Diffuse Lung Disease
David Turner, M.D.
I. Clinical Evaluation of the Chest Radiograph
A. Radiographic patterns
1.
Interstitial - reticulonodular
a.
Known cause - inorganic dust (pneumoconiosis), organic dust
(hypersensitivity pneumonitis), iatrogenic (drugs, radiation
therapy)
b.
Unknown cause - sarcoidosis, idiopathic pulmonary fibrosis,
pulmonary fibrosis with connective tissue disease
2.
Alveolar - fluffy, often with air bronchograms
a.
Acute - cardiogenic pulmonary edema, non-cardiogenic
pulmonary edema (ARDS), diffuse alveolar pneumonia, alveolar
hemorrhage
b.
Subacute or chronic - sarcoidosis, bronchioloalveolar cell
carcinoma, lymphoma, pulmonary alveolar proteinosis,
desquamative interstitial pneumonitis
3.
Nodular - often suggests hematogenous origin
a. Disseminated malignancy, tuberculosis, fungal disease,
pneumoconiosis, sarcoidosis, eosinophilic granuloma
B. Distribution of disease
1.
Lower lobe - idiopathic pulmonary fibrosis, pulmonary fibrosis
associated with connective tissue disease, asbestosis
2.
Upper lobe - silicosis, sarcoidosis, eosinophilic granuloma
3.
Non-anatomic margins - radiation-induced pulmonary disease
4.
Peripheral distribution - chronic eosinophilic pneumonia;
occasionally bronchiolitis obliterans with organizing pneumonia
C. With hilar adenopathy - sarcoidosis, silicosis, berylliosis, malignancy
D. With pleural disease - asbestosis, RA, lupus, occasionally sarcoidosis. In
AIDS, suggestive of KS.
It is important to recognize that when we are faced with a patient with diffuse lung
disease there are several radiographic patterns. It is often useful to separate out 3 types
of radiographic patterns. First of all an interstitial pattern, often called reticulonodular.
Secondly there is an alveolar pattern, and thirdly there is a nodular pattern.
The interstitial pattern or reticulonodular pattern is characterized by a lot of lines, dots,
and streaks. There are about 150 different disorders that can produce this type of
pattern. That makes it very difficult to create a realistic sort of differential diagnosis. I
think when approached with this type of radiograph the best thing is to try to break
down the long differential diagnosis. I find it is easiest to break it down into 3
categories. First of all, diseases of known cause, second of all, diseases of unknown
cause, and third, mimicking causes, or causes that look like interstitial lung disease but
in fact really fall out of the diagnostic category of what we usually consider in this broad
group of disease. Under each of these 3 categories there are 3 separate sub-categories.
For example, disease of known cause is inorganic dust, organic dust, and iatrogenic.
Within the iatrogenic ones would be things such as drugs and radiation therapy. The
drugs include cancer chemotherapeutic agents. Disease of unknown cause is sarcoidosis,
idiopathic pulmonary fibrosis, and pulmonary fibrosis associated with connective tissue
disease. The mimicking causes are congestive heart failure, malignancy, and infections,
and of the infections, particularly viral pneumonia and Pneumocystis carinii pneumonia.
When faced with a patient that has this type of interstitial pattern, it is actually
worthwhile to go first to the 3rd cause, the mimicking causes and make sure that your
not dealing with someone who might have heart failure, tumor, or infection.
The second category is an alveolar pattern, and, unlike the interstitial pattern, this is a
pattern that is more fluffy, cloudlike, or cottony and represents filling of alveolar spaces
with fluid or an inflammatory infiltrate often. With the alveolar lung diseases I think it
is actually best to separate out 2 types of presentation either an acute presentation or a
subacute or chronic presentation. With an acute presentation the easiest way to
categorize of characterize alveolar lung disease is by thinking about the types of the
things that can fill alveolar spaces. For example, we can have a relatively low protein or
transudative type of fluid as we might see in a patient with cardiogenic pulmonary
edema. We can see more of a relatively high protein fluid due to abnormal permeability
of the alveolar epithelium as we might see in the acute respiratory distress syndrome.
Inflammatory fluid can occur in diffuse alveolar pneumonia, and we can have blood
with diffuse alveolar hemorrhage. The subacute or chronic disorders that can fill
alveolar spaces. Those include sarcoidosis, bronchioloalveolar cell carcinoma,
lymphoma, alveolar proteinosis, and DIP or desquamative interstitial pneumonitis.
The 3rd radiographic pattern is a pattern of nodular lung disease and these discrete
nodules. This is actually from a patient with disseminated cancer. I should mention that
the interstitial pattern was from scleredema interstitial lung disease. The diffuse alveolar
pattern was from acute respiratory distress syndrome. This one though is from a patient
who has disseminated carcinoma. For nodular lung disease, often what we are thinking
about are disorders that spread to the lung by hematogenous spread. For example,
disseminated malignancy or some of the granulomatous diseases when there has been
spread of the organism to the lung that has resulted from hematogenous spread.
Disseminated malignancy, tuberculosis, and fungal disease are examples of this.
However, there are some disorders that actually can produce a nodular pattern because
of airway access to the lung such as the pneumoconiosis, the inhaled dust disorders.
Then there are a couple of idiopathic disorders, like sarcoidosis and eosinophilic
granuloma, that can produce nodular lung disease. One point to keep in mind is that
sarcoidosis falls into all 3 categories, so sarcoid can produce an interstitial pattern, an
alveolar pattern, and a nodular pattern.
The distribution of disease, and by this I mean radiographic distribution of disease
where it is in the lungs, can actually be very helpful as one try’s to put together the
differential diagnosis. For example, lower lobe disease is relatively common in
idiopathic pulmonary fibrosis, pulmonary fibrosis associated with connective tissue
disease, or asbestosis related. In contrast, upper lobe disease is seen with silicosis,
sarcoidosis, and eosinophilic granuloma. If we see margins that are non-anatomic and
by that I mean relatively sharp margins that do not follow the distribution of lobar
II.
Diagnosis and Treatment of Diffuse Lung Disease
A. Idiopathic pulmonary fibrosis (IPF)
1.
Original description of Hamman-Rich syndrome was an acute
interstitial pneumonia with rapid progression and death within
months; this is different from chronic idiopathic pulmonary fibrosis
2.
Desquamative interstitial pneumonia (DIP) - not clear if a subtype of
IPF, a cellular variant of IPF, or a different disease. Desquamated
cells are primarily alveolar macrophages
a.
Respiratory bronchiolitis in smokers may be associated with
interstitial lung disease resembling DIP; ? part of a spectrum,
since large majority of patients with DIP are also smokers
3.
Therapy
a.
Standard therapy is still prednisone
b.
Increasing interest in cyclophosphamide or azathioprine
used instead of, or in conjunction with steroids, but relative
role of steroids and other immunosuppressives is not yet
clear
B. Sarcoidosis
1. Despite common finding of depressed cell-mediated immunity with
cutaneous anergy, cell-mediated immune processes are enhanced
locally in the lung
a. Bronchoalveolar lavage - increased lymphocytes with
increased CD4/CD8 ratio
2.
Pattern of parenchymal infiltrates on chest X-ray can be
reticulonodular, nodular, or alveolar
3.
Endobronchial involvement can cause chronic cough and/or airflow
obstruction
4.
Angiotensin converting enzyme levels - generally not useful for
diagnosis or for following disease activity
5.
Standard treatment is still corticosteroids; results with cyclosporine
have been disappointing. ? role for methotrexate.
C. Hypersensitivity pneumonitis
1.
Examples - farmer's lung; air conditioner or humidifier lung
2.
Pathology shows mononuclear cell infiltrate with poorly formed
granulomas
3.
Distinction between acute hypersensitivity pneumonitis (fever,
cough, dyspnea, pulmonary infiltrates hours after exposure) and
chronic hypersensitivity pneumonitis (mimics other forms of
chronic interstitial lung disease)
boundaries or fissures then we will often think about something like radiation
pneumonitis or radiation fibrosis, which often tends to follow the ports of the radiation
therapy. Finally a peripheral pattern and I will show you an example of this later where
the infiltrates are primarily along the periphery of the lung is seen in chronic
eosinophilic pneumonia and sometimes in bronchiolitis obliterans with organizing
pneumonia.
Associated features on the radiograph may be helpful if there is hilar adenopathy we
tend o think of sarcoid, silicosis, berylliosis, and malignancy. Silicosis and berylliosis
are the 2 inhaled disorders for pneumoconiosis that can be associated hilar adenopathy.
If we see associated pleural disease then obviously asbestosis, a couple of the connective
tissue diseases particularly rheumatoid arthritis and lupus and occasionally with sarcoid,
although less than 10% of patients with sarcoid will have involvement of the pleural. In
a patient who has AIDS and has pleural disease then we often think about coexisting
Kaposi sarcoma or Kaposi sarcoma really is the cause of the pleural disease particularly
pleural effusion.
