Table of Contents
1
UI - 11686030
AU - Giaccone G; Smit EF
TI -
Lung cancer.
SO - Cancer Chemother Biol Response Modif 2001;19():485-534
AD - Department of Medical Oncology, Academic Hospital Vrije Universiteit,
1117 De Boelelaan, HV 1081 Amsterdam, The Netherlands.
2
UI - 11740999
AU - Shepherd FA
TI -
Angiogenesis inhibitors in the treatment of lung cancer.
SO - Lung Cancer 2001 Dec;34 Suppl 3():S81-9
AD - Division of Medical Oncology, Department of Medicine, Princess Margaret
Hospital, 610 University Avenue, 5-104, University of Toronto, Ont.,
Toronto, Canada, M5G 2M9. frances.shepard@uhn.on.ca
Numerous inhibitors of angiogenesis are currently under study in lung
cancer. Four trials of adjuvant interferon after chemotherapy for small
cell lung cancer (SCLC) were negative. Several metalloproteinase
inhibitors (MMPIs) are now in study in SCLC and non-small cell lung
cancer (NSCLC). Two large randomized trials have closed recently in
which Marimastat 10 mg bid was compared to placebo in responding
patients with SCLC. Two randomized studies of Prinomastat versus placebo
with combination chemotherapy in advanced NSCLC have also completed
accrual. The results of these trials are not yet available, but should
be reported in mid-2001. A Phase III trial of BMS-275291, a
broad-spectrum MMPI in combination with paclitaxel and carboplatin is
open for patients with advanced NSCLC. Neovastat, a standardized shark
cartilage extract is under study in inoperable Stage III NSCLC. VEG-F
gene expression is increased in many tumors including NSCLC, and may act
as a paracrine mediator of growth. A randomized Phase II trial of
paclitaxel and carboplatin with or without a recombinant humanized
anti-VEG-F has been undertaken in NSCLC. Modestly better response and
survival were seen with anti-VEG-F and a large Phase III trial is
planned. Numerous receptor tyrosine kinases (TK) have been found to be
directly or indirectly involved in angiogenesis including Flk-1, Flt-l,
Tie-1 and Tie-2. SU5416 is a small molecular TK inhibitor and potent
inhibitor of VEG-F-mediated Flk-1 receptor signaling. Another TK
inhibitor SU6668 blocks VEG-F, bFGF and PDGF receptor signaling. It is
orally available, and it may be evaluated in lung cancer trials in the
near future. ZD4190 is an inhibitor of KDR/Flk-1 that may be evaluated
in SCLC. Thalidomide has recently been shown in pre-clinical models to
be anti-angiogenic. A randomized trial of paclitaxel/carboplatin and
radiation with or without thalidomide is open for patients with Stage
IIIB NSCLC in the United States. Numerous other anti-angiogenesis agents
are in early clinical trials, but have not been evaluated in lung cancer
yet.
3
UI - 11894010
AU - Arteaga CL; Khuri F; Krystal G; Sebti S
TI -
Overview of rationale and clinical trials with signal transduction
inhibitors in lung cancer.
SO - Semin Oncol 2002 Feb;29(1 Suppl 4):15-26
AD - Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt
University School of Medicine, Nashville, TN 37232-6307, USA.
Most cellular proto-oncogenes encode proteins that participate in
signaling pathways by which cells receive and execute instructions that
lead to mitogenesis, differentiation, lineage determination, cell
migration, extracellular matrix production, and apoptosis, among others.
These proto-oncogene protein products include transmembrane receptor
tyrosine kinases and receptor substrates, serine/threonine kinases,
receptor adaptor molecules, low-molecular-weight GTPases, and
transcription factors that, when overexpressed or mutationally
activated, can lead to cell transformation and tumor progression. The
large number of oncogenic protein tyrosine kinases plus the rare
presence of phosphotyrosine in nontransformed cells argue persuasively
that tyrosine phosphorylation and activation of signaling molecules
downstream from receptor tyrosine kinases are critical events in growth
control and transformation and are, therefore, rational targets for
anticancer molecular therapies. We will review some of the more recent
treatment strategies in non-small cell and small cell lung cancer
targeted to dysregulated signaling pathways that are causally associated
with tumor maintenance and progression.
4
UI - 11894017
AU - Bonomi P
TI -
Matrix metalloproteinases and matrix metalloproteinase inhibitors in
lung cancer.
SO - Semin Oncol 2002 Feb;29(1 Suppl 4):78-86
AD - Department of Medical Oncology, Rush Cancer Institute, Chicago IL
60612-3824, USA.
Preclinical studies have provided evidence that matrix
metalloproteinases (MMPs), a family of zinc-containing proteolytic
enzymes, facilitate tumor invasion, the establishment of metastases, and
the promotion of tumor-related angiogenesis. Matrix metalloproteinase
inhibitors (MMPIs) have been shown to inhibit tumor growth and
dissemination in preclinical models. Not all lung cancers express the
MMPs believed to be most important in promoting the neoplastic process,
and there are conflicting reports regarding the prognostic significance
of MMPs in lung cancer. However, it is possible that these observations
are because of limitations in the procedures for measuring MMPs. Many
investigators believe that MMPs are universally involved in tumor
progression; this hypothesis was the basis for initiating seven phase
III MMPI trials in lung cancer. Four studies were closed at completion
of the predefined accrual goal, and three were closed early. There were
no significant differences in survival in a non-small cell lung cancer
prinomastat study, and in a small cell lung cancer marimastat trial. The
results of the remaining five studies have not been reported. At this
point it appears that MMPIs will probably not play a major role in the
treatment of advanced lung cancer patients.
