Gene therapy approaches for neoplastic diseases relevant to thoracic surgical practice have spawned several other strategies that seek to destroy the tumor cells, directly or indirectly.
Trang 1term survivor is more likely to have a second primary
malignancy than a relapse of the small cell lung cancer,
and many of these new tumors arise in the lung In the
University of Toronto series, eight patients underwent
surgical resection at the time of “relapse” following a long
disease-free interval after initial treatment for small cell
lung cancer Two were found to have nonsmall cell
tumors, and both achieved long-term survival after
surgery It is recommended, therefore, that a biopsy
should be undertaken for long-term survivors of small
cell lung cancer who develop a new lung lesion If
nons-mall cell pathology is documented, the patient should be
staged completely, and surgery should be considered if
the standard medical and surgical criteria for resection
that would be applied to all patients with nonsmall cell
tumors are met
Summary
Combined modality therapy with surger y and
chemotherapy is feasible; the toxicity is manageable and
postoperative morbidity and mortality rates acceptable
Patient selection is important, and the results of the
LCSG trial indicate that surgical resection does not
bene-fit the majority of patients with limited small cell lung
cancer The chances of long-term survival and cure are
strongly correlated with pathologic TNM subgroups, and
consideration of surgery for patients with small cell lung
cancer should be limited to those with stage I and
perhaps stage II cancer Therefore, before surgery is
undertaken, patients should undergo full staging of the
mediastinum, including mediastinoscopy
Surgery may be considered for patients with T1–2N0
small cell tumors, and whether it is offered as the initial
treatment or after induction chemotherapy does not
seem to be important, as has been shown by Wada and
colleagues and the University of Toronto Group.28,34 If a
small cell tumor is identified unexpectedly at the time of
thoracotomy, complete resection and mediastinal lymph
node resection should be undertaken if possible
Chemotherapy is recommended postoperatively for all
patients, even those with pathologic stage I tumors
Surgery likely has very little role to play for most
patients with stage II tumors and virtually no role for
those with stage III tumors Even though chemotherapy
can result in dramatic shrinkage of bulky mediastinal
tumors, the addition of surgical resection does not
contribute significantly to long-term survival for the
majority of patients, as has been shown conclusively by
the LCSG trial
The final group of patients who may benefit from
surgical resection are those with combined small cell and
nonsmall cell tumors If a mixed histology cancer is
iden-tified at diagnosis, the initial treatment should bechemotherapy to control the small cell component of thedisease, and surgery should be considered for the non-small cell component For patients who demonstrate anunexpectedly poor response to chemotherapy, and forthose who experience localized late relapse after treatmentfor pure small cell tumors, a repeat biopsy should beperformed Surgery may be considered if nonsmall cellpathology is confirmed
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112 / Advanced Therapy in Thoracic Surgery
Trang 4Gene therapy can be broadly defined as the
administra-tion of nucleic acids that direct the producadministra-tion of a new
protein within targeted cells By this definition,
oligonu-cleotide therapeutics are not considered gene therapy
since these short deoxyribonucleic acid (DNA) sequences
do not, themselves, direct new protein production In
addition, lytic viruses that only contain viral genes and
function as cytolytic therapy are not considered gene
therapy for the discussion here
Specific proteins have been identified that play a
criti-cal role in the initiation or regulation of many clinicriti-cal
entities affecting the thorax Since gene therapy has the
potential for modifying proteins critical to a given disease
state, the rationale for developing this modality is
intu-itively obvious As technologies developed in the past 10
to 15 years enabled a relatively large number of basic
“proof of concept” gene therapy studies in preclinical
models, many proponents of gene therapy made
over-reaching predictions of success in the clinical utility of
present-day gene therapy It is now widely appreciated
that gene therapy has not yet fulfilled these prophecies of
rapid success, owing largely to the limitations of current
gene-delivery technologies
This chapter endeavors to achieve two specific
objec-tives: (1) to provide an understanding of the most
common gene therapy technologies, with some
apprecia-tion for the limitaapprecia-tions that need to be overcome for
improved efficacy, and (2) to review specific gene therapy
approaches directed toward clinical problems facing the
thoracic surgeon, including lung cancer, mesothelioma,
and lung transplantation
Gene Therapy Basics
Choice and Engineering of the Therapeutic Gene
Although messenger ribonucleic acid (RNA) has beenused as the nucleic acid in a handful of preclinical genetherapy studies, the vast majority of gene therapy strate-gies employ the administration of DNA The primaryDNA components required for the production of thenew protein within the host cells include the transcrip-tion regulatory sequence (also known as the promoter)and the contiguous coding sequence, a combination vari-
ably designated as the transgene, expression cassette, or
therapeutic gene (Figure 9-1) Several commonly used
transcription regulatory sequences continuously directrelatively high levels of coding sequence transcription
Transgene
FIGURE 9-1 Transgene components The typical transgene employed
for gene therapy is a deoxyribonucleic acid containing a promoter (transcription regulatory sequence) that directs the production of tran- scripts from the contiguous coding sequence Variations in types of promoters and coding sequence options are indicated in the figure text.
Trang 5and are commonly referred to as constitutive promoters It
is also possible, depending on the host cell target, to
select a transcription regulatory sequence that will only
be active in specific tissues such as hepatocytes or
prostate cells The selection of such tissue-specific
regula-tory sequences obviously can be exploited as a means of
targeting the new protein production to specific sites or
tissues, a strategy sometimes referred to as transcription
targeting.
Almost any coding sequence can be used in a gene
therapy context, but experience over the past decade has
defined several different thematic approaches (Table 9-1)
The initial gene therapy approaches focused primarily on
protein replacement/augmentation for heritable protein
deficiencies such as 1-antitrypsin deficiency or cystic
fibrosis More recently, the administration of transgenes
encoding for angiogenic factors that stimulate new
vascu-lature (eg, VEGF) has received significant attention based
on potential efficacy observed in small numbers of
patients Gene therapy approaches for neoplastic diseases
relevant to thoracic surgical practice have spawned several
other strategies that seek to destroy the tumor cells,
directly or indirectly Direct antineoplastic genetic therapy
approaches include toxin therapies in which the cancer
cells are modified to produce a toxin (eg, diphtheria
toxin) or a protein that converts a prodrug into a toxin
(herpes simplex virus thymidine kinase [HSVTK])
Another direct antineoplastic strategy is the production of
a protein that can dominantly suppress the effects of
mutated oncogenes/tumor suppressor genes that
perpetu-ate the neoplastic phenotype (eg, the introduction of
wild-type TP53 into neoplastic cells with mutated or
deleted TP53) Indirect antineoplastic strategies include
the introduction of genes that direct the production of
immunomodulatory agents with the aim of increasing the
immune response directed against the neoplastic cells (eg,
granulocyte-macrophage colony–stimulating factor)
Standard genetic engineering technologies have been
exploited to further improve the native coding sequences
For example, fusion genes have been made so that the
protein produced in transduced cells may be
bifunc-tional, or targeted to a specific cellular compartment The
portion of the gene coding for an enzyme active site can
be mutated to code for “superenzymes” that are more
efficient than the normal gene product
Vectors
The fundamental requirement for any gene therapy
strat-egy is a delivery system, that is, a vector, that effectively
delivers the therapeutic nucleic acid The vectors can be
used to facilitate gene delivery in two contexts The first
approach, ex vivo gene therapy, refers to a process
wherein the target tissue is removed from the individual,
exposed to the gene therapy vector in a tissue culturecontext, and at some point thereafter reintroduced intothe host Ex vivo gene therapy can be accomplished byevery gene therapy vector system and has been shown to
be quite safe This gene therapy paradigm is obviouslylimited to those clinical situations in which the geneti-cally modified cells are replaced within the host so as todirect an immune response or produce a deficientprotein The second gene delivery approach is in vivogene therapy, which refers to the administration of thegene therapy vector directly into the host/patient As isintuitively obvious, the vector requirements here aremore stringent than in ex vivo gene therapy, becausevector toxicity, host cell inactivation of the vector, andachievement of therapeutically meaningful delivery ofthe vector and its gene to the targeted tissue are allimportant barriers to success
The ideal gene therapy vector is one that efficientlytransfers the functional, therapeutic DNA into all cells of
a target tissue following intravenous administration, an
ideal that can be designated as a targetable-injectable
vector This targetable-injectable vector system is also
nontoxic and easily manufactured and stored In the verybrief review of currently available vector systems, thereader will appreciate that the ideal vector has not yetbeen developed, and the significant limitations of avail-able vector systems is the greatest impediment to clinicalefficacy attained by gene therapy
viral vector systems
A variety of viruses have been modified for gene therapyapplications (Figure 9-2) In most cases portions of theviral genome have been deleted so as to render the virusreplication defective as well as provide space for the addi-tion of the therapeutic transgene At the time of thiswriting, three viral vector systems have played a domi-nant role in both preclinical and in human clinical trials:retroviruses, adenoviruses, and adeno-associated viruses(Table 9-2)
