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Prognostic Significance of Tumoral Angiogenesis in
Completely Resected Late Stage Lung Carcinoma
(Stage lllA-N2)
Impact of Adjuvant Therapies in a Subset of Patients at High Risk of Recurrence
Carlo Albert0 Angeletti, M.D.’
Marco Lucchi, M..D.’
Gabriella Fontanini, M.D?
Alfredo Mussi, M.D.’
Antonio Chella, M.D.’
Alessandro Ribechini, M.D.’
Sitvana Vignati, M.D.*
Generoso Bevilacqua, M.D?
’ Department
of Surgery, University of Pisa,
Pisa, Italy.
Institute of Pathology, University of Pisa, Pisa,
Italy.
BACKGROUND. Angiogenesis plays a critical role in human tumor growth and metastasis. Microvessel count (MC), as a measure of tumor angiogenesis, has been
significantly correlated with metastatic disease in cutaneous, mammary, prostatic,
head and neck, and early stage lung carcinoma.
METHODS. Ninety-six consecutive patients affected by T1-3N2MO nonsmall cell
lung carcinoma (NSCLC), who underwent radical surgery between March 1991
and March 1995 (in many cases followed by adjuvant therapies) were prospectively
investigated to assess the prognostic significance of both traditional and new biologic parameters like proliferative activity, blood vessel invasion by tumoral cells,
and neovascularization (estimated by the MC).
RESULTS. With a median follow-up of 24 months, the projected 3-year survival
was 42.1%. Forty-eight of the patients (50%) had already experienced a local (n =
14) or systemic (n = 34) relapse. The extent of resection (lobectomy vs. pneumonectomy; P = 0.0045), the number of mediastinal lymph node levels (single vs. multifield; P = 0.015) correlated significantly
ple; P = 0.014), and the MC (on a ~ 2 0 0
with metastatic disease. By univariate analysis, significant predictors of survival
were: the extent of surgery ( P = 0.031, adjuvant therapy ( P = 0.05), and MC ( 5 vs.
> cut-off;P = 0.00076). On multivariate analysis, however, only the MC ( P = 0.02)
retained its level of prognostic significance.
CONCLUSIONS. Our results provide evidence that neovascularization, estimated by
the MC, can predict metastatic disease and survival in patients with completely
resected T1-3N2MO NSCLC, and may also be useful in patient selection for effective
adjuvant treatment. Cancer 1996; 78409- 15. 0 1996 American Cancer Society.
KEYWORDS nonsmall cell lung carcinoma (NSCLC), surgery, mediastinal lymph
node metastasis (N2), angiogenesis, microvessel count, survival.
Presented at the Sixth International Congress
on Anti-Cancer Treatment, Paris, France, February 6-9, 1996.
Supported in part by grants of the Italian Minis-
try of Education (60%) and of Italian Association for Cancer Research (ARC).
Address for reprints: C.A. Angeletti, M.D., Service of Thoracic Surgery, Department of Surgery, Via Roma 67, 56100 Pisa, Italy.
Received December i27, 1995; revision received
April 24, 1996; accepted April 24, 1996.
0 1996 American Cancer Society
I
n the last few years, a number of biologic studies have lead to the
identification of new factors of prognostic significance in nonsmall
cell lung carcinoma (NSCLC) that may add useful information to the
traditional parameters. If these prognostic factors may have a fundamental role in the prediction of failure of surgical cure for early stage
disease (Stage I, NO),’-3they also may have the same importance in
late stage disease, aiding in patient selection before planning adjuvant
strategies after radical surgery.
Neoangiogenesis and invasion of vascular channels by tumor cells
are two fundamental steps in the process of m e t a s t a s i ~ .If
~ .the
~ ingrowth of new capillaries increases the opportunity for malignant
cells to enter the blood stream, tumoral cells invading a blood vessel
410
CANCER August 1,1996 I Volume 78 I Number 3
can disseminate and, upon reaching the target organ,
induce angiogenesis.
