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Thoracic Surgery: Answers
239
metastases (density > 10 Hounsfield units) and 11% of true metastases may be mistaken for
adenomas (density < 10 Hounsfield units). CT-scan has 100% sensitivity in detecting the
metastatic nature of adrenal masses; however, 50% of adenomas may be mistaken as
metastasis. Diagnostic accuracy of adrenal metastasis typically increased with detection of a
primary tumor, as well as changes in the size and architecture of the parenchyma over time or
during treatment. In equivocal cases, CT-scan-guided percutaneous biopsy of the adrenal
mass is a safe and reliable method for the diagnosis of the lesion (sensitivity 81%, specificity
99%, potential complications 2.8%).
Table. Differential diagnosis of incidentally discovered adrenal mass on imaging
Adrenal metastasis
Nonfunctional adenoma
Primary carcinoma in adrenal glands
Adrenal cyst
Nonfunctional pheochromocytoma
Other causes
– Myelolipoma
– Lymphoma
– Aldosteronoma
– Neuroblastoma
– Pheochromocytoma
In presence of adrenal metastasis the disease is staged as stage IV, which demonstrates
the aggressive biological behavior and systemic dissemination of secondary lesions. These are
treated as any other metastatic neoplasm and the appropriate chemotherapy is started. In
select patients, where the primary lung site is surgically resectable (T1, T2 and maybe T3),
with no involvement or the involvement of only the peribronchial and portal lymph nodes
(N0, N1) and where the adrenal metastasis constitutes the unique indication of the disease,
simultaneous adrenalectomy along with resection of the primary can increase overall survival.
Technically, this can be achieved with thoracoabdominal or transabdominal approaches, or
laparoscopically in cases of small tumors (< 5 cm). A recent meta-analysis suggests that the
latter technique, when it is feasible, is associated with fewer complications than open
adrenalectomy. However, adrenal metastases are usually larger than 5 cm, which makes this
approach inappropriate for general application. There is also a perceived increased risk of
local tumor recurrence and intraperitoneal tumor dissemination occurring after laparoscopic
resection of malignant adrenal tumors.
References
Shen KR, Meyers BF, Larner JM, et al. Special treatment issues in lung cancer: ACCP
evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3
Suppl):290S-305S.
Karanikiotis C, Tentes AA, Markakidis S, Vafiadis K. Large bilateral adrenal metastases in
non-small cell lung cancer. World J Surg Oncol. 2004;2:37.
Shahzad G. Raja
240
Porte HL, Ernst OJ, Delebecq T, et al. Is computed tomography guided biopsy still necessary
for the diagnosis of adrenal masses in patients with resectable non-small-cell lung
cancer? Eur J Cardiothorac Surg. 1999,15:597-601.
Heniford BT, Arca MJ, Walsh RM, Gill IS. Laparoscopic adrenalectomy for cancer. Semin
Surg Oncol. 1999,16:293-306.
Beitler AL, Urschel JD, et al. Surgical management of adrenal metastases from lung cancer. J
Surg Oncol. 1998,69:54-57.
Welch TJ, Sheedy PF 2nd, Stephens DH, et al. Percutaneous adrenal biopsy: review of a 10-
year experience. Radiology. 1994, 193:341-344.
3.41 Answer: D
Approximately 25% of patients with stage IV NSCLC have a brain
metastasis as well as
other sites of metastatic disease. The
median survival of patients with a brain metastasis is
approximately
2 months when treated with steroids alone and 3 to 6 months
when treated with
whole-brain radiotherapy (WBRT). Because
the survival of patients with a brain metastasis is
so short,
there is reason to consider aggressive treatment of the brain
metastasis with either
surgical resection or radiosurgery as
a palliative treatment to prolong survival. However, a
subset
of patients with stage IV disease have a brain metastasis as
the only site of metastatic
disease. In this group, it is reasonable
to consider aggressive therapy of both the primary
lesion and
the isolated metastatic site as a potentially curative therapy.
