at least one site of measureable or
evaluable disease. Patients were ineligible for inclusion in the
study if they had received prior treatment for their disease, with the
exception of surgery, or if their left ventricular ejection fraction,
by gated blood pool scan, was too low to permit treatment with
Adriamycin (doxorubicin).
Pretreatment staging evaluation included history and physical
examination with evaluation of performance status. Blood tests
included CBC, platelet count, BUN, creatinine, bilirubin
(total/direct), alkaline phosphatase, glucose, electrolytes,
prothrombin time/partial thromboplastin time, cortisol, and studies
for ectopic hormones as indicated.
54
Diagnostic procedures included bone marrow biopsy and aspirate;
chest x-ray with tomography in all patients with limited-stage disease
and others as indicated; liver-spleen scan and bone radionuclide
scans; CT scan of the head; skin tests for SKSD, PPD, Candida, mumps;
electrocardiogram; and left ventricular ejection fraction gated blood
pool scan.
Patients were defined as having limited-stage disease (LD) if the
disease was confined to one hemithorax, with or without involvement of
hilar, mediastinal and ipsilateral supraclavicular lymph nodes.
Extensive-stage disease (ED) was defined as disease beyond these
confines.
For treatment, patients were randomized prospectively to CAV
(cyclophosphamide, Adriamycin, vincristine) or CAV/E (the above plus
2
Etoposide (VP-16-213). Drug dosages were: Adriamycin 40 mg/m ;
2 2
cyclophosphamide 1000 mg/m IV; vincristine 1.4 mg/m IV (not to
2
exceed a total dose of 2 mg); Etoposide 125 mg/m IV. CAV cycles were
every 21 days. CAV/E cycles were every 42 days, with CAV given on day
2
1, Etoposide 125 mg/m IV on each of days 21, 23, and 25, beginning
again with CAV on day 42.
In limited disease, 3000 rads of radiation therapy (RT) to the
primary tumor, mediastinum, and bilateral supraclavicular nodes as 300
rads per day, 5 treatments per week (10 treatments total) was given
initially. Vincristine and cyclophosphamide in the doses above were
given after staging, concurrent with the first phase of RT, followed
by 4 cycles of CAV or 2 cycles of CAV/E. Adriamycin-containing
I
;■ t
^ni l.'i
55
combination therapy thus began after completion of the first phase of
RT and at least 21 days after initial cyclophosphamide and
vincristine. An additional 2400 rads of RT to the primary sites, with
concurrent cyclophosphamide and vincristine, were given as 8
treatments of 300 rads each, after the first 4 cycles of CAV or 2
cycles of CAV/E, before completing 6 more cycles of CAV or 3 more
cycles of CAV/E.
In extensive disease, treatment was as above, except irradiation
of the primary site was at the option of the responsible clinician.
After cycle 4 of CAV or cycle 2 of CAV/E, all complete responders
with no known brain metastases received prophylactic whole brain
irradiation as 3000 rads over 2 weeks at 300 rads per treatment,
regardless of disease extent at presentation.
Treatment was continued to 10 cycles of CAV or 5 cycles of CAV/E.
See Tables 9 and 10 for summaries of the treatment protocols.
If, after 6-8 weeks of chemotherapy, there was disease
progression, patients were considered off-study and treatment was
individualized. Otherwise, patients were treated per protocol until
clear-cut evidence of progression or relapse. Subsequent therapy was
individualized.
At the conclusion of therapy, patients were restaged to document
response.
Dose attenuations were guided by CBC prior to therapy.
Complete response was defined as total disappearance of all
disease with biopsy confirmation (e.g., for bone marrow or liver)
56
lasting at least 30 days.
Partial response was defined as a 50% decrease in the product of
2 tumor diameters perpendicular to one another, without associated
progression of any other lesions or the appearance of a new lesion.
Regression had to last a minimum of 60 days.
Stable disease was defined as less than 50% regression of
measureable lesions with the appearance of no new lesions and no
deterioration of performance status.
Progression of disease was defined as the appearance of any new
lesion or the increase in size of any measureable lesion by greater
than 50%.
In this report, patients with stable disease and progressive
disease are grouped together as "non-responders."
ECOG toxicity criteria were used as a basis for patient
comparison.
Performance status was defined as follows: 0-asymptomatic ;
1-fully ambulatory with symptoms; 2-bedridden less than 50% of the
time; 3-bedridden 50% of the time or more; 4-100% bedridden.
Statistical analysis of time to relapse and survival was
performed using Kaplan-Meier plots; comparisons were made using the
generalized Wilcoxon (Breslow) test of statistics. All median values
are from the Kaplan-Meier plots and therefore may be projections.