A few points about the pulmonary function features in a patient who has diffuse
parenchyma lung disease we generally will see a restrictive pattern of lung volumes
characterized by a relatively symmetric decrease in lung volumes, total lung capacity,
functional residual capacity, vital capacity, and residual volume. If we had to choose
one of them that is most important I would have to say it is the total lung capacity and
the low total lung capacity is really what defines the presence of a restrictive physiologic
pattern. We generally do not see airflow obstruction and that means that the FEV1/
forced vital capacity ratio is normal or actually may even be increased. However, if we
look at the FEV1 in isolation or if we look at the forced vital capacity in isolation they
may be down, but they are down in proportion to the other lung volumes. The key thing
is they may be decreased but the ratio between them the FEV1/forced vital capacity
ratio is normal. If we do see coexisting airflow obstruction based on a low FEV1 to
forced vital capacity ration then that may clue us in to a few disorders such as
histiocytosis X, which is the same as eosinophilic granuloma,
lymphangioleiomyomatosis a rare disorder that I will mention later, sarcoid, and cystic
fibrosis. All of those can have coexisting airflow obstruction. Typically the diffuse and
capacity is decreased in the diffuse parenchyma lung diseases. However, the diffuse and
capacity if it is increased we should think about alveolar hemorrhage because of red
cells in the alveolar spaces taking up carbon monoxide, or because of coexisting high
left atrial pressures because of increased blood volume within the lungs capable of
taking up carbon monoxide. That would be the case obviously with heart failure or
mitral valve disease.
Next I would like to go through a number of the specific disorders. I’ll try to focus on a
few of the interesting clinical features and treatment aspects of some of the diffuse
parenchyma lung diseases. I’ll start by talking about idiopathic pulmonary fibrosis or
IPF. If I gave this talk in England I would be talking about cryptogenic fibrosing
alveolitis. That is synonymous with idiopathic pulmonary fibrosis. Many people have
heard and think about the term Hamman-Rich syndrome, which was the term that was
coined in the 1940’s down at Hopkins for a disorder that was subsequently thought
perhaps to be idiopathic pulmonary fibrosis. If one goes back and looks at the original
cases of Hamman-Rich syndrome it turns out that these cases were actually quite a bit
different from what we think of as idiopathic pulmonary fibrosis now. The Hamman-
Rich cases were much more rapidly progressive and often lead to death within 6 months.
In contrast idiopathic pulmonary fibrosis is really a slowly progressive disease and one
that progresses with fibrosis that occurs over the course of years rather than months.
Although it can and certainly often does lead to respiratory failure and death as I said
the issue is that it progresses over years rather than months. The term DIP or
desquamative interstitial pneumonitis is in some ways similar to idiopathic pulmonary
fibrosis, but in some ways different. The pathology is slightly different in the sense that
there are cells within the alveolar spaces that actually represent macrophages. They are
not desquamative alveolar cells, but rather are intra-alveolar inflammatory cells. The
question that has come up is whether DIP represents a sub-type of idiopathic pulmonary
fibrosis with a fair amount of inflammation, or whether it represents a different disease
and that is really not clear. It has been however, suggested that maybe there is actually
more of an association with some small airways disease. Many of the patients who have
desquamated interstitial pneumonitis actually are smokers and they also often will have
an inflammatory process in the small airways and one of the questions that comes up is
this more of a smoking related disease as opposed to a non-smoking related disease such
as idiopathic pulmonary fibrosis. The treatment of IPF has really not improved much
over the past decade or even a couple of decades. We tend to just try to suppress the
inflammatory response with prednisone generally. There are many people who favor
using an immunosuppressive agent other than prednisone like cyclophosphamide has
been used. There has not been really good head to head studies comparing those and I
4.
Bronchoalveolar lavage (BAL) fluid shows lymphocytosis with
low
CD4/CD8 ratio
D. Eosinophilic granuloma (histiocytosis X)
1.
Atypical histiocytes (Langerhans' cells) in infiltrate; variety of cell
types in infiltrate with scattered eosinophils
2.
May have airflow obstruction; may have surprisingly normal lung
volumes for degree of interstitial disease seen on radiograph
3.
Chest X-ray and CT scan may show numerous small cysts and
nodules; eventual progression to fibrosis and honeycombing
4.
Presence of cysts explains possible clinical presentation with
spontaneous pneumothorax
5.
Very high association with smoking
6.
Quite variable natural history ranging from spontaneous resolution
to marked progression with honeycombing and endstage lung
7.
No clear response to any form of therapy, though
steroids/immunosuppressives often used
E.
Lymphangioleiomyomatosis
1.
Exclusively in women, almost all of childbearing age
2.
Atypical smooth muscle proliferation around lymphatics,
bronchioles, small pulmonary vessels
3.
Clinical presentation with any of the following: pleural effusion
(chylothorax), interstitial lung disease (with cysts, similar to
eosinophilic granuloma), spontaneous pneumothorax, hemoptysis
4.
Like eosinophilic granuloma, may have airflow obstruction, normal
lung volumes despite interstitial pattern on chest radiograph
5.
Treatment - alteration of hormonal milieu, e.g., progesterone,
oophorectomy
F.
Chronic eosinophilic pneumonia
1.
Often in patients with underlying asthma
2.
Term refers to eosinophils in the pulmonary, infiltrate, which is
interstitial and intra-alveolar
a.
Peripheral blood eosinophilia common but not present in all
patients
3.
Often subacute presentation with dyspnea, cough, fever, other
constitutional symptoms
4.
Typical peripheral distribution of infiltrates - photographic negative
of pulmonary, edema
5.
Often dramatic response to steroids - can be used for diagnostic trial
would say that if you’d look across the country as far as what pulmonologist do I would
say maybe 60% will start with prednisone and about 40% will start with an agent such
as cyclophosphamide. There really is no good data for head to head comparison.
Sarcoidosis is my favorite of the interstitial lung diseases. It also I think it is fair to say
the most common of the interstitial lung diseases. We still to this day do not what causes
sarcoidosis. The presumption is that sarcoid reflects a response to some agent, an
immunologic response to some agent, whether or not it is an exogenous agent or perhaps
even an indigenous agent isn’t really clear. It is also though that it may occur in any
genetically susceptible host, although that has also not been well worked out. At the
moment the National Institutes of Health has a multi-center study to try to sort out the
ideology of the sarcoid. We have medical center and one of the 10 centers and the hope
is by applying newer molecular biologic techniques we’ll be able to try to figure out
what the ideology of sarcoid is. However, we can state a few points about sarcoid in
terms of describing what happens. One of the interesting immunologic features is that
there seems to be a hyperactive T cell mediated immunologic response in the lungs that
seems to result in the formation of granulomas. If we look in the lungs to do a
bronchoalveolar lavage for example, we can find an increased number of lymphocytes in
the lungs and also a high helper to suppressor cell ratio, high CD4 to CD8 ratio. In
contrast, if we look in the peripheral blood for example, we find a depression of T cell
mediated responses as we think about things such as impaired delayed hypersensitivity
patients are often anergic on skin testing. However, unlike patients with HIV infection
this cutaneous anergy and sarcoid is not associated with an increased risk of
opportunistic infections. As I mentioned earlier radiographic patterns can be anything.
It can be reticulonodular, nodular, or alveolar. We often will see endobronchial
involvement. If we look with a bronchoscope we will see that there are often little bumps
sometimes called cobble stoning in the airway surface that is often responsible for a
significant problem with cough. In general angiotensin converting enzyme levels, which
had been proposed in the past to be useful in the diagnosis of follow-up of patients with
the disease. I would have to say, in general, most people felt that they are not useful.
There are a number of diseases that have been associated to high elevated levels
including other granulomas diseases and the correlation is not necessarily all that great
with activity of the disease. Corticosteroids remain the mainstay of therapy, but we
really do not have any good evidence that corticosteroids alter the overall natural history
of the disease even though they will acutely suppress many of the manifestations of the
disease. One might think because of the presumed pathogenic role of T cells
particularly T helper cells in this disease that cyclosporine might be useful, but actually
when it has been looked at the results have been quite disappointing so far. The other
agent that there is a lot of interest in is methotrexate used primarily as a steroid sparing
agent in this disease, but also potentially as a steroid alternative. There are some trials
that are going on right now, but I don’t think that we really have any definitive
information about the role of methotrexate versus steroids for sarcoid.
Another disorder in the lung that will often have some granulomas on pathology,
although they are not as well formed as the granulomas of sarcoid. This is
hypersensitivity pneumonitis. Examples are being farmer’s lung, air conditioner or
humidifier lung. For all of these basically the underlying pathogenesis is an
immunologic response to an inhaled organic antigen. In the case of farmer’s lung and
all of these what we are dealing with is a response to thermophilic Actinomyces, a mold
that can grow either in hay or can grow in a forced air system. The other common type
of organic antigen would be an antigen from animals such as antigens form birds as
could be seen in bird breeders. The pathology is poorly formed granulomas. The disease
can present either in an acute form or in a more chronic form. The acute form often
presents as fever, constitutional symptoms, shortness of breath, and pulmonary infiltrates
occurring 4 to 6 hours after exposure. The chronic form presents more as a diffuse
interstitial lung disease often in those patients where the underlying exposure is not
being recognized and they have repeated exposure. Interestingly enough if you look in
the lungs by doing a bronchoalveolar lavage and recover cells you’ll find that there is a
increased number of lymphocytes very similar to what we see in sarcoid, but they are
different lymphocytes. In sarcoid we have a high CD4 to CD8 ration where as in
hypersensitivity pneumonitis the converse is true where the CD4 to CD8 ratio is actually
low.