Aggressive treatment of a brain metastasis may involve either
surgical resection of the
metastasis or ablation of the metastasis
by radiosurgery. This latter technique involves a
precisely
focused beam of radiation with a steep fall-off of the dose
outside the target area,
hence the name radiosurgery. Although
no randomized trial of surgery vs radiosurgery has
ever been
completed, comparison of the results of these techniques in
patients who have been
treated palliatively suggests that they
are similar with regard to survival, local control,
morbidity,
and mortality.
Patients with a brain metastasis should be selected for curative
treatment only after a
thorough search for other sites of disease
has been negative. Furthermore, it is fairly obvious
that only
patients in whom both the brain metastasis and the primary tumor
can be completely
resected can be considered candidates for
curative treatment (synchronous presentation). It
seems reasonable
to assume that patients with N2,3 involvement and a brain metastasis
are not
good candidates for curative therapy, although data
demonstrating this are lacking. Therefore,
it seems reasonable
to perform mediastinoscopy in selecting patients for resection
of the brain
metastasis and the primary lesion. The histologic
subtype does not play a role. The number of
brain metastases
may not play a role as long as the number is small (≤3) and
they all can be
completely resected (as has been demonstrated
by several retrospective studies in patients
who were treated
for palliation). The outlook is likely to be more optimistic for patients who
are younger or female or have a metachronous presentation.
The outlook may also be better in
patients with supratentorial
lesions and those with a brain metastasis < 3 cm in diameter.
However, these considerations are relative and should not necessarily
exclude patients who
are otherwise fit and in whom a complete
resection is likely to be achieved.
Survival statistics of patients who have a brain metastasis
and were treated with curative
intent have been reported by
a number of studies. The overall survival for all patients
is fairly
consistent and averages 14% (range, 8 to 21%). The
5-year survival for patients in whom
complete resection has
been achieved averages 21% (range, 16 to 30%). The operative
Thoracic Surgery: Answers
241
mortality in these studies has been low, averaging 2%. Approximately
two thirds of the cases
involved a metachronous presentation.
There are conflicting data regarding the role of adjuvant WBRT
after resection of an
isolated brain metastasis. Retrospective
analyses of patients who were primarily treated with
curative
intent have suggested either no survival benefit or a significant
benefit. The rate of
intracranial recurrence among patients
who were treated primarily with palliative intent was
lower
after WBRT in a randomized study, whereas retrospective analyses in such patients
have shown conflicting results. It is likely
that a benefit might be seen only in patients without
other
sites of metastases, given the experience with prophylactic
cranial irradiation in patients
with small cell lung cancer.
There are no data regarding the role of adjuvant chemotherapy
in
patients who have undergone curative resection of a brain
metastasis.
References
Shen KR, Meyers BF, Larner JM, et al. American College of Chest Physicians. Special
treatment issues in lung cancer: ACCP evidence-based clinical practice guidelines (2nd
edition). Chest. 2007;132(3 Suppl):290S-305S.
Bindal AK, Bindal RK, Hess KR, et al. Surgery versus radiosurgery in the treatment of brain
metastasis. J Neurosurg. 1996;84,748-754.
Mandell L, Hilaris B, Sullivan M, et al. The treatment of single brain metastasis from non-oat
cell lung carcinoma. Surgery and radiation versus radiation therapy alone. Cancer.
1986;58:641-9.
3.42 Answer: D
Although there are scattered reports of long-term survivors
from extended resections of
lung cancers involving the superior
vena cava, aorta, esophagus, or vertebral body, there are
fewer
solid data to support these extended operations. There are no
consistent data regarding
these resections of T
4
lung cancers.