57
Patients and Results
Of the 47 patients entered into the study, 8 were inevaluable.
Five of the 8 patients had extensive disease (ED). Of these 5: 2
patients never got Adriamycin due to inadequate pre-treatment cardiac
function; 1 had intercurrent prostatic cancer; 1 chose to leave the
care of a physician participating in the study after one visit, for
unknown reasons; and 1 patient had a sudden cardiac death 48 hours
after her only cycle of CAV therapy.
Three of the 8 inevaluable patients had limited disease (LD).
Of these 3: 1 patient had not been on-study long enough to evaluate
response — in addition, this patient's tumor was of mixed small
cell/large cell histology; 1 had intercurrent prostate cancer; and 1
patient's chemotherapy was discontinued at the patient's request when
symptoms of congestive heart failure developed after one dose each of
cyclophosphamide and vincristine (the cycle contained no Adriamycin).
On-study time was defined as the date treatment started to the
date last seen or date of death. The 39 evaluable patients had a
median on-study time of 219 days (range 6-907 days).
Twenty-eight of 39 patients have relapsed. Eleven of 39 patients
have not relapsed, one of whom died without apparent relapse (of
infection or radiation pneumonitis, as will be described later); the
other ten patients are still living and are disease-free. Sixteen of
39 patients are still alive, including 6 who have relapsed. The
median follow-up for patients still alive is 219 days (two shortest
58
follow-ups: 70 and 97 days; two longest: 674 and 907 days).
Patient characteristics are presented in Table 11, subdivided by
extent of disease and treatment arm. Fifteen of 39 patients (38%) had
limited disease (LD). Twenty-four of 39 (62%) had extensive disease
(ED). Two ED patients presented with superior vena cava syndrome; 1 ED
patient had SIADH on presentation. One LD patient had significant
non-neoplastic disease on presentation (diffuse scleroderma; she is
the only patient whose initial performance status is unknown).
As expected, LD patients had better initial performance status
than ED patients (LD — 11 of 15 patients fully ambulatory (performance
status 0 or 1); ED — 11 of 24 patients fully ambulatory). The LD group
was slightly younger than the ED group (median ages: LD-60 years;
ED-63.5 years). The LD group contained a greater proportion of women
(LD- 9 women: 6 men; ED- 11 women: 13 men).
Comparing treatment arm groups (Table 11): On the whole, the CAV
group contained younger patients (median ages: CAV-59 years; CAV/E-66
years). LD-ED distribution was similar for both treatment groups: of
21 CAV patients, there were 8 LD (38%) and 13 ED (62%); of 18 CAV/E
patients, there were 7 LD (39%), 11 ED (61%).
Fourteen of 21 CAV patients (67%) were fully ambulatory
(performance status 0 or 1) versus 8 of 18 CAV/E patients (44%). Most
of this difference can be accounted for by the fact that 8 of 13
patients (62%) in the ED-CAV group were fully ambulatory versus 3 of
11 patients (27%) in the ED-CAV/E group.
59
The CAV/E group contained a greater proportion of women (CAV/E-
10 women: 8 men; CAV- 10 women: 11 men).
Three patients had surgery before beginning the protocol: 2 LD,
1 ED. Patient characteristics are continued in Tables 12 and 13.
Eighteen of 24 ED patients presented with metastatic disease in
more than one site. Sites of presenting metastases, by treatment arm,
with the number and percentage of patients presenting with them are
shown in Table 12. Six of 24 ED patients presented with metastatic
disease involving single sites (see Table 12).
Sites of relapse among all 39 patients (ED + LD) with the number
and percentage of patients relapsing at those sites are presented in
Table 13. There were 10 relapses in sites of initial disease,
excluding the chest (see Table 13).
Of the 5 brain relapses, 4 occurred in ED patients who had
received no prophylactic cranial irradiation (PCI). Three of these 4
patients received no CT scan or radionuclide brain scan on diagnosis.
One of the 5 brain relapses occurred in an LD patient with negative CT
scan on diagnosis who relapsed 4 months after 3000 rads of PCI. The
ED patient who experienced a choroidal relapse had no PCI.
Two LD patients deserve special mention. The first patient had a
palpable subcutaneous nodule at diagnosis, refused biopsy, and later
relapsed in the same site; the second had a radionuclide scan
equivocal for liver involvement at diagnosis and later relapsed in
liver, bone and bone marrow.
60
Nine patients had chest relapses. Five of the 9 had ED and
received no thoracic irradiation. It is not known whether the
remaining 4 patients (2 LD; 2 ED) relapsed within their radiation
therapy portals.