5
UI - 11905738
AU - Rintoul R C; Sethi T
TI -
The role of extracellular matrix in small-cell lung cancer.
SO - Lancet Oncol 2001 Jul;2(7):437-42
AD - Centre for Inflammation Research, University of Edinburgh, UK.
Lung cancer is the most common fatal malignant disease in the western
world, accounting for 42,000 deaths each year in the UK alone.
Small-cell lung cancer (SCLC), accounts for 25% of all lung cancers. It
is a particularly aggressive form of the disease, characterised by
widespread metastases and the development of resistance to chemotherapy.
Even with combination chemotherapy and radiotherapy treatments, the
5-year survival is only about 5%. We review recent insights into the
mechanisms underlying the development of metastases and resistance to
chemotherapeutic agents in SCLC, focusing on the role of the
extracellular matrix (ECM). We discuss the regulation of the
interactions between cells and the ECM and the effects of these
interactions on cellular phenotypes, together with some of the new
approaches for combating drug resistance and metastases in this disease.
6
UI - 11760556
AU - Johnson BE; NCCN Small Cell Lung Cancer Practice Guidelines Panel
TI -
NCCN: Small cell lung cancer.
SO - Cancer Control 2001 Nov-Dec;8(6 Suppl 2):32-43
AD - Dana-Farber Cancer Institute, USA.
7
UI - 11699727
AU - Mitani S; Kamata H; Fujiwara M; Aoki N; Tango T; Fukuchi K; Oka T
TI -
Analysis of c-myc DNA amplification in non-small cell lung carcinoma in
comparison with small cell lung carcinoma using polymerase chain
reaction.
SO - Clin Exp Med 2001 Jun;1(2):105-11
AD - Department of Pathology, Kanagawa Prefectural College of Nursing and
Medical Technology, Yokohama, Japan. hf25-mtn@asahi-net.or.jp
Previous studies of c-mvc DNA amplification in lung cancer have focused
primarily on analysis of small cell carcinoma or its tumor cell lines.
There are few data about c-myc DNA amplification in histological types
of lung cancer other than small cell carcinoma. Therefore the present
study was conducted to investigate c-myc oncogene amplification in
non-small cell lung carcinoma. We studied 46 lung tumor specimens for
c-myc DNA amplification (15 adenocarcinomas, 15 squamous cell
carcinomas, 6 large cell carcinomas, and 10 small cell carcinomas).
Polymerase chain reaction, digoxigenin DNA labeling, and electrophoresis
were utilized to investigate the c-myc copy number in the lung tumor
specimens. The c-myc copy number of non-small cell carcinoma ranged from
1.5 to more than 20.0 in adenocarcinoma and squamous cell carcinoma, and
from 6.0 to 12.0 in large cell carcinoma. That of small cell carcinoma
ranged from 1.8 to 12.0. The c-myc copy number of non-small cell
carcinoma was significantly higher than that of small cell carcinoma
(Wilcoxon rank sum test, Z=2.06 P=0.040). However, the differences in
c-myc copy number among these four histological types were not
statistically significant. Amplification of c-myc (more than 4 copies)
was observed not only in small cell carcinoma but also in nonsmall cell
carcinoma at similarly high frequency (12/15 in adenocarcinoma and
squamous cell carcinoma, 6/6 in large cell carcinoma, and 9/10 in small
cell carcinoma).
8
UI - 11900243
AU - Watine J
TI -
Prognostic factors for patients with small cell lung carcinoma.
SO - Cancer 2002 Jan 15;94(2):576-8
9
UI - 11762805
AU - Tjan-Heijnen VC; Postmus PE; Ardizzoni A; Manegold CH; Burghouts J; van
TI -
Meerbeeck J; Gans S; Mollers M; Buchholz E; Biesma B; Legrand C;
Debruyne C; Giaccone G; European Organisation for Research and Treatment
of Cancer-Lung Cancer Group
Reduction of chemotherapy-induced febrile leucopenia by prophylactic use
of ciprofloxacin and roxithromycin in small-cell lung cancer patients:
an EORTC double-blind placebo-controlled phase III study.