Although limited T
4
involvement of the superior vena
cava, intrapericardial
pulmonary artery, phrenic nerve, or left atrium may allow resection,
most authorities consider invasion of the esophagus, vertebral
bodies, or great vessels as
contraindications to surgery. Systemic
arterial (aorta) and esophageal invasion of T
4
lung
cancer carry
the poorest long-term outcome. Limited local invasion of the
intrapericardial
pulmonary artery or left atrium can be resected
completely with expected 5-year survival rates
of ≈ 20% to 30%.
In general, if there is less than 1 to 1.5 cm of intrapericardial
involvement of
these structures, they can usually be resected
with negative margins and a safe vascular
closure. Most authorities
have viewed the need for more complex reconstructions that require
cardiopulmonary bypass as a contraindication to resection, although
occasional patients may
have anatomy where bypass may be a useful
adjunct to resection. Vascular resection and
reconstruction
of the superior vena cava, aorta, and left atrium have been
safely described
with 5-year survival rates of 20%. Along with
limited left atrial resection, superior vena cava
resection
is the most accepted extended vascular resection for T
4
disease
with an acceptably
low mortality rate and 5-year survival rates
ranging from 10% to 30%. Combined
pulmonary
and aorta resection is described by Fukuse et al. with 5-year survival rates of 31% (n = 15).
Combined pulmonary
and left atrial resection has been described most recently by
Bobbio et
al. with 5-year survival rates of 10% (n = 23).
Finally, T
4
lung cancers invading the vertebral
body can be
resected with a 5-year survival rate of 15%. A multidisciplinary
team is essential
for these complex resections and reconstructions.
Shahzad G. Raja
242
References
DiPerna CA, Wood DE. Surgical management of T3 and T4 lung cancer. Clin Cancer Res.
2005;11(13 Pt 2):5038s-5044s.
Bobbio A, Carbognani P, Grapeggia M, et al. Surgical outcome of combined pulmonary and
atrial resection for lung cancer. Thorac Cardiovasc Surg. 2004;52:180-2.
Grunenwald DH. Surgery for locally advanced non-small cell lung cancer. Semin Surg Oncol.
2003;21:85-90.
Pitz CC, Brutel de la Rivière A, van Swieten HA, et al. Results of surgical treatment of T4
non-small cell lung cancer. Eur J Cardiothorac Surg. 2003;24:1013-8.
Fukuse T, Wada H, Hitomi S. Extended operation for non-small cell lung cancer invading
great vessels and left atrium. Eur J Cardiothorac Surg. 1997;11:664-9.
3.43 Answer: C
The 2003 ACCP recommendations defined platinum-based doublets as the standard of
care for patients with stage IV non-small cell lung cancer (NSCLC) and good performance
status (PS). Delbaldo et al. reported a metaanalysis that included 13,601 patients in 65 trials
and showed that two chemotherapeutic agents led to superior response and survival rates in
patients with stage IV NSCLC compared with single agents. Since the report of that
metaanalysis, platinum-based doublets were shown to be superior to single-agent therapy in
three randomized trials. Although overall survival was statistically superior in only one of the
three trials, the overall therapeutic efficacy, including response rate and progression-free
survival, improved with the doublets with no significant cost in toxicity or quality of life
(QOL).
Several large, randomized trials have compared various platinum doublets (both cisplatin
based and carboplatin based) and failed to identify a superior regimen. The only potential
exception was the TAX 326 trial, which demonstrated improved QOL and a trend toward
improved survival (statistically, it was ―noninferior‖) for cisplatin-docetaxel compared with
cisplatin-vinorelbine. This experience, although valid, remains an exception, and cisplatin-
docetaxel has not been widely adopted as the ―preferred regimen.‖ There is general agreement
that either cisplatin or carboplatin combined with a taxane (paclitaxel or docetaxel),
gemcitabine, vinorelbine, or irinotecan can be used in the first-line treatment of patients with
advanced NSCLC and good PS.