114 / Advanced Therapy in Thoracic Surgery
TABLE 9-1 Thematic Gene Therapy Approaches
Theme Common Targets Coding Sequence
Example Protein augmentation Heritable protein 1 -Antitrypsin
deficiencies Direct toxins Neoplasia Diphtheria toxin A Indirect toxins Neoplasia Herpes simplex virus
thymidine kinase (HSVTK)
Dominant suppression Neoplasia TP53
Immunopotentiation Neoplasia Granulocyte-macrophage
colony–stimulating factor Angiogenesis Vascular disease, VEGF
neoplasia Radiosensitizers Neoplasia Cytosine deaminase
Trang 6article by Gao and colleagues for a recent, comprehensive
review of AAV vectors.3) In spite of these limitations,
AAVs have recently been shown to have potential utility
in hemophilia
nonviral vector systems
A large number of nonviral vector systems have been
employed for basic studies of gene transfer (see
Figure 16–2), but the majority of these methods are too
toxic or impractical for clinical applications The clinically
relevant methods use one or more compounds that
condense the DNA and facilitate target cell entry (For a
comprehensive review of nonviral vectors, see Nishikawa
and Huang’s article.4) Cationic lipids have been the most
widely used class of nonviral vectors These positively
charged lipids form a complex with the negatively
charged DNA to condense the DNA and serve to mask the
negative charges that otherwise repel the DNA from cell
membranes that are also slightly negative in charge The
lipids interact with the cell membranes by a
receptor-independent mechanism, resulting in cytoplasmic entry
by endocytosis Cationic lipids have been combined with
other condensing agents as well as targeting moieties as a
means of improving efficacy and attempting to target the
delivery to specific cell types The advantages of cationic
lipids over the viral vectors include (1) the elimination of
many biohazard concerns associated with recombinant
virus systems, and (2) the potentially greater uniformity,
longer shelf-life, and easier storage than the viral agents
However, the central limitation of the lipid-based vectors
is the markedly lower gene-transduction efficiency
compared with that of the viral systems, in part the
consequence of host cell destruction of the therapeutic
DNA that gains entry into the cytoplasm by
receptor-independent pathways Some specific formulations have
been developed that can improve the efficiency, but a
large gap in efficiency remains between cationic lipids and
viral vectors
practical implications of the limitations posed
by available gene therapy vector systems
In the context of pathophysiologic states addressed by
thoracic surgeons, the shortcomings of currently available
vectors both limit the utility of intrathoracic gene therapy
and dictate the means of administration All intrathoracic
gene therapy strategies have required direct, local
admin-istration of the vector at the target For example, the TP53
gene therapy for nonsmall cell lung cancer (NSCLC) has
used intratumoral injections containing the vectors with
the wild-type TP53 expression cassette This means of
vector administration results in limited distribution of the
vector within the target tissue site, although efficacy can
be better than expected owing to “bystander effects.”
Bystander Effects
If one accepts the premise that gene therapy works bymodifying the genetic makeup of cells one cell at a time,then the corollary of this expectation is that the majority
of cells within a target tissue must be transduced with thetherapeutic gene for efficacy In a variety of contexts,preclinical animal models have shown that some genetherapy strategies overcome this apparent limitation ofgene therapy by a bystander effect The bystander effectsimply refers to the transduced cells exerting therapeuti-cally desirable effects on surrounding, nontransducedcells that have not been genetically modified (Figure 9-3).The existence of the bystander effect was first described
with the HSVTK system, in which cells modified to
express the viral thymidine kinase convert the antiviraldrug ganciclovir into its toxic form, which subsequentlykills the cell In preclinical studies it was found that theproportion of cells killed greatly exceeded the proportion
of cells actually modified to contain the HSVTK protein
Mixing experiments, in which HSVTK-containing cells
were mixed with naive cells, confirmed that ganciclovirsensitivity had apparently spread to neighboring cells thathad not been genetically modified It was subsequently
shown that the HSVTK bystander effect was largely the
consequence of the modified ganciclovir produced withinthe genetically modified cells disseminating to neighbor-ing cells by intercellular junctional communications.5Other bystander effects for other transgenes have beenidentified, although the mechanisms are not all ascompletely understood
116 / Advanced Therapy in Thoracic Surgery
FIGURE 9-3 Bystander effect Shown is a schematic representation of
nine cells, but only the cell in the center of this group has received the intact viral transgene represented by the bar in the nucleus However, all
of the neighboring cells are killed with the single genetically modified cell as a consequence of the bystander effect Several bystander effects have been described that work by different mechanisms.
New Gene Recipient
Trang 7Gene Therapy and Thoracic Surgery / 117
Summary
The initial gene therapy experience has identified genetic
strategies that can be effective in modifying target tissues
in a clinically meaningful way, based on preclinical
animal models These “proof of principle” studies have
helped identify gene products that play essential roles in
a variety of pathophysiologic states
It should be clear from the previous sections that the
greatest barrier to broad, clinical use of gene therapy for
any clinical situation, including intrathoracic diseases, is
the development of better vector systems Incremental
improvements have been made in the extant vector
systems, such as the development of some rudimentary
targeting methodologies that can direct the vector away
from some tissues that may sustain vector damage (eg,
hepatocytes) and toward the desired target However, it
can be argued that the vector field has not produced any
vector systems that are not simply modifications of
exist-ing vectors in more than a decade Once the vector
barrier is overcome, gene therapy will become a
main-stream therapeutic modality—but for the present, it
remains one with narrow applications that can be
addressed with the limited vector technology we have
today
Intrathoracic Gene Therapy Relevant
to Thoracic Surgical Problems
The remainder of this chapter highlights selected gene
therapy strategies that have been most extensively studied
for intrathoracic conditions encountered by the thoracic
surgeon Lung cancer and mesothelioma are the two
conditions relevant here that have been subjected to the
majority of gene therapy investigations, although a few
studies have addressed aspects of lung transplantation
Preclinical Studies of Lung Cancer Gene Therapy
There are two overriding rationales for the interest in
exploring the feasibility and efficacy of gene therapy for
lung cancer First, novel therapy development is highly
appropriate for this common neoplasm that has an
unac-ceptably low disease-free survival Second, the past two
decades have led to the identification of common
somatic mutations that have been shown to play a key
role in the initiation and perpetuation of the
trans-formed respiratory epithelium that comprises lung
cancer The identification of these mutations has
provided targets for gene therapy, and, in fact, some of
the gene therapy experiments have demonstrated the
critical role that some mutations play in perpetuation of
the transformed state
Table 9-3 lists strategies and specific transgenes that
have been employed in preclinical gene therapy studies
for lung cancer Given the propensity for small cell lungcancer (SCLC) to undergo widespread metastasis and thecurrent lack of a targetable-injectable vector system, theinterest in pursuing gene therapy for this category oflung cancer has been relatively limited The efforts forSCLC have been primarily restricted to using tissue-
specific promoters to direct HSVTK expression within
the neoplastic cells There have been no clinical trials ofgene therapy for SCLC
The preclinical studies of gene therapy listed inTable 9-3 illustrate that considerably more effort has beenexpended in exploring gene therapy for NSCLC Various
HSVTK strategies have been employed that use
tissue-specific promoters or fusion proteins, for example.Although NSCLC has not been a favorite target ofimmunotherapy studies, several studies have employedcytokines, immunogenic proteins (MDA7), or cofactorsthat promote immune responses Radiosensitization andantiangiogenesis strategies have also been exploited in alimited number of studies As Table 16-3 shows, thelargest effort has been directed toward the addition ofgenes encoding proteins that counteract a variety of onco-genes, antioncogenes, or other proteins that are essential
in maintaining the neoplastic phenotype, a process that is
broadly defined here as dominant suppression In most of
these studies, the successful production of the transgeneprotein leads to the death of the neoplastic cell
TABLE 9-3 Examples of Preclinical Gene Therapy Strategies for Lung Cancer
Cancer Gene Therapy Strategy Example Small cell lung cancer Indirect toxin GRP promoter-directed
HSVTK26
Neuron-specific, enolase-directed
Trang 8Clinical Studies of Lung Cancer
The tumor suppressor (antioncogene) gene TP53 encodes
a protein that serves as a critical transcriptional regulator
of many other genes that modulate cell growth/division
and apoptosis (as reviewed in Malkin’s article6) One of
the most important TP53 functions relevant to cancer
therapy is its function as a genomic quality-control
moni-tor, whereby damaged DNA is detected early in the course
of the cell cycle Normally functioning TP53 halts the
progression of the cell cycle in those cells with damaged
DNA and initiates either a process of DNA repair or the
onset of apoptosis Since many chemotherapies, as well as
radiotherapy, act by inducing DNA damage in the
malig-nant cells, those cells with mutated or absent TP53
protein might be expected to demonstrate resistance to
the therapy as they continue to complete cell cycles in the
absence of the TP53 checkpoint This expectation has
been confirmed experimentally and has led to a broad
interest in the development of therapies that can
compen-sate for the loss of TP53 function.