SO - Ann Oncol 2001 Oct;12(10):1359-68
AD - Department of Medical Oncology, University Medical Center Nijmegen,The
Netherlands. V.Tjan@onco.azn.nl
BACKGROUND: CDE (cyclophosphamide, doxorubicin, etoposide) is one of the
standard chemotherapy regimens in the treatment of small-cell lung
cancer (SCLC), with myelosuppression as dose-limiting toxicity. In this
trial the impact of prophylactic antibiotics on incidence of febrile
leucopenia (FL) during chemotherapy for SCLC was evaluated. PATIENTS AND
METHODS: Patients with chemo-naive SCLC were randomized to standard-dose
CDE (C 1,000 mg/m2 day 1, D 45 mg/m2 day 1, E 100 mg/m2 days 1-3. i.v.,
q 3 weeks, x5) or to intensified CDE chemotherapy (125% dose, q 2 weeks,
x4, with filgrastim 5 microg/kg/day days 4-13) to assess the impact on
survival (n = 240 patients). Patients were also randomized to
prophylactic antibiotics (ciprofloxacin 750 mg plus roxithromycin 150
mg, bid. days 4-13) or to placebo in a 2 x 2 factorial design (first 163
patients). This manuscript focuses on the antibiotics question. RESULTS:
The incidence of FL during the first cycle was 25% of patients in the
placebo and 11% in the antibiotics arm (P = 0.010; 1-sided), with an
overall incidence through all cycles of 43% vs. 24% respectively (P =
0.007; 1-sided). There were less Gram-positive (12 vs. 4), Gram-negative
(20 vs. 5) and clinically documented (38 vs. 15) infections in the
antibiotics arm. The use of therapeutic antibiotics was reduced (P =
0.013; 1-sided), with less hospitalizations due to FL (31 vs. 17
patients, P = 0.013: 1-sided). However, the overall number of days of
hospitalization was not reduced (P = 0.05; 1-sided). The number of
infectious deaths was nil in the antibiotics vs. five (6%) in the
placebo arm (P = 0.022; 2-sided). CONCLUSIONS: Prophylactic
ciprofloxacin plus roxithromycin during CDE chemotherapy reduced the
incidence of FL, the number of infections, the use of therapeutic
antibiotics and hospitalizations due to FL by approximately 50%, with
reduced number of infectious deaths. For patients with similar risk for
FL, the prophylactic use of antibiotics should be considered.
10
UI - 11801571
AU - Kohara H; Tabata M; Kiura K; Ueoka H; Kawata K; Chikamori M; Aoe K;
TI -
Chikamori K; Matsushita A; Harada M
Synergistic effects of topoisomerase I inhibitor,
7-ethyl-10-hydroxycamptothecin, and irradiation in a cisplatin-resistant
human small cell lung cancer cell line.
SO - Clin Cancer Res 2002 Jan;8(1):287-92
AD - Department of Internal Medicine II, Okayama University Medical School,
Okayama 700-8558, Japan. hkohara@kb4.so-net.ne.jp
7-ethyl-10-[4-(1-piperidyl)-1-piperidyl] carbonyloxy-camptothecin, a
topoisomerase I (topo I) inhibitor, is one of the most active agent
against lung cancer, and its radiosensitizing effect has been reported
recently. We evaluated a combination in vitro effect of irradiation and
7-ethyl-10-hydroxy-CPT (SN-38), an active metabolite of 7-ethyl-10-[4-
(1-piperidyl)-1-piperidyl] carbonyloxy-camptothecin, on a human small
cell lung cancer cell line (SBC-3) and its cisplatin-resistant subline
(SBC-3/CDDP). Growth-inhibitory effects of irradiation with or without
SN-38 were determined by the
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. A
modified isobologram method was used to evaluate the treatment
interaction. The combination of irradiation and SN-38 showed a
synergistic inhibitory effect on the growth of SBC-3/CDDP despite its
cross-resistance to irradiation and SN-38. In contrast, the same
combination showed only an additive effect on the growth of parental
SBC-3 cells. There was no significant difference in topo I protein
expression between these two cell lines. In SBC-3 cells, topo I
catalytic activity was suppressed by 4 Gy of irradiation, without a
decrease of nuclear topo I protein, whereas the exposure of SBC-3 cells
to 1 microM SN-38 subsequent to irradiation showed no remarkable
additional effects on both topo I activity and protein content. On the
other hand, in SBC-3/CDDP cells, topo I activity was unchanged by
irradiation, but the subsequent exposure to SN-38 gave rise to a
decrease in topo I activity, which was accompanied by a significant
decrease in the topo I protein content (P = 0.02). These observations
may indicate that SN-38 induces sequestration of topo I onto DNA in
radiation-treated SBC-3/CDDP cells and suggest that the synergistic
effect of irradiation and SN-38 in SBC-3/CDDP cells was considered
attributable to DNA repair-related enhanced recruitment of topo I onto
the damaged DNA.
11
UI - 11804684
AU - Rachtan J
TI -
Smoking, passive smoking and lung cancer cell types among women in
Poland.
SO - Lung Cancer 2002 Feb;35(2):129-36
AD - Epidemiology Unit, Centre of Oncology, M. Sklodowska-Curie Memorial
Institute, Garncarska 11, 31-115 Cracow, Poland. z5rachta@cyf-cr.edu.pl
A case-control study involving 242 women with histologically confirmed
lung cancer and 352 healthy controls, was conducted in Cracow, Poland
between 1991 and 1997. Subjects were interviewed about their exposure to
smoking, passive smoking and other suspected risk factors, according to
a structured questionnaire. Multivariate analysis has shown that
cigarette smoking was the most strongly active risk factor in female
lung cancer. The strongest influence of this factor was observed with
reference to small cell carcinoma and squamous cell carcinoma. It has
also been observed that passive smoking exposure during childhood before
the age of 18, significantly increased risk of squamous cell carcinoma,
small cell carcinoma and all cell types combined. A similar effect was
observed for adenocarcinoma, but there was no statistical significance.
12
UI - 11804690
AU - Takeuchi E; Yanagawa H; Suzuki Y; Shinkawa K; Ohmoto Y; Bando H; Sone S
TI -
IL-12-induced production of IL-10 and interferon-gamma by mononuclear
cells in lung cancer-associated malignant pleural effusions.