A few less common disorders and one is eosinophilic granuloma, which is also called
histiocytosis X. It turns out that the name of this is somewhat of a misnomer in the sense
that they really are not a huge number of eosinophils and we do not see well formed
granulomas in this disease. Rather what we see is an accumulation of a type of
histiocytic cell called the Langerhans’ cell, which is normally found in the dermis, but
there are also Langerhans’ cells that appear to be important in the antigen processing in
the lungs. These cells accumulate and they seem to proliferate in the lungs. It is not a
neoplastic disorder of these cells. What we see often is that airflow obstruction is
in setting of typical chest X-ray. Prolonged therapy (at least 6
months) usually necessary.
6.
Distinguish from acute eosinophilic pneumonia, an acute febrile
illness with hypoxemic respiratory, failure, diffuse pulmonary.
infiltrates, BAL eosinophilia, and a dramatic response to steroids
without recurrence after withdrawal
G. Bronchiolitis obliterans with organizing pneumonia (BOOP)
1.
Pathology - fibrous plugs in small airways; organizing inflammatory.
infiltrate in pulmonary, parenchyma
2.
Can be idiopathic (often called cryptogenic organizing
pneumonitis), related to infection, associated with connective tissue
disease
3.
Subacute illness with dyspnea, cough, constitutional symptoms
4.
Chest radiograph often with patchy or localized alveolar infiltrates;
can mimic bacterial pneumonia
5.
Responds well to steroids; generally treated for months
relatively common in eosinophilic granuloma largely because there are cysts that form.
I will show you this later. If one sees a combination of interstitial disease plus large
lung volumes, or associated obstructive disease then eosinophilic granuloma is one of
the disorders to consider. Chest x-rays and CT scans will often show nodular disease as
well as cysts. Because of the cysts patients may develop spontaneous pneumothorax if a
subpleural cyst ruptures. Interestingly enough there is an epidemiologic association of
this disorder with smoking that has never really been well worked out. We don’t
exactly know what it is, but the overwhelming majority of patients who have this disease
our smokers. The natural history is variable. In some cases the disease will resolve on
its own and in other cases the disease goes on to progressive respiratory insufficiency
and may require transplantation or it may lead to death. There is no proven treatment.
Often people will use things like corticosteroids, but in fact they have never been shown
to work. This is an example of a high resolution CT scan of a patient who has
eosinophilic granuloma and what you can see first of all is that there are some nodular
changes here. At the same time there are impressive cystic changes as well and these are
responsible to some extent for the airflow obstruction and also for the spontaneous
pneumothoraces that can develop. It is pretty is easy to see that if this thing adjacent to
the visceral pleural will rupture one will end with a spontaneous pneumothorax.
Another disease that in some respects looks a little bit similar, but also is different from
eosinophilic granuloma is the one that has the longest name of all the interstitial lung
diseases, which is, lymphangioleiomyomatosis often called LAM. It is an interesting
disorder and it occurs exclusively in women. Almost all of who are of childbearing age
and that certainly raises the issue if whether or not there may be a hormonal influence in
the production of the disease. The disease is characterized by atypical smooth muscle
cell proliferation. The smooth muscle cells will proliferate around lymphatics,
bronchioles, and small vessels. Involvement of each of these can lead to clinical
manifestations. For example, one can see pleural effusion as a result of lymphatic
blockage. You can see interstitial lung disease just as a result of the increased number of
smooth muscle cells. Pneumothorax can develop as a result of involvement of
bronchioles and airflow obstruction and cyst formation. Hemoptysis can occur as a
result of vessel involvement. Like eosinophilic granuloma airflow obstruction is
common, so one can see relatively normal lung volumes despite the presence of
interstitial lung disease on chest x-ray. The treatment of the disease is felt to be
hormonal manipulation and often what that may mean is progesterone therapy or
actually going ahead to oophorectomy. This is an example of a chest radiograph of
women with LAM. You can see that the lung volumes are actually very large here. The
diaphragms are down. If you could see the lateral you’d actually see that the
diaphragms are relatively flat. There is also sort of a hazy appearance over here. This is
not just breast shadow, but there is a very subtle interstitial pattern there as well.
Perhaps most dramatic though is the CT scan in someone like that. This is near the top
of the lungs in the patient with LAM and what you see in this case is a very severe
disease essentially all of the parenchyma is replaced with these cysts. It is really quite
striking. You really don’t see anything that looks like gas exchanging area of the lungs.
In fact, recognizing that this on a gross scale of a CT scan and this is more of what you
would expect to see microscopically histologically of what alveolar septi look like. It is
really quite striking.
Another disorder is one that I think is very important to recognize for clinicians because
it is really quite treatable and that is the disorder called chronic eosinophilic pneumonia.
This is a disorder that is characterized by eosinophils in a parenchymal infiltrate within
the lungs. The name eosinophilic pneumonia does not necessarily refer to peripheral
eosinophils. It refers to eosinophils in the infiltrate. It turns out that these patients often
will have peripheral eosinophilia, but they so not have to. The patients often will have
underlying asthma, but again they do not have to have that either. When they present
they present often over the course of weeks to even a month or two, so the presentation
is more subacute. They will often have respiratory symptoms and they may have
constitutional symptoms as well. By constitutional symptoms here I mean basically
they may have fever, fatigue, etc. One often makes attentive diagnosis or one thinks
through the diagnosis because of the finding of peripheral infiltrates, a so-called
photographic negative of pulmonary edema. Many people feel that this radiographic
pattern is typical enough so that one does not actually need to do a biopsy and one can
treat the patient with corticosteroids and use that as an empiric diagnostic and
therapeutic trial. The patients respond exquisitely to steroids so that often very dramatic
radiographic infiltrates will melt over the course of a few days. This is an example of a
patient who has chronic eosinophilic pneumonia and let me just point out toward the
periphery of the lung here, these whitish areas, this doesn’t represent scapula. It does not
represent pleural disease. It is actually parenchymal disease. On the other side as well
you can see that there is this extra white stuff here and some up in the upper lung zones
where as the more central areas are spared. Unlike what we think of with relatively
central pulmonary edema, often a butterfly pattern, this is the opposite of that and that is
III. Important diagnostic methods
A. High resolution CT scanning
1.
Width of cuts decreased from 10 mm to 1.0 or 1.5 ram, and special
algorithm used for spatial reconstruction
2.
Can detect subtle disease not apparent on chest X-ray
3.
Certain patterns suggestive of specific diagnoses
a.
Lymphangitic carcinoma - polygonal pattern
b.
Eosinophilic granuloma and lymphangioleiomyomatosis multiple
small cysts
c.
Sarcoidosis - bronchovascular pattern
d.
Idiopathic pulmonary fibrosis - heterogeneous pattern with
prominent subpleural disease and cyst formation
B. Bronchoalveolar lavage
1.
Most useful for recovery of organisms, e.g., Pneumocystis in AIDS
2.
Typical patterns in some diseases, but generally not specific enough
to replace biopsy
a.
Lavage lymphocytosis in sarcoidosis and hypersensitivity
pneumonitis; CD4/CD8 >2 in sarcoidosis and <1 in
hypersensitivity pneumonitis
b.
Profile variable in idiopathic pulmonary fibrosis - some with
increased PMNs, some with increased lymphocytes
3.
Histiocytosis X cells (with S-100 antigen) in eosinophilic granuloma
C. Thoracoscopic lung biopsy - has generally replaced open lung biopsy
because of better patient tolerance and shorter hospitalization
why this is called the photographic negative of pulmonary edema. We see this chronic
eosinophilic pneumonia and we also will see it in another slide after this. We may see it
in bronchiolitis obliterans with organizing pneumonia. In contrast to eosinophilic
pneumonia I do want to mention a disorder that is called acute eosinophilic pneumonia,
which does not develop over weeks to months, but rather often develops over days as an
acute febrile illness that is associated with hypoxemic respiratory failure. The patients
will have diffuse pulmonary infiltrates rather than the peripheral pulmonary infiltrates.
Like the patients with chronic eosinophilic pneumonia they will have lots of eosinophils
in the lung parenchyma. If you do a bronchoalveolar lavage on either of the disorders
you’ll find lots of eosinophils. These patients like the chronic eosinophilic pneumonia
patients will respond dramatically to steroids, but what is different and what is
interesting is that in the acute eosinophilic pneumonia patients once they are treated the
infiltrates melt and you taper them off steroids. They do not get a recurrence of their
disease. In contrast, patients with chronic eosinophilic pneumonia often need to be
treated over a number of months and if you withdrawal the steroids prematurely then the
disease will recrudesce.
The next disorder is bronchiolitis obliterans with organizing pneumonia or BOOP is
really characterized by the pathology, which reflects the title. The pathology will show
bronchiolitis obliterans, which in practice means that there are fibrous plugs in small
airways. The organizing pneumonia component means that one often sees in adjacent
alveolar spaces is what looks like a chronic or resolving inflammatory infiltrate often
with mononuclear cells. The ideology is there are a number of disorders that can be
associated with bronchiolitis obliterans with organizing pneumonia and therefore, rather
than being a specific disease that actually may be a syndrome that has several
underlying ideologies. The probably most common is idiopathic. It can also be
associated with infection as a post-infectious probably in the stage of resolution. It can
also be associated with some underlying connective tissue diseases. Like chronic
eosinophilic pneumonia the presentation is often subacute with respiratory and often
with constitutional symptoms. The chest x-ray shows patchy or localized infiltrates and
the treatment is generally with corticosteroids. These patchy or localized infiltrates may
be very non-specific. They may look just like pneumonia and sometimes may have a
peripheral distribution mimicking chronic eosinophilic pneumonia. This is an example
of a patient with BOOP. You should ignore the fact that there is an enlarged heart here.