Not surprisingly, gene therapy has been investigated as
one means of correcting the somatic mutations of TP53
in neoplastic cells In the context of intrathoracic disease,
NSCLC has been most extensively studied in both
preclin-ical and clinpreclin-ical studies of TP53 gene therapy Since
neoplastic cells have multiple somatic mutations in
addi-tion to those associated with TP53, it was not intuitively
obvious that the correction of the TP53 protein alone by
the addition of a wild-type TP53 gene would be sufficient
to change the cell phenotype However, extensive
experi-mentation with multiple neoplastic cell types, including
NSCLC, has firmly established that addition of wild-type
TP53 into neoplastic cells with defective/absent TP53
generally induces those cells to undergo apoptotic cell
death.7In other words, these experiments showed that it
was not necessary to address the multiple other mutations
in oncogenes and other growth regulatory genes that are
commonly present in concert with TP53 mutations for
TP53 gene therapy to trigger neoplastic cell death.
Since approximately 50% of NSCLCs contain a
defec-tive or absent p53 gene product, Dr Jack Roth and
colleagues pioneered studies that examined the effects of
transducing wild-type TP53 genes into NSCLC with
defective or absent TP53 Initial studies established that
NSCLC cell lines with mutated or deleted TP53—but not
those with wild-type TP53—were killed by the addition
of the normal TP53 gene.8 Other in vitro studies by
several groups have also shown that TP53 gene therapy
can also function to both chemosensitize and
radiosensi-tize NSCLC cells that are defective in TP53.9However,
many expected that TP53 gene therapy was little more
than an in vitro laboratory phenomenon, where
condi-tions allowed a large majority of the cells to receive the
wild-type TP53 gene Since there was no apparent anism for a TP53 bystander effect, it was not clear that
mech-TP53 gene therapy would be efficacious in vivo, where
only a minority of cells would receive the new genebecause of the current vector limitations Importantly,subsequent animal studies established that the intratu-
moral administration of wild-type TP53 into engrafted NSCLC with mutant/absent TP53 by either retroviral or
adenoviral vectors resulted in a marked reduction intumor nodule growth.10 The preclinical efficacy in thetumor nodules could only be explained by some type of
bystander effect There is some data suggesting that TP53
gene therapy may exert a bystander effect via genic effects, but this is not yet completely understood.11,12The success of the preclinical studies has been followed
antiangio-by an initial phase I clinical study in which wild-type
TP53 carried within an adenoviral vector was
adminis-tered via intratumoral injection into inoperable NSCLC
with mutated/absent TP53. In this escalation trial that included 25 evaluable patients, 23 of
dose-25 received multiple intratumoral injections with minimal toxicity Two of 25 patients had a partialresponse (PR), 16 of 25 had stable disease over 2 to 14months, and the remainder progressed.1 3 Toxicity associated with the gene therapy was minimal A sub-sequent phase I trial by the same group assessed the safety
of using adenoviral-mediated TP53 gene therapy in
conjunction with chemotherapy In this trial 24 patientsreceived cisplatin, followed 3 days later by an intratumoral
administration of TP53 Two of 24 patients had a PR, and
17 of 24 had stable disease; again, toxicity was minimal.14
A phase II trial by a different group also examined
adenoviral-mediated TP53 gene therapy in combination
with chemotherapy In this trial 25 patients received an
intratumoral TP53 gene in combination with one of two
chemotherapy regimens (carboplatin plus paclitaxel, orcisplatin plus vinorelbine) given to patients withadvanced-stage disease Response rates and mediansurvivals in patients receiving either chemotherapy regi-
men with the TP53 gene therapy were not significantly
improved relative to the controls who received thechemotherapy alone.15A second phase II trial has beenreported by the Swisher and colleagues in abstract form
that examined TP53 gene therapy in combination with
radiotherapy.16 In this trial, subjects receiving apy concomitantly received intratumoral injections ofAd-p53 on days 1, 18, and 32 There were 13 evaluablepatients: 5 of 13 had a complete response and 2 of 13 a
radiother-PR, but 19% of the patients also experienced grade 3/4toxicities
It is worth noting here that one small, earlier phase Istudy examined the safety of administering a recombi-
118 / Advanced Therapy in Thoracic Surgery
Trang 9nant adenovirus with a -galactosidase gene that
func-tions as a marker without any known therapeutic effect
into NSCLC.17 In this trial of six patients, the virus
administration was well tolerated and, surprisingly, four
of six patients had PRs in the treated tumors This result
raises a question about the mechanism responsible for
the responses seen in some of the adenovirus-p53 trials
that may involve effects related to the adenoviral vector
as well as the p53 gene product resulting from the
successful gene transfer in the treated lung cancers
In summary, TP53 gene therapy has certainly
substan-tiated the importance of mutated TP53 in the
mainte-nance of the neoplastic phenotype Since many
carcinomas contain a multitude of somatic mutations in
genes relevant to cell growth, it was particularly
notewor-thy that the preclinical studies of TP53 gene therapy have
identified mutant TP53 as a key target for future
thera-pies—whether they be gene therapy or other modalities
The limited clinical studies have generally shown that the
adenoviral delivery of wild-type TP53 is well tolerated,
although the studies of concomitant radiotherapy and
Ad-p53 did reveal significant toxicity that might temper
further increases in the amount of gene therapy vector
administered The efficacy suggested by these early studies
of very few patients has been quite modest, and certainly
the data do not yet support the widespread use of TP53
gene therapy in NSCLC However, as pointed out in
earlier sections, it seems highly probable that the
develop-ment of better vector systems could dramatically improve
the efficacy of TP53 gene therapy for NSCLC, as well as
reducing toxicity associated with the adenoviral vector
system It should also be noted that approximately 50% of
NSCLCs involve wild-type TP53 and are therefore not
expected to derive any benefit from TP53 gene therapy, no
matter how ideal a future vector system may be
Mesothelioma
Malignant mesothelioma of the pleural space is a
rela-tively rare neoplasm that responds poorly to
conven-tional therapy The team of Albelda and Kaiser has
pioneered efforts to develop a gene therapy approach for
this problematic neoplasm Their efforts have focused on
a toxic gene therapy strategy employing an
HSVTK-plus-ganciclovir system.18As was briefly alluded to earlier, the
HSVTK gene encodes for the viral thymidine kinase that,
in and of itself, is not toxic to cells However, cells
containing the HSVTK protein phosphorylate
antiher-petic drugs such as ganciclovir into a nucleotide analog
that kills the host cell The HSVTK-plus-ganciclovir
system has been widely examined in preclinical and
clini-cal gene therapy investigations for three reasons: (1) the
protein encoded by the HSVTK gene is not, itself, toxic,
so nonspecific gene transfer (into untargeted cells) does
not lead to problems, (2) the drugs used in conjunction
with HSVTK are already approved and available for
human use, and (3) the toxicity is conferred only whenganciclovir is present, and in the event of undesirabletoxicity, further problems could be greatly mitigated bysimply withholding further ganciclovir infusions
In preclinical studies of HSVTK gene therapy for
mesothelioma, investigators employed an animal model
in which human mesothelioma was engrafted into theperitoneal cavities of immunosuppressed mice or thepleural space of rats.19 Multiple intraperitoneal adminis-
trations of adenovirus with an HSVTK transgene
resulted in significant reductions in tumor burden andsurvival advantage compared with those of controls.These promising findings led to a phase I trial of
adenoviral-mediated HSVTK gene therapy that was
administered via thoracoscopic injection into the tumormass The results of this phase I trial of 20 evaluablepatients revealed some transient side effects, but only 11
of 20 had demonstrable gene transfer in spite of thedirect thoracoscopic administration of the adenoviralvector into the tumor masses, a result that underscoresthe limitations of available vector systems.20In this initialphase I report, investigators were unable to identifytumor reduction in any of the patients, although aminority of the patients appeared to have stable disease
An extension of this trial is currently underway
A novel alternative form of the
HSVTK-plus-ganciclovir approach has been developed bySchwarzenberger and colleagues.21In their strategy anovarian carcinoma cell line designated PAI-STK is geneti-cally modified to permanently express the HSVTKprotein In preclinical animal studies of ovarian cancer aswell as mesothelioma, it was observed that these PAI-STKcells preferentially adhere to the neoplastic cells withinthe host by an unclear mechanism, and subsequently lead
to the killing of the neoplastic cells when ganciclovir isadministered, presumably by the bystander mechanism.The results of the first phase I trial of this strategy formesothelioma have reported that the intrapleural infu-sion of the PAI-STK cells were well tolerated up to themaximal infused dose (3 109 cells).22Some scinti-graphic data suggested that the PAI-STK cells did home
to areas of mesothelioma within the pleural space In thisstudy there was no report of efficacy
In summary, the current status of gene therapy formesothelioma is similar to that for NSCLC, in that somesmall clinical trials have shown that the gene therapyapproaches used have been relatively safe However, thecurrently published trials of gene therapy for mesothe-lioma have not shown any significant clinical efficacy Theformidable challenge for mesothelioma gene therapy isthe development of a gene-delivery system that will trans-
Gene Therapy and Thoracic Surgery / 119
Trang 10duce the therapeutic gene into more than that portion of
the tumor that resides at the edge of the pleural effusion
space into which the vectors have been administered
Lung Transplantation
A small number of preclinical studies have started
addressing lung allografts as targets of gene therapy
These proof of principle investigations have sought to
examine the feasibility of modifying allograft cells as a
means of mitigating acute rejection, although other
longer-term objectives may also be achieved by similar
means One important aspect of lung allografts is the
opportunity to infuse the vasculature or the bronchial
tree in an isolated fashion for extended periods of time
without the concern of vector effects beyond the lung, as
would be the case in an intact host
Rat lungs have been excised, and either naked plasmid
DNA or cationic lipid complexes of plasmid containing
marker genes have been instilled into the bronchial
tree.23,24
In these studies successful gene transfer and
subsequent gene expression were documented One study
infused Brown Norway rat lungs with an adenoviral
vector containing a transgene for CTLA-4Ig protein that
greatly mitigates acute rejection in the rat allograft lung
transplant model system.25 The lungs were subsequently
engrafted into allogeneic Lewis rat recipients, and lungs
that had been treated with the vector had a significant
reduction in the histologic grade of rejection
Certainly the handful of gene therapy studies directed
toward lung transplantation have not clearly defined the
optimal target genes and strategies necessary for a
thera-peutically meaningful intervention, but they are likely to
stimulate further studies
The author thanks Dr Paul Reynolds for his
thought-ful review of this chapter This work was supported in
part by a VA Merit Review awarded to Robert I Garver Jr
References
1 Hu WS, Pathak VK Design of retroviral vectors and helper
cells for gene therapy Pharmacol Rev 2000;52:493–511.