A number of randomized trials have tested the addition of a third chemotherapeutic agent
to existing doublets. These ―triplets‖ consistently failed to show superiority over established
two-drug combinations with regard to survival, although response rates were improved. In
most trials, these efficacy parameters were at best comparable, whereas toxicity was
substantially more pronounced with the triplets. Only one trial showed better results for a
triplet compared with a doublet, but the result seen in this trial stands alone and has not been
reproduced by other investigators.
References
Socinski MA, Crowell R, Hensing TE, et al. Treatment of non-small cell lung cancer, stage
IV: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007
Sep;132(3 Suppl):277S-289S.
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243
Paccagnella A, Oniga F, Bearz A, et al. Adding gemcitabine to paclitaxel/carboplatin
combination increases survival in advanced non-small-cell lung cancer: results of a phase
II–III study. J Clin Oncol 2006;24,681-68.
Delbaldo C, Michiels S, Syz N, Soria JC, et al. Benefits of adding a drug to a single-agent or
a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: a meta-
analysis. JAMA 2004;292,470-484.
3.44 Answer: B
The advent of molecular-targeted agents has raised expectations that these agents, which
are different from traditional chemotherapeutic drugs, could be added to standard doublets
with enhanced efficacy and no additional toxicity. Large, randomized trials tested the two
available tyrosine kinase inhibitors, gefitinib and erlotinib, in combination with cisplatin-
gemcitabine and carboplatin-paclitaxel. Unfortunately, no significant difference in survival
was observed with the addition of the two novel agents when used concomitant with
chemotherapy in any of the four trials, which together accrued nearly 4,000 patients
worldwide. However, in a subset analysis of one of the trials, patients with no history of
smoking experienced a significant benefit when treated with erlotinib plus chemotherapy
compared with chemotherapy alone. This observation is being tested in a prospective manner.
Other promising agents, including but not limited to metalloproteinase inhibitors
(prinomastat), antisense therapy (ISIS 3521), farnesyl transferase inhibitors (lonafarnib), and
retinoid derivatives (bexarotene), all failed to improve outcomes when added to standard
chemotherapy in patients with advanced NSCLC.
References
Socinski MA, Crowell R, Hensing TE, et al. Treatment of non-small cell lung cancer, stage
IV: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007
Sep;132(3 Suppl):277S-289S.
Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride
(OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-
small-cell lung cancer. J Clin Oncol 2005;23,5892-5899.
Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and
carboplatin in advanced non-small-cell lung cancer: a phase III trial; INTACT 2. J Clin
Oncol 2004;22,785-794.
Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and
cisplatin in advanced non-small-cell lung cancer: a phase III trial; INTACT 1. J Clin
Oncol 2004;22,777-784.
3.45 Answer: B
Molecular biologic staging refers to the assessment of tumor markers associated with
various oncogenic mechanisms to improve the risk stratification provided by conventional
TNM staging. Biologic staging may target oncogenes, oncogenic protein products, growth
factors, or receptors. The biologic techniques used include analysis of DNA, RNA, or protein
products. Molecular biologic staging may potentially be applied to the primary tumor, lymph
nodes, bone marrow, or serum, to establish the diagnosis of malignancy at earlier stage, assess
prognosis, detect occult metastases, select therapy, and predict chemotherapy sensitivity or
resistance.
Shahzad G. Raja
244
The purpose of the assessment of prognostic markers in the primary tumor is to identify
patients-or groups of patients-with early-stage disease whose risk of recurrence is sufficiently
high enough to justify adjuvant therapy. In addition, the assessment of the primary tumor may
also enable more accurate selection of adjuvant therapy, either cytotoxic chemotherapy or
targeted therapy. Assessment of lymph nodes may allow identification of micrometastatic
disease: occult metastases not identified on routine pathologic examination. Correct
assessment of micrometastatic lymph node involvement improves assessment of extent of
disease, prognostic stratification, and choice of adjuvant therapy. Assessment of bone marrow
and serum may identify evidence of occult distant metastatic disease (Stage IV).
