International
Symposium
on
Respiratory Oncology -
Leuven, March 31, 2001
Report of Working Group 2: Prognostic factors in non-small cell
lung cancer

Authors:
Vansteenkiste J.
1,
Buccheri G. 2,
Carney D. 3,
Eberhardt W. 4,
Fontanini G. 5,
Jeremic B. 6,
Junker K. 7,
Niklinski J. 8,
Paesmans M. 9,
Verbeken E. 10,
Co-workers of
Working Group 2 .
Affiliation of authors:
1 Respiratory Oncology Unit, Univ. Hosp. Gasthuisberg, Leuven, Belgium
2 Respiratory Unit, Santa Croce e Carle Hospital,
Cuneo, Italy
3 Ireland
4 Internal Medicine Dept., Univ. Essen, West German
Cancer Centre, Essen, Germany
5 Oncology Dept., University of Pisa, Italy
6 Radiotherapy Dept., Radiologische
Universitätsklinik, Tübingen, Germany
7 Pathology Dept., Bergmannsheil
Universitätsklinik, Bochum, Germany
8 Thoracic Surgery Dept., Bialystok, Poland
9 Jules Bordet Institute, Brussels, Belgium
10 Pathology Dept., Univ. Hosp. Gasthuisberg, Leuven,
Belgium.
Address for correspondence:
Johan
Vansteenkiste, MD, Ph.D.
Respiratory
Oncology Unit (Dept. of Pulmonology)
University
Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
Tel
++32-16-346802
Fax
++32-16-346803
E:
johan.vansteenkiste@uz.kuleuven.ac.be
Introduction to prognosis of
lung cancer
Together with the performance
status, the TNM-staging - based on anatomical spread - nowadays still is the most
important tool to make estimates of prognosis for lung cancer patients, and to choose the
best combination of treatment modalities such as surgery, radiation and chemotherapy. The
TNM-staging gives an answer to the question where in the body is the disease?.
The clinical, or even pathological, TNM-staging, however, does not always give a
satisfactory explanation for differences in survival. Resected stage I NSCLC is a typical
example: many patients are cured, but some have an early relapse and die.
In recent years, it has
become clear that, in order to understand more about different patterns of survival in
resected stage I NSCLC, and lung cancer in general, we should also answer the question
what is the character of the disease?. Standard pathological typing and
grading is only a rough answer to this question. Better understanding of the factors
determining aggressiveness of lung cancer, would help us to determine which patients
should be followed more closely, which patients are candidates for (neo)-adjuvant
treatments, or even find out which patients are poor surgical candidates even if they have
apparently localised disease.
In recent years, many groups
have analysed different potentially important prognostic factors, especially in the field
of molecular biology, and this has generated an overwhelming amount of data. A Medline
search using the terms prognostic factor and cancer produced 2,393
papers according to a recent editorial [1]. A major challenge for future revisions of the
TNM-system will be to what extent the influence on prognosis of the rapidly evolving data
on these prognostic factors will be integrated in the staging system for lung cancer, in
order to implement new techniques in the best interest of the patient, without loosing the
widespread applicability of the TNM-system.
It is not and cannot be the
aim of this contribution to give a comprehensive overview of all potentially relevant
prognostic factors in non-small cell lung cancer (NSCLC), but rather to put the different
contributions of this symposium into clinical perspective.
Clinical factors in stage III
NSCLC
Pre-treatment prognostic
factors
Apart from the TNM and
performance status, some other clinical characteristics have also been reported to be of
prognostic relevance. Probably one of the most important is weight loss, but even other
symptoms such as haemoptysis, cough, or chest pain might also have some importance. In a
study on 289 consecutive stage I NSCLC patients, it was reported that patients without
symptoms had a 5-year survival of 74%, while this was only 41% in case of symptoms
(P=0.001), and that this factor remained significant in a multivariate analysis
(P<0.05) [2]. The use of clinical factors for staging non-metastatic lung cancer
nevertheless is of limited value, first because of the low prevalence of symptoms in these
patients, and second because of the subjective nature of symptoms.
When looking at prognostic
factors in locally advanced NSCLC, we should realise that the recently revised staging
system has mainly been derived from a patient population database where the majority of
patients were treated with surgery as the dominant treatment modality [3]. As we have
learned from other solid tumour models as well as from other systemic malignancies (such
as lymphomas or leukaemias), prognostic factors are also closely related to the
treatment that is performed. Any introduction of new or different, e.g. more aggressive
treatment strategies, may thus lead to a change in the pattern of prognostic factors being
of significance within these patient populations. With the treatment of stage III NSCLC
being currently under a rapidly changing influence of new developments from combined
modality treatment protocols, one has to keep in mind this background when looking at any
evaluation of prognostic factors [4].
At the meeting, Eberhardt
presented an overview on possible relevant prognostic factors in stage III disease NSCLC
by carefully reviewing the current literature concerning that issue. A major impact was
laid on the availability of long-term survival data (at least 3-, 4- or 5-year survival
rates) from analysis of different treatment strategies and within distinct patients
populations. Analysis was separated into a) surgical treatment alone (table 1); b) radiation or combined chemoradiation treatment
(table 2); and c) combined modality protocols
including surgery (table 3). As said above, one has to be cautious to differentiate pre-treatment
prognostic factors from prognostic factors with any relation/dependence on treatment
effects (e.g. clinical or pathological treatment response, as explained in the
paragraph below) that cannot be used as parameters to be potentially included into a
conventionally intended pre-treatment staging system but possibly into patients selections
procedures during complex treatment protocols.
In tables 1, 2 and 3, a brief
overview on potential pre-treatment prognostic factors under investigation in the
different treatment strategies is given. Factors, which have a significant influence on
long-term survival in individual publications only are listed in italics.
Only a very small group of
patients of stages III is nowadays still considered for any upfront surgical
approach (table 1): patients with either minimal mediastinal N2 involvement and
some selected T4N0-1 patients are taken to thoracotomy in different institutions with
experience in such extensive surgical approaches [5-7].
Patients who are taken onto
radiotherapy or combined chemoradiation trials have been analysed on possible
prognostic factors in large databases (e.g. the Radiation Therapy Oncology Group (RTOG)
database). With radiotherapy included, factors of tumour size/tumour volume or tumour
burden become of critical importance (table 2). Interestingly, pre-treatment haemoglobin
levels seem to be of major impact once radiotherapy is to be included into treatment
(table 2). The RTOG and his personal experience was put into perspective by Jeremic.