2 Hitt MM, Graham FL Adenovirus vectors for human gene
therapy [review] Adv Virus Res 2000;55:479–505.
3 Gao GP, Wilson JM, Wivel NA Production of recombinant
adeno-associated virus Adv Virus Res 2000;55:529–43.
4 Nishikawa M, Huang L Nonviral vectors in the new
millen-nium: delivery barriers in gene transfer Hum Gene Ther
2001;12:861–70.
5 Mesnil M, Yamasaki H Bystander effect in herpes simplex
virus–thymidine kinase/ganciclovir cancer gene therapy:
role of gap-junctional intercellular communication Cancer
Res 2000;60:3989–99.
6 Malkin D The role of p53 in human cancer [review] J
Neurooncol 2001;51:231–43.
7 Baker SJ, Markowitz S, Fearon ER, et al Suppression of
human colorectal carcinoma cell growth by wild-type p53.
Science 1990;249:912–5.
8 Fujiwara T, Grimm EA, Mukhopadhyay T, et al A retroviral
wild-type p53 expression vector penetrates human lung
cancer spheroids and inhibits growth by inducing sis Cancer Res 1993;53:4129–33.
apopto-9 Fujiwara T, Grimm EA, Mukhopadhyay T, et al Induction
of chemosensitivity in human lung cancer cells in vivo by adenovirus-mediated transfer of the wild-type p53 gene.
Cancer Res 1994;54:2287–91.
10 Fujiwara T, Cai D, Georges RN, et al Therapeutic effect of a
retroviral wild-type p53 expression vector in an orthotopic
lung cancer model J Natl Cancer Inst 1994;86:1458–62.
11 Rizk NP, Chang MY, Kouri CE, et al The evaluation of
adenoviral p53-mediated bystander effect in gene therapy
of cancer Cancer Gene Ther 1999;6:291–301.
12 Nishiszaki M, Fujiwara T, Tanida T, et al Recombinant
adenovirus expressing wild-type p53 is antiangiogenic: a
proposed mechanism for bystander effect Clin Cancer Res 1999;5:1015–23.
13 Swisher SG, Roth JA, Nemunaitis J, et al
Adenovirus-mediated p53 gene transfer in advanced non-small cell lung
cancer J Natl Cancer Inst 1999;91:763–71.
14 Nemunaitis J, Swisher SG, Timmons T, et al
Adenovirus-mediated p53 gene transfer in sequence with cisplatin to
tumors of patients with non-small cell lung cancer J Clin Oncol 2000;18:609–22.
15 Schuler M, Hermann R, DeGreve 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;19:1750–8.
16 Swisher S, Roth JA, Komaki R, et al A phase II trial of
aden-oviral mediated p53 gene transfer (IRPR/INGN 201) in
conjunction with radiation therapy in patients with ized non-small cell lung cancer (NSCLC) [abstract] Proc
local-Am Soc Clin Oncol 2000;19:461a.
17 Tursz T, Cesne AL, Baldeyrou P, et al Phase I study of a recombinant adenovirus-mediated gene transfer in lung cancer patients J Natl Cancer Inst 1996;88:1857–63.
18 Smythe WR, Hwang HC, Amin KM, et al Use of nant adenovirus to transfer the herpes simplex virus thymi-
recombi-dine kinase (HSVtk) gene to thoracic neoplasms: an effective in vitro drug sensitization system Cancer Res
1994;54:2055–9.
19 Smythe WR, Kaiser LR, Hwang HC, et al Successful adenovirus-mediated gene transfer in an in vivo model of human malignant mesothelioma Ann Thorac Surg 1994;57:1395–401.
120 / Advanced Therapy in Thoracic Surgery
Trang 1120 Sterman DH, Treat J, Litzky LA, et al Adenovirus-mediated
herpes simplex virus thymidine kinase/ganciclovir gene
therapy in patients with localized malignancy: results of a
phase I clinical trial in malignant mesothelioma Hum
Gene Ther 1998;9:1083–92.
21 Schwarzenberger P, Lei D, Freeman SM, et al Antitumor
activity with the HSV-tk-gene-modified cell line PA-1-STK
in malignant mesothelioma Am J Respir Cell Mol Biol
1998;19:333–7.
22 Harrison LHJ, Schwarzenberger PO, Byrne PS, et al Gene
modified PA1-STK cells home to tumor sites in patients
with malignant pleural mesothelioma Ann Thorac Surg
2000;70:407–11.
23 Nagahiro I, Mora BN, Boasquevisque CH, et al Toxicity of
cationic liposome-DNA complex in lung isografts.
Transplantation 2000;69:1802–5.
24 D’Ovidio F, Daddi N, Suda T, et al Efficient naked plasmid
cotransfection of lung grafts by extended lung/plasmid
exposure time Ann Thorac Surg 2001;71:1817–23.
25 Ugurlu MM, Griffin MD, O’Brien T, et al The effects of
CTLA-4Ig on acute lung allorgraft rejection: a comparison
of intrabronchial gene therapy with systemic
administra-tion of protein Transplantaadministra-tion 2001;71:1867–71.
26 Morimoto E, Inase N, Mlyake S, et al Adenovirus-mediated
suicide gene transfer to small cell lung carcinoma using a
tumor-specific promoter Anticancer Res 2001;21:329–31.
27 Tanaka M, Inase N, Miyake S, et al Neuron specific enolase
promoter for suicide gene therapy in small cell lung
carci-noma Anticancer Res 2001;21:291–4.
28 Nishino K, Osaki T, Kumagai T, et al Adenovirus-mediated
gene therapy specific for small cell lung cancer cells using
Myc-Max binding motif Int J Cancer 2001;91:851–6.
29 Smith MJ, Rousculp MD, Goldsmith KT, et al Surfactant
protein A–directed toxin gene kills lung cancer cells in vitro.
Hum Gene Ther 1994;5:29–35.
30 Trudeau C, Yuan S, Galipeau J, et al A novel parasite-derived
suicide gene for cancer gene therapy with specificity for lung
cancer cells Hum Gene Ther 2001;12:1673–80.
31 Tan Y, Xu M, Wang W, et al IL-2 gene therapy of advanced
lung cancer patients Anticancer Res 1996;16:1993–8.
32 Esandi MC, van Someren GD, Bout A, et al IL-1/IL-3 gene
therapy of non-small cell lung cancer (NSCLC) in rats using
“cracked” adenoproducer cells Gene Ther 1998;5:778–88.
33 Noguchi M, Imaizumi K, Kawabe T, et al Induction of
antitu-mor immunity by transduction of CD40 ligand gene and
interferon-gamma gene into lung cancer Cancer Gene Ther 2001;8:421–9.
34 Saeki T, Mhashilkar A, Chada S, et al Tumor-suppressive
effects by adenovirus-mediated mda-7 gene transfer in
non-small cell lung cancer cell in vitro Gene Ther 2000;7:2051–7.