This patient also had an underlying cardiomyopathy that was really not related. What
the patient did have were these infiltrates. Here is one that is actually very much an
alveolar filling pattern on the left side as well as another patchy infiltrate on the right.
This patient was found by biopsy to have BOOP and was treated with steroids and the
infiltrates melted.
Diagnostic methods and some of the newer diagnostic methods that are used in patients
that have diffuse parenchymal lung disease. First of all, high resolution CT scan is now
very important in the diagnostic evaluation of these patients for 3 reasons. First of all,
there are some patients where we can detect very subtle disease where the chest x-ray is
actually normal, but the CT scan will show subtle abnormalities that just were not
detected. Secondly, there are some disease specific patterns and I’ll show you some of
these things such as lymphangitic spread of carcinoma, eosinophilic granuloma, and
lymphangioleiomyomatosis. All of those have relatively typical patterns on CT scans
that can suggest the diagnosis. Finally there is interest in whether or not the pattern of
abnormality on CT scan reflects the activity of the disease with a ground-glass pattern
suggesting more active and more inflammatory disease. This is an example of a CT
scan in a patient who was short of breath, had restrictive disease on pulmonary function
tests, and had a normal chest x-ray. The high resolution CT scan shows a patchy pattern
of a sort of ground-glass increase in density and in between the areas of increased
density are relatively normal areas that look sort of hypodense here. It turns out that the
blacker areas are not the abnormal areas. It is not like these are cysts or areas of
emphysema. If you could see the original you’d see that there are actually lung
markings going through these areas, rather it is the ground-glass or somewhat whitish
areas that are the abnormal areas. This patient on biopsy turned out to have a
hypersensitivity pneumonitis and actually this particular pattern is often seen in patients
who have a hypersensitivity pneumonitis. In contrast, this is sort of a linear pattern and
actually is affecting a lot of interlobular septi and this is a pattern that we commonly
will see in the spread of tumor throughout the lungs. Sometimes it is described as a
polygonal pattern and may have geometric shapes. This is a high resolution CT scan of
the patient with idiopathic pulmonary fibrosis, which often has a pattern of distribution
of a fair amount of fibrosis out toward the periphery of the lungs. You can see several
areas here often patchy and are often associated with some cyst formation. This is a
pattern that is quite typical.
Another technique that is used and is relatively new is one called bronchoalveolar
lavage. It is used primarily for recovery of organisms certainly in patients who have
References
1.
DePaso WJ, Winterbauer RH. Interstitial lung disease. Dis Mon 37:61-133,
1991. Excellent recent review of the interstitial lung diseases.
2.
Silver RM, Miller KS, Kinsella MB, Smith EA, Schabel SI. Evaluation and
management of scleroderma lung disease using bronchoalveolar lavage. Am
J Med 88:470-476, 1990. 49% of patients with scleroderma had BAL
evidence of an active alveolitis; these patients appeared to have some
improvement following
treatment with cyclophosphamide and prednisone.
3.
Panos RJ, Mortenson RL, Niccoli SA, King TE Jr. Clinical deterioration in
patients with idiopathic pulmonary fibrosis. Am J Med 88:396-404, 1990.
Besides progression of disease, patients may have disease-related
complications, e.g., lung cancer (10%), pneumothorax, corticosteroid side
effects, including immunosuppression.
4.
Lower EE, Baughman RP. Prolonged use of methotrexate for sarcoidosis.
Arch Intern Med 155:846-851, 1995. The authors present their generally
positive (but uncontrolled) experience with methotrexate in sarcoidosis.
5.
Muller NL, Miller RR. Computed tomography of chronic diffuse infiltrative
lung disease. Am Rev Respir Dis 142:1206-1215, 1440-1448, 1990.
Excellent review of CT scanning, including high resolution CT scanning, in
the evaluation of diffuse infiltrative lung disease.
6.
Kalassian KG, Doyle R, Kao P, Ruoss S, Raffin TA.
Lymphangioleiomyomatosis: new insights. Am J Respir Crit Care Med
155:1183-1186, 1997. A recent short review of LAM.
7.
Muller NL, Ostrow DN. High-resolution computed tomography of chronic
interstitial lung disease. Clin Chest Med 12:97-114, 1991. Excellent
overview of high-resolution CT scanning in interstitial lung disease.
HIV infection, but in addition it can be used for cell characterization more actually on a
research basis then for differential diagnosis of patients with interstitial lung disease.
However, as I mentioned earlier one does find an increased number of lymphocytes in
sarcoid and in hypersensitivity pneumonitis, but the CD4/CD8 ratios are different. The
CD4 to CD8 is high in sarcoid and it is actually low in hypersensitivity pneumonitis.
Idiopathic pulmonary fibrosis will have high numbers of either polys or lymphocytes, so
that is not particularly useful diagnostically. In histiocytosis X or eosinophilic
granuloma one can actually find certain changes in the cells. One can detect what’s
called the S-100 antigen, which identifies those Langerhans’ cells and one can
potentially even make a diagnosis of EG just on the basis of lavage. Finally,
thoracoscopic lung biopsy is where the surgeon will go in with what is the equivalent of
the chest version of laparoscopy where a scope is used to get into the pleural space and
get lung biopsy specimens. That now has really essentially in many cases replaced open
lung biopsy for obtaining a diagnosis in some of these patients, so when we are thinking
of getting diagnostic tissue are main options these days are either transbronchial biopsy
or a thoracoscopic lung biopsy.
Friday, August 20, 2010
Health Care Costs is Risings day by day
By: Peter Joseph
The cost of providing employees with health insurance coverage continues to increase at a double-digit rate. We've read a lot about cost drivers in health care - exorbitant hospital charges, rising prescription drug costs, expenses associated with developing new technologies and treatments, an aging population and litigation. Nurturing these factors is an environment in which the demand for health care seems to be increasing.
For the most part, there is little employers can do to control what is driving health care costs out of their reach. Health benefits companies can and do negotiate discounts, and while those help, the underlying costs continue to skyrocket. The increases created by these cost drivers flow through the health benefits companies and eventually trickle down to employers in the form of higher health insurance premiums.
In this soft economy, declining revenue is putting a squeeze on company expenses. It is likely that you will experience a 15 percent to 20 percent increase in your group health insurance when a renewal form lands on your desk.
Can you raise the cost of your company's product or service as quickly as your health insurance premiums are increasing?
Probably not. However, there are steps you can take to gain some control over your health care costs.
Finding a solution
Employers can exercise some control over their costs by finding a health benefits company that provides the "best" value for their company's premium dollars. The way in which you "shop" a health plan can impact the price. I'll use an analogy. Your travel agent has a great deal for you - air, car, hotel and meals included. You tell your agent to book it.
Coincidently, your neighbors just booked that same trip for $1,000 less through their travel agent. One agent shopped for the best price, the other agent arranged the trip through his or her vendor of choice. Whether it's a family vacation, buying a car or choosing a health benefits plan, how you shop can impact your cost. Make sure your insurance agent doesn't "arrange" your health plan for you. How many providers are enough? The more participating providers a health plan has, the more you're likely to pay in premiums. If you are considering a health plan that doesn't include a few desired physicians, request that the carrier add them to its network.
Physicians participate in many different health plans and are usually willing to participate in one more. Don't get caught in the trap of paying 10 percent to 15 percent more for your health insurance premiums because one or two doctors are notparticipating in the plan. It's reasonable that an employee can find another physician out of the thousands on the plan.
The power of marketing
Living in the United States affords us exceptional opportunities and choices. Along with that privilege comes a barrage of communications designed to influence our decision-making. What we read in the papers, see on television, hear on the radio, see flashed across a billboard, get stuffed in our mailboxes or pops up on the Internet is designed to predispose us to a company or its product.
Marketing can be an effective tool, and depending on how much is spent, can be quite influential. What marketing cannot do, however, no matter how much is spent, is replace what it takes to come up with an affordable health benefits solution that works for you. Be sure to look for a health benefits company that is flexible, listens and is willing to roll up its sleeves to provide you with a package of health benefits that you can afford.
The cost of providing employees with health insurance coverage continues to increase at a double-digit rate. We've read a lot about cost drivers in health care - exorbitant hospital charges, rising prescription drug costs, expenses associated with developing new technologies and treatments, an aging population and litigation. Nurturing these factors is an environment in which the demand for health care seems to be increasing.
For the most part, there is little employers can do to control what is driving health care costs out of their reach. Health benefits companies can and do negotiate discounts, and while those help, the underlying costs continue to skyrocket. The increases created by these cost drivers flow through the health benefits companies and eventually trickle down to employers in the form of higher health insurance premiums.
In this soft economy, declining revenue is putting a squeeze on company expenses. It is likely that you will experience a 15 percent to 20 percent increase in your group health insurance when a renewal form lands on your desk.