SO - Lung Cancer 2002 Feb;35(2):171-7
AD - Third Department of Internal Medicine, The University of Tokushima
School of Medicine, Kuramoto-cho 3, Tokushima 770-8503, Japan.
Interleukin (IL)-12 enhances natural killer (NK) activity and induces
interferon gamma (IFN-gamma) production. Recently, it was shown that
IL-12 induces IL-10 production by human T cells and NK cells, as a
negative feedback for IL-12-induced immune responses. In the present
study, in order to investigate the functions of host immune cells
existing in contact with cancer cells, we examined the effect of IL-12
on the induction of non-major histocompatibility complex
(MHC)-restricted killer activity and of IFN-gamma and IL-10 production
by pleural and peripheral blood mononuclear cells (MNC), isolated from
40 lung cancer patients and 20 control subjects. IL-12 induced
significant killer activity in pleural MNC from lung cancer patients, as
well as those in peripheral blood, against a small cell lung cancer cell
line (SBC-3). In lung cancer patients, pleural MNC incubated with IL-12
produced more IFN-gamma than blood MNC. In addition, when stimulated
with both IL-12 and IL-2, pleural MNC produced more IL-10 than blood
MNC. This is the first study reporting that MNC from pleural effusions
of patients with lung cancer can produce both type 1 (IFN-gamma) and
type 2 (IL-10) cytokines following exposure to IL-2 and IL-12. These
observations suggest that control of IL-10 production at the
microenvironment level may be important for the efficacy of human lung
cancer immunotherapy with IL-12.
13
UI - 11888007
AU - Sozzi G
TI -
Molecular biology of lung cancer.
SO - Eur J Cancer 2001 Oct;37 Suppl 7():S63-73
AD - Istituto Nazionale Tumori, Divison of Experimental Oncology A, Milan,
Italy.
14
UI - 11888009
AU - Van Houtte P
TI -
The role of radiotherapy and the value of combined treatment in lung
cancer.
SO - Eur J Cancer 2001 Oct;37 Suppl 7():S91-8
AD - Institut J. Bordet, Department of Radiotherapy, Brussels, Belgium.
15
UI - 11888010
AU - Giaccone G
TI -
State of the art in systemic treatment of lung cancer.
SO - Eur J Cancer 2001 Oct;37 Suppl 7():S99-114
AD - Vrije Universiteit Amsterdam, Department of Medical Oncology, The
Netherlands.
16
UI - 11917286
AU - Arquette M; Wasserman T; Govindan R; Garfield D; Senzer N; Gillenwater
TI -
H; Socinski M
Phase II evaluation of amifostine as an esophageal mucosal protectant in
the treatment of limited-stage small cell lung cancer with chemotherapy
and twice-daily radiation.
SO - Semin Radiat Oncol 2002 Jan;12(1 Suppl 1):59-61
AD - Washington University, St Louis, MO 63110, USA.
For limited-stage small cell lung cancer, twice-daily radiation with
concurrent chemotherapy improves survival rate, but has dose-limiting
esophageal toxicity. The authors studied 34 patients treated with
amifostine in an attempt to decrease the incidence and grade of
esophagitis. The results indicate that there was no reduction in
toxicity, but the authors were able to maintain the high complete
response rate that had been reported previously. These results differ
from the use of amifostine in non-small cell lung cancer in which there
is the observation of esophageal protection. Copyright 2002, Elsevier
Science (USA). All rights reserved.
17
UI - 7506925
AU - Zangemeister-Wittke U; Collinson AR; Frosch B; Waibel R; Schenker T;
TI -
Stahel RA
Immunotoxins recognising a new epitope on the neural cell adhesion
molecule have potent cytotoxic effects against small cell lung cancer.
SO - Br J Cancer 1994 Jan;69(1):32-9
AD - Division of Oncology, University Hospital, Zurich, Switzerland.
The present study describes a comparison of two potent immunotoxins
which utilise an identical targeting component, a monoclonal antibody
(SEN7) specific for small cell lung cancer (SCLC), conjugated to two
different effector components, blocked ricin (bR) and Pseudomonas
exotoxin A (PE). SEN7 recognises a novel epitope on the neural cell
adhesion molecule (NCAM) which is highly associated with SCLC. The
immunotoxins SEN7-PE and SEN7-bR were selectively and potently active
against a number of SCLC cell lines, of both classic and variant
morphologies, inhibiting the incorporation of [3H]leucine with IC50
values ranging between 22 pM and 85 pM and between 7 pM and 62 pM for
SEN7-PE and SEN7-bR respectively. Intoxication by both immunotoxins
proceeded rapidly following short 2 h lag phases; the initial rates of
protein synthesis inhibition occurred with t50 values of 6.5 h for
SEN7-PE and 5.5 h for SEN7-bR. Monensin drastically enhanced the
cytotoxic activity of the weakly active SEN7-ricin A-chain by 2,100-fold
and of SEN7-bR by 80-fold but had no effect on SEN7-PE. In limiting
dilution assays, four and more than 4.5 logs of clonogenic SW2 tumour
cells were selectively eliminated from the cultures during continuous
exposure to the immunotoxins SEN7-PE and SEN7-bR respectively, while
antigen-negative cells required up to 1,000-fold more drug for a similar
cell kill. SW2 cells surviving SEN7-bR treatment in the cultures did not
express NCAM and consequently were not selectively killed by SEN7
immunotoxins. SW2 cells surviving continuous exposure to SEN7-PE showed
no alteration in NCAM expression but were more resistant to intoxication
mediated by PE. These cells were still sensitive to SEN7-bR.