Although gender was occasionally examined as potential prognostic factor in inoperable
NSCLC, results obtained are conflicting. While surgical studies and some studies using
chemotherapy alone in metastatic disease did not indicate clear impact of gender,
International Association for the Study of Lung Cancer (IASLC) indicated gender as
possible prognostic factor [8]. If so, then impact of gender needs to be better explained
since it was observed that females have better outcome, even when stratified for stage and
other adverse risk factors [9]. This has been observed in a number of studies which used
chemotherapy with or without radiotherapy or in the studies using radiotherapy alone
[10,11]. Age was not consistently shown to have an independent influence on survival.
Possible difference in biological aggressiveness, or lower survival in older (e.g. >70
years) patients due to pre-existing co-morbidity, may be the reason. The latter case is
well proven in surgical series, but not in unresectable disease. Some indicated only a
minor influence of age as prognostic factor in studies that used chemotherapy with or
without radiotherapy [11], sometimes favouring older patients [10]. Others indicated that
age may be an important prognostic factor [12-14], favouring younger patients. In a
quality-adjusted survival analysis of the RTOG, patients <70 years had improved
survival with more aggressive therapy (induction chemotherapy and radical standard
radiotherapy or concurrent chemotherapy and hyperfractionated radiotherapy, in contrast to
patients >70 years who qualitatively benefited mostly from less aggressive therapy such
as standard fraction radiotherapy alone [15]. IASLC indicated probable lack of independent
influence in their statement in 1994 [8]. With respect to performance status (PS), almost
all series that evaluated the impact of this potential prognostic factor reported a
significant difference in survival favouring patients with higher PS [16-23]. Recent IASLC
consideration of prognostic factors in NSCLC, clearly indicated PS as one of he two
definite prognostic factors influencing survival [8]. Recently, RTOG [24] noted that of
all patients with unresectable NSCLC treated with either radiotherapy alone or various
chemoradiotherapy regimens, those with poor PS were at high risk for death without
progression, so that they should probably be removed from the context of current clinical
trial and possibly be investigated as a separate entity requiring a different approach. In
another RTOG report [15], quality-adjusted survival showed that patients with poor KPS
(50-70) had the lowest median survival (7.8 months) and the lowest quality-adjusted
survival time (6.7 months). Influence of weight loss was evaluated in many studies and
almost uniformly it was found that patients having marked weight loss did worse than those
with less pronounced weight loss [11,16-23]. Weight loss indicates a generalised influence
of the disease, having interrelation with the stage of the disease and performance status
and it is not surprising that patients with previous weight loss have a worse prognosis.
International Association for Study of Lung Cancer (IASLC) indicated the weight loss as
probable prognostic factor in NSCLC [8]. An
issue remains on the table when dealing with
weight loss as a potential prognostic factor for NSCLC: weigth loss definitions are many
and different, and may have influenced the value attributed to such a prognostic factor. A recent study, evaluating the most commonly
adopted definitions (i.e., less or mor than 10 pounds, less or more than 5 or 10 percent
of the weight measured at 6 months prior to diagnosis), seems to suggest that the
percentage of the total weight loss -with no time bounderies-
is the most prognostically meaningful way to record it.
Considering the primary
tumour, squamous histology was usually considered as more localised form of
NSCLC, while there were observations that this may not be the case for adenocarcinoma and
large cell carcinoma. RTOG [24] observed that when treated with chemoradiotherapy,
adenocarcinomas was less likely to progress at the primary than either squamous cell or
large cell carcinomas, but adenocarcinomas were more likely to spread to brain and other
distant sites than squamous cell carcinomas. The authors concluded that squamous cell
carcinomas should be treated with more local forms of treatment. The
significantly higher risk of brain metastasis in patients harbouring either adenocarcinoma
or large cell carcinoma may warrant for new strategies, including prophylactic cranial
radiotherapy in selected cases and more efficient chemotherapy, needed also to combat
distant spread. Finally, an interesting finding that squamous histology carried increased
risk of death without progression, may suggest that this histological subtype of NSCLC
might require a different approach.
In those patients put on preoperative
chemotherapy or chemoradiotherapy trials, patient selection to an inclusion of
possible surgical resection becomes important. Therefore, patients subgroups with T4N0-1
disease and without any mediastinal involvement seem to have the best prognosis among
those with stage IIIB (table 3). Within stage IIIA, of major importance seems to be the
detailed extent of mediastinal involvement, especially the number of involved mediastinal
lymph nodes (levels) [5,7]. Pre-treatment LDH seems to reflect the overall tumour burden
and may therefore be of major influence on long-term survival for these groups (table 3).
In general, it has to be critically remarked, that most investigations on prognostic
factors in stage III patients groups did not perform multivariate statistical analyses.
Most factors have only been investigated by univariate analyses, mainly because the
patients numbers of individual investigations were mostly very small.
In conclusion, the existence
of different multimodality strategies at the moment does not allow to define a more
generally available prognostic index for stage III NSCLC. Therefore, planned improvements
in pre-treatment staging systems for these patients groups will probably be hampered by
the existing different treatment approaches and will also be difficult to be generalised
[25]. This will even more depend on the use of newer and more sensitive staging
investigations such as more widespread use of mediastinoscopy or FDG-PET. Therefore, any
group presenting data on treatment in stage III NSCLC has to define clearly their upfront
staging investigations, their prospectively planned treatment protocol, and has to record
prospectively different pre-treatment parameters of their included patient population.
Therapy-related prognostic
factors in locally advanced NSCLC
With the advent of several
combined modality treatment strategies, these prognostic factors, usually parameters that
reflect the clinical and even more the pathological response to any induction therapy have
become of special importance (table 4). It seems that the performance of a complete
resection of any residual (vital) tumour into the treatment is one of the major
independent factors determining long-term survival both in the IIIA as well as the IIIB
subset.
The importance of the morphology
of tumour response to chemo- and radiotherapy in correlation with prognosis was
presented in more detail by Junker.