35 Lee JH, Lee CT, Yoo CG, et al The inhibitory effect of
adenovirus-mediated P16INK4a gene transfer on the
prolifer-ation of lung cancer cell line Anticancer Res 1998;18:3257–61.
36 Claudio PP, Howard CM, Pacilio C, et al Mutation in the
retinoblastoma-related gene RB2/p130 in lung tumors and
suppression of tumor growth in vivo by retrovirus-mediated gene transfer Cancer Res 2000;60:372–82.
37 Zhang YA, Nemunaitis J, Scanlon KJ, et al Anti-tumorigenic effect of a K-ras ribozyme against human lung cancer cell line heterotransplants in nude mice Gene Ther 2000;7:2041–50.
38 Park KH, Seol JY, Yoo CG, et al Adenovirus expressing
p27(Kip 1) induces growth arrest of lung cancer cell lines and
suppresses the growth of established lung cancer xenografts Lung Cancer 2001;31:149–55.
39 Schrump DS, Chen A, Consoli U Inhibition of lung cancer proliferation by antisense cyclin Cancer Gene Ther 1996;3:131–5.
40 Chang JY, Xia W, Shao R, et al Inhibition of intratracheal
lung cancer development by systemic delivery of E1A.
Oncogene 1996;13:1405–12.
41 Casalini P, Menard S, Malandrin SM, et al Inhibition of
tumorigenicity in lung adenocarcinoma cells by c-erB-2
anti-sense expression Int J Cancer 1997;72:631–6.
42 Hochscheid R, Jaquest G, Wegmann B Transfection of human insulin-like growth factor–binding protein 3 gene inhibits cell growth and tumorigenicity: a cell culture model for lung cancer J Endocrinol 2000;166:553–63.
43 Boland A, Ricard M, Opolon P, et al Adenovirus-mediated transfer of the thyroid sodium/iodide symporter gene into tumors for a targeted radiotherapy Cancer Res 2000;60:3484–92.
44 Kong HL, Hecht D, Song W, et al Regional suppression of tumor growth by in vivo transfer of cDNA encoding a
secreted form of the extracellular domain of the flt-1 vascular
endothelial growth factor receptor Hum Gene Ther 1998;9:823–33.
Gene Therapy and Thoracic Surgery / 121
Trang 12Quality improvement in cardiac care during the past
three decades has made substantial progress
Multi-institutional databases have been developed specifically
to monitor outcomes in cardiac surgery The leaders in
this effort include the Department of Veterans Affairs
(VA) National Cardiac Database, the Society of Thoracic
Surgeons (STS) National Database, the Northern New
England (NNE) Database, and the New York State
Database Historically, a primary focus of these databases
was to collect and track cardiac surgical outcomes, with
the specific aim that feedback to participating programs
could improve outcomes Secondarily, these databases
also provide enormously powerful multi-institutional
data from which clinical questions can be effectively
answered.1,2Continued challenges include measuring
other outcomes and extending these databases to other
areas in cardiothoracic surgery including congenital
heart surgery and general thoracic surgery These models
have been rigorously developed for cardiac surgery and
should be easily adaptable for other areas of surgery for
monitoring and improving quality of care The purpose
of this chapter is to review the status of the General
Thoracic Surgery Database and to provide an overall
perspective of the existing models of cardiac surgical
databases
Historical Perspective: The
Development of the VA and STS
Databases
Beginning in 1987 and 1989, respectively, the VA
Department and the STS developed national cardiac
surgical databases to risk adjust outcomes and to lish a process of quality improvement in cardiac surgery.Although these two databases evolved from the sameparadigm, they differ substantially The VA database(Continuous Improvement in Cardiac Surgery Program)involves mandatory reporting The purpose of this data-base is to screen quality of outcomes, provide qualityimprovement, and determine the viability of cardiacsurgery programs Conversely, the STS National AdultCardiac Surgery Database is a voluntary, surgeon-drivenprocess This latter database is primarily aimed towardproviding internal assessments of quality of cardiacsurgical care and local, institutional guidance in qualityimprovement
estab-In 1972 the VA established the Cardiac SurgeryConsultants Committee to monitor cardiac surgicaloutcomes within the nationwide VA system Thiscommittee originally used unadjusted raw mortalitystatistics to evaluate volume and death rates among VAmedical centers The committee realized that raw deathstatistics represented an unappealing and inadequatemethod to determine the quality of cardiac care betweenthe participating centers Thus, in 1987 the VA CardiacSurgery Consultants Committee implemented risk-adjusted methodology to appropriately track cardiacsurgical outcomes The obvious benefits of risk adjustingdata include that a more fair and accurate assessment ofquality of care can be achieved, and it prevents surgeonsfrom denying operations to patients deemed “high risk”with the perception that one or two excess deaths inhigh-risk patients could adversely affect raw mortalityresults To implement this risk-adjusted mortality, a data
Trang 13Databases and Clinical Outcomes: The General Thoracic Surgery Database / 123
form was developed that captures variables relative to
coronary artery bypass grafting (CABG), valvular
surgery, and great vessel surgery
The primary end point for analysis is 30-day surgical
death The definition of 30-day surgical death includes
any death from any cause within 30 days after surgery, or
death occurring after 30 days that is a direct result of a
perioperative complication Multivariate logistic
regres-sion analysis was employed to identify significant risk
factors and to determine the odds ratios that were
initially predictive of death and complications for CABG
only and valve-CABG procedures Semiannually, masked
confidential reports are distributed to each VA center
performing cardiac surgery for local quality
improve-ment Thus, since 1990 risk-adjusted outcomes have been
used within the VA system to provide local
self-assessment and quality outcomes purposes
The STS initiated the development of a voluntary,
national, adult cardiac surgery database in 1989 The
motivation for the development of this database included
the desire for surgeons to conscientiously review their
surgical results, and to allay the growing concerns of
vari-ous public (Health Care Financing Administration) and
private entities regarding the results of cardiac surgery
Under the leadership of Fred Edwards, MD, chair of the
adult cardiac surgery database committee, the statistical
methodology and risk adjustment in the STS Database
used Bayes’ theorem Subsequently, in 1995 this
risk-adjustment modeling was changed to multivariate
analy-sis During the period from 1990 to 1997, the STS
National Cardiac Surgical Database was maintained with
Summit Medical Inc., which warehoused the data and
developed the software package for the database In 1997
the STS executive leadership decided to license multiple
software vendors and to move the data storage and
analy-sis to the Duke Clinical Research Institute This move has
enabled easier data analysis and queries of the database
for research purposes A copy of the current STS software
with core STS data elements and definitions is available
at <http://www.sts.org/doc/4502> Biannual reports are
generated for participants in the STS database, and these
reports graphically display the observed-to-expected
ratios of death and major complications for the
partici-pating center, its region, and the nation
Both the STS and VA databases have been used for 10
to 12 years Although many similarities exist with regard
to sharing common risk factors and similar odds ratios
for outcomes, distinct differences are also present The
VA is composed of a 99% male population with a high
incidence of comorbidities, and many VA patients lack
insurance Also, as noted previously, the VA database
involves mandatory reporting Although the VA database
is used for oversight and the authority exists to close
programs with poor outcomes, this occurrence rarelyhappens The review of programs in the VA systemincludes outside consultants who offer constructiveadvice rather than providing a punitive construct Incontrast, the STS database is voluntary, with over 450centers currently participating Both databases reportoutcomes every 6 months, and both databases havemeasured processes of care such as internal mammaryartery use and length of stay
Challenges Facing Both the STS and
VA Databases
Recent changes in patient confidentiality and datareporting will require creative solutions Currently, theSTS database strips all patient identifiers and scramblesthe surgery and birth dates However, it is unknown whatimpact the laws of the new Health Insurance Portabilityand Accountability Act (HIPAA) of 1996 will exert overthe collection and reporting of patient data It is hopedthat reason will prevail and that these federal regulationsimposed upon the STS database will not be overly oner-ous or difficult
The second major challenge facing the STS database isthe cost of maintaining the database In the past, hospi-tals shared the cost of data managers (usually nurses), thesoftware, and data storage and analysis As hospitals areforced to justify costs and minimize expenses, they areshifting more of the cost burden to the individual cardio-thoracic surgical practices The current cost of software
in the STS is approximately $9,000 (US), and the cost ofdata storage is roughly $2,000 (US) This cost is notinsignificant, and it discourages universal participation inthe database Clearly, at a time when increasing scrutinyexists regarding surgical outcomes, cardiothoracicsurgeons need to offer a unified front in supporting theefforts of the database Software and data analysis areprovided in the VA system Clearly, these issues will alsoplay a role in the implementation and development ofthe General Thoracic Surgical Database
Extrapolating from Current Databases
to the General Thoracic Surgery
Database
For the past several years, the STS has been developing aGeneral Thoracic Surgery Database This is takingconsiderable effort and is being led by David Harpole,
MD, and Bill Putnam, MD, in conjunction with theGeneral Thoracic Committee and the General ThoracicSurgery Club This database has been developed to be asimple one with only two pages of data elements, includ-ing a small administrative section; a demographic
Trang 14124 / Advanced Therapy in Thoracic Surgery
section; and data elements involving preoperative risk
factors, operative details, and postoperative events such
as pulmonary, cardiovascular, gastrointestinal, and other
organ system morbidities, infections, and bleeding In
addition, air leak data is collected and, obviously,
mortal-ity data at 30 days
Included are tracheal/bronchial, pulmonary,
esopha-gogastric, chest wall, diaphragm, mediastinum, neck and
pleural, pericardial, vascular, and cardiac procedures as
they pertain to general thoracic procedures In addition,