18
UI - 8622688
AU - Sithanandam G; Latif F; Duh FM; Bernal R; Smola U; Li H; Kuzmin I;
TI -
Wixler V; Geil L; Shrestha S
3pK, a new mitogen-activated protein kinase-activated protein kinase
located in the small cell lung cancer tumor suppressor gene region.
SO - Mol Cell Biol 1996 Mar;16(3):868-76
AD - Biological Carcinogenesis and Development Program, PRI/DynCorp, National
Cancer Institute, Frederick Cancer Research and Development Center,
Maryland 21702-1201, USA.
NotI linking clones, localized to the human chromosome 3p21.3 region and
homozygously deleted in small cell lung cancer cell lines NCI-H740 and
NCI-H1450, were used to search for a putative tumor suppressor gene(s).
One of these clones, NL1G210, detected a 2.5-kb mRNA in all examined
human tissues, expression being especially high in the heart and
skeletal muscle. Two overlapping cDNA clones containing the entire open
reading frame were isolated from a human heart cDNA library and fully
characterized. Computer analysis and a search of the GenBank database to
reveal high sequence identity of the product of this gene to
serine-threonine kinases, especially to mitogen-activated protein
kinase-activated protein kinase 2, a recently described substrate of
mitogen-activated kinases. Sequence identitiy was 72% at the nucleotide
level and 75% at the amino acid level, strongly suggesting that this
protein is a serine-threonine kinase. Here we demonstrate that the new
gene, referred to as 3pK (for chromosome 3p kinase), in fact encodes a
mitogen-activated protein kinase-regulated protein serine-threonine
kinase with a novel substrate specificity.
19
UI - 10211098
AU - Sirzen F; Nilsson A; Zhivotovsky B; Lewensohn R
TI -
DNA-dependent protein kinase content and activity in lung carcinoma cell
lines: correlation with intrinsic radiosensitivity.
SO - Eur J Cancer 1999 Jan;35(1):111-6
AD - Department of Oncology, Radiumhemmet, Karolinska Institute, Stockholm,
Sweden.
Intrinsic radiosensitivity and rejoining of radiation-induced DNA
double-strand breaks (DNA-dsb) were analysed in five lung carcinoma cell
lines: U-1285, U-1906, H-69, H-82 and U-1810. RS correlated with both
the initial phase of DNA-dsb rejoining, at 15 min (r2 = 0.818) and the
late phase, at 120 min postirradiation (r2 = 0.774), the most sensitive
cell line (U-1285) showing least dsb rejoining and the most resistant
(U-1810) showing most dsb rejoining of all five cell lines studied. As
DNA-PK has been recognised as an important molecular component involved
in DNA-dsb repair, we analysed content and activity of this kinase. We
found that DNA-PK content and activity correlated with RS (r2 = 0.941
and r2 = 0.944, respectively). The lowest DNA-dependent content/activity
was found in the most radiosensitive cells, U-1285 and H-69, whilst the
highest content/activity was found in the most radioresistant cells
U-1810. These results suggest a correlation between RS and DNA-PK
content/activity in lung carcinoma cell lines.
20
UI - 10561178
AU - Rusthoven JJ; Eisenhauer E; Butts C; Gregg R; Dancey J; Fisher B;
TI -
Iglesias J
Multitargeted antifolate LY231514 as first-line chemotherapy for
patients with advanced non-small-cell lung cancer: A phase II study.
National Cancer Institute of Canada Clinical Trials Group.
SO - J Clin Oncol 1999 Apr;17(4):1194
AD - Hamilton Regional Cancer Centre, Hamilton, Ontario, Canada.
PURPOSE: To evaluate the efficacy and safety of the multitargeted
antifolate LY231514 (MTA) in patients receiving initial chemotherapy for
unresectable, advanced non-small-cell lung cancer (NSCLC). PATIENTS AND
METHODS: Patients with measurable, advanced NSCLC who had not received
previous chemotherapy for advanced disease were considered for this
study. Eligible patients who gave written informed consent initially
received MTA 600 mg/m(2) intravenously (IV) for 10 minutes every 3
weeks. After three patients received treatment at this dose, the dose
was reduced to 500 mg/m(2) IV at the same infusion time and frequency
because of toxicity seen in this study and another Canadian MTA trial in
colorectal cancer. Patients received up to four cycles after complete or
partial remission or six cycles after stable disease was documented.
RESULTS: Thirty-three patients were accrued onto the study. All were
assessable for toxicity, and 30 patients were assessable for response.
All but one patient had an Eastern Cooperative Oncology Group
performance status score of 0 or 1, 18 patients (55%) had
adenocarcinoma, and nine patients (27%) had squamous cell carcinoma.