Response to therapy, grouped by disease extent and treatment arm,
is presented in Table 14. Objective responses (CR + PR) occurred in 28
of all 39 patients (72%); in 13 of 15 LD patients (87%); 15 of 24 ED
patients (63%); 8 of 8 LD-CAV patients (100%); 5 of 7 LD-CAV/E
patients (71%); 9 of 13 ED-CAV patients (69%); and 6 of 11 ED-CAV/E
patients (55%).
The following sections present data from Kaplan-Meier curves for
time to relapse and survival. Subgrouping was performed in analyzing
the data by treatment group (e.g., LD-CAV responders vs. LD-CAV/E
responders); such subgrouping is intended only to reflect the
distribution of the data, since the small number of patients in these
subgroups precludes in-depth analysis.
Time to relapse was defined as the date treatment began to the
date of disease progression. The data are presented in Table 14 and
Figures 1-4.
Median time to relapse was 361 days in responders (CR + PR) with
LD; for ED responders, the median was 188 days. Analysis of these
relapse curves showed a significantly longer time to relapse for the
LD responders (£_=.0001). (See Figure 1.) Time to relapse for ED
non-responders (median: 71 days) was significantly shorter than for
ED responders (£_=.006). (See Figure 2.)
61
Time to relapse was studied by treatment group. For patients
with LD, time to relapse on CAV (median: 334 days) versus time to
relapse on CAV/E (median: 361 days) was not significant
(£=•55). (See Figure 3.) In contrast, time to relapse for all ED
patients on CAV (median: 193 days) compared to ED patients on CAV/E
(median: 109 days) was barely significant (£=.04). (See Figure
4. ) Further subgrouping revealed that time to relapse of ED
responders (CR + PR) on CAV versus those on CAV/E was not significant
(£=.77); but comparison of ED non-responders on CAV versus ED
non-responders on CAV/E was significant (£=.02).
Survival data, the main criteria by which protocols are
evaluated, are presented in Table 15 and Figures 5-9.
Median survival for all patients was 301 days. (See Figure
5. ) Median survival for LD complete responders was 560 days.
Survival of LD responders (CR + PR) (median: 560 days) was
compared to survival of ED responders (median: 230 days) and found to
be significant (£=.0007). (See Figure 6.) Survival of ED responders
versus ED non-responders (median: 198 days) was not significant
(£=.24). (See Figure 7.)
Survival by treatment group was analyzed. When survival of LD
patients on CAV (median: 560 days) was compared to LD patients on
CAV/E (median: 424 days), no significant difference was found
(£=.24). (See Figure 8.) Survival of ED patients on CAV
(median: 230 days) versus ED patients on CAV/E (median: 186 days)
was not significant (£=.23). (See Figure 9.)
62
A glance at the survival curve for all patients shows a plateau
at about 6%. (See Figure 5.) The curve for LD complete responders
plateaus at 35%. But 8 of the 12 patients in this group were still
alive and those 8 had a median follow-up of only 305 days, while
projected median survival was 560 days.
Thusfar, 4 patients have lived 1-1/2 years or more. Two are
described in some detail below because they will be mentioned in the
discussion of treatment results later on.
First, a male patient presented at 51 years of age with
performance status 1 and extensive disease — bone involvement, pleural
effusion of unknown cytology, a subcutaneous nodule in the left flank
and a supra-clavicular node. After 4 cycles of therapy, his chest
disease had not changed significantly; however, he experienced a
choroidal relapse in the left eye, with detachment and uplifting of
the retina. The patient received radiation therapy to the eye and
additional cycles of CAV. His chest x-ray shov;ed no significant
improvement during 7 months of therapy — thus, he was a non-responder.
However, he did not expire until 847 days after the start of therapy.
Second, a 60-year-old woman with limited disease and performance
status 0 underwent a left lower lobectomy then received CAV therapy,
achieving complete response. She was still alive at 907 days, without
relapse.
Some toxicities were common but not severe enough to cause great
concern: radiation esophagitis (never causing strictures or requiring
hospitalization); nausea and vomiting (controllable); mucositis (never
63
precluding oral food consumption); alopecia. All were ECOG #2
(moderate toxicity) or better.
Myelosuppression significant enough to cause a drop in WBC count
to <2000 (ECOG #3 or worse) was experienced by 24 of 39 patients
(62%): 14 of 24 patients with ED (58%) and 10 of 15 with LD (67%); by
treatment group: 16 of 21 CAV patients (76%); 8 of 18 CAV/E patients
(44%).