Identification of these patients would prevent unnecessary surgical resection and allow
patients to receive systemic therapy sooner.
Studies that evaluate molecular prognostic variables must be limited to early-stage
disease; the inclusion of patients with advanced-stage disease dilutes the potential prognostic
value of the markers, since this subgroup of patients will have a dismal prognosis, regardless
of marker status.
The proto-oncogene c-erbB-1 encodes for epidermal growth factor receptor (EGFr), a
tyrosine kinase-type membrane receptor. Ligand binding to EGFr results in receptor
dimerization, autophosphorylation, activation of cytoplasmic proteins, and eventually DNA
synthesis. Mutations in erbB-1 can result in constitutive activation of EGFr despite the
absence of ligand, with the result being uncontrolled tumor growth. In NSCLC, elevated
levels of EGFr have been shown to be present compared with normal lung tissue. ErbB-2
(also known as HER-2/neu) shares extensive homology (80%) with erbB-1 and encodes for a
transmembrane tyrosine kinase receptor (p185neu) that also functions as growth factor
receptor. Kern and colleagues found 10 of 29 patients with adenocarcinoma overexpressed
p185neu, and this overexpression was associated with decreased survival.
The class of EGFR-targeted therapies contains several agents in various stages of
development. EGFR expression is also associated with resistance to chemotherapy and
radiotherapy. Two general approaches have been pursued to modify EGFR activity:
monoclonal antibodies directed at EGFR or its ligand (EGF) and small molecule inhibitors of
the EGFR tyrosine kinase. Both approaches inactivate the EGFR pathway and inhibit tumor
activity.
Two small molecule inhibitors in particular have been well studied: gefitinib and
erlotinib. Of the EGFR-targeted agents, gefitinib is approved for the treatment of NSCLC;
erlotinib is currently under Food and Drug Administration (FDA) review for an indication in
NSCLC. Initial studies of gefitinib demonstrated favorable tolerability and antitumor activity,
and the FDA granted an indication for this agent as monotherapy in advanced NSCLC after
failure of both platinum-based and docetaxel chemotherapies. Two large-scale clinical trials
(INTACT-1and INTACT-2) evaluated the use of gefitinib in combination therapy compared
with chemotherapy alone. In these 2 studies, there were no significant differences between
groups in median survival.
References
D‘Amico TA. Molecular staging and the selection of therapy for non small cell lung cancer.
Semin Thorac Cardiovasc Surg. 2005;17:180-85.
D‘Cunha J, Corfits AL, Herndon JE 2nd, et al. Molecular staging of lung cancer: real-time
polymerase chain reaction estimation of lymph node micrometastatic tumor cell burden
Thoracic Surgery: Answers
245
in stage I non–small-cell lung cancer-preliminary results of cancer and leukemia group B
trial 9761. J Thorac Cardiovasc Surg. 2002;123:484-491.
Langer CJ. Emerging role of epidermal growth factor receptor inhibition in therapy for
advanced malignancy: focus on NSCLC. Int J Radiat Oncol Biol Phys. 2004;58:991-
1002.
Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and
cisplatin in advanced non–small-cell lung cancer: a phase III trial—INTACT 1. J Clin
Oncol. 2004;22:777-784.
Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and
carboplatin in advanced non–small-cell lung cancer: a phase III trial—INTACT 2. J Clin
Oncol. 2004;22:785-794.
3.46 Answer: E
The human p53 protein is a tumor suppressor nuclear phosphoprotein. p53 activates the
growth-arrest pathway to allow DNA repair or the apoptotic pathway leading to programmed
cell death. Once p53 genes are deleted or mutated, cells become susceptible to DNA damage
and dysregulated cell growth. This is associated with poor prognosis in patients with NSCLC
and may also identify patients more likely to be resistant to chemotherapy or radiotherapy.