in patients with carcinoma, the final pathology and TNM
status are captured
In July 2002 the STS offered this database to interested
surgeons, the cost of which was quite reasonable, with
the software package included in the annual fees of $750
to $1,250 (US) depending on the number of active
surgeons performing these procedures per center or
group Data on patients operated on during the calendar
year 2002 were sent to the Duke Clinical Research
Institute (the data warehousing and analysis center for
the general thoracic and adult cardiac databases) for
analysis and reports The data forms and definitions are
available on the STS Web page (<http://www.sts.org>)
It is envisioned that this database will continue to be
expanded over time and will serve as a quality-improvement
tool for those performing general thoracic surgery in a
simi-lar fashion to the way that the adult cardiac surgery and
congenital databases are useful for those performing cardiac
surgery It is also expected that, pending HIPAA regulations,
provisions will be made for long-term follow-up of these
patients
The STS has also developed a minimal data set for
congenital heart procedures, with an expected data
harvest and analysis for the fall of 2002 This follows a
long period of planning under the leadership of
Constantine Mavroudis, MD, who is charged with
devel-oping the congenital heart database, including major
international collaboration on defining congenital
cardiac surgical procedures and diseases In addition,
data from this basic congenital cardiac database will be
analyzed by the Duke Clinical Research Institute for the
STS, with reports being generated and distributed to the
congenital heart surgery members There is also a more
complex, complete data set available for the large centers
desiring detailed information
Remarkably, both the VA and STS databases during
their existence have demonstrated a very significant
reduc-tion in risk-adjusted operative mortality approaching 25 to
30% (Figures 10-1 and 10-2).2This has occurred in spite of
patient risk factors increasing throughout the 1990s
Similar reductions in mortality following the
implementa-tion of analysis of outcome data and their distribuimplementa-tion to
surgeons and their colleagues have occurred in northern
New England, where they noted a 24% reduction in deathsfollowing the institution of round-robin site visits for feed-back of outcome data and training in quality improve-ment.3New York State has also reported a similarreduction in risk-adjusted operative mortality Of greatinterest is the fact that for three of these databases (those
of the STS, VA, and northern New England), there hasbeen no public reporting of data, just internal dissemina-tion of these data to those providing the care
References
1 Mavroudis C, Jacobs J Congenital Heart Surgery Nomenclature and Database Project: overview and mini- mum dataset Ann Thorac Surg 2000;69:1–387.
2 Grover FL, Cleveland JC Jr, Shroyer AL Quality improvement
in cardiac care Arch Surg 2002;137:28–36.
3 O’Connor GT, Plume SK, Olmstead EM, et al for the Northern New England Cardiovascular Disease Study Group A regional intervention to improve the in-hospital mortality associated with coronary bypass grafting surgery JAMA 1996;275:841–846.
FIGURE 10-1 Unadjusted and adjusted operative mortality rates
between April 1987 and September 1991.
FIGURE 10-2 Ratio of observed-to-expected mortalities between
1990 and 1999.
Trang 15CHAPTER 11
L PENFIELD FABER,MD
Chest wall tumors are neoplasms in the bones or soft
tissues of the thoracic cage Primary tumors of the chest
wall develop in the bones or soft tissues of the thorax
Bony tumors include chondroid, osseous, giant cell, and
marrow-derived tumors Soft tissue tumors include those
of a fibrous, fibrohistiocytic, adipose, neurologic, and
muscular character Secondary chest wall tumors include
tumors that arise from an adjacent organ that invade the
chest wall, and tumors that have metastasized to the
bones or soft tissue of the chest from a distant site
Malignant tumors arising from the lung are the most
common of these, followed by breast cancer and
malig-nant tumors of the pleura
Hedblom reviewed and reported on 213 tumors of the
chest wall collected from the literature between 1898 and
1921 and updated his collected series to 313 cases in
1933.1The majority of these cases, unlike findings in
other series, involved primary chest wall malignancies,
and Hedblom was among the first to pathologically
cate-gorize the various primary tumors of the thoracic wall
Primary chest wall tumors are a heterogeneous group
of tumors of bone and soft tissue ( Table 11-1)
Altogether, they comprise only 1 to 2% of all primary
tumors of the body.2Primary malignant chest wall
tu-mors account for approximately 4% of all new cancers
diagnosed annually Malignant tumors of the soft tissues
are slightly more common than malignant tumors of
bone, and soft tissue sarcoma is the most common
pri-mary chest wall malignancy.3
The most common benign tumors of chest wall bone,
in decreasing order of frequency, are osteochondroma
and fibrous dysplasia, chondroma, aneurysmal bone cyst,
and eosinophilic granuloma Osteochondroma
consti-tutes approximately 30 to 50% of benign bony lesions
The incidence of fibrous dysplasia is approximately thesame as that of osteochondroma, whereas chondromaand bone cysts account for approximately 10 to 25% ofbenign lesions of bone.4
TABLE 11-1 Primary Tumors of the Chest Wall
Tissue Involvement Tumor Benign tumors of bone
Bone Osteoid osteoma Cartilage Enchondroma
Osteochondroma Fibrous Fibrous dysplasia Vascular Hemangioma Marrow Eosinophilic granuloma Osteoclast Giant cell tumor
Aneurysmal bone cyst Benign tumors of soft tissue
Fibrous Fibroma Adipose Lipoma Nerve Schwann cell
Neurofibroma Muscle Angioleiomyoma Malignant tumors of bone
Bone Osteosarcoma Cartilage Chondrosarcoma Fibrous Malignant fibrous histiocytoma Vascular Hemangiosarcoma
Marrow Plasmacytoma Cellular Ewing’s sarcoma
Askin’s tumor (peripheral neuroectodermal tumor) Malignant tumors of soft tissue
Fibrous Desmoid
Fibrosarcoma Fibrohistiocytic Malignant fibrous histiocytoma Adipose Liposarcoma
Nerve Neurofibrosarcoma
Schwann cell sarcoma Muscle Rhabdomyosarcoma
Trang 16The most common malignant tumors of the bony
thorax, in decreasing order of frequency, include
chon-drosarcoma, Ewing’s sarcoma, osteosarcoma, and solitary
plasmacytoma Chondrosarcoma is the single most
common malignant tumor of the chest wall Myeloma of
the bony chest wall must be considered a systemic disease
and not a primary lesion Solitary plasmacytoma,
al-though commonly associated with the development of
multimyeloma, is defined as a primary lesion and is less
frequently identified
The most common benign lesions of thoracic soft tissue
are fibroma, hemangiomas, lipomas, and giant cell tumors
Malignant fibrous histiocytomas, desmoid tumors,
liposarcomas, and fibrosarcomas are the most common
malignant soft tumors of the chest wall Primary soft
tissue sarcomas of the thoracic wall are more common
than malignant tumors of the bony thorax, and when
considered as a group constitute the most common form
of chest wall malignancy
Secondary chest wall tumors are most commonly lung
cancer, breast cancer, and metastatic disease
Clinical Presentation
Approximately one-half of malignant tumors of the bony
chest wall occur in the ribs, with the remainder presenting
in the scapula, sternum, and clavicle Malignant tumors of
the ribs are frequently found in the anterior aspect of the
upper seven ribs, but there is an equal distribution of
benign rib tumors throughout the thorax.5Specific
tumors are found in particular areas of the bony thorax;
the chondroma and endochondroma often arise
anteri-orly in the costal cartilages or sternum The
chondrosar-coma most often occurs anteriorly at the costochondral
junction Benign and soft tissue malignancies of the chest
wall occur in all locations with equal frequency In Dahlin
and Unni’s series, 96% of sternal tumors were malignant,
with the most common types being chondrosarcoma,
plasmacytoma, and osteogenic sarcoma.6
Chest wall tumors occur in all age groups Ewing’s
sarcoma occurs in younger patients, and plasmacytoma
presents in the elderly Chondrosarcoma commonly
occurs in adults A male-to-female ratio of 2 to 1 occurs
for malignant chest wall tumors, whereas desmoid tumors
are more common in females Burt reported that only 2%
of malignant chest wall tumors were asymptomatic.3Fifty
percent of patients presented with a painless mass,
whereas 33% had a painful mass and 15% had pain
with-out a mass being present Pain is not necessarily a
predic-tor of malignancy; in Hedblom’s series, pain was present
in 40% of benign chondromas.1Benign osteoma presents
with severe pain relieved only by medication
Asym-ptomatic lesions are more often benign, and most of these
are detected on chest radiographs Soft tissue sarcomaspresent as a painless mass, but tumors of bone and carti-lage, both benign and malignant, present with pain.Generalized symptoms of fever, malaise, and fatigue can
be presenting complaints associated with eosinophilicgranuloma and Ewing’s sarcoma Rapidly growing tumorsare more likely to be malignant
It is difficult to differentiate a benign from a nant chest wall tumor by physical examination Bonytumors are fixed to the chest wall; soft tissue tumors mayalso be fixed, but others are quite mobile Both malignantand benign lesions can be tender to palpation
malig-Diagnosis
The chest radiograph is the initial study to be obtained.Comparison with prior films is important to evaluate therate of growth Computed tomography (CT) defines theextent of pleural, mediastinal, and soft tissue involvement(Figure 11-1) Metastatic disease to the lung is readilyidentified, and the radiologic characteristics of the tumorcan assist in the clinical diagnosis Magnetic resonanceimaging (MRI) has become extremely valuable in evaluat-ing chest wall tumors (Figure 11-2) It precisely defines theanatomic extent of the tumor, as well as showing adjacentorgan involvement A significant advantage of MRI is thatmultiplanar imaging with high-contrast resolution definesanatomic planes for planned resection Differential signalintensity evaluates adjacent vascular structures andbecomes critical in the assessment of the upper chest withinvolvement of the brachial plexus and subclavian vessels.The MRI is supplemental to the CT, and both studies assist
in the planning of extensive and difficult chest wall tions Positron emission tomography (PET) is useful todefine metastatic disease when a secondary chest walltumor is present This particularly applies to lung andbreast cancer PET is not particularly helpful in definingthe extent of a primary chest wall tumor
resec-126 / Advanced Therapy in Thoracic Surgery
FIGURE 11-1 Computed tomography scan illustrating the
involve-ment of ribs, sternum, and mediastinum by a chondrosarcoma.