Some reports have provided evidence that microvessel count (MC), as a measure of tumor angiogenesis, correlates with metastasis in several types of
human solid cancers such as cutaneous melanoma,'
m a m m a ~ y prostate,'
,~,~
ovarian," head and neck," and
lung carcinomas. L2.1'i
On this basis, we prospectively investigated traditional as well as newer biologic prognostic factors in
a group of 96 consecutive patients affected by Stage
IIIA (N2) NSCLC who underwent surgery, which was
in many cases followed by adjuvant therapies.
Our goal was to detect a subset of patients with
the worst prognosis, who could benefit from effective
adjuvant therapy strategies.
MATERIALS AND METHODS
Patients
The subjects of the current prospective study were 96
patients affected by Stage IILA (N2) NSCLC who were
treated by radical surgery alone or by radical surgery
and adjuvant therapies between March 1991 and
March 1995.
There were 80 males and 16 females with a median
age of 64 years (range, 41-79 years). The follow-up
lasted until May 1995. No patient was lost at followup, which had a median of 24 months (range, 3-50
months).
Preoperative evaluation included a detailed history and physical examination, biochemical profile,
chest X-ray, computed tomography (CT) of the chest,
abdominal ultrasound scan, and common cardiopulmonary tests; CT scan of the brain and the bone scan
were performed in the majority of patients. Mediastinoscopy was performed in five patients in whom CT
showed a positive mediastinal window; however, because it was negative, the patients underwent thoracotomy.
Operative Procedures
The extent of surgery and the adjuvant therapies are
listed in Table 1. A careful intraoperative staging at the
time of surgical resection was performed dissecting
all the available mediastinal lymph node stations in
agreement with the assessment of Martini et al.'* The
primary tumor and lymph node status were classified
according to the TNM staging system.15 Surgery was
considered radical only in presence of a negative distal
lymph node and in the absence of lymph node extracapsular spread.
Adjuvant Therapies
Adjuvant therapies began 30-45 days after surgery.
With regard to radiotherapy, it had as its target the
TABLE 1
Operative Procedures
~
~
Features
Side of surgery
Right vs. left
Extent of surgery
Pneurnonectomy
Lobectomy
Wedge resectionlsegmentectomy
Adjuvant therapies
No therapy
Chemotherapy
Radiotherapy
Chemoradiotherapy
~~
No. of patients
43/53
31
65
0
31
9
33
23
homolateral hilum, mediastinum, and both supraclavicular fossae in the case of upper lobar neoplasia; the
mediastinum and only the homolateral supraclavicular fossa in the case of lower and middle lobar neoplasia with involvement of carinal and inferior mediastinal lymph nodes; and only the mediastinum in the
case of lower and middle lobar neoplasia with metastasis to the inferior mediastinal lymph nodes. The
doses were between 45 and 50 Gray (Gy).
Chemotherapy was comprised of 4-6 courses of
cisplatin, 90 mglmqlday, and vindesine, 5 mglmq, on
Days 1, and 8 (replaced by vinorelbine tartrate, 25 mgl
mq, after March 1992 in an effort to reduce neurologic
toxicity), recycled every 3 weeks.
In the case of combined chemoradiotherapy, we
never exceeded 3 chemotherapeutic courses followed
by radiotherapy, up to 45 Gyldose.
Thirty-one patients (32%) were precluded from
adjuvant therapies because of refusal of treatment (n
= 15),poor performance status [n = lo), and postoperative complications (n = 6).
Pathologic Studies
All surgical specimens were analyzed with respect to
the conventional pathologic features (tumor size, histology, and number and level of lymph node involvement) according to the World Health Organization
(WHO) histological classification'' and to the guidelines of the American Joint Committee on Cancer
(AJCC) Staging.l7 Formalin fixed, paraffin embedded
samples were also used for the immunohistochemical
analysis of factor VIII-related antigen by a monoclonal
antibody (MAb) (Dako Corp., Santa Barbara, CA) diluted 1:50 overnight, displayed by the avidin-biotin
complex method, after predigestion with 0.1% trypsin
for 10 minutes at 37 "C. MAb anti-factor VIII highlights
vascular endothelial cells. Thus, the identification of
Angiogenesis in Late Stage Lung Carcinoma/Angeletti et al.