Anemia severe enough to require transfusion (ECOG #3) was
experienced by 9 of 39 patients overall (23%): 5 of 24 with ED (21%);
4 of 15 with LD (27%); 6 of 21 on CAV (29%); 3 of 18 on CAV/E
(17%). Three patients require special mention: one extensive disease
patient on CAV had a Hgb/Hct of 8.6/25.3 but no transfusion
documented; one LD-CAV/E patient had Hgb/Hct of 10.1/25.5 but refused
transfusion; one ED-CAV patient had chronic anemia status post Bilroth
II surgery and his anemia was not evaluable as a toxicity.
No platelet counts <50,000 (ECOG #3 or worse) were documented and
there were no episodes of bleeding.
Six patients were hospitalized 8 times for pneumonia; 3 episodes
of concurrent sepsis were documented. Two patients were hospitalized
three times for fever: one of these patients was hospitalized
separately for pneumonia, and is included among such patients above;
one patient was hospitalized twice with negative cultures but a left
upper lobe cavitary lesion on chest x-ray and a positive PPD test.
The latter patient was treated with INH and Rifampin.
64
One patient was hospitalized once with a lung abcess and failure
to thrive.
One patient was hospitalized once for pancytopenia (WBC count of
300) but neither fever nor infection was documented.
Eight patients were thus considered to have been hospitalized at
some time for infection (all those described above except the patient
with pancytopenia only). Seven of these 8 patients had ED; the one LD
patient was hospitalized twice, once for pneumonia without sepsis,
once for fever only.
Thus, 7 of 24 ED patients (29%) experienced significant infection
as did 1 of 15 LD patients (7%); 7 of 21 CAV patients (33%); and 1 of
18 CAV/E patients (6%). One patient not included above may have died
of treatment-related infection, as discussed below.
Two patients, both with LD on CAV/E, experienced radiation
pneumonitis, one requiring treatment with steroids. A third patient,
with ED on CAV, who had superior vena cava syndrome and liver
involvement at presentation, was hospitalized 12 days after her last
chemotherapy cycle, 5 weeks after radiation therapy to the chest, with
leukopenia, fever, chills, and bilateral pulmonary infiltrates.
Cultures were negative, but she was begun on antibiotics. Her lung
disease was thought to be consistent with radiation pneumonitis, but
this was diagnosed by chest x-ray and clinical impression only. The
patient progressed to "Adult Respiratory Distress Syndrome" after one
week of hospitalization and expired two and one-half weeks after
admission. This patient almost certainly died of treatment-related
\
65
toxicity. Infection is thought to be the most likely cause; radiation
pneumonitis is a possibility. The patient died without documented
relapse after a partial response to therapy.
One inevaluable patient had a possible treatment-related death.
She was a 70-year-old woman who presented with performance status 4,
SIADH and extensive disease. Her cardiac ejection fraction was
50%. She received one cycle of CAV therapy and had a sudden cardiac
death 48 hours later.
Three other patient deaths should be described.
A patient with LD on CAV therapy who received prophylactic
cranial irradiation (PCI) developed dementia, dizziness, and double
vision. Her CNS symptoms progressed, and, in light of a lumbar
puncture and CT scan negative for tumor, she was felt to have died of
paraneoplastic encephalopathy. However, combined Adriamycin-radiation
therapy toxicity cannot be ruled out.
One patient with ED, a non-responder to CAV therapy, experienced
dementia with memory loss and confusion. The patient’s CNS symptoms
progressed and, in light of a CT scan and lumbar puncture negative for
tumor, his death was felt to be consistent with paraneoplastic
encephalopathy. The patient received no PCI. However, death due to
toxicity of chemotherapy alone cannot be ruled out.
Finally, a 58-year-old man presented with significant liver
involvement, bilateral lymphadenopathy , and performance status of
3. He was randomized to CAV/E therapy and died due to progression of
his disease in the liver 6 days after his only therapy cycle, which
66
consisted of CAV. This patient is mentioned because his case will be
noted in the discussion of treatment results later in the paper.
Three patients experienced significant cutaneous infections. Two
patients — one LD on CAV/E, one ED on CAV — experienced H. simplex
infections while being hospitalized for concurrent problems. An ED
patient on CAV/E experienced an H. Zoster infection as an outpatient.
Three patients had rash reactions to chemotherapy: one to
Adriamycin; one to Adriamycin and cyclophosphamide or cyclophosphamide
alone; one unknown. Two patients required treatment with IV
steroids.