Trang 17Benign Bony Tumors
Fibrous Dysplasia
Fibrous dysplasia is a common lesion of the chest wall,
accounting for 20 to 30% of rib tumors.5,10 This lesion
occurs equally in males and females and is common in
the second and third decades of life It usually presents as
a painless mass involving the bony chest wall; most
lesions are solitary, but multiple areas are seen
occasion-ally Fibrous dysplasia usually is a painless mass identified
on a routine chest radiograph, but it can be painful in
association with a pathologic fracture or an expansion
and stretching of the periosteum Patients with multiple
lesions show abnormal skin pigmentation and
preco-cious puberty (Albright’s syndrome)
The radiographic appearance is that of a lytic lesion
involving one or more ribs (Figure 11-3) There
fre-quently is an expansion of the rib with significant ning of the cortex, and the medullary aspect of the ribhas a homogeneous ground-glass appearance Pathologicfracture is a frequent cause of diagnosis precipitatingradiologic evaluation The gross appearance of theaffected rib identifies a central fibrous area with a shell ofexpanded cortex on the surface (Figure 11-4) Malignanttransformation into osteosarcoma or fibrous sarcoma isexceedingly rare and is not an indication for excision ofthis lesion.11Excision of fibrous dysplasia is indicated forpain or uncertainty of the diagnosis In cases in whichthe diagnosis is questioned, incisional or excisionalbiopsy is indicated Recurrence after complete excision israre
thin-Osteochondroma
Osteochondroma is among the most common benignneoplasms of the chest wall The rib is the common loca-tion for these tumors, which usually begin in childhoodand continue to grow until skeletal maturation is attained.Patients with osteochondromas are usually < 30 years ofage, and males are more commonly affected than females
A chest radiograph is usually diagnostic with the ing of a pedunculated or sessile bony excrescence on thesurface of the rib, with the medulla of the bone continu-ous with the medulla of the lesion A thin cartilaginouscap is present with areas of scattered calcification Multi-ple lesions suggest a diagnosis of familial osteochondro-matosis
find-Treatment for the osteochondroma is complete excision,and recurrence is rare Malignant transformation of theselesions is suggested by pain and continued growth afterclosure of the epiphyseal plate.5Malignancy of these lesions
is rare and is estimated to occur in < 1% Malignant formation can occur in 20% of these lesions in cases offamilial osteochondromas or multiple exostoses Themalignant tumor is well differentiated, and local recurrence
trans-is unusual if complete resection trans-is accompltrans-ished
128 / Advanced Therapy in Thoracic Surgery
FIGURE 11-3 A, Chest radiograph depicting a chest wall mass B,
Computed tomography scan showing classic appearance of fibrous
dysplasia with cortical thinning.
FIGURE 11-4 Resected rib of fibrous dysplasia Cortical thinning is
noted Reprinted with permission from Faber LP, Somers J, Templeton
AC Chest wall tumors Curr Probl Surg 1995;32:661–756.
Trang 18Chondromas constitute approximately 15 to 20% of all
benign tumors of the chest wall They may occur in the
medulla as an enchondroma (Figure 11-5) or less
frequently on the periosteum as a periosteal chondroma,
but most commonly from costal cartilage They usually
present anteriorly at the costal chondral junction and are
a slowly enlarging painless mass Pain can also be present
Chondromas occur in all age groups, most frequently
between the ages of 10 and 30 years Males and females
are affected equally On radiographs, the chondroma
appears as a small lytic area in the bone with sclerotic
margins The lytic areas are typically round or oval, and a
rib lesion is expansile with thinning of the cortex
There is no reliable imaging technique to distinguish a
low-grade chondrosarcoma from a chondroma Histologic
differentiation between a low-grade chondrosarcoma and
a cellular chondroma can also be difficult Because of this
problem, en bloc resection is recommended with wide
margins All tumors arising from the costal cartilages
should be considered malignant and treated with wide
excision Inadequate resection frequently results in local
recurrence of the malignant form
Eosinophilic Granuloma
Eosinophilic granuloma is a part of the spectrum of
Langerhans cell histiocytosis, a diffuse infiltrative process
of antigen-presenting macrophages together with a
vari-able accompaniment of eosinophils, lymphocytes, and
plasma cells Eosinophilic granuloma is limited to bone,
whereas other forms of the disease are systemic In infants
it presents as an infiltration of lymph nodes, liver, spleen,
and bone marrow (Letterer-Siwe disease)
Hand-Schuller-Christian disease presents with bone involvement
accom-panied by diabetes insipidus Isolated rib involvement
occurs in 10 to 20% of instances of eosinophilic loma, and there is a strong predilection in males
granu-If there is localized chest pain, chest radiography isrequired to determine whether there is an expansilelesion of the rib (Figure 11-6) Malignancy cannot be
Primary and Secondary Chest Wall Tumors / 129
FIGURE 11-5 Anterior chest wall enchondroma (arrow).
FIGURE 11-6 A, Radiograph of the rib illustrates eosinophilic
granu-loma (arrow) B, Computed tomography scan depicts the lesion
(arrows) C, Resected rib specimen.