Adenoviral p53 gene therapy has been studied as a strategy to improve survival with
minimal toxicity. The additional benefit from intratumoral adenoviral p53 gene therapy was
studied in patients undergoing first-line chemotherapy for advanced NSCLC. In this study,
there was no difference between the response rate of lesions treated with p53 gene therapy in
addition to chemotherapy (52% objective responses) and lesions treated with chemotherapy
alone (48% objective responses). There was no survival difference between the 2 regimens.
Intratumoral adenoviral p53 gene therapy provided no additional benefit in patients receiving
an effective first-line chemotherapy for advanced NSCLC.
A phase II trial of combination radiotherapy in patients with localized NSCLC revealed
an improved pathologic control rate of 62% among eight patients evaluated compared with
historical controls receiving chemoradiation or radiation alone. Five (39%) of 13 patients
achieved complete response, whereas two others (15%) had partial responses. However, in a
multicenter nonrandomized phase II study of combination chemotherapy and direct
intratumor wild-type p53 gene transfer, comparing the isolated responses of treated tumor
lesions with a comparable lesion not receiving gene therapy within each patient, there was no
additional benefit in patients with advanced NSCLC receiving effective first-line
chemotherapy. Like most gene therapy strategies, problems of efficient gene transfer delivery
and replication-defective vector spreading remain. In addition, adenoviruses can bind and
inactivate wild-type p53 in normal cells.
References
D‘Amico TA. Molecular staging and the selection of therapy for non small cell lung cancer.
Semin Thorac Cardiovasc Surg. 2005;17:180-85.
Swisher SG, Roth JA, Komaki R, et al. A phase II trial of adenoviral mediated p53 gene
transfer (RPR/INGN 201) in conjunction with radiation therapy in patients with localized
non-small cell lung cancer (NSCLC) [abstract]. Proc Am Soc Clin Oncol. 2000;19:. 461a
no. 1807)
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246
Schuler M, Herrmann R, De Greve JL, et al. Adenovirus-mediated wild-type p53 gene
transfer in patients receiving chemotherapy for advanced non–small-cell lung cancer:
Results of a multicenter phase II study. J Clin Oncol. 2001;19:1750-1758.
Dy GK, Adjei AA. Novel targets for lung cancer therapy: part II. J Clin Oncol.
2002;20:3016-3028.
3.47 Answer: A
The cyclooxygenase-2 (COX-2) enzyme produces prostaglandin E2 (PGE2), which
stimulates bcl-2 and thus inhibits apoptosis. This process results in increased tumor invasion,
angiogenesis, and metastasis. The frequent expression of COX-2 in early lesions combined
with the known reduction of tumor burden in animals treated with COX-2 inhibitors before
carcinogen exposure indicate that COX-2 could be a promising target for lung cancer
chemoprevention. Although single-agent COX-2 inhibitors may have limited utility in the
treatment of lung cancer, use of COX-2 inhibitors is currently being tested in an ongoing pilot
phase II chemo-preventive trial. In addition, synergistic cytotoxicity has been observed with
combination of COX-2 inhibitors and several chemotherapeutic agents, including the taxanes,
platinum compounds, and topoisomerase I inhibitors, in NSCLC cell lines. In a phase II
clinical trial, 29 patients with stages IB to IIIA NSCLC were treated with two preoperative
cycles of paclitaxel and carboplatin, as well as daily celecoxib, followed by surgical resection.
There were no complete pathologic responses, but 24% had minimal residual microscopic
disease. The addition of celecoxib to paclitaxel and carboplatin may enhance the response to
preoperative paclitaxel and carboplatin in patients with NSCLC compared with historical
controls.
References
D‘Amico TA. Molecular staging and the selection of therapy for non small cell lung cancer.
Semin Thorac Cardiovasc Surg. 2005;17:180-85.
Fosslien E. Molecular pathology of cyclooxygenase-2 in neoplasia. Ann of Clin Lab Science.
2000;30:3-21.