Can you raise the cost of your company's product or service as quickly as your health insurance premiums are increasing?
Probably not. However, there are steps you can take to gain some control over your health care costs.
Finding a solution
Employers can exercise some control over their costs by finding a health benefits company that provides the "best" value for their company's premium dollars. The way in which you "shop" a health plan can impact the price. I'll use an analogy. Your travel agent has a great deal for you - air, car, hotel and meals included. You tell your agent to book it.
Coincidently, your neighbors just booked that same trip for $1,000 less through their travel agent. One agent shopped for the best price, the other agent arranged the trip through his or her vendor of choice. Whether it's a family vacation, buying a car or choosing a health benefits plan, how you shop can impact your cost. Make sure your insurance agent doesn't "arrange" your health plan for you. How many providers are enough? The more participating providers a health plan has, the more you're likely to pay in premiums. If you are considering a health plan that doesn't include a few desired physicians, request that the carrier add them to its network.
Physicians participate in many different health plans and are usually willing to participate in one more. Don't get caught in the trap of paying 10 percent to 15 percent more for your health insurance premiums because one or two doctors are notparticipating in the plan. It's reasonable that an employee can find another physician out of the thousands on the plan.
The power of marketing
Living in the United States affords us exceptional opportunities and choices. Along with that privilege comes a barrage of communications designed to influence our decision-making. What we read in the papers, see on television, hear on the radio, see flashed across a billboard, get stuffed in our mailboxes or pops up on the Internet is designed to predispose us to a company or its product.
Marketing can be an effective tool, and depending on how much is spent, can be quite influential. What marketing cannot do, however, no matter how much is spent, is replace what it takes to come up with an affordable health benefits solution that works for you. Be sure to look for a health benefits company that is flexible, listens and is willing to roll up its sleeves to provide you with a package of health benefits that you can afford.
Thursday, August 19, 2010
Atrial fibrillation
Atrial fibrillation
Janet Wong, M.D.
Emergent/urgent Cardioversion Atrial fibrillation is the most frequently occurring cardiac arrhythmia,
and it is the main problem that we have to deal with when it comes
. Poorly tolerated atrial ablation:
Significant hypotension
Pulmonary edema
to cardiac arrhythmias. There is a 2% risk of atrial fibrillation over
20 years, and the risk increases with age. By the time people reach
75, there is a high prevalence of atrial fibrillation. The risk also
increases with other associated diseases like hypertension, coronary
disease, and diabetes.
Significant ischemia
The main thing we worry about is the risk of stroke in people with
. DC cardioversion: atrial fibrillation. People can be very symptomatic and have functional
limitations due to rapid ventricular rate, loss of AV synchrony,
Minimum 200 J. synchronized shock
variability of ventricular response, and tachycardia-induced
cardiomyopathy.
Poorly tolerated atrial fibrillation is characterized by significant
hypotension. If their BP is 50, you are going to want to treat it as an
emergency. So you have someone that comes in, their blood
pressure is maintained, but they are developing severe pulmonary
edema or they are complaining of crushing chest pain with ECG
changes, I think you are not wrong in that case to urgently DC
cardiovert those people.
Atrial fibrillation is probably the most difficult arrhythmia to electrically
cardiovert. Certainly harder than ventricular tachycardia, often
harder than ventricular fibrillation. It usually takes high energy.
There are two reasons to start with a higher energy. A shock of 50
joules externally stimulates skeletal muscle and that's what makes
it painful. A shock of 200 joules or 300 joules or even 360 joules
your patient any discomfort by using a lower energy. When youhurts just as much. It doesn't hurt any more. So, you are not saving
immediately because when you shock somebody there is always
shock somebody, you should always recharge the defibrillator
the risk you are going to put them into VF. The risk of causing VFwith the shock is related to the energy. The lower the energy, the
higher the risk of VF because you have incompletely depolarized
the heart.
You can decrease the number of shocks if you use a higher energy
and you can also reduce the risk of causing VF. I routinely start at
200 to 300 joules, and if I have a big barrel-chested person or an
obese person, I just start with 360.
3
Acute Rate Control
. IV calcium channel blockers
Diltiazem 20 - 25 mg bolus, then 10-15 mg/hour infusion
Verapamil 2.5 - 5 mg bolus
. IV Digoxin
What if the person is stable and you want to just control them
medically when they come in? The rate can be controlled with a
variety of agents. One group of agents is the IV calcium channel
blockers. IV diltiazem is the drug of choice because of the ease of
use. After you have loaded the patient with a bolus, which is usually
20 to 25 mg, you can start the patient on an infusion of 10 to 15
mg/hour, and you can titrate the infusion rate to achieve the appropriate
heart rate. This strategy is very effective in the short term at
controlling ventricular rate. You want to convert people over that
can take p.o. medications early on if you are going to continue to
need to rate control them.
IV beta blockers work very well. IV Inderal, IV metoprolol; the short-
acting one is esmolol which is difficult to dose. Diltiazem is easier
for that reason.
IV digoxin is not usually recommended for acute rate control because
the onset of action is very long; it can take hours before you
rate control someone. Digoxin is not good at rate control in somebody
with a high catecholamine state. IV digoxin is no longer used
for acute rate control. There is no difference in conversion rate with
IV digoxin.
Rate control that in atrial fibrillation in the setting of the WPW
syndrome. In WPW, there is an accessory pathway connecting the
atrium to the ventricle which bypasses the AV node. The problem
with that is that the AV node limits the number of impulses that can
reach the atrium from the ventricle, maybe in a young healthy
person, to 200 to 220 beats per minute. The accessory pathway
doesn't have that same function and can let 250, even 300, beats
per minute through to the ventricle. The hallmarks of WPW in atrial
fibrillation are a wide QRS complex that is an irregular tachycardia,
and you have changing amounts of preexcitation. So, the QRS is
almost changing beat to beat by the amount of excitation of the
ventricle.
If you give typical AV node blocking drugs in these patients, they
will block the AV node fine, but the ventricle is still going to be
activated rapidly over the accessory pathway. If you give a drug like
verapamil, you may increase conduction over the accessory pathway.
If you give these patients, digoxin, verapamil, or beta blockers,
you can degenerate them to ventricular fibrillation.
The treatment of choice for atrial fibrillation in the setting of WPW
is electrical cardioversion if the patient is unstable. Procainamide is
the drug of choice given intravenously because it may convert the
atrial fibrillation, and it suppresses conduction over the accessory
pathway, and it will limit the number of impulses getting to the
ventricle. A potentially life-threatening complication may occur with
the usual rate control medications.
4
Elective Cardioversion
. > 24 - 48 hours
. Pharmacologic
Intravenous: procainamide/ibutilide
Oral loading
. Electrical
External
Internal
Anticoagulation for three months after cardioversion is recommended
because of high-risk of embolic events during this
period.
Patients who have been in atrial fibrillation for less than 48 hours
can be safely cardioverted without anticoagulation. Elective cardioversion
can be accomplished pharmacologically with either intravenous
procainamide or ibutilide. Or you can use oral loading of
quinidine or disopyramide (Norpace). External electrical cardioversion
can be used. Internal cardioversions may also be effective in
the patients who are resistant to external DC cardioversions.
In atrial fibrillation that has been present for more than 48 hours,
after you cardiovert them, you need to maintain anticoagulation due
to the high risk of embolic events during that period. Patients that
have been in chronic atrial fibrillation, the atria are stunned and
they don't contract very well. Patients are at continued risk for
stroke even though they are in sinus rhythm for a period of three
months after conversion from atrial fibrillation.
The standard approach is you put them on Coumadin and wait four
to six weeks and then bring them in for an elective cardioversion.
The down side is there is a delay in cardioversion. You also end up
having more prolonged anticoagulation with the risks attendant with
warfarin and you delay the recovery of atrial function. The longer
you leave somebody in atrial fibrillation, the longer it takes the
atrium to recover. The quicker you get somebody out of atrial
fibrillation, the longer they will stay out of fibrillation.
Transesophageal echo should be used to select candidates for
early cardioversion. Heparin therapy should be instituted and the
rate should be controlled, and you do a TEE and you look for
thrombus. In patients who do not have a thrombus, you can go
ahead and cardiovert. So, you have an overall shorter duration of
warfarin therapy--four to six weeks less–and a more rapid return of
atrial function, and fewer incidents of thromboembolism. In patients
in whom left atrial thrombi was excluded, you can safely cardiovert
these people.
If you decide to cardiovert somebody you don't always have to
shock them right off. What we do in our hospital is often bring them
in for elective cardioversion, we will give them a load of intravenous
procainamide, and if they don't convert then we go ahead and do
the DC cardioversion. The standard dose of procainamide, 15
mg/kg over 20 to 30 minutes. It is probably more effective at this
faster rate because you get a higher peak plasma level of the
procainamide, and that is probably what accounts for the acute
conversions. The patient should be monitored for hypotension,
QRS widening and QT prolongation.
A new class III antiarrhythmic drug called ibutilide (Corvert) works
by prolonging the action potential duration. It works well for up to
50%. With atrial fibrillation, with a 30% conversion rate. There is a
significant risk of torsades de pointes with ibutilide. It is much
easier to give than procainamide - you can give it quicker. Patients
develop polymorphic VTs, sustained in almost 2%, 2.5% non-
sustained. Some people even developed monomorphic VT. You
can see a 9% incidence of ventricular proarrhythmia in these patients.