411
TABLE 2
Tumor Characteristics
Features
FIGURE 1. Anti-factor Vlll immunoreactivity in t h e cytoplasm of endothelial cells (avidin-biotin complex method, x200).
neoplastic emboli within tumor vessels was easily accomplished.
A single rnicrovessel was defined as any brown
immunostained endothelial cell separated from adjacent microvessels, tumor cells and other connective
tissue elements (Fig. 1).Areas of highest neovascularization were found by scanning sections at low power
(x10 objective lens and x10 ocular lens) and microvessels were carefully counted on a x200 field (x25
objective lens and x 8 ocular lens, 0.78 mm’ per field).
The MC was expressed as the highest number of microvessels identified within the x200 field.
Proliferative activity of the tumors was determined
by estimating the expression of the proliferating cell
nuclear antigen with monoclonal antibody PClO (Novocastra Laboratories, Newcastle, UKj‘.
Statistical Analysis
All statistical analysis were performed by the Statistica
(Stat-Soft)software system. Univariate analysis by the
Mann-Whitney Utest for continuous variables and the
chi-square test for discrete variables were used to assess differences between patient and tumor characteristics and development of metastasis.
Overall survival was calculated from the date of
surgery until death or the date of last follow-up (censored). Nine patients who died of a cause other than
primary NSCLC without evidence of disease were censored at deaih.
The median value of the MC (31) was chosen as
the cutoff paint.
Survival was estimated by the product-limit method’*
and differences in distribution were evaluated by the
log rank test for univariate analysis. The influence of
significant variables generated by the univariate analysis was then assessed by stepwise logistic regression
Tumor size (cni)
Mean 2 SD
Median (95% CI)
Tumor histology
Squamous vs. nonsquamous
Mediastinal lymph node involvement
Single level vs. multiple levels
Carina vs. other sites
Tumor proliferation (PCNA)
Mean 2 SD
Median (95% CI)
BVI
Absent vs. present
Microvessel count ~ 2 0 field
0
Mean ISD
Median (95% CI)
No.
4.49 ? 2.13
4 (4.05-4.92)
47/49 patients
67/29 patients
32164 patients
33.20 5 20.42
34 (29.06-37.34)
63/33 patients
28.66 5 14.75
31 (25.65-31.67)
SD: standard deviation: CI: confidence interval; PCNA: proliferating cell nuclear antigen: B \ l blood
vessel invasion.
analysis. The a priori level of significance was set at P
< 0.05; all tests were two-sided.
Numbers were expressed either as mean t standard deviation of n, the number of observations, or
the median and 95% confidence intervals (CI).
RESULTS
The surgical procedures, adjuvant therapies, and tumoral characteristics of the 96 patients included in
this study are illustrated in Table 1 and Table 2.
The resection was histologically complete in all
patients. The only postoperative complications verified were six pleural emphyemas, associated with
bronchopleural fistulas, in patients who underwent
pneumonectomies.
With a 24-month median follow-up (range, 3-50
months), the projected overall 3-year survival was
42.1%, with 51 patients alive and 39 of them disease
free. Among the 45 deaths, 9 occurred from noncancer-related causes (3 due to respiratory failures, 2 to
chemotoxicities, 1to radiotoxicity, 2 to pulmonary embolisms, and 1 to sepsis), whereas the remaining 36
deaths were due to first recurrence in the ipsilateral
mediastinum (n = 8) or recurrences in extrathoracic
sites (n = 28). Of 12 patients living with metastasis, 6
had local relapse and 6 systemic relapse.
As shown in Table 3, patients who developed metastasis (regional or distant) more frequently underwent pneumonectomy ( P = 0.00451, had more than 1
level of lymph node involvement ( P = 0.0141, and a
higher MC ( P = 0.015) than those patients without
relapse.