Wardlaw SA, March TH, Belinsky SA. Cyclooxygenase-2 expression is abundant in alveolar
type II cells in lung cancer-sensitive mouse strains and in premalignant lesions.
Carcinogenesis. 2000;21:1371-1377.
Hida T, Kozaki K, Muramatsu H, et al. Cyclooxygenase-2 inhibitor induces apoptosis and
enhances cytotoxicity of various anticancer agents in non-small cell lung cancer cell
lines. Clin Cancer Res. 2000;6:2006-2011.
Altorki NK, Keresztes RS, Port JL, et al. Celecoxib, a selective cyclo-oxygenase-2 inhibitor,
enhances the response to preoperative paclitaxel and carboplatin in early-stage non–
small-cell lung cancer. J Clin Oncol. 2003;21:2645-2650.
3.48 Answer: D
Tumor-induced neovascularization (angiogenesis) is necessary for both tumor growth and
metastatic spread, and a large research effort currently is directed into studying its role in
cancer development. Immunohistochemical staining for factor VIII, vascular endothelial
growth factor (VEGF), CD-31, and CD-34 can be used to assess microvessels; and number of
microvessels in a NSCLC can be used to assess angiogenesis. VEGF, strongly induced by
Thoracic Surgery: Answers
247
hypoxia, promotes vascular permeability, endothelial cell replication, and migration. By
inhibiting angiogenesis, tumor growth and metastatic spread can be controlled.
Both recombinant humanized anti-VEGF antibodies (RhuMAb VEGF) and VEGFr
tyrosine kinase inhibitors have been tested in animal models and are being investigated in
clinical trials. In animal studies, anti-VEGF antibodies suppressed tumor growth, metastatic
spread, and ascites formation in tumor-bearing nude mice but did not cause tumor regression.
Hurwitz and coworkers reported that rhuMAb VEGF (bevacizumab) plus chemotherapy
resulted in increased survival, progression-free survival, response rate, and duration of
response (compared alone in patients with colon cancer), increasing the interest in the study
of this agent in patients with other types of cancer, including NSCLC. A randomized study of
rhuMAb VEGF was conducted in patients with advanced NSCLC (Stage IIIB with pleural
effusion, Stage IV, or recurrent disease). Patients were randomized to carboplatin and
paclitaxel (CP) alone, CP plus low-dose rhuMAb VEGF (7.5 mg/kg every 3 wks), or CP plus
high-dose rhuMAb VEGF (15 mg/kg every 3 wks). Sudden and life-threatening hemoptysis
occurred in 6 rhuMAb VEGF-treated subjects and was fatal in four, which occurred in
subjects with squamous cell histology. In this study, rhuMAb VEGF (15 mg/kg) in
combination with CP chemotherapy was associated with improved response rates and
prolonged time to disease progression compared with carboplatin/paclitaxel chemotherapy
alone. Subsequently, a subset analysis of nonsquamous (non-SQ) patients was performed.
Median survival for the non-SQ population was improved in both rhuMAb VEGF-dose
groups, and compared favorably with that achieved with CP chemotherapy alone. Thus,
treatment of selected patients with NSCLC—noncentral, nonsquamous—may improve
survival with minimal side effects and may represent an important treatment strategy in the
future.
Matrix metalloproteinases (MMP) have been implicated in the breakdown of vascular
barriers, allowing tumor cells to infiltrate blood vessels. Plasminogen activators are members
of the serine protease family. They are responsible for converting plasminogen to plasmin.
Plasmin can degrade various proteins in the extracellular matrix. Plasminogen activators are
regulated by plasminogen activator inhibitors. Another means through which basement
membrane degradation occurs through the plasminogen activation system is the secretion of
urokinase plasminogen activator (uPA) in its inactive form (pro-uPA) by tumor cells. Pro-
uPA is converted to its active form (uPA) upon binding to its specific membrane-bound
receptor, u-PAR. This activated form of uPA then converts plasminogen into plasmin, which
degrades the protein components of the extracellular matrix, such as laminin and fibronectin.