Studies on neoadjuvant
therapy have demonstrated that the degree of tumour regression in resection specimens of
primary tumour and lymph nodes is suggestive for long-term survival [26,27]. To determine
whether reproducible pathological-anatomical findings of therapy-induced tumour regression
could be demonstrated, resection samples of locally advanced NSCLC after neoadjuvant
multimodality treatment were analysed. The neoadjuvant treatment, consisting of 2 cycles
of carboplatin-etoposide-ifosfamide chemotherapy, followed by a third cycle of concurrent
chemoradiotherapy (carboplatin-vindesine plus twice daily 1.5 Gy radiation therapy up to
45 Gy), has been described in detail elsewhere [28]. After completion of combined
chemoradiotherapy, patients who remained free of distant metastases underwent resection
with extensive mediastinal lymph node sampling. For the first time in this treatment
approach, a regression grading scheme (table 5) was applied and its impact on survival was
assessed [29].
Of the 54 patients (25 stage
IIIA and 29 stage IIIB) treated in this multimodality protocol, 40 went on to resection.
Examination of these 40 resection specimens revealed type III regression in 7 (17.5%),
type IIa regression in 20 (50%), type IIa in 10 (25%), and type I in 3 (7.5%). Grouped
together, 27 tumours (67.5%) showed regression grades IIb or III, 13 (32.5%) regression
grades I or IIa.
In 24 patients with
regression grades IIa to III, different-sized target like foci with central necrosis,
narrow foam cell rim, vascular granulation tissue and marked peripheral scarring were
demonstrated in the tumour region. In addition, foam cell nests without central necrosis
were present in four resection specimens. Towards the periphery, the foam cell rims and
nests showed transition into vascular granulation tissue and adjoining cicatrisation,
sometimes forming large scar areas. Comparatively large tumour areas were present in the
three samples classified as regression grade I. The areas of tumour necrosis, seen in
these cases, did not exceed the extent of spontaneous tumour regression. In tumours after
neoadjuvant therapy classified as regression grade IIa, signs of spontaneous and
therapy-induced tumour regression were found simultaneously.
Correlation between
pre-surgical clinical response (based on CT) and therapy-induced tumour regression in the
resection specimen was poor (P=1.0). Of 8
patients with no change on CT, five had less than 10% vital tumour tissue
(regression grades IIb/III).
Patients with regression
grades IIb and III (n=27) showed a significantly longer survival compared to those
classified as regression grades I and IIa (n=13) (median survival, 36 vs. 14 months;
3-year survival rate 52% vs. 9%; P=0.02). In a multivariate analysis according to the Cox
proportional hazards regression model, independent prognostic factors were the grade of
tumour regression (I/IIa vs. IIb/III, P=0.007), the resection status (complete vs.
incomplete, P=0.009), but not clinical response as assessed on CT (response vs. no change
or progression, P=0.1).
In multimodality induction
protocols, spontaneous and therapy-induced tumour regression thus can be distinguished
with high certainty [29]. Several morphological changes which are due to neoadjuvant
chemoradiotherapy were demonstrated. The described regression foci may be seen as the
morphological expression of therapy-induced
tumour regression. However, it has to be pointed out that the single changes are merely
non specific, but, in their entirety, enable us to draw reliable conclusions regarding the
response to pre-surgical therapy.
Several groups have reported
a positive correlation between histologically confirmed complete tumour regression after
neoadjuvant chemotherapy, alone or in combination with radiotherapy, and favourable
prognosis [30-36]. Moreover, several trials demonstrated a significant survival advantage
according to the extent of histomorphological response after chemoradiation [26-28,33]. A
high rate of pathological complete response (39%) was reported by Eberhardt et al., but no
differences in long-term survival were found between patients who had a pathological
complete response and those with persistent viable tumour [37]. In contrast to the trials
mentioned above, no standardised histological examination of the entire tumour area was
carried out in the study of Eberhardt et al.
The determination of complete
or predominant tumour regression immediately after completion of neoadjuvant therapy may
offer information on the potential benefits of a therapy concept. So, this parameter may
be included as an intermediate end point in future neoadjuvant trials on patients with
stage III NSCLC [26,33]. However, complete step-by-step processing of the primary tumour
area in the resection specimens and the resected mediastinal lymph nodes is mandatory. A
favourable or unfavourable value of the therapy concept may possibly be determined
immediately after completion of the therapy and before reaching a certain follow-up
period. Thus, following studies may be started earlier. Standardised classification of
tumour regression may also assist in creating an unambiguous description and subsequently
better comparability of this parameter in different studies.
The finding that response on
CT is a poor predictor for histomorphologically determined tumour regression has been
discussed by several other authors [38,39]. This can be explained by the fact that vital
tumour can not be differentiated from already necrotic tumour tissue or scar formation on
CT. After neoadjuvant therapy, tumours of several centimetres may well show
marked or even complete tumour regression, so that a generous indication for surgery is
justified in cases of no change under therapy. Recent pilot data have
suggested that FDG-PET might be a better imaging technique to assess pathological tumour
response [40].
Standard biological factors
Amongst the different
standard biological tests of potential relevance to the prognosis of NSCLC, the role of
leukocytes and tumour markers was highlighted at this workshop.
Leukocytes
The experience of the
European Lung Cancer Working Party about the usefulness of leukocyte and neutrophil counts
as additional independent prognostic factor in NSCLC was reviewed by Paesmans.
A prognostic factor analysis
on a series of 1052 patients with advanced NSCLC included in seven clinical trials
performed by this Group during a ten years period from December 1980 to August 1991 was
carried out [41]. These trials were mainly randomised trials testing chemotherapy regimens
based on platinum derivatives. By uni- and multivariate parametric and non-parametric
methods, the prognostic value of 23 routinely assessed variables including clinical
factors related to the patient or to the tumour (sex, age, body weight loss, histology,
prior therapy, type of lesions, disease extent and metastatic sites) and biological
factors (leukocytes, neutrophils and platelets counts, haemoglobin, serum alkaline
phosphatases, serum LDH, bilirubin, creatinine and calcium) were assessed. Survival was
measured from the day of registration in the trials. All biological covariates were
dichotomised. Pre-therapeutic absolute white blood cell and relative neutrophil counts
were respectively considered as abnormal if >10 x 103 cells/µl and >75%
of the total white blood cells. At the time of analysis, median follow-up was 270 weeks
and 951 events (90%) were observed. Both abnormal white blood cell and neutrophil counts
were identified as poor prognostic factors (median survival times of 24 versus 32 weeks
for white blood cells, P<0.0001 and 22 versus 32 weeks for neutrophils, P<0.0001).