CANCER August 1,1996 I Volume 78 I Number 3
412
TABLE 3
Tumor Characteristics and Surgical Procedures in Relation to Development or Absence of Metastasis
Features
Tumor size (cm)a
Tumor histology
Squamous vs. nonsquamous
Mediastinal lymph nodes
Single vs. multiple levels
Carina vs. other sites
Extent of surgery
Lobectomv vs. pneumonectomy
Adjuvant therapies
Yes vs. no
Tumor proliferation (PCNA)a
BVI
Absent vs. present
Microvessel count per ~ 2 0 fielda
0
No metastasis
(n = 48 patients)
Metastasis
(n = 48 patients)
4.30 ? 1.9
4 (3.74-4.86)
4.67 ? 2.32
4 (4-5.35)
NS
26/22
21127
NS
39/9
12/36
28/20
20/28
0.014
NS
3919
26/22
0.0045
35113
35.31 ? 19.54
35.3 (29.63-40.98)
30118
31.09 t- 21.25
26.85 (24.92-37.26)
NS
NS
34/14
25.21 5 13.27
23.5 (21.35-29.06)
29/19
32.19 t 15.48
34 (27.64-36.74)
P value
NS
0.015
NS: not significant; PCNA: proliferating cell nuclear antigen; BVI: blood vessel invasion.
Data are expressed as the mean i standard deviation and as the median (95% confidence interval].
100
E
.&'
._
n
.....,
7.
80
......
I
Lobedomy
n
e
(z
a
>
.z
z
!_____.
60
40
7
.._..._..._........_..~-~..-..
Pneumoneclomy
:
No lherapy
20
p = 0.03
0
,
OL
0
I
p = 0.05
5
10
15
20
25
30
35
I
40
45
50
55
Months
FIGURE 3. Actuarial survival curves of patients who underwent adjuvant
therapies and those patients who did not.
At univariate analysis, the best survival results
were achieved in patients who underwent lobectomy
( P = 0.03) (Fig. 21, adjuvant therapies ( P = 0.05) (Fig.
31, and those with a low MC ( 5 3 1 ) in their tumors ( P =
0.00076) (Fig. 4). No other variable influenced survival
(Table 4).
By multivariate analysis, however, only MC retained an independent level of significance ( P = 0.024)
(Table 5).
On this basis, we analyzed the role of adjuvant
therapies, stratifymg the patients according to the MC
factor. We verified no improvement in terms of survival with adjuvant therapies in patients with a MC less
than the median value (Fig. 51, despite a significantly
better prognosis ( P = 0.04) for patients with a MC
value greater than the median (Fig. 6).
DISCUSSION
It is generally accepted that NSCLC patients with clinical NO-1 disease, and in whom N2 disease is found
and completely removed at thoracotomy, may benefit
from surgical treatment, achieving a 3- and 5-year survival rate of 40% and 20%, respe~tively.'~-~~
Conversely, patients with clinical N2 involvement, detected at CT, bronchoscopy, mediastinoscopy, or diag-
Angiogenesis in late Stage lung Carcinoma/Angeletti et al.
loo
I
p = 0.00076
0
0
5
10
15
20
25
30
35
40
45
50
Months
FIGURE 4. Actuaria.1 survival curves according to microvessel count
median vs. . : mediaii).
(5
TABLE 4
Univariate Survival .4nalysis
Features
Tumor size
c vs. > median (4 cni)
T classification
T1-2 VS. T3
Tumor histology
Squamous vs. nonsquarnous
Extent of surgery
Lobectomy vs.
pneumonectomy
Adjuvant therapies
Yes vs. no
Tumor proliferation (PCNA)
5 median vs. > median (34)
Survival (Pvalue)
NS
NS
NS
0.03
0.05
NS
BW
Absent vs. present
Microvessel count ~ 2 0 0field
5 median vs. > median (31)
NS
0.00076
NS: not statisticallv sianificant; PCNA oroliferatina cell nuclear antieen: BVI: blood vessel invasion.
nostic thoracoscopy, are commonly precluded from
surgery and started on clinical trials of neoadjuvant
~heniotherapy,”-’~
indeed, the first results of prospective randomized trials are positive and hopeful.“
However, i n patients with N2 NSCLC detected at
thoracotomy in whom a curative resection is performed,
a common concern is the impact of adjuvant therapies
in terms of recurrence rate and s~rvival.’~-‘~
The answer should come from the results of prospective randornized studies in course of realization. In
the interim, better patient selection according to traditional and newer prognostic factors would be desirable.