Twenty-five patients (76%) had stage IV disease, and the remainder had
stage IIIB disease at trial entry. Seven patients experienced a
confirmed partial response and no complete responses were seen; thus,
the overall response rate was 23.3% (95% confidence interval, 9.9% to
42.3%). The median duration of response was 3.1 months (range, 2. 3 to
13.5 months) after a median follow-up period of 7.9 months. Four (67%)
of six patients with stage IIIB disease and three (12.5%) of 24 with
stage IV disease responded to treatment. Four patients (13.3%)
experienced febrile neutropenia and 13 (39%) experienced grade 3 or 4
neutropenia, whereas only one patient (3%) developed grade 4
thrombocytopenia. Nonhematologic toxicity was generally mild or
moderate, but 39% of patients developed a grade 3 skin rash. Most other
toxicities comprised grade 1 or 2 stomatitis, diarrhea, lethargy, and
anorexia. Ten patients stopped protocol therapy because of toxicity.
CONCLUSION: MTA seems to have clinically meaningful activity as a single
agent against advanced NSCLC. Toxicity is generally mild and tolerable.
Further study of this agent in combination with cisplatin and other
active drugs is warranted in this disease.
21
UI - 11687105
AU - Rowell NP; Gleeson FV
TI -
Steroids, radiotherapy, chemotherapy and stents for superior vena caval
obstruction in carcinoma of the bronchus.
SO - Cochrane Database Syst Rev 2001;(4):CD001316
AD - Kent Oncology Centre, Hermitage Lane, Maidstone, Kent, UK, ME16 9QQ.
nrowell@lineone.net
BACKGROUND: Superior vena caval obstruction (SVCO) is an uncommon
manifestation of carcinoma of the bronchus characterised by neck
swelling and distended veins over the chest. In recent years, the
majority of patients with small cell lung cancer (SCLC) with SVCO at
diagnosis have tended to receive chemotherapy whilst the majority of
patients presenting with non-small cell lung cancer (NSCLC) and SVCO
have tended to receive radiotherapy. Steroids may also be prescribed.
Stenting now provides a further treatment option which may be combined
with radiotherapy and chemotherapy or used on its own. The optimal
timing of stenting at present is unclear. OBJECTIVES: To determine the
relative effectiveness of treatments currently employed in the
management of SVCO. SEARCH STRATEGY: Electronic searching of Cochrane
Clinical Trials register, Medline and Embase. Identification of further
studies from references cited in trials identified by electronic
searching. SELECTION CRITERIA: Both randomised and non-randomised
controlled trials in which patients with carcinoma of the bronchus and a
diagnosis of SVCO had been treated with any combination of the following
treatment modalities: steroids, chemotherapy, radiotherapy or insertion
of an expandable metal stent. DATA COLLECTION AND ANALYSIS: There were 3
randomised and 98 non-randomised studies of which 2 and 44 respectively
met the inclusion criteria. MAIN RESULTS: SVCO was present at diagnosis
in 10.0% of patients with SCLC and 1.7% of patients with NSCLC. In one
randomised trial in SCLC, the rate of SVCO relapse was not significantly
reduced by giving radiotherapy on completion of chemotherapy. In the
other, in NSCLC, the addition of induction chemotherapy to a course of
synchronous chemo-radiotherapy did not increase the rates of relief of
SVCO. In SCLC, chemotherapy and/or radiotherapy relieved SVCO in 77%;
17% of those treated had a recurrence of SVCO. In NSCLC, 60% had relief
of SVCO following chemotherapy and/or radiotherapy; 19% of those treated
had a recurrence of SVCO. Insertion of an SVC stent relieved SVCO in
95%; 11% of those treated had further SVCO but recanalisation was
possible in the majority resulting in a long-term patency rate of 92%.
Morbidity following stent insertion was greatest if thrombolytics were
administered. No study described the effectiveness of steroids in SVCO.
REVIEWER'S CONCLUSIONS: Chemotherapy and radiotherapy are effective in
relieving SVCO in a proportion of patients whilst stent insertion
appears to provide relief in a higher proportion and more rapidly. The
optimal timing of stent insertion (whether at diagnosis or following
failure of other modalities) is currently uncertain. The effectiveness
of steroids in SVCO remains uncertain.
22
UI - 11911271
AU - Xing T; Brattstrom D; Bergqvist M; Isaksson U; Wagenius G; Brodin O
TI -
Radiation responsiveness of human lung cancer cell lines measured with a
short term semiautomatic assay.
SO - Anticancer Res 2001 Nov-Dec;21(6A):3925-8
AD - Department of Oncology, Radiology and Clinical Immunology, Uppsala
University Hospital, Sweden.
BACKGROUND: Fluorometric microculture cytotoxicity assay (FMCA) is a
short-term semi-automatic method, based on dye-inclusion of surviving
cells. The assay was developed for investigations of drug resistance on
tumour cells from biopsy material. In the present study, this short-term
assay was evaluated, regarding usefulness in determining
radio-sensitivity. MATERIALS AND METHODS: Eight human lung cancer cell
lines were used. There were five small cell lung cancer (SCLC and three
non-small cell lung cancer (NSCLC cell lines. Results were compared with
the corresponding data derived from the clonogenic assay and/or the
extrapolation method. RESULTS: The surviving fraction (SF) after 2, 5
and 10 Gy compared with data from the clonogenic assay were not in
accordance for 5 of the 8 cell lines. The FMCA assay overestimated SF-
values for the SCLC cell lines. CONCLUSION: The FMCA assay is not useful
as a quick screening method for the radioresponsiveness in vitro of
human tumour cell lines.