Rates of abnormal values were 40% and 36%. On parametric multivariate analysis, an
independent prognostic value was found for these two covariates with hazard ratios of 1.33
(95% CI 1.10-1.63, P=0.0003) for abnormal white blood cells count and of 1.27 (95% CI
1.08-1.59, P=0.02) for abnormal rate of neutrophils. The other variables explaining
heterogeneity in survival were disease extent, Karnofsky performance index, age, sex,
presence of skin metastases and serum calcium level. Using non-parametric recursive
partitioning and amalgamation algorithms, we constructed a patients classification into
four groups with different survival distributions. White blood cell and neutrophil counts
were implied in the definition of the two intermediate groups.
In a second step, the data
relative to the clinical trials performed during the last decade were analysed, in order
to see if this prognostic value found for leukocyte count and neutrophil count were
reproducible. The first trial was one in patients with unresectable locoregional NSCLC,
who were treated with an induction chemotherapy regimen (mitomycin
C-ifosfamide-cisplatin). The objective responders to this induction treatment were
randomised to three further courses of the same chemotherapy or to chest radiation. Four
hundred sixty-two eligible patients were registered. The univariate prognostic value of
both haematological counts were confirmed with median survival times of 36 weeks vs. 48
(P=0.001) in case of elevated leukocytosis and of 33 weeks vs. 51 (P<0.001) in case of
abnormal neutrophil count. Using Cox multivariate regression models, the independent value
of neutrophil count was found again with a hazard ratio of 1.48 (95% CI 1.19-1.83,
P<0.001) adjusted for performance status, age, platelets count and combination of T3-4
tumour stage and N3 nodal status. The second trial was done in stage IV NSCLC and compared
a treatment with mitomycin-ifosfamide plus standard dose cisplatin to mitomycin-ifosfamide
plus moderate dose cisplatin and carboplatin. Two hundred ninety-seven patients were
eligible. The results were similar to those found for locoregional disease. Univariate
analysis confirmed the prognostic value of both counts and in multivariate Cox regression.
A hazard ratio significantly different from 1 (1.73, 95% CI 1.32-2.28, P<0.001) for
abnormal neutrophil count was found, with adjustment for performance index, sex and prior
therapy.
Biological interpretation of
the prognostic relevance of white blood cell indices is not obvious, but we can
hypothesise that increased neutrophilia might be a marker of a respiratory infection
linked to the bronchial tumour and therefore associated with a poorer prognosis. The
assessment of the prognostic value of leukocytosis and neutrophil count has not been
extremely frequent in the literature, at least on large series of patients, but some other
authors, but not systematically, identified hyperleukocytosis as an independent factor
associated with a worse prognosis in NSCLC [42,43].
Standard serum tumour markers
The potential use of serum
tumour markers was summarised by Buccheri. Neoplastic cells produce and release
several substances. Such substances are tumour-specific and can be produced by one, few,
or several types of cancer. Other substances are produced by tumour cells in larger
amounts than by normal cells. Occasionally, normal cells release abnormal quantities of
their products in response to invasion by cancer cells. Independently of the mechanism of
production, an array of biological substances marks the existence, clinical
course, and the destiny of certain types of cancer. These substances are called tumour
markers.
The term tumour marker is
sometimes broadly used to include any tumour cell surface antigen, intracellular protein,
or even chromosomal or genetic abnormality detectable in the patients body fluids,
tissue or cytological specimens [44]. In this contribution, serum tumour marker refers
exclusively to substances present in the blood of patients with lung cancer, that are
suitable for an easy and inexpensive serum test.
The expression of lung tumour
markers is known since many years [45-47]. Lung tumour markers fall into several
categories, including oncofetal proteins, structural proteins, enzymes, membrane antigens,
peptide and non-peptide hormones, and other tumour-associated antigens [46]. A list of
lung tumour markers that were used frequently over the past 10 years has been published
recently [48]. Lung tumour markers may play different roles in clinical practice including
the assessment of prognosis [48].
At least 3 classes of tumour
markers have prognostic significance in NSCLC: CEA [7,49-53] and the two
cytokeratin-derived markers TPA [54-58] and Cyfra 21-1 [59-61]. Of course, these tumour
markers may predict clinical outcome mainly because their evaluation correlates with the
tumour mass [48]. However, there are examples in which the correlation with prognosis
directly reflects the malignant potential of the tumour. In a recent French study on the
prognostic value of 6 different tumour markers, the analysis was based on multivariate
models of survival [62]. It was found that, besides metastases (P=0.017), Cyfra 21-1
(P=0.017) and CA125 (P=0.03) were significantly correlated with the outcome of 88
non-surgical NSCLC patients. Furthermore, elevated levels of Cyfra 21-1 during the course
of disease were also independent predictors of poor survival. In a recent study on lung
cancer prognosis, 1296 consecutive patients seen over a 16-year period (1983-1998) were
analysed by Cox regression models [63]. In every multivariate test, TPA emerged among the
most important predictors of survival. Depending on the combination of variables in the
model, TPA proved to be the second most important factor after either stage or performance
status, but preceding other important clinical factors such as the number and type of
metastatic sites, the T- and N-factor, or the weight loss.
Pathological factors
T- and N-status
The prognostic importance of
the T- and N-stages, and even substages, was detailed in the first report of this working
group.
Subtypes
According to the WHO
histological subtyping, there are 4 major subtypes of lung cancer (squamous cell
carcinoma, adenocarcinoma, large cell carcinoma, and small cell lung carcinoma). Whether
there is a difference in survival between the 3 major types of NSCLC still remains
controversial, but many groups suggest a difference between squamous versus non-squamous
tumours. In a multivariate model of recurrence of the Lung Cancer Study Group based on 392
stage I NSCLC cases with final pathological review, it was reported that patients with
squamous cell tumours had a lower risk of recurrence and tumour-related death [64]. A
review of several large series on the treatment outcome in patients with pathological
stage I or II came to the same conclusion [65]. A Japanese group reported a more
favourable outcome for squamous cell tumours in stage II [66]. In the Leuven Lung Cancer
Group experience on 140 surgically treated patients with IIIA-N2 NSCLC, patients with
non-squamous cell tumours had a significantly increased risk of tumour-related death
(relative risk 1.29, 95%CI 1.02-1.63, P=0.03) [7]. The same group reported a similar
finding in IIIA-N2 patients treated with induction chemotherapy followed by surgery [67].