Trang 19ruled out by the radiologic appearance, and excisional
biopsy is performed to establish the diagnosis and
provide a cure if the lesion is solitary.5Radiation therapy
can be effective for multiple lesions or tumors in areas
that are difficult to resect
Aneurysmal Bone Cysts
Bone cysts account for < 1% of chest wall tumors
(Figure 11-7) They commonly occur in the ribs and
usually are associated with a pathologic fracture
(Figure 11-8) A chest radiograph can be diagnostic if it
shows a demarcated lytic lesion surrounded by a thin
shell of periosteum Callus formation may be present if
there has been a previous fracture The lesion is usually
asymptomatic unless fracture has occurred Simple
exci-sion is indicated for associated pain or when there is a
question of metastatic cancer
Osteoid Osteoma
Osteoid osteoma is a rare benign tumor of the rib or
vertebral body The presentation is usually sharp pain
that requires radiography; films demonstrate a small,
radiolucent area surrounded by a marked area of
sclero-sis A bone scan illustrates intense uptake in the center of
the lesion, with less dense activity surrounding thecentral nidus
Surgical resection is recommended for pain, and localrecurrence is rare after complete excision Lesions of thescapula and sternum can be treated with exposure of thenidus by cortical shaving and curetting of the nidus
Hemangioma
Hemangiomas present in the vertebral body or ribs andare pain free The tumor can arise in the soft tissue andprotrude into the thorax or develop in a rib with a sclerotic-reticular pattern (Figure 11-9).12 Increasedblood flow through the rib causes absorption, and adja-cent slow flow causes deposition of new bone The lesionpresents as linear areas of bone deposition and lucency.Diagnosis is usually made by radiography and CT, andexcision is not required except in cases of fracture orcosmetic deformity Low-grade malignant hemangioen-dothelioma presents with soft tissue involvement outsidethe rib; in this instance, excision is recommended Clearmargins must be obtained as there is a significant inci-dence of local recurrence with this lesion.13
Other benign bony lesions of the chest wall includeosteoblastoma, ossifying fibroma, nonossifying fibroma,ossifying lipoma, and giant cell tumors These lesions canusually be diagnosed by precise radiologic interpretationand do not require excision unless there is associatedpathologic fracture or a question of malignancy
Malignant Bony Tumors
Chondrosarcoma
Chondrosarcoma is the most common primary nant neoplasm of the chest wall and commonly presentsanteriorly, arising from either the costochondral arches
malig-or the sternum It is also the most common primarymalignant tumor of the sternum It most commonlyaffects males and is found in people 20 to 40 years old.McAfee and colleagues reported that 12.5% of patientswith chondrosarcomas reported a previous history ofchest wall trauma in the location of the tumor.1 4Chondrosarcomas also develop as a result of malignantdegeneration of a benign chondroma or osteochon-droma and are categorized as secondary chondrosarco-mas These lesions are usually of low-grade malignancy,appear at an earlier age, and have a better prognosis thanthe standard primary chondrosarcoma
The tumor usually presents as a slowly enlarging,painful mass located on the anterior chest wall or sternum.The mass is hard, slightly tender, and fixed firmly to thechest wall (Figure 11-10) The radiographic appearancedefines a lobulated mass arising in the medullary portion
of the bone with radiolucency and stippled calcification
130 / Advanced Therapy in Thoracic Surgery
FIGURE 11-7 Resected bone cyst.
FIGURE 11-8 Bone cyst with rib fracture (arrow).
Trang 20recurrence significantly decreases survival and also
increases the risk of distant metastasis There is no
effec-tive chemotherapy for chondrosarcoma
Radiation therapy is ineffective as the primary
treat-ment McNaney and colleagues have reported some
success with combination photon and neutron
radiation.17Postoperative radiation is mandatory if
oper-ative margins are microscopically positive for tumor
Ewing’s Sarcoma
Ewing’s sarcoma constitutes 6 to 10% of all malignant
chest wall tumors and is the most common primary chest
wall tumor in children It is more common in males than
females, and white people are more commonly affected
than are those of African descent Ewing’s sarcoma
usually presents as a painful, palpable mass, and pain is
the presenting symptom in 90% of patients.18 Systemic
manifestations include fever, malaise, and weight loss
These symptoms in association with pain and the classic
appearance on radiographs are diagnostic
Chest wall Ewing’s sarcomas frequently present in theribs but also arise from the scapula, sternum, and clavi-cle.19 Gross metastatic disease is present at the time ofdiagnosis in 20 to 30% of patients, and common sites ofmetastatic disease include the lungs, bone, and bonemarrow Malignant pleural effusion is a common form ofmetastatic presentation with primary Ewing’s sarcoma ofthe chest wall
Radiographs reveal destruction of bone with lytic andblastic areas, and elevation of the periosteum with multi-ple layers of subperiosteal bone formation creates theclassic “onion skin” appearance (Figure 11-12) Thesurface of the bone may contain radiating ossifiedspicules, as are commonly seen in osteosarcoma Patho-logic fractures are uncommon CT and MRI scans areimportant in evaluating soft tissue, lung, and mediastinalinvolvement, and a bone scan is necessary to rule outbone metastasis Excisional biopsy is recommended fordiagnosis, and the biopsy should be performed in amanner that will allow for definitive resection
132 / Advanced Therapy in Thoracic Surgery
FIGURE 11-11 A, Computed tomography scan illustrating an anterior chest wall chondrosarcoma Note the patchy calcification B, Resected
specimen included cartilages and ribs C, Reconstruction with GORE-TEX (W L Gore and Associates, Flagstaff, AZ) D, Photomicrograph showing
histologic appearance of a chondrosarcoma ( 800 original magnification; hematoxylin and eosin stain).
Trang 21Askin’s tumors occur mainly in children and young
adults; they frequently present in the posterior chest wall
and are often thought to be a posterior chest wall tumor
(Figure 11-13) Depending on the location, the diagnosis
can be made with percutaneous needle biopsy A trephine
specimen is advantageous Preoperative chemotherapy is
recommended, followed by wide surgical resection for
local control (similar to the treatment of Ewing’s
sar-coma) Positive resection margins are treated with
radia-tion therapy
Osteosarcoma
Osteosarcomas represent 5 to 10% of primary malignant
tumors of the chest, and occurrence is noted in the second
and third decades of life, as well as in the elderly.25The
clini-cal presentation is that of a painful, rapidly enlarging mass
Radiographs may show calcified spicules extendingfrom the bone cortex, which produce the classic
“sunburst” appearance However, the sunburst ance is noted in other diseases of bone and is probablyseen in only 25% of osteosarcoma lesions.5Cortical bonedestruction with irregular margins that merges into adja-cent normal bone with lytic or blastic changes is usuallyapparent (Figure 11-14) CT is required to evaluate theextent of involvement and also the presence of metastaticlesions to the lung (Figure 11-15) Diagnosis can beachieved in the soft tissue component of the lesion bytrephine needle biopsy or incisional biopsy
appear-134 / Advanced Therapy in Thoracic Surgery
FIGURE 11-13 A, Apical and posterior chest wall tumor as seen on a
radiograph B, Computed tomography scan shows the extent of this
Askin’s tumor Reprinted with permission from Faber LP, Somers J,
Templeton AC Chest wall tumors Curr Probl Surg 1995;32:661–756.
FIGURE 11-14 A, Posterior osteogenic sarcoma B, Radiograph of
resected osteogenic sarcoma Reprinted with permission from Faber
LP, Somers J, Templeton AC Chest wall tumors Curr Probl Surg 1995;32:661–756.
Trang 22must be obtained including serum and urine
elec-trophoresis, serum ionized calcium level, bone marrow
aspiration, and a complete blood count A patient with a
true solitary plasmacytoma usually has a normal calcium
level and is not anemic Monoclonality of one of the
immunoglobulins with normal levels of other circulating
immunoglobulins suggests that the plasmacytoma is
truly solitary
Radiation is the primary treatment for solitary
plasma-cytoma.28The role of surgery is to make the diagnosis, and
wide excision for this lesion is not indicated Radiationtherapy yields a 90% local control rate.19Following localcontrol with radiation, multiple myeloma develops in 45
to 50% of patients Patients must be followed carefullywith periodic evaluation after treatment for a solitaryplasmacytoma The 5-year survival rate for patients withthis disease is approximately 20 to 30%.7,29
Benign Soft Tissue Tumors of the
Chest Wall
Lipoma
Lipoma is a benign tumor of fat and occurs superficially aswell as deeper; it can protrude through the intercostal spaceinto the thoracic cavity Subcutaneous lipomas are non-tender, well circumscribed, and mobile They are distrib-uted equally throughout the chest wall and are painless andusually asymptomatic These lesions are frequently notedincidentally on a routine chest radiograph, and a CT scanshows the typical density of fat The differential diagnosislies between lipoma and the rarer liposarcoma
These lesions are well circumscribed, thinly lated tumors of mature adipose tissue (Figure 11-17).Surgical excision is indicated for cosmetic purposes or ifmalignancy cannot be ruled out Usually, the diagnosis isstrongly suspected, and only local excision is required
encapsu-Neurofibroma
Neurofibromas are commonly multiple and occur as part
of the complex of von Recklinghausen’s disease, a familialdisorder characterized by these growths that can occur inany part of the body The disease may be transmitted as
an autosomal dominant trait as a result of a gene tion on chromosome 17, but 50% of cases are sporadic
muta-In addition to multiple neurofibromas, the disease ischaracterized by café au lait spots of the skin and menin-giomas A chest radiograph demonstrates a mass, andfrequently there is associated rib notching (Figure 11-18)
In the chest they frequently arise from interthoracicnerves but can occur in bone without nerve sheathinvolvement The lesions are usually benign, but malig-nant degeneration occurs in 5 to 40% of cases.30Surgicalexcision is recommended for symptoms of pain or forrapid enlargement
Related to the neurofibroma is the Schwann cell tumor
or neurilemoma This lesion is usually solitary and occurs
on a nerve with clear demarcation The ribs can be involved(Figure 11-19) Excisional biopsy and resection are recom-mended for diagnosis and treatment It may be difficult todifferentiate the malignant form of this tumor from thebenign form This tumor can be a low-grade malignancy,which is associated with a high recurrence rate Mitoses
136 / Advanced Therapy in Thoracic Surgery
FIGURE 11-16 A, Radiograph showing a solitary plasmacytoma of
the chest wall B, Computed tomography scan of the same lesion.