It is okay to use it; you just have to be aware of this and use
it in the proper setting. So, if you give this in the ER, patients have
to be monitored closely for 4 hours after you use it. If you use it in
the hospital, they have to be in a telemetry setting where you are
comfortable with the people on your telemetry floors that they can
recognize this and treat it very rapidly.
How do you convert somebody electrically? When external cardioversion
fails, internal cardioversion with a catheter may be success
5
Treatment of Atrial Fibrillation
. Treat underlying cause if present
. Rate control
. Anticoagulating
. Maintenance of sinus rhythm in selected patients
ful. The catheter has a platinum electrode on it is floated into the
right atrium, and then you shock between the tip of the catheter and
the back patch. So, you are actually shocking from inside the heart.
The results have been really encouraging. Significantly more people
were cardioverted with internal cardioversion than with external.
The long-term outcomes were no different. It is useful in the patients
who will benefit from sinus rhythm, but you can't get into
sinus rhythm with external shocks.
Treatment of atrial fibrillation includes treatment of underlying
causes. The most common disorders are thyrotoxicosis and
pericarditis.
6
Anticoagulation Recommendations
. Strong contraindication to warfarin: Aspirin 325 mg per day
. Lone atrial fibrillation, less than 65: No treatment or aspirin
. Low-risk: Aspirin
. One or more risk factors: Warfarin (INR 2.0-3.0)
. $70, low-risk: Warfarin (INR 2.0) or aspirin
People who have atrial fibrillation have a 6-fold increased risk of
stroke. The very high risk patients tend to be the older patients with
diabetes, hypertension, previous strokes and TIAs, CHF, coronary
disease, and mitral valve disease. High risk patients greater than
65, with one of these risk factors have a 5% per year risk. The low
risk patients are the patients less than 60 with normal hearts, with
normal blood pressures and glucoses, and the risk is probably even
less than 1% per year.
With Coumadin there is an overall 65% reduction in stroke presentations
with atrial fibrillation. Anticoagulation is important in atrial
fibrillation.
There is a significant reduction in the risk of stroke with Coumadin
over platelet inhibitors. So, in the general population, including the
high-risk patients, Coumadin is clearly better than aspirin alone. In
patients that are low-risk, who have essentially structural normal
hearts, that have no hypertension, no LV dysfunction, no prior
embolic events, even if they are older, aspirin is probably better
than warfarin in those patients. High risk patients should be on
Coumadin.
With strong contraindications to warfarin, you need to put them on
aspirin. In patients with lone atrial fibrillation that are relatively
young, either nothing or aspirin is recommended. If it is a male
patient that is 55 years old, having him take an aspirin a day may
have some added benefit in coronary disease, so I like to tell them
to take an aspirin anyway.
Low-risk patients can be treated with aspirin alone. If they have one
or more risk factors, warfarin is recommended with an INR between
2 and 3, usually shooting between 2 to 2.5. Greater than 70 puts
them in high-risk; however, those are the people that have a higher
incidence of bleeding. What I tend to do in people that have relatively
normal hearts even if they are older than 70, I will often use
aspirin alone, or if I do use Coumadin I will tend to shoot on the
lower side of the INR. You have to individualize it for each patient.
7
Treatment Goals
. Alleviate symptoms
. Prevent ischemia
. Improve hemodynamics
. Prolonge life in prevent sequelae
Maintenance of sinus rhythm with an antiarrhythmic has not
been proven to reduce risk of stroke or prolong life
Treatment goals in treating atrial fibrillation include alleviation of
symptoms, prevention of ischemia with high heart rates. Some
patients with atrial fibrillation due to the loss of AV synchrony and
the irregularness of their rate have more CHF and keeping them in
sinus will improve hemodynamics. You would like to prolong life
and prevent sequelae.
There is no data at present that supports reduction in stroke or
prolongation of life with antiarrhythmic maintenance of sinus
rhythm.
Antiarrhythmics in patients that had no history of CHF did not
cause a significant increase in mortality. Patients with a history of
CHF and no antiarrhythmics, clearly they did less well than those
patients that had no history of CHF, but the surprising finding was
that if you looked at the survival curve for the patients that both had
a history of CHF and were receiving antiarrhythmics to maintain
sinus rhythm, their survival is much worse than the other groups.
8
Rate Control
. Pharmacological
Calcium blockers
Beta-blockers
Digitalis
Amiodarone
. Non-pharmacological
AV node modification
AV node ablation plus physiologic pacing
Rate control in chronic atrial fibrillation. There are pharmacologic
agents, digitalis, beta blockers, calcium channel blockers and even
amiodarone for rate control and there are some non-pharmacologic
approaches such as AV node modification or ablation of the AV
node and physiologic pacing.
9
Pharmacologic Rate Control
. Digitalis is indicated if history of CHF
Poor choice in active patients
Excessive slowing during sinus rate or at rest
. Beta-blockers
Excellent in active patients
Using combination with and antiarrhythmics
First choice in thyrotoxicosis
First choice in ischemic patients
May not be tolerated in patients with CHF or lung disease
ISA in patients with tachy-bradycardia syndrome
. Calcium channel blockers
Good in active patients
First choice in patients with lung disease
Acceptable in patients with ischemia
May not be tolerated in patients with CHF
. Amiodarone
May work when nothing else does
Good in patients with enhanced AV conviction
May be beneficial in patients with LV dysfunction
and/or Nonsustained ventricular tachycardia
If you are going to go ahead with pharmacologic rate control it is
important to confirm that the patient is rate controlled. A significant
number of patients who their physicians thought were adequately
rate-controlled were in atrial fibrillation with rates of 140 to 150 at
rest. Before people leave the hospital, I will get them up and put
them on the stairs while they are still on telemetry and see what
their heart rate does. After I send them out, I will either get a treadmill
test, or it is even better to send them home with a Holter monitor
and tell them, "I want you to go do all of the things that you are
normally going to do." You really want to do surveillance Holters
when they are back doing the things that they do because when
these people get active, their heart rates often shoot up much
higher than you thought.
Beta blockers are an excellent choice for active patients. Use in
combination with antiarrhythmics is well tolerated. It is the first
choice in patients with thyrotoxicosis. It is the first choice in patients
with ischemia. It may not be tolerated in patients with moderate
CHF or lung disease, although patients with mild CHF should be
put on beta blockers. A beta blocker like Pindolol, with intrinsic
sympathomimetic activity, may be advantageous in patients with
tachy-bradycardia syndrome, where you could avoid a pacemaker.
But I am not sure how good that is.
Calcium channel blockers, I think, are very good agents for rate
control. They are good in the active patients. They are the first
choice of patients with lung disease who can't use beta blockers. I
think they are the first choice of patients with atrial fibrillation and
LVH because of the beneficial effects of calcium channel blockers
in these patients and the regression of LVH. It may not be tolerated
in patients with CHF. Negative inotropic effects.
Digitalis is only recommended in patients with a history of CHF
because you have the added benefit in those patients. It is very
poor in active patients. The problem with digoxin is that you have
excessive slowing of the sinus rate at rest but not good control
during exertion. So, you push the dig to a point where someone has
a heart rate of 60 at rest and then they get up and start doing things
like climbing stairs and stuff and their heart rate goes up to 170 or
140. Digoxin, especially in the active patient, is not recomended.
Amiodarone may work when nothing else can control the heart rate.
It is good in patients that have enhanced AV nodal conduction is a
very rare entity where people go into atrial fibrillation and go very
rapidly up to 250 or 350 beats per minute. It may be beneficial in
patients with LV dysfunction and/or nonsustained VT where you get
the added benefit of reducing the risk of sudden death.
AV junctional ablation for rate control of atrial fibrillation. The
response of patients is really dramatic, and people do really well
with this procedure. Indications include failure of the multiple AV
nodal blocking drugs. So, patients that you just can't rate control no
matter what you use. Patients in whom even though their rate is
controlled the irregularity of the atrial fibrillation still bothers them.
Drug intolerance. Patients that when they take the drugs that rate
control, they get admitted five times a year with CHF and their heart
rate is 150 because they never take their medications. Also, patient
preference.
What do we do with patients with atrial fibrillation and heart failure?
Twenty five percent of patients with heart failure may also have
atrial fibrillation. These are the patients that are at highest risk of
proarrhythmia from antiarrhythmic drugs. Congestive heart failure
10
Chemical Cardioversion
. Procainamide
15 mg/kg IV over 20-30 minutes (750-1500 mg)
Watch for hypotension, QRS widening, QT prolongation.
can lead to atrial fibrillation, and atrial fibrillation can lead to and
worsen congestive heart failure. Chronic tachycardia is associated
with the development of a cardiomyopathy and it appears to be
reversible.
Ablation and pacing results in an improvement in EF from 25% to
52%. Dramatic increases in injection fraction. With severe LV
dysfunction, after you ablate their AV node and put in a pacemaker;
it is almost back to normal. I think that is a really important point
that people don't fully understand yet. Patients with mean heart
rates of 60 to 100 beats per minute on a Holter that had depressed
LV function underwent AV junctional ablation and showed a significant
improvement in function after this.
Regularization of ventricular response. Even if you have somebody
rate controlled, the ventricle is being activated very irregularly.