Adriamycin had to be discontinued in 2 patients due to
cardiotoxicity . None experienced heart failure (both toxicities ECOG
#2). One inevaluable patient experienced heart failure after a single
cycle of chemotherapy which did not contain Adriamycin. Chemotherapy
was discontinued at the patient's request.
Vincristine neurotoxicity was significant enough to cause
discontinuation of the drug in 4 patients (3 LD on CAV; 1 ED on
CAV/E). One of these patients (ED) experienced "Etoposide accentuated
vincristine neuropathy with foot drop” and both drugs were
discontinued. The only other documented attenuation of Etoposide was
one cycle of 3 doses for myelosuppression just before the patient
relapsed. Vincristine dose attenuation of more than 50% was required
in 4 patients (2 ED-CAV; 1 ED-CAV/E; 1 LD-CAV) for whom
discontinuation of the drug was not necessary.
67
Finally, 7 patients required significant attenuations (>50%) in
the dose of their chemotherapy (cyclophosphamide and/or Adriamycin)
for myelosuppression alone: 3 ED-CAV; 1 ED-CAV/E; 2 LD-CAV/E; 1
LD-CAV.
Discussion
The International Association for the Study of Lung Cancer
Workshop has published its treatment result expectations for
SCCL.^^ Expectations include complete response of 50% in LD and 20%
in ED; median survival of at least 14 months in LD and 7 months in ED;
and 15-20% 3 year disease-free survival among LD patients. These
expectations may be excessively optimistic (especially those for
long-term survival — see Table 8), but at least they establish some
standard for comparison. Table 7 presents treatment results from
selected studies; direct comparisons are not possible between
studies.
The response rates in the present series were generally good,
with 80% of LD patients achieving complete response. Just 12% of ED
patients achieved complete response, a low but acceptable number.
Projected median survival was very good, ranging from about 6.5
months for ED non-responders to more than 18 months for LD complete
responders. As expected, both time to relapse and survival were
significantly longer for LD responders (CR + PR) than for ED
responders. The presence in the ED non-responder group of a patient
who survived 847 days after a choroidal relapse must be kept in mind
68
when evaluating the projected survival data for this relatively small
group (n=9). The unusual choroidal relapse appears to have had no
significant negative influence on this patient's survival. The
projected median survival of 560 days for LD complete responders must
also be approached with some caution since the projection is based on
data from 12 patients, 8 of whom were still living. The living
patients had a median follow-up of just 305 days.
Of the 12 LD patients achieving complete response, one was alive
and disease-free at 907 days (slightly less than 2.5 years).
Interestingly, this patient had surgery prior to beginning the
protocol, adding further anecdotal evidence to the efficacy of
adjuvant surgery in achieving local control and the importance of
local control in long-term survival. In fact, it is too soon to
predict the number of long-term survivors from this study.
The two treatment groups were very similar in survival results.
The CAV/E group had shorter projected median survival in both ED and
LD, but no comparison with CAV survival curves was significant. Time
to relapse was shorter for the ED-CAV/E group than the ED-CAV group
and the comparison was barely significant (_p^=.04). Further
subgrouping showed a significantly shorter time to relapse for the ED
non-responders on CAV/E than those on CAV. Comparison of time to
relapse for ED responders was not significantly different for the two
treatment groups. There are numerous reasons for quicker time to
relapse in ED non-responders on CAV/E. These include the fact that
the ED-CAV/E group contained a substantially smaller proportion of
69
fully ambulatory patients than the ED-CAV group (62% vs. 27%). The ED
non-responder CAV group contained that patient with the choroidal
relapse who went on to relatively long survival while the ED-CAV/E
non-responder group contained the patient who died of progressive
disease in only 6 days. ED non-responders on CAV survived longer than
ED non-responders on CAV/E but the groups are small and comparison
didn't quite reach significance (2.= . 053). Interestingly, survival was
better for the ED responders on CAV/E than those on CAV, but the
comparison was not significant (2=*'^1)*
Clearly, the addition of Etoposide to CAV produced no difference
139,140
in treatment results worthy of mention. iwo previous reports
cited better response rates with the addition of Etoposide to CAV;
still, the studies found no significant differences between the
treatment groups in survival.
No unexpected toxicities arose in the study. Myelosuppression
was no greater than that consonant with a good therapeutic response.
Etoposide added no apparent additional toxicity to the CAV
regimen. In fact, only 1 of the 18 CAV/E patients (6%) required
hospitalization for infection versus 7 of the 21 CAV patients
(33%). The 33% rate for CAV patients is higher than the 11.7%
"standard" infection rate for combined modality protocols cited in one
120
review of SCCL treatment complications.