23
UI - 11911315
AU - Gridelli C; Curcio C; Iaffaioli R V; Brancaccio L; D'Aprile M; Gebbia V;
TI -
Rossi A; Tortoriello A; Veltri E; Maione P; Barbarisi A; Gallo C; Guida
C; Perrone F
Carboplatin + epirubicin +VP-16 + lenograstim followed by radiotherapy +
carboplatin as radiosensitizer in limited small cell lung cancer. A
multicenter phase II study.
SO - Anticancer Res 2001 Nov-Dec;21(6A):4179-83
AD - Oncologia Medica B, Istituto Nazionale Tumori, Napoli, Italy.
cgridelli@sirio-oncology.it
A phase II trial was undertaken to test the activity and toxicity of
carboplatin (300 mg/m2, i.v. day 1) + epirubicin (75 mg/m2, i.v. day 1)
+ VP-16 (100 mg/m2, i.v. days 1 to 3) + lenograstim (5 mcg/kg, s.c. days
6 to 15) administered every 3 weeks for 4 cycles and subsequent chest
irradiation (50 Gy) + daily carboplatin (25 mg/m2) in the first-line
treatment of adults affected by limited small cell lung cancer (SCLC).
PATIENTS AND METHODS: A single-stage phase II design was used; the
complete response (CR) rate after chest radiotherapy was the primary
end-point. Twenty-three CRs were required out of 38 patients to consider
the treatment worthy of further study. Prophylactic cranial irradiation
(PCI) was planned in case of CR. Patients aged < or = 70 were eligible
if they had limited SCLC, a performance status not worse than 2 by the
ECOG scale and no prior chemotherapy or radiotherapy. RESULTS: From
was 60 years. All the patients started chemotherapy; 23 patients
received chest irradiation and concurrent daily carboplatin; 11 patients
also received PCI. Toxicity was generally mild. Sixteen CRs (48.5%, 95%
CI: 30.8-66.5) were recorded; the objective response rate was 72.7% (95%
CI: 54.5-86.7). The median time-to-progression was 7.9 months (95% CI:
6.5-10.4). The median-survival was 10.7 months (95% CI: 9.2-16.1).
CONCLUSION: Induction chemotherapy with carboplatin + epirubicin + VP-16
followed by chest irradiation plus concurrent daily carboplatin is
well-tolerated but not sufficiently active to warrant further study in
the treatment of patients with limited SCLC.
24
UI - 11904983
AU - Kato Y; Saijo N
TI -
[Developed new agents for lung cancer]
SO - Nippon Geka Gakkai Zasshi 2002 Feb;103(2):218-23
AD - Department of Internal Medicine, National Cancer Center Hospital, Tokyo,
Japan.
Platinum-based chemotherapy is considered to be the standard
chemotherapy of non-small cell lung cancer (NSCLC) at present. New
agents such as irinotecan, paclitaxel, docetaxel, vinorelbine,
gemcitabine, topotecan, and amurubicin were developed in the 1990s.
Combination chemotherapy using new agents improved survival rates
compared with the classic regimen. Irinotecan, paclitaxel, docetaxel,
vinorelbine, and gemcitabine have been confirmed to be effective against
NSCLC. However, chemotherapy for NSCLC is controversial because the
differences in the efficacies of combination chemotherapies including
new agents have not been recognized in randomized controlled trials. The
Four-Arms Cooperative Study is an ongoing postmarketing clinical trial
in Japan. The a ntitumor agents irinotecan, topotecan, paclitaxel, and
amurubicin have been confirmed to be effective in small cell lung cancer
(SCLC). The combination of etoposide and cisplatin (PE) is the standard
regimen for SCLC in Western countries. However, the combination of
irinotecan and cisplatin (CP) resulted in higher response rates and
better median survival times than PE for extensive-disease SCLC in a
JCOG trial. At present, CP is considered to be the standard chemotherapy
regimen to treat SCLC in Japan. The development of new agents,
particularly molecular target-based drugs and multimodality treatment,
is necessary to improve the therapeutic results in lung cancer further.
25
UI - 11948426
AU - Osada H; Tatematsu Y; Yatabe Y; Nakagawa T; Konishi H; Harano T; Tezel
TI -
E; Takada M; Takahashi T
Frequent and histological type-specific inactivation of 14-3-3sigma in
human lung cancers.
SO - Oncogene 2002 Apr 4;21(15):2418-24
AD - Division of Molecular Oncology, Aichi Cancer Center Research Institute,
1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. hosada@aichi-cc.jp
One isoform of the 14-3-3 family, 14-3-3sigma, plays a crucial role in
the G2 checkpoint by sequestering Cdc2-cyclinB1 in the cytoplasm, and
the expression of 14-3-3sigma is frequently lost in breast cancers. This
loss of expression is thought to cause a G2 checkpoint defect, resulting
in chromosomal aberrations. Since lung cancers frequently carry numerous
chromosomal aberrations, we examined the DNA methylation status and
expression level of the 14-3-3sigma gene in 37 lung cancer cell lines
and 30 primary lung tumor specimens. We found that small cell lung
cancer (SCLC) cell lines frequently showed DNA hypermethylation (9 of 13
lines, 69%), and subsequent silencing of the 14-3-3sigma gene. Among
non-small cell lung cancers (NSCLC), large cell lung cancer cell lines
showed frequent hypermethylation and silencing of 14-3-3sigma (4 or 7
lines, 57%). In contrast, in other NSCLC cell lines, hypermethylation
occurred very rarely (1 of 17 lines, 6%). All eight primary SCLC
specimens examined also showed a loss or significant reduction in
14-3-3sigma expression in vivo, while a loss or reduction of 14-3-3sigma
expression was very rare in primary NSCLC specimens (1 of 22 tissues,
5%). This is the first description that indicates lung cancers
frequently show significant inactivation of the 14-3-3sigma gene mainly
due to DNA hypermethylation in SCLC, but rarely in NSCLC, suggesting
involvement of the 14-3-3sigma gene in lung tumorigenesis in a
histological type-specific manner.