Regularization of rhythm provides significant hemodynamic benefits.
In patients with AF, an increase in pulmonary capillary wedge
pressure were seen with irregular rhythm as opposed to regular
rhythm; therefore, both rapid rate and irregularity leads to decreased
LV function.
If you have patients that are difficult to manage and are having
repeated visits to the hospital with CHF and have chronic atrial
fibrillation, AV junctional ablation with pacing is something to
consider. It may help you manage their CHF.
11
Maintenance of Sinus to Rhythm
. Pharmacologic
. Preventive pacing
. Implantable defibrillator
. Ablative therapy
Surgical
Catheter
Maintenance of sinus rhythm. There is a subset of patients in whom
we are going to want to try and maintain sinus rhythm. There are
pharmacologic approaches, preventative pacing, implantable
defibrillators and ablative therapy.
12
Pharmacologic Maintenance of Sinus
to Rhythm
. Class IA
Quinidine: diarrhea
Procainamide: arthritis/rash/lupus
Disopyramide: urinary retention
..Class IC
Flecainide: avoided in ischemia/poor LV function
Propafenone: avoided in ischemia/poor LV function
. Class III
Sotalol: CHF, asthma, bradycardia
. Amiodarone: end organ toxicity
Pharmacologic agents. The class-I agents are sodium channel
blockers. There is quinidine, procainamide, disopyramide.
Quinidine is a drug that has been used for years and years, but 40
to 50% of patients can't take it because of the diarrhea.
Procainamide maintenance is not recommended because of arthritis,
rash, and lupus-like syndromes. Disopyramide (Norpace) is not
good in older men because of urinary retention, but it is very well-
tolerated in younger patients, and in patients with vagally mediated
atrial fibrillation.
The class 1C agents. Flecainide got a very bad name because of
the excess mortality in patients post MI. But I think in patients with
structurally normal hearts, it is probably one of the most effective
agents that we have for controlling atrial fibrillation. It should be
avoided it in patients with ischemia or poor LV function. The same
thing with propafenone (Rythmol). A newer agent, Sotalol can be
very effective because it offers both rate control and an
antiarrhythmic properties, but the beta blocking properties can
cause problems in patients with CHF, asthma, and it can cause
bradycardia.
Amiodarone is a very good drug for controlling atrial fibrillation, but
the end organ toxicities are something to be concerned about. Over
one year's time on quinidine, about 50% are maintained in sinus
rhythm. Propafenone and Sotalol, 50%. With the exception of
amiodarone, the antiarrhythmic drugs are all about 50% effective at
one year. Amiodarone appears to be the most effective
antiarrhythmic at maintaining sinus rhythm. It is 78% effective at
maintaining sinus rhythm in people who had failed a type-I
antiarrhythmic. Amiodarone versus quinidine, again right around
50% versus 79%. Same thing for amiodarone versus Norpace.
Amiodarone is the best drug available for maintaining sinus rhythm.
We have had a lot of good success with using amiodarone, and we
use it in a lot of patients. Toxicity tends to be dose related. So, in
the doses we use in ventricular tachycardia, 400 to 600 mg/day,
there is a significant incidence of pulmonary fibrosis and other end
organ toxicities. At the dose we use for atrial fibrillation, it is 200
mg/day, which is one pill, or even 200 mg every other day, the
incidence of these side effects are very low. The side effects are
reversible. In patients that have failed other drugs and patients that
have LV dysfunction, amiodarone is the drug of choice.
Amiodarone is a very unique drug. The half-life is one month to five
months. It is a very lipophilic drug so when you give it to people it
immediately gets sucked up into their fat stores. Start with a much
higher dose and then we cut the dose back. Start them on 800
mg/day for about two weeks, then I will put them on 400 mg/day for
about a month, then cut them back down to 200 mg/day. Results
have been very good. Patients have tolerated it well and it clearly
works much better than other agents. Anybody over 70 who presents
with atrial fibrillation or who has any LV dysfunction, should be
started on amiodarone as a first line agent.
13
No Structural Heart Disease
. First-line agents
Class IC (flecainide, propafenone)
Disopyramide (especially if vagally mediated)
. Second-line
Sotalol
. Third line
Amiodarone
If you have a patient that has no structural heart disease with lone
AF, they are very symptomatic, you don't want to leave these
people in AF all the time and make them take aspirin and have
them in atrial fibrillation. You can give them drugs to try to maintain
sinus rhythm. We have had a lot of success with flecainide in this
population. Norpace is very good especially in vagally mediated AF.
There is a group of patients who get atrial fibrillation after they eat
big meals or they wake up in the middle of the night. Vagal surges
change the electrophysiologic properties of the atrium and make it
more susceptible to atrial fibrillation. Norpace has some vagolytic
effects and may be effective in those patients. Second line, Sotalol
is often good in these patients, and you can use amiodarone.
14
Ischemic Heart Disease
. First-line:
Sotalol
. Second-line:
Amiodarone
. Avoid class IC
In patients with ischemic heart disease, the class 1C drugs should
be avoided. Sotalol may be a good drug. The beta blocking properties
are good for the ischemic patient, and amiodarone is a good
agent in those patients.
15
CHF/LV Dysfunction
. First-line:
Amiodarone
. Consider non-pharmacologic approach
. Avoid class IC
In the patients with CHF and LV dysfunction, you have to avoid
those drugs that are proarrhythmic. Amiodarone may be the best
drug in these patients because you get the added protection from
sudden death. You should also consider the non-pharmacologic
approach in these patients because you may see an increase in LV
function after you control their rate with ablation and regularize their
ventricular response with pacing.
16
LVH/HCM
. First-line
Class 1C (flecainide, propafenone)
. Second-line:
Sotalol
Amiodarone
. Consider nonpharmacologic management (HCM)
In patients that have left ventricular hypertrophy or hypertrophic
cardiomyopathy, class 1C agents are also good. Disopyramide is
specifically good in patients with hypertrophic cardiomyopathy
because of the negative inotropic effects. It may decrease the
gradient. Sotalol also is very good in these patients, and
amiodarone is good. In patients with hypertrophic cardiomyopathy,
you should consider non-pharmacologic management, such as
ablation, because dual-chamber pacing will decrease the pressure
gradient so you get the added benefit of those two things.
17
Outpatient loading of antiarrhythmic medications utilizing a monitoring device is probably safe and cost-effective. Patients get their
first dose of the drug in the hospital, and then were sent out with a loop recorder for 10 days. Every day they transmit a tracing of
their heart rate and their QT interval and they also transmit any palpitations or any adverse effects that they had.
Prophylactic pacing for atrial fibrillation. It is thought that atrial fibrillation is due to multiple re-entrant wave fronts throughout the
atria. Excitation and therefore prolongation of the refractoriness of the tissue in the critical regions of the atrium may prevent the
initiation or maintenance of atrial fibrillation. If you stimulate the heart in more than one place, you may be able to prevent these reentrant
wave fronts and prevent atrial fibrillation. There are trials that have looked at patients with sick sinus syndrome that got either
dual chamber pacers or ventricular pacers alone. The studies showed that in patients that had atrial pacing, it was a significantly
much lower incidence of atrial fibrillation that had active atrial pacing suggesting that somehow pacing the atrium will decrease the
incidence of atrial fibrillation.
Implantable ventricular defibrillators. This is a device that goes in the pectoral region, has two leads in the right atrium. One in the
right atrium, one in the coronary sinus and one for R-wave synchronization in the RV apex. It is used to cardiovert people out of atrial
fibrillation. It can be done when you have two leads inside the heart like this and you are not shocking externally and you are not
stimulating skeletal muscle. The amount of energy required is only in some patients 0.5 Joule or 1 or 2 Joule. So, although in some
patients that causes a fair amount of discomfort, in some patients it doesn't and the idea of atrial defibrillators are being tested right
now. The big questions are safety. The first patient that has an atrial defibrillator that gets shocked or it fails and they get put into VF
and then dies, that will be the end of the whole idea.
Surgical treatment of atrial fibrillation. The Maze procedure consists of multiple atriotomies which interrupt all the potential re-entrant
circuits. This will restore control of the heartbeat to the atrial pacemaker, which is the sinus node, and it allows activation of the entire
atrial myocardium. The long term results are unclear.
Atrial flutter. Typical atrial flutter is characterized by the typical saw-tooth flutter wave in the inferior leads beneath the positive flutter
wave in lead V1. It is a macroreentrant electrical rhythm confined to the right atrium. So, the electrical wave front goes around the
right atrium, up the septum, down the lateral wall and through this isthmus of tissue between the opening of the IVC and the tricuspid
annulus and the coronary sinus. If we can create a line of conduction block, the patient should not have atrial flutter anymore.
We are now able to terminate atrial flutter and cure people that have typical atrial flutter in about 95% of cases. Antiarrhythmic drugs
are not very effective for atrial flutter, and rate control is much more difficult in atrial flutter than atrial fibrillation because it is hard to
get a reasonable rate control. When somebody presents with atrial flutter for the first time, cardioversion is recommended, and then
the patients are discharged and observed to determine what the natural history is going to be. If they are not going to have atrial
flutter for the next five years, no treatment is necessary. The first time they return with atrial flutter, if it is early on, the first line of
therapy now is ablative therapy and our success rate is very good and the risk is low.