The 6% rate with CAV/E is
lower than the "standard" rate and unexpected. Leukopenia (WBC count
<2000) was experienced by 16 of 21 CAV patients (76%) versus 8 of 18
CAV/E patients (44%). Perhaps this underlies the difference in
#
70
infection rates, unless Etoposide has some heretofore undiscovered
antibiotic properties.
One treatment-related death was probably caused by infection
(although radiation pneumonitis is possible), yielding a fatal
infection rate of 1 in 39 patients (2.6%). This is reasonable for a
120
combined modality study. Sudden cardiac death occurred after a
single cycle of cyclophosphamide and vincristine in a patient
presenting with extensive disease, SIADH, poor performance status
(bedridden) and a cardiac ejection fraction of 50%. This must be
viewed as a possible treatment-related death although no Adriamycin
was given.
In summary, the present study employed state-of-the-art design
(prophylactic cranial irradiation after complete response, thoracic
irradiation in limited disease, and use of Etoposide, an agent with
significant activity against SCCL) and achieved early treatment
results comparable to those in the current literature. It is too
early to evaluate long-term survival.
Addition of Etoposide to CAV therapy yielded no improvement in
initial treatment results, including survival. However, an
unexpectedly low rate of infections requiring hospitalization was
found in the CAV/E group, substantially lower than that in the CAV
141
group, perhaps secondary to a lower rate of leukopenia with the use
of Etoposide in half the treatment cycles.
71
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127. Valdivieso, M. , Cabanillas, F., et al.: Effects of intensive
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128. Smith, I.E., Evans, B.D., Har^and, S.J.: High dose
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84
138. Livingston, R., Mira, J.: Extensive small cell lung
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2:193, 1983.
140. Messeih, A., Schweitzer, J.M., et al . , : The addition of
VP-16-213 to Cytoxan, Adriamycin and Vincristine for remission
induction, and survival in patients with small cell lung
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141. Rome, L.S., Portlock, C.S., et al . : Cyclophosphamide,
Adriamycin, vincristine (CAV) vs. cyclophosphamide, Adriamycin,
vincristine alternating with VP-16 (Etoposide) (CAV/E) in the
treatment of small cell cancer (SCC) of the lung. Proc. ASCO 4,
1985 (in press).
Ex-cigarette
smokers
<1 pack
a day
1-2 packs
a day
14.5%
19.2%
23.9%
Total subjects = 163
From;
Auerbach, 0.,
Garf inkel , L. ,
and Parks,
V.R.
[14;
Table _1 — Age Standardized Percentage Distribution of
Cigarette Smoking Habit
2+ packs
a day
31.1%
SCCL by
vr
Exposure Group+
Excess Cases
1 - 359
8.27*
360 - 1779
22.07*
> 1800
33.69*
Combined groups
64.03*
= significantly different from expected number of cases (£.<.01)
+Exposure is quantified by "Working Level Month" (WLM) Groups. One
WLM is a month's work performed in an atmosphere containing a standard
radiation dose per liter of air.
From:
Archer, J.E., Saccomano, G.,
and Jones,
J.H.
[16]
Table 2. — Distribution of Excess (Presumably Radiation-Induced)
Bronchogenic Cancers by Radiation Exposure Group
87
Symptom
Percentage of patients with the symptom
Cohen and Matthews
[12]
Friesenhahn ,
et al.
[44]
Cough
76
37
Chest pain
36
28
Dyspnea
34
31
Pneumonitis
25
NR
Wheeze
22
NR
Hemoptysis
15
17
Fatigue
NR
21
Hoarseness
15
NR
SVC syndrome
12
NR
NR = Not Reported
Table _3 — Symptoms of SCCL
88
At Presentation^ At Autopsy^
( total pts = 375) ( total pts = 163)
Liver
32
61.7
Bone
30
35
Bone marrow
16
NR
Brain
14
50
Skin, soft tissue,
nodes
16
75.5 (excluding
"chest wall")
Effusion/pleura
15
22.7
Heart
NR
20.3
NR = Not Reported
[45 ]
From: Livingston, R.B., Trauth, C.J., Greenstrget, R.L. and
Auerbach, 0., Garfinkel, L. , Parks, V. ^
Table _4 — Percent Distribution of Metastases at Presentation and
at Autopsy in Two Studies
From
d1
Site
Procedure
Refommended
Primary
Mediant inum
Bone marrow
Liver
Chest X-ray
Fiberoptic bronchoscopy
Mediastinoscopy*
Gallium scan
Biopsy and aspiration
Bilateral biopsies
Scintifrrams
Peritoneoscopy and
liver biopsy
Ultra so no^aphy
CT scan
Lymph nodes and skin Fine-needle aspiration
CSS
Retropentoneal
organs
CT scans
Scintigrams
Lumbar puncture
Myelograms
CT scans
Ultrasonography
Laparotomy
4
4
4
If poiiitive
initially
If signs'
symptoms
4
•Whenever possible.