Regarding relapse patterns, different authors suggested that squamous cell tumours are
more prone to locoregional recurrence and adenocarcinomas to distant recurrence [68-70].
In contrast with all this
evidence, some other groups reported no survival differences across the 3 major subtypes
of NSCLC [2,71].
Differentiation and invasion
Absence of differentiation
and presence of lymphatic or blood vessel invasion are considered to be pointing at
aggressiveness of lung tumours. Although this seems quite obvious, the data on this matter
are far from unequivocal. This a probably due the limited sensitivity of standard light
microscopy to describe these findings, and to the important influence of the pathologist
in the interpretation, and thus the possible intra- and inter-observer variability.
Nevertheless, it must be decided whether vascular or lymphatic invasion should be
implemented in a next staging revision.
Based on light microscopy, a
distinction can be made between well, moderate, poor, or non differentiated lung tumours.
Less differentiation has been associated with decreased survival in NSCLC in some series
[2,66]. In a UK experience based on 479 consecutive resections, undifferentiated carcinoma
had a significantly worse survival than the other NSCLC types [72]. In a Japanese series
on 151 patients with p-stage I NSCLC, grade of differentiation was one of the predominant
prognostic factors in the multivariate analysis [73].
In some studies, the presence
of blood vessel invasion was associated with decreased survival. In a US study on 289
consecutive stage I NSCLC patients, vascular invasion proved to be of significant
prognostic value both in univariate (P<0.01) and multivariate (P<0.05) analysis [2].
Japanese investigators found that venous invasion in different stages of resected NSCLC
was of prognostic significance [66]. In a French study on 593 patients with completely
resected NSCLC, it was found that major blood vessel invasion was the most important
prognostic factor in the multivariate analysis, T-stage and lymph node metastasis being
the remaining independent prognostic factors [74]. In a modern prognosis study, using
different molecular-biological markers (bcl-2, p53, Ki-67, angiogenesis) in resected stage
I or II NSCLC, vascular invasion was the only independent prognostic factor for survival
and recurrence in the patients without lymph node involvement (P=0.02) [75]. An Italian
study looking at the prognostic impact of both traditional and newer tumour parameters in
95 patients with resected T1N0M0 NSCLC, mentioned blood vessel invasion by tumour cells to
be of independent prognostic value, both for survival (P=0.0001) as for disease-free
survival (P=0.0004) [76].
In a recent retrospective
study on 244 patients with resected stage I NSCLC, lymphatic invasion was of independent
prognostic significance besides other standard and molecular tumour characteristics [77].
A French group reported that venous but not arterial vascular invasion correlated with the
T-factor and p-TNM, whereas lymphatic vessel invasion correlated with the N-factor and
p-TNM [78]. In their multivariate model on 96 resected NSCLC patients, lymphatic vessel
invasion and p-TNM were important predictors for poor disease-free and overall survival.
Finally, a Japanese group
reported a significant correlation between survival and blood vessel (P=0.044) or
lymphatic vessel invasion (P=0.042) in a group of 66 patients with resectable NSCLC with
intrapulmonary metastases [79].
Neuro-endocrine
differentiation
The prognostic importance of
neuro-endocrine differentiation was reported by Verbeken.
The most simple
classification of the common lung carcinomas makes a distinction between two types, SCLC
and NSCLC. This has paramount therapeutic and prognostic consequences. Yet, even between
expert pathologists, the inter-observer agreement in classifying tumours into those two
categories is not higher than 89 to 94% [80,81]. For the classification of the major
subtypes and WHO-variants of NSCLC, the agreement is not better in particular for
adenocarcinomas [82] and large cell carcinomas [83].
The classification of the 4
common lung neoplasms is simple and clinically useful, with regard to diagnosis and
treatment. Also, each tumour is conceptually associated with a single cell of origin, the
SCLC being derived from the neuroendocrine Kulchitsky cell.
There are, however, major
arguments against the morphologic discontinuity between SCLC and NSCLC. In a well
conducted morphometric study, Brämer et al. showed a continuity and impressive overlap
between both nuclear diameters and cell diameters between SCLC (formerly oat-cell and
intermediate cell carcinomas), adeno-, squamous- and large cell carcinomas [84].
Secondly, it is well
appreciated that lung carcinomas are heterogeneous tumours. Roggli et al. reported that
only 34 of 100 lung tumours were homogenous, when assessed by 5 expert pathologists. In
their study, 45% showed a major heterogeneity according to the WHO-classification [85], a
figure that is now widely accepted [86]. Tumour heterogeneity is also documented
ultrastructurally [87]. It reflects that lung carcinomas are derived from pluripotential
cells, and that different differentiation levels within an individual case do occur and
determine morphology. This is in keeping with Yesner's diagram [88] proposing a common
histogenesis and a continuity between small cell undifferentiated and large cell
undifferentiated carcinoma (with in between an intermediate small cell type), and even
squamous carcinoma at the one and adenocarcinoma at the other end. Yesner thus proposed a
more dynamic interpretation of tumour morphology. As pointed out by Colby et al. [89], it
is at present not clear how heterogeneity should impact on routine practice and diagnosis
of lung carcinomas.
Thirdly, and not
unexpectedly, the accuracy of histological subclassification is influenced by the
technique used to make the diagnosis. Of a total of 96 light microscopic large cell
carcinomas, 18% showed ultrastructurally squamous, 34% adenocarcinomatous, 19%
adenosquamous and 14% neuroendocrine differentiation, whereas 14% remained large cell
carcinomas [89]. Transmission electron microscopy obviously contributes to accurately
diagnose a lung tumour. In consequence, the need for a double standard, a light optical
and an ultrastructural one, may be questioned [90].
Neuroendocrine lung tumours
include with increasing malignancy: typical carcinoid (TC) atypical carcinoid (AC), large
cell neuroendocrine carcinoma (LCNEC) and SCLC.
In the WHO classification,
LCNEC is considered a variant of large cell carcinoma, in which neuro-endocrine
differentiation is confirmed by immunohistochemistry and/or electron-microscopy.