The overall1 survival reported in our study (42.1%
at 3 years) is in keeping with the largest studies ap-
413
pearing in the surgical l i t e r a t ~ r e . ~ ~ -Even
‘ ’ ~ ~if~ the
~~’
median follow-up time (24 months) isn’t conspicuous,
it may be considered sufficient for drawing interesting
considerations about a group of patients (stage IIIAN2) in whom metastasis is usually detected in the first
2 years after surgery.
Extent of operation, the number of lymph node
levels involved, and adjuvant therapies were found to
predict recurrence and survival in univariate analysis.
Patients treated by lobectomy and with a single
involved lymph node level did significantly better than
those treated by pneumonectomy and with metastatic
lymph node involvement in more compartments; in
addition, patients who underwent adjuvant therapies
had a better survival than those who did not. These
findings may be related both to the more favorable
biology of tumors, requiring less radical resections,
and to the higher percentage of adjuvant therapies in
the first group (72% vs. 58%). Furthermore, the fact
that both the extent of resection and adjuvant therapies lose significance in multivariate analysis suggests
caution in making statements regarding the treatment
of choice for patients with T1-3N2MO NSCLC.
TNM staging has been recognized in the last few
years as the most important prognostic factor,” determining the planning of treatment of NSCLC. Nevertheless, the different and unpredictable outcomes
among patients with the same stage of disease necessitate further information concerning the biologic pathway of these t u m o r ~ . ~ ’
Blood vessel invasion by tumor cells was present
in 34.4% (33 patients) of the specimens, a clearly
higher percentage than in early stage NSCLC,’,‘ but no
predictive information was added either in terms of
recurrence or survival. It now seems clear that blood
vessel invasion by tumor cells plays a role at the beginning of the metastatic process, sending it into the vascular phase; however, in a following phase, when the
disease is advanced, it may be overcome by some undetected factors. What we stated above for BVI has
value for the proliferative activity, not being a significant factor in late stage (N2) NSCLC.
The only independent prognostic factor at multivariate analysis was the MC. In this series, the median
value of the MC is 31, decidedly higher than we reported in TlNOMO NSCLC.3 This consideration supports the correlation between the number of tumor
vessels and lymph node metastasis we proved in a
study of a larger number of patients at different stages
of disease.13
MC appears to be a promising prognostic factor in
the management of resected patients with Stage IIIA
NSCLC, discerning those patients suitable for clinical
trials.
CANCER August 1,1996 / Volume 78 I Number 3
414
TABLE 5
Multivariate Survival Analysis
Features
p coefficient
SD
t
P value
Microvessel count ~ 2 0 field
0
5 vs. > median (31)
0.1472
0.0641
2.2857
0.02
S D standard deviation; fl: beta; t Student’s tstatistic.
100,
1
1
.
I00
....-.
:
Tumors with high (> 31) MC
Tumors with low ( 5 31) MC
-33
80
60
n
e
ii
n 40
>
‘5
v)
20
Ll
-
p 0.04
0
5
10
15
20
25
30
35
40
45
01
50
Months
0
5
10
15
20
25
I
No therapy
30
35
40
45
50
Months
FIGURE 5. Actuarial survival curves of patients with lung tumors at low
FIGURE 6. Actuarial survival curves of patients with lung tumors at high
microvessel count (531) who underwent adjuvant therapies and those
patients who did not.
microvessel count (>31) who underwent adjuvant therapies and those
patients who did not.
There is no evidence in the literature that adjuvant
1. Macchiarini P, Fontanini G, H.ardin MJ, Pingitore R, Angeltherapies either impact survival or reduce recurrence
etti CA. Most peripheral, node negative, non small cell lung
in patients with NSCLC. As suggested by H o l m e ~it, ~ ~
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may be due to the low therapeutic index of actual
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cytotoxic ~ h e m o t h e r a p ydespite
, ~ ~ a well documented
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2. Macchiarini P, Fontanini G, Hardin MJ, Hsu C, Bigini D,
Vignati S, et al. Blood vessel invasion by tumor cells preseries, we identified a subset of patients (MC > 31) at
dicts recurrence in completely resected TlNOMO non
higher risk of recurrence, in whom adjuvant therapies
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106:80-9.
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etti CA. Relation of neovascularisation to metastasis of non
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