26
UI - 10976695
AU - Ordonez NG
TI -
Value of thyroid transcription factor-1 immunostaining in distinguishing
small cell lung carcinomas from other small cell carcinomas.
SO - Am J Surg Pathol 2000 Sep;24(9):1217-23
AD - University of Texas M.D. Anderson Cancer Research Center, Houston,
77030, USA.
The distinction between small cell lung carcinoma (SCLC) and small cell
carcinomas of other sites is difficult by routine histology. Thyroid
transcription factor-1 (TTF-1) is a homeodomain-containing transcription
factor that is selectively expressed in thyroid and pulmonary epithelial
cells. TTF-1 expression has also been demonstrated in adenocarcinomas of
the thyroid and lung, and SCLC. However, the value of TTF-1
immunostaining in discriminating between SCLC and nonpulmonary small
cell carcinomas has not been investigated. In the present study using an
immunoperoxidase staining procedure on paraffin sections, we
investigated the expression of TTF-1 and cytokeratin 20 (CK20), a marker
that has previously been demonstrated in small cell carcinomas of the
skin (Merkel cell carcinomas), in 82 small cell carcinomas from a wide
variety of sites (28 lung, 18 skin, 12 gastrointestinal tract, 8
sinonasal, 5 bladder, 3 prostate, 3 uterine cervix, 2 thyroid, 2
salivary gland, and 1 pancreas). Twenty-seven (96%) of the 28 SCLCs were
positive for TTF-1. Among the nonpulmonary small cell carcinomas, two
tumors of the gastrointestinal tract, one of the bladder, and one of the
uterine cervix exhibited TTF-1 positivity. Sixteen (89%) of the 18
Merkel cell carcinomas and one SCLC were CK20-positive. All other small
cell carcinomas were negative for this marker. These results indicate
that although TTF-1 is not a specific marker for SCLC, it may assist in
distinguishing SCLC from some nonpulmonary small cell carcinomas,
particularly Merkel cell carcinoma, especially when it is used in
conjunction with CK20.
27
UI - 11257635
AU - Cheuk W; Chan JK
TI -
Thyroid transcription factor-1 is of limited value in practical
distinction between pulmonary and extrapulmonary small cell carcinomas.
SO - Am J Surg Pathol 2001 Apr;25(4):545-6
28
UI - 11901539
AU - Thomas JP; Moore T; Kraut EH; Balcerzak SP; Galloway S; Vandre DD; Ohio
TI -
State University Phase II Research Consortium Study
A phase II study of CI-980 in previously untreated extensive small cell
lung cancer: an Ohio State University phase II research consortium
study.
SO - Cancer Invest 2002;20(2):192-8
AD - Division of Hematology/Oncology, James Cancer Hospital and Solove
Research Institute, Ohio, USA.
CI-980, (ethyl (S)-(5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]
pyrazine-7-yl) carbamate 2-hydroxyethansulfonate (1:1)), is a
water-soluble mitotic inhibitor. It acts by binding to the
colchicine-binding site on tubulin, a site different from that of the
vinca alkaloids, inhibiting tubulin polymerization. Cells exposed to
CI-980 accumulate in M phase and die. In preclinical tumor models,
CI-980 showed a broad spectrum of activity, including in multi-drug
resistant tumor cell lines, with activity at least equal to that of
vincristine. Extensive small cell lung cancer, despite its
responsiveness to chemotherapy, is usually an incurable disease with
survival in patients of less than one year. Due to the preclinical
activity of CI-980 and its similar mechanism of action to drugs
effective in small cell lung cancer, a phase II trial in extensive small
cell lung cancer was initiated by The Ohio State University Phase II
Research Consortium. A "window of opportunity" design was chosen where a
short six-week trial of the drug was given unless there was significant
objective response. Twelve patients were entered in the study and
underwent a total of 16 cycles of chemotherapy. The median age of the
patients was 54 years old (range 34-71) and performance status was ECOG
0 (four patients), ECOG 1 (seven patients), and ECOG 2 (one patient).
The patients were treated with a 72-hr infusion at a dose of 4.5
mg/m2/day. Toxicity was predominantly myelosuppression with
granulocytopenia (nine episodes), and anemia (seven episodes). There
were no objective responses with 11 patients being removed from study
due to progressive disease. Evaluation of leukocyte microtubule
structure in peripheral blood revealed microtubule depolymerization,
which was seen after treatment (t = 72 hr) and was reversible within 24
hr of stopping the drug. We conclude that despite antitumor activity
demonstrated in preclinical studies, CI-980 does not have biological
activity in previously untreated small cell lung cancer at this dose and
infusion protocol.
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