TC and AC are straight
forward neuroendocrine tumours occurring within and outside the lung, that can be
accurately diagnosed by light microscopy alone. This does not account for SCLC and large
cell carcinoma. The latter tumours represent heterogeneous groups: some 25% of the SCLC
fails to stain with an immunohistochemical panel of neuroendocrine markers, and, in an
identical proportion, ultrastructural evidence of neuroendocrine differentiation is
lacking. Furthermore, LCNEC may be closely related to a neuro-endocrine type small cell
lung carcinoma: 30% of cultured SCLC cell lines develop features of large cell carcinoma
[91]. Przygodski et al. [92] found that TC and AC where genetically distinct from the
higher grade neuroendocrine SCLC and LCNEC. Additionally, they concluded that, although
LCNEC is categorised as a NSCLC, it is more akin genetically to SCLC.
Neuroendocrine
differentiation can also be documented often in carcinomas without neuroendocrine (so
called organoid) morphology, most often encountered in adenocarcinomas. It is doubtful
whether the latter has significant prognostic implications. The phenomenon of scattered
neuroendocrine differentiation is also observed in adenocarcinomas outside the lung
(breast, gastrointestinal tractus, oesophagus, ovary, prostate) without being a prognostic
factor. It may be wise to conclude today, that in the lung also, neuroendocrine
differentiation in those cases is ranking in the lowest category of prognostic factors,
that are not yet sufficiently studied.
Molecular biological factors
The last decade has been
characterised by an overwhelming amount of new information on the molecular-biological
processes that take place in lung cancer. A large scala of potentially important
prognostic factors has emerged from this research. As mentioned above, a recent Medline
search using the terms prognostic factor and cancer produced no
less than 2,393 papers [1]. Some aspects of 2 important fields in molecular biology,
neo-angiogenesis and changes in tumour suppressor genes, were reported at this workshop.
Neo-angiogenesis
Fontanini started her
contribution with the fact that the first observation that neo-angiogenesis occurs around
tumours, was already made by Goldman about 100 years ago [93]. A great amount of data has
been collected up to now about the role of neo-angiogenesis in cancer, and, at the
beginning of the third millennium, we are still discussing whether neo-angiogenesis may
really be a crucial point in the clinical evaluation of cancer [94]. Much data in a great
number of human tumours, emphasise that the angiogenic phenomenon is a useful indicator of
clinical outcome. The observation of increased microvessel density in tumours not only
serves as an independent prognostic indicator, but also suggests that anti-angiogenic
therapy may be an important component of treatment regimens for cancer patients [95].
Tumour angiogenesis is a complex process arising through sprouting and intussusception
from pre-existing vessels, which involves both positive and negative regulators. Although
complex, the angiogenic phenomenon provides a number of targets for therapy. Many positive
regulators, including growth factor receptors, matrix metalloproteinases, and integrins,
have been correlated with increased vascularity of tumours and poor prognosis for patients
survival. Thus, these mediators may represent ideal targets for anti-angiogenic therapy
[96]. In tumour samples, neo-angiogenesis may be evaluated as vascular density and as
expression of angiogenic regulators, and both these methods may provide useful indications
from a prognostic point of view [97].
In the last ten years, more
than 100 papers have been published [98] concerning the role of angiogenic phenomenon in
the outcome of lung carcinoma, and despite the large amount of data, no confirmatory data
is available, nor has the clinical practice been
altered up to now. However, interesting results have been obtained in a number of these
studies, since a great number of patients have been analysed and some of these analyses
enrolled consecutive and prospective series of patients. In a series of 407 NSCLC, the
number of microvessels was significantly associated with poor prognosis in terms of
overall survival [99]. Angiogenesis was quantified as microvessel count and the median
value of this series was 20 vessels; the counts were categorised as low vs. high, or in
five categories of increasing microvessels. In the univariate analysis, patients with
larger tumours, more advanced stage, greater degree of regional lymph node involvement, or
more vascular tumours experienced reduced overall survival. When microvessel count was
analysed in five categories, a highly significant trend towards a worse prognosis with
increasing tumour vascularity was observed. Moreover, the probability of two years
survival was significantly influenced by microvessel counting, adding strong prognostic
information to tumournode metastasis staging. In multivariate analysis microvessel
count retained its prognostic role on overall survival, with a relative risk of 8.38
associated with the highest number of microvessels. Other important studies demonstrated
the same prognostic impact of neo-angiogenesis in clinical outcome of NSCLC. In
particular, Giatromanolaki et al. [100] and Harpole et al. [101] analysed large
retrospective series of patients, although using slightly different methodologies.
However, even if in lung
cancer the majority of studies made evident that neo-angiogenesis has an important
prognostic role, there has been negative data reported. A large number of stage I NSCLC
has been reviewed by Pastorino et al. [102], in order to perform a biological assessment
of tumours including neo-angiogenesis. The authors analysed 515 cases, with a median
follow-up of 102 months. In that series, tumour extension represented the most powerful
prognostic factor for survival and relapse. Among the immunohistochemical markers
investigated, none emerged as an independent prognostic indicator for survival. On the
basis of this discrepancy it appears particularly useful that neo-angiogenesis should be
appropriately evaluated in further prospective and multi-center studies, able to provide
confirmatory data in this important field.
Vascular endothelial growth
factor (VEGF) is one of the most important tumour-derived cytokines which contributes to
the increased permeability of tumour vasculature, and which shows a mitogenic activity on
endothelial cells. A great number of studies demonstrated its influence in lung cancer
progression, with both VEGF-protein and mRNA expression being associated with bad overall
survival of NSCLC in univariate and in multivariate analyses. OByrne et al., [103]
in a retrospective study of 223 NSCLC, pointed out the prognostic role of VEGF and PD-ECGF
protein expression, and similar results have been obtained by our group in a series of 105
NSCLC patients, in which the expression of VEGF protein
showed an independent prognostic role on overall and disease-free survival
[104]. Important results have also been obtained by other groups, who demonstrated the
necessity of evaluating angiogenic mediators in lung cancer, either in relation to their
prognostic impact or for the possibility that they represent relevant therapeutic targets
in this type of cancer [105,106]. This data may thus also be a basis for conducting an
extensive investigation into the utility of treating cancer patients with anti-angiogenic
agents.
Prognostic value of p53 and
p16 gene abnormalities
Advances in molecular biology
have provided clues to the pathogenesis of cancer and shown the involvement of oncogene
activation and tumour-suppressor gene inactivation. Recent evidence suggests that
epigenetic regulations are also of critical importance during tumorigenesis. Among several
genetic aberrations that have been implicated in lung cancer, alterations in the p53 and
p16 tumour suppressor genes are the most common.