Osterlind K., Ihde, D.C. et al
[57]
Table _5 — Recommendations for Restaging
Definite
Stage of disease
Performance status
Probable
Liver or CNS metastases
Laboratory parameters
Possible
Weight loss
Number of metastatic sites
Age
Sex
Size of lesion ("very limited" vs. other)
None
Histologic subtype (1977 WHO classification)
Invest isational
Histologic subtype (small cell-large cell vs
classic small cell)+
Adapted from Ihde D.C.,
and Hansen, H.H.[48]
+Proposed by pathology panel of the International Association for the
Study of Lung Cancer. [73b]
Table ^ — Prognostic Factors in SCCL
91
Number
Complete
Median
Survival
of
Pts
Response
(weeks)
Treatment
LD
ED
LD
ED
LD
ED
Placebo^^^^
38
108
+
+
11.7
5.0
Placebo
29
+
+
+
>16
+
Surgery^^®^
68
+
+
+
28.5^
+
Radiation^
70
+
*«•
+
44^
+
D [88]
Radiation
53
+
+
>16
+
CAV + RT^^^^
108
250
41%
14%
52
26
CME + RT^^^^
(38 LD
+ ED)
86%
27%
56
20
CAVE + RT^^^^
33
11
76%
34%
92
36
CAVE + RT^^"^^
28
29
61%
21%
60
37
MEV/ CAV/^^^^
MEV - CAV
+
453
+
16%
+
31
+ = Inapplicable
C =
cyclophos
phamide
M = methotrexate
= Not Reported
A =
Adriamycin
RT = Radiation
Therapy
a = Mean Survival
V =
vincristine
E = Etoposide
(VP 16-213)
Table 7 — Treatment Results in SCCL: Selected Studies
92
Number of
Treatment
Patients
o [90]
Surgery
58
Radiation^
70
Chemotherapy ± RT^^^^
255
CAV + RT^^^^
400
Patient Long-Term
Characteristics Survivors
All
LD
0%
LD
All
LD
5%
LD
+
6%
LD +
ED
100
LD
4%
(LD +
ED)
300
ED
11%
LD
2%
ED
+ = Not Reported RT = Radiation Therapy
C = cyclophosphamide A = Adriamycin (doxorubicin)
V = vincristine
Table 8 — Long-Term Survival (>_5 years) in SCCL
Treitntfit Sctifwi
GROUP I - LfmfM Disease
I oe Lu i/> t— < o
« u >
«<(■>>
«e < u»>
tf) «cu >
•CU>pr>
I
%. MCC
•— *5 H- <->
^ U >
T»<«
3>- u ^
o >
Ta b 1 e 9 — Treatirient Protocol for Limited Disease
1
I
I
Treatment Schema
GROUP 2 • Extensive Disease
cycle
1
2
3
4
5
6 7
8
9
Adri a
A
A
A
A
A A
A
A
Diagnosis
CTX
C
C
C
C
C C
C
C
- >^VCR
V
V
V
V
V V
V
V
Elective
Rad Rx
Prophylactic
j
b
Whole Brain
Rad
CTX
VCR
Adri a A A A A
CTX VP-16 C VP-16 C VP-16 C VP-16 C VP-16
VCR V V V V
1 2, 3 H S
cycle
R
E
S
T
A
G
E
2
Adri a : Adriamycin 40 mg/m IV day 1
2
CTX : Cyclophosphamide 1000 mg/m IV day 1
2
VCR : Vincristine 1.4 mg/m IV day 1 (each dose limited to 2 mg total)
VP-16 125 mg/m^ IV days 1, 3, 5
Table 10 — Treatment Protocol for Extensive Disease
CAV Therapy Patients
n = 21 (54%)
10 females: 11 males
Median age (range): 59 years (49-71)
Subgroup : CAV - Limited Disease Patients
n = 8 (38%)
P.S. 0 = 1 - -
— - ^6 pts. fully am
P.S. 1 = 5 -
^ (75%)
P.S. 2 = 0 - _ _
1 pt. not fully
P.S. 3 = 1
am b u 1 a t o r y
P.S. 4 = 0^- —
(12%)
P.S. unknown = 1
Subgroup : CAV - Extensive Disease Patients
n = 13 (62%)
P.S. 0 = 0 -
■—-——^8 pts. fully ambulatory
P.S. 1 = 8 - '
(62%)
P.S. 2 = 4^^
5 pts. not fully
P.S. 3=0
ambulatory
P.S. 4 = 1^^
(38%)
CAV/E Therapy Patients n = 18 (46%)
10 females: 8 males
Median age (range): 66 years (53-72)
Subgroup : CAV/E - Limited Disease Patients n = 7 (39%)