Plasmin can also activate pro-enzyme forms of MMPs to further break down the extracellular
matrix. U-PAR is expressed on stromal cells as well as tumor cells. Cluster designation 44
(CD-44), an integral membrane glycoprotein, is a receptor for hyaluronan (a component of
the extracellular matrix). CD-44 is involved in cell-to-cell and cell-to-extracellular matrix
interactions and is correlated with metastatic spread.
Several MMP inhibitors (MMPI) against various isoforms have been developed and were
reviewed recently. The most studied of these agents include marimastat, the first orally
available synthetic MMPI, and prinomastat. Recent analyses of randomized, placebo-
controlled phase III trials of these agents in SCLC and NSCLC revealed no survival benefit or
prolongation in time to disease progression. The negative results led to the termination of
lung cancer studies with other MMPIs; however, this strategy may be effective in
combination with other agents.
Shahzad G. Raja
248
References
D‘Amico TA. Molecular staging and the selection of therapy for non small cell lung cancer.
Semin Thorac Cardiovasc Surg. 2005;17:180-85.
Hurwitz H, Fehrenbacher L, Cartwright T. Bevacizumab (a monoclonal antibody to vascular
endothelial growth factor) prolongs survival in first-line colorectal cancer (CRC): results
of a phase III trial of bevacizumab in combination with bolus IFL (irinotecan, 5-
fluorouracil, leucovorin) as first-line therapy in subjects with metastatic CRC [abstract].
Proc Am Soc Clin Oncol. 2003;. 22a (no. 3646)
DeVore RF, Fehrenbacher L, Herbst RS, et al. A randomized phase II trial comparing
rhumAb VEGF (recombinant humanized monoclonal antibody to vascular endothelial
cell growth factor) plus carboplatin/paclitaxel (CP) to CP alone in patients with stage
IIIB/IV NSCLC [abstract]. Proc Am Soc Clin Oncol. 2000;19:485a. (no. 1896)
Johnson DH, et al. Carboplatin (C) + paclitaxel (P) + rhuMab-VEGF(AVF) may prolong
survival in advanced non-squamous lung cancer [abstract]. Proc Am Soc Clin Oncol.
2001;20:315a. (no. 1256)
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3.49 Answer: C
Lung cancers that occur in the apex of the chest and invade
apical chest wall structures
are called superior sulcus tumors,
or Pancoast tumors. The classic description of such patients
involves a syndrome of pain radiating down the arm as a manifestation
of brachial plexus
involvement. With improvements in radiographic
techniques, earlier diagnosis, and a more
detailed understanding
of the anatomy, a tumor can be classified as a Pancoast tumor
when it
invades any of the structures at the apex of the chest,
including the most superior ribs or
periosteum, the lower nerve
roots of the brachial plexus, the sympathetic chain near the
apex
of the chest, or the subclavian vessels. These tumors are
now divided into anterior, middle,
and posterior compartment
tumors depending on the location of the chest wall involvement
in
relation to the insertions of the anterior and middle scalene
muscles on the first rib. A
syndrome of pain radiating down
the arm is no longer a prerequisite for an apical tumor to be
designated a Pancoast tumor.
The classic approach to curative treatment of Pancoast tumors
has been preoperative
radiotherapy followed by surgical resection.
This dates back to an experience published in
1961 by Shaw et
al. in which 12 of 18 patients who were treated with this approach
were still
alive at the time the article was written. However,
the follow-up was < 2 years in 90% of the
patients. Alternatives
are treatment with radiation alone, preoperative chemoradiotherapy
and
resection, or chemoradiotherapy without resection.
Treatment with radiation alone has achieved good palliation
of pain in approximately
75% of patients. In general, very
few patients who are treated with radiation alone are long-