At the workshop, Niklinski
explained that mutations in the p53 gene usually result in increased steady-state levels
of p53, which may play a role in carcinogenesis through trans-dominant mechanisms, perhaps
involving oligomerisation between mutant and wild-type proteins. During the last ten
years, a large number of studies have evaluated p53 alterations in lung cancer [107].
However, no general conclusions have been reached with respect to their clinical impact.
Considering the rates of detected mutations in published reports, these are very variable,
from 20 to 60% [107]. With respect to prognosis after surgical treatment of NSCLC, some
studies have demonstrated that a p53 mutation is associated with poor prognosis [108-110],
while others have reported no significant effect [111], or have even concluded that p53
protein overexpression can be a good prognostic characteristic [112]. It has been
suggested that these discrepancies may be due to the methods used for the determination of
p53 function. Most studies relied on screening tests such as SSCP, or DGGE, which are
burdened with about 20% false-negative and false-positive results as much as
immunohistochemistry [113].
Recently, another method
based on a yeast functional assay was developed to detect p53 abnormalities [114]. Recent
data indicates that a functional assay combined with molecular analysis is the most
powerful and useful approach for the study of p53 alterations [115]. In this assay, loss
of DNA binding and transcriptional transactivation function in mutant p53 is detected by
the colony colour of the yeast [114].
Genetically, the p16 gene can
be inactivated by point mutation or homozygous deletion, as observed in various human
primary tumours, including lung cancer. Furthermore, recent studies have demonstrated that
de novo methylation, i.e., hypermethylation, of 5CpG islands of the promoter region
represented another important mechanism for the transcriptional inactivation of the p16
gene. It has been shown that the methylation profile commands 2 major mechanisms
responsible for the process of tumorigenesis. First, DNA methylation is a significant
contributor of point mutations at CpG dinucleotides in a variety of growth-regulatory
genes. Secondly, methylation controls the regulation of gene expression and its presence
in DNA is correlated with gene silencing [116]. Several studies have demonstrated that CpG
islands within the p16 promoter are frequently hypermethylated in lung cancer, with rates
of 30-50% [117,118]. Recently Belinsky et al. [119] for the first time have shown that
inactivation of the p16 gene by aberrant methylation is an early and likely critical event
in the development of lung cancer.
At the workshop, more details
on the prognostic significance of p53 mutations (by direct sequencing through exons 5 to
8), p53 alterations (by Yeast Functional Assay) and p16 abnormalities (mutations by
sequencing and hypermethylation by methylation-specific PCR) in radically resected NSCLC
were reported. The exact methodology of these different assays has been reported elsewhere
[110,120].
In a group of 98 surgically
treated stage I-IIIA NSCLC patients, p53 mutations were detected in 46 (47%) cases and p16
abnormalities in 42 (43%) (point mutations in 8 and promoter hypermethylation in 34). No
correlation was found between p53 and p16 abnormalities and various clinicohistological
factors, including age, sex, histological type of tumour and TNM stage.
Survival analysis revealed
that both the patients with p53 and p16 abnormalities tended to have a poorer prognosis
than the patients without p53 (P= 0.02) and p16 (P= 0.01) abnormalities. In the
multivariate analysis, however, when the types of p16 inactivation were analysed, p16
hypermethylation rather than point mutation was associated with poor prognosis.
Evaluation of p53 by Yeast
Functional Assay was performed in 42 patients. Twenty-seven of the 42 (64%) NSCLC samples
contained mutant p53 in the yeast functional assay with a higher frequency in squamous
cell carcinoma 16/22 (73%) than in large cell carcinoma 4/7 (57%) and adenocarcinoma 7/13
(54%) (P< 0.02). There were no significant differences in the frequency of positive
test with respect to sex and TNM stage. Preliminary prognostic analysis showed that
patients scoring positive for yeast test had significantly shorter disease-free survival
(median 11 months) than those that scored negative (median 23+ months).
p53 point mutation and p16
hypermethylation thus could be useful molecular markers for the prognosis of patients with
surgically resected NSCLC. Yeast functional assay for p53 is not only an improved
methodology to examine the status of p53, but might hopefully improve understanding of the
role of mutant p53 in the prognosis of NSCLC.
Glucose metabolism (FDG-PET)
NSCLC is characterised by
carbohydrate metabolic derangements, which have been identified as independent
prognostic factors correlated with poor treatment response and survival [42]. Increased
glycolysis results in upregulation of glucose tranporter proteins (especially subtype
Glut-1) and increased hexokinase activity [121]. Overexpression of the Glut-1 transporter,
an important feature of the glucose disturbance in NSCLC, was linked to a worse prognosis
[122]. FDG-uptake in NSCLC cells has also been correlated with growth rate and
proliferation capacity [123]. These glucose metabolism derangements can be measured
quantitatively in vivo by positron emission tomography (PET) after administration of 18F-fluoro-2-deoxy-glucose
(FDG).
Two larger studies have
analysed whether the Standardised Uptake Value (SUV), a semi-quantitative measurement of
FDG-uptake in NSCLC on PET is useful for prognostic purposes.
One study by the Leuven Lung
Cancer Group reported on 125 potentially operable NSCLC patients, of whom 91 underwent
complete resection [124]. In a univariate analysis, it was found that performance status
(P=0.002), stage (P=0.001), tumour diameter (P=0.06), tumour cell type (P=0.03) and
SUV>7 (P=0.001) were correlated with survival. In a multivariate Cox-analysis,
performance status (P=0.02), stage (P=0.01), and SUV (P=0.007) were retained as
independent prognostic factors. In the operated patients, those with a tumour <3 cm had
an expected 2-year survival of 86% if the SUV was below 7, and 60% if above 7; nearly all
resected tumours >3 cm had SUVs of more than 7, and an expected 2-year survival
of 43%. The SUV seemed to be more important than the tumour diameter. It was concluded
that the FDG-uptake in primary NSCLC on PET has an important and independent prognostic
value, and might be of help in the decision on adjuvant treatment protocols.
A study from Duke University
reported an SUV of more than 10 to be of significant adverse prognostic importance [125].