P.S. 0=3
P.S. 1 = 2
P.S. 2=2
P.S. 3=0
P.S. 4=0
5 pts. fully ambulatory
(71%)
2 pts. not fully
ambulatory
(29%)
Subgroup : CAV/E - Extensive Disease Patients n = 11 (61%)
P.S. 0 = - -
- — -—^3 pts. fully ambulatory
P.S. 1 = 2^-—
■ - ^ (27%)
P.S. 2 = 4-^^ _
8 pts. not fully
P.S. 3=3
ambulatory
P.S. 4 = 1— ^ ■
(73%)
E = Etoposide (VP-16-213)
A = Adriamycin (doxorubicin)
C = cyclophosphamide
V = vincristine
Table 11 — Patient Characteristics by Treatment Arm
96
Number of pts
% of
ED pts
with disease
with
disease
Number of pts with
at
site+
at site
this site as only
involvement beyond
Site
CAV
CAV/E
CAV
CAV/E
primary tumor
Liver
8
6
62%
55%
3
Bone
7
5
54%
45%
1
Bone Marrow
6
1
46%
9%
2
Nodes (excluding chest)
3
2
23%
18%
-
Pleura
2^:-
2.VX-
15%
18%
-
Bilateral Lung
1
1
8%
9%
-
Subcutaneous Nodules
2
-
.5%
-
-
Brain
-
1
-
9%
-
Neither confirmed
1 by
cytology
+ Total ED patients = 24
1 of 2 confirmed
by
cytology
ED-CAV = 13
ED-CAV/E = 11
Table 12 — Metastatic Sites at Diagnosis in Extensive Disease (ED)
Patients by Treatment Arm
97
Number of patients
% of all patients who
Site
with relapse at site+
who relapsed >
Chest (excluding pleura)
9
23%
Liver
7
18%
Bone
5
13%
Brain
5
13%
Nodes (excluding chest)
4
10%
Pleura
2.':-
5%
Bone Marrow
1
3%
Subcutaneous Nodules
1
3%
Others CNS (choroidal)
1
3%
Neither confirmed by cytology; one recurrent
+Total pts = 39
Relapses at Sites of Initial Disease'’"'
Site Number of Relapses
Liver 4
Bone 3
Nodes (excluding chest) 2
Pleura 1
Excludes chest relapses, except in pleura
Table 13 — Sites of Relapse
i
tp
98
Response to Therapy by Stage and Treatment Arm
All patients (n=39) (no.(%))
Limited Disease (n=15)
Extensive Disease (n=24)
CAV-LD (n=8)
CAV/E-LD (n=7)
CAV-ED (n=13)
CAV/E-ED (n=ll)
CR
PR
NR
15
(38%)
13 (33%)
11
(28%)
12
(80%)
1 ( 7%)
2
(13%)
3
(12%)
12 (50%)
9
(38%)
7
(88%)
1 (12%)
0
5
(71%)
0
2
(29%)
2
(15%)
7 (54%)
4
(31%)
1
( 9%)
5 (45%)
5
(A5%)
Time to Relapse
Group
LD- CR+PR
ED- CR+PR
ED- NR
CAV-LD
CAV/E-LD
CAV-ED
CAV/E-ED
LD = Limited-stage disease
CR = Complete response
NR = Non-responders
C = cyclophosphamide
V = vincristine
Median ( pro jected)
361 days
188 days
71 days
p-value
334 days
361 days
.55
193 days
109 days
.04
ED = Extensive-stage disease
PR = Partial response
A = Adriamycin (doxorubicin)
E = Etoposide (VP-16-213)
Table 14 — Treatment Results; Response and Time to Relapse
1
Group
All patients
LD - CR
Median ( pro jected)
99
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ED- NR
CAV-LD
CAV/E-LD
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p-value
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560 days
560 days
230 days
198 days
2. =
£ =
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LD = Limited-stage disease
CR = Complete response
NR = Non-responders
C = cyclophosphamide
V = vincristine
ED = Extensive-stage disease
PR = Partial response
A = Adriamycin (doxorubicin)
E = Etoposide (VP-16-213)
Table 15 — Survival
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