When they used the cut-off point of 10, seventy-six percent of the patients fell below
this value. In the Leuven experience, using the cut-off point of 7, seventy-five percent
of the patients were above this value. It seems reasonable to hypothesise that there is no
true cut-off point, but rather a transition zone, where the prognosis gradually worsens.
At present, it remains
intriguing whether there is a relationship regarding prognosis between FDG-uptake and
other molecular-biological factors such as proliferation, apoptosis or angiogenesis.
Future study must concentrate on the question whether the glucose disturbances and other
molecular-biological aberrations in NSCLC are independent or linked findings, and what is
the contribution of each of these features to the prognosis.
The concept of
molecular-biological staging
The massive amount of new
information on the molecular biology from the last decade has certainly improved our
knowledge and understanding of lung cancer tumorigenesis to a large extent. The prognostic
information of these new molecular markers, however, is not always unequivocal. Indeed,
for many of these markers, conflicting results have been reported, with either worse
prognosis, no significant effect, or even a more favourable prognosis. Two major factors
might account for the contradictions in these results. First, differences in methodology
and assays for the determination of these markers. Second, the complexity of the
multi-step process of tumorigenesis makes it very hazardous to make prognostic
speculations based on one factor only.
Some groups have therefore
examined the concept of so-called molecular-biological staging. Based on the
Boston experience, for instance, where angiogenesis, proto-oncogene erbB-2, suppressor
gene p53, and the proliferation marker KI-67 were included in a prognostic model, Harpole
et al. reported a 5-year survival of 81% in resected stage I NSCLC patients without any
adverse marker, but only 49% in those with 3 or more markers [101,126]. Similar findings
were reported by Apolinario et al. based on the series from Amsterdam, where p53, bcl-2,
bax, and neo-angiogenesis were included in a model on 116 radically resected NSCLC. p53
status, assessed with one monoclonal antibody, was not predictive for survival. However, a
combination of expression p53+(antibody PAb1801) and bcl2- had the worst survival in stage
I patients (P=.034). In multivariate analysis including all patients, the presence of
p53+/ bcl2- tumour expression and large tumour diameter (ò4 cm) were independent
prognostic factors for shorter survival duration. For stage I, only the presence of bax+/
bcl2- Tumor expression had a significant negative influence on survival.
It was strongly suggested in
this working group that these so-called molecular-biological staging systems
should not be included in the general staging system at this moment. Indeed, these
systems are not unequivocal (e.g. differences in methodology and contradictions in
prognostic consequence) and are not based on straightforward techniques accessible to all,
two vital conditions of any good staging system. They may serve, however, as very
interesting prognostic tools in highly specialised centres, but will probably not find
their way to general clinical staging in the near future, where the TNM remains the
central tool.
Table 1 : Potential prognostic factors in stage III NSCLC :
surgery only
Stage IIIA
-
microscopic involvement of
one/two vs. multi-level lymph node involvement
-
peripheral T3N1 versus
centrally located T3N1
-
superior sulcus T3N1 vs
non-superior sulcus T3 N1
-
tumour size
Stage IIIB
-
T4 carinal
involvement
-
T4 spine involvement
-
T4 vena cava
involvement
-
T4 - involvement of right
atrium
-
selected T4N0/1 versus any N3
Table 2 : Potential
prognostic factors in stage III NSCLC : radiotherapy or combined chemoradiotherapy
Stage III general
· stage IIIA vs. stage IIIB
· performance status (WHO)
· weight loss
· tumour size/tumour volume
· pre-treatment serum LDH
· pre-treatment haemoglobin
values
· age
Stage IIIA
· bulky vs. non-bulky N2
· centrally located T3 vs.
peripherally located T3
· superior sulcus tumours vs.
non-superior sulcus tumours
Stage IIIB
· T4 carinal involvement
· T4 spine involvement
· T4 vena cava
involvement
· T4 any involvement of
the heart
· T4 oesophageal
involvement
· any N3 contralateral
mediastinal nodes
· N3 supraclavicular
nodes
· T4N0-N1 vs. T4N2 vs. T1-2N3
vs. T3-4N3
· T4 any pleural
effusion
· post-obstructive
pneumonia/infection
Table 3 : Potential
prognostic factors in stage III NSCLC : chemo(radio-)therapy followed by surgery
Stage III general
· stage IIIA vs. stage IIIB
· performance status (WHO)
· weight loss
· histology
· tumour size/tumour volume
· pre-treatment serum LDH
· pre-treatment haemoglobin
values
· age
· post-obstructive
pneumonia/infection
Stage IIIA
· bulky vs. non-bulky N2
· microscopic involvement of
one/two vs. multi-level lymph node involvement
· centrally located T3 vs.
peripherally located T3
· superior sulcus tumours vs.
non-superior sulcus tumours
Stage IIIB
· T4 carinal involvement
· T4 spine involvement
· T4 - vena cava involvement
· T4 pulmonary artery
involvement
· T4 involvement of the
right atrium
· any N3 contralateral
mediastinal nodes
· N3 supraclavicular
nodes
· T4N0-N1 vs. T4N2 vs. T1-2N3
vs. T3-4N3
Table 4. : Potential
prognostic factors in stage III NSCLC : treatment related factors
Stage III general
· objective clinical response
(chest X-ray/chest CT scan)
· functional response
of primary tumour on repeat PET-scan
· pathological response
(pathological CR) at the time of thoracotomy
· amount of pathological
response at time of thoracotomy (major pathological. response)
· complete resection possible
following induction treatment (R0 vs R1/2)
· mediastinal downstaging
(PET/repeat mediastinoscopy)
· pulmonary risk of
radiotherapy (mean lung dose depending on tumour volume/location)
Stage IIIB
· selective T4
potentially resectable vs not potentially resectable
Table 5 : Regression grading
system used for the assessment of resection specimens after neoadjuvant therapy
Grade I : no or only
spontaneous tumour regression in the primary lesion and mediastinal lymph nodes
Grade II : morphological
evidence of therapy-induced tumour regression
Grade IIa at least 10% residual tumour
cells in the sections of the primary lesion and/or mediastinal lymph nodes presenting more
than focal microscopic disease
Grade IIb less than 10% residual
tumour cells in the sections of the primary lesionand/or mediastinal lymph nodes
presenting focal microscopic disease
Grade III : complete tumour
regression with no evidence of vital tumour tissue in the sections of the primary lesion
and mediastinal lymph nodes
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