18
Janet Wong, M.D.
Emergent/urgent Cardioversion Atrial fibrillation is the most frequently occurring cardiac arrhythmia,
and it is the main problem that we have to deal with when it comes
. Poorly tolerated atrial ablation:
Significant hypotension
Pulmonary edema
to cardiac arrhythmias. There is a 2% risk of atrial fibrillation over
20 years, and the risk increases with age. By the time people reach
75, there is a high prevalence of atrial fibrillation. The risk also
increases with other associated diseases like hypertension, coronary
disease, and diabetes.
Significant ischemia
The main thing we worry about is the risk of stroke in people with
. DC cardioversion: atrial fibrillation. People can be very symptomatic and have functional
limitations due to rapid ventricular rate, loss of AV synchrony,
Minimum 200 J. synchronized shock
variability of ventricular response, and tachycardia-induced
cardiomyopathy.
Poorly tolerated atrial fibrillation is characterized by significant
hypotension. If their BP is 50, you are going to want to treat it as an
emergency. So you have someone that comes in, their blood
pressure is maintained, but they are developing severe pulmonary
edema or they are complaining of crushing chest pain with ECG
changes, I think you are not wrong in that case to urgently DC
cardiovert those people.
Atrial fibrillation is probably the most difficult arrhythmia to electrically
cardiovert. Certainly harder than ventricular tachycardia, often
harder than ventricular fibrillation. It usually takes high energy.
There are two reasons to start with a higher energy. A shock of 50
joules externally stimulates skeletal muscle and that's what makes
it painful. A shock of 200 joules or 300 joules or even 360 joules
your patient any discomfort by using a lower energy. When youhurts just as much. It doesn't hurt any more. So, you are not saving
immediately because when you shock somebody there is always
shock somebody, you should always recharge the defibrillator
the risk you are going to put them into VF. The risk of causing VFwith the shock is related to the energy. The lower the energy, the
higher the risk of VF because you have incompletely depolarized
the heart.
You can decrease the number of shocks if you use a higher energy
and you can also reduce the risk of causing VF. I routinely start at
200 to 300 joules, and if I have a big barrel-chested person or an
obese person, I just start with 360.
3
Acute Rate Control
. IV calcium channel blockers
Diltiazem 20 - 25 mg bolus, then 10-15 mg/hour infusion
Verapamil 2.5 - 5 mg bolus
. IV Digoxin
What if the person is stable and you want to just control them
medically when they come in? The rate can be controlled with a
variety of agents. One group of agents is the IV calcium channel
blockers. IV diltiazem is the drug of choice because of the ease of
use. After you have loaded the patient with a bolus, which is usually
20 to 25 mg, you can start the patient on an infusion of 10 to 15
mg/hour, and you can titrate the infusion rate to achieve the appropriate
heart rate. This strategy is very effective in the short term at
controlling ventricular rate. You want to convert people over that
can take p.o. medications early on if you are going to continue to
need to rate control them.
IV beta blockers work very well. IV Inderal, IV metoprolol; the short-
acting one is esmolol which is difficult to dose. Diltiazem is easier
for that reason.
IV digoxin is not usually recommended for acute rate control because
the onset of action is very long; it can take hours before you
rate control someone. Digoxin is not good at rate control in somebody
with a high catecholamine state. IV digoxin is no longer used
for acute rate control. There is no difference in conversion rate with
IV digoxin.
Rate control that in atrial fibrillation in the setting of the WPW
syndrome. In WPW, there is an accessory pathway connecting the
atrium to the ventricle which bypasses the AV node. The problem
with that is that the AV node limits the number of impulses that can
reach the atrium from the ventricle, maybe in a young healthy
person, to 200 to 220 beats per minute. The accessory pathway
doesn't have that same function and can let 250, even 300, beats
per minute through to the ventricle. The hallmarks of WPW in atrial
fibrillation are a wide QRS complex that is an irregular tachycardia,
and you have changing amounts of preexcitation. So, the QRS is
almost changing beat to beat by the amount of excitation of the
ventricle.
If you give typical AV node blocking drugs in these patients, they
will block the AV node fine, but the ventricle is still going to be
activated rapidly over the accessory pathway. If you give a drug like
verapamil, you may increase conduction over the accessory pathway.
If you give these patients, digoxin, verapamil, or beta blockers,
you can degenerate them to ventricular fibrillation.
The treatment of choice for atrial fibrillation in the setting of WPW
is electrical cardioversion if the patient is unstable. Procainamide is
the drug of choice given intravenously because it may convert the
atrial fibrillation, and it suppresses conduction over the accessory
pathway, and it will limit the number of impulses getting to the
ventricle. A potentially life-threatening complication may occur with
the usual rate control medications.
4
Elective Cardioversion
. > 24 - 48 hours
. Pharmacologic
Intravenous: procainamide/ibutilide
Oral loading
. Electrical
External
Internal
Anticoagulation for three months after cardioversion is recommended
because of high-risk of embolic events during this
period.
Patients who have been in atrial fibrillation for less than 48 hours
can be safely cardioverted without anticoagulation. Elective cardioversion
can be accomplished pharmacologically with either intravenous
procainamide or ibutilide. Or you can use oral loading of
quinidine or disopyramide (Norpace). External electrical cardioversion
can be used. Internal cardioversions may also be effective in
the patients who are resistant to external DC cardioversions.
In atrial fibrillation that has been present for more than 48 hours,
after you cardiovert them, you need to maintain anticoagulation due
to the high risk of embolic events during that period. Patients that
have been in chronic atrial fibrillation, the atria are stunned and
they don't contract very well. Patients are at continued risk for
stroke even though they are in sinus rhythm for a period of three
months after conversion from atrial fibrillation.
The standard approach is you put them on Coumadin and wait four
to six weeks and then bring them in for an elective cardioversion.
The down side is there is a delay in cardioversion. You also end up
having more prolonged anticoagulation with the risks attendant with
warfarin and you delay the recovery of atrial function. The longer
you leave somebody in atrial fibrillation, the longer it takes the
atrium to recover. The quicker you get somebody out of atrial
fibrillation, the longer they will stay out of fibrillation.
Transesophageal echo should be used to select candidates for
early cardioversion. Heparin therapy should be instituted and the
rate should be controlled, and you do a TEE and you look for
thrombus. In patients who do not have a thrombus, you can go
ahead and cardiovert. So, you have an overall shorter duration of
warfarin therapy--four to six weeks less–and a more rapid return of
atrial function, and fewer incidents of thromboembolism. In patients
in whom left atrial thrombi was excluded, you can safely cardiovert
these people.
If you decide to cardiovert somebody you don't always have to
shock them right off. What we do in our hospital is often bring them
in for elective cardioversion, we will give them a load of intravenous
procainamide, and if they don't convert then we go ahead and do
the DC cardioversion. The standard dose of procainamide, 15
mg/kg over 20 to 30 minutes. It is probably more effective at this
faster rate because you get a higher peak plasma level of the
procainamide, and that is probably what accounts for the acute
conversions. The patient should be monitored for hypotension,
QRS widening and QT prolongation.
A new class III antiarrhythmic drug called ibutilide (Corvert) works
by prolonging the action potential duration. It works well for up to
50%. With atrial fibrillation, with a 30% conversion rate. There is a
significant risk of torsades de pointes with ibutilide. It is much
easier to give than procainamide - you can give it quicker. Patients
develop polymorphic VTs, sustained in almost 2%, 2.5% non-
sustained. Some people even developed monomorphic VT. You
can see a 9% incidence of ventricular proarrhythmia in these patients.
It is okay to use it; you just have to be aware of this and use
it in the proper setting. So, if you give this in the ER, patients have
to be monitored closely for 4 hours after you use it. If you use it in
the hospital, they have to be in a telemetry setting where you are
comfortable with the people on your telemetry floors that they can
recognize this and treat it very rapidly.
How do you convert somebody electrically? When external cardioversion
fails, internal cardioversion with a catheter may be success
5
Treatment of Atrial Fibrillation
. Treat underlying cause if present
. Rate control
. Anticoagulating
. Maintenance of sinus rhythm in selected patients
ful. The catheter has a platinum electrode on it is floated into the
right atrium, and then you shock between the tip of the catheter and
the back patch. So, you are actually shocking from inside the heart.
The results have been really encouraging. Significantly more people
were cardioverted with internal cardioversion than with external.
The long-term outcomes were no different. It is useful in the patients
who will benefit from sinus rhythm, but you can't get into
sinus rhythm with external shocks.
Treatment of atrial fibrillation includes treatment of underlying
causes. The most common disorders are thyrotoxicosis and
pericarditis.
6
Anticoagulation Recommendations
. Strong contraindication to warfarin: Aspirin 325 mg per day
. Lone atrial fibrillation, less than 65: No treatment or aspirin
. Low-risk: Aspirin
. One or more risk factors: Warfarin (INR 2.0-3.0)
. $70, low-risk: Warfarin (INR 2.0) or aspirin
People who have atrial fibrillation have a 6-fold increased risk of
stroke. The very high risk patients tend to be the older patients with
diabetes, hypertension, previous strokes and TIAs, CHF, coronary
disease, and mitral valve disease. High risk patients greater than
65, with one of these risk factors have a 5% per year risk. The low
risk patients are the patients less than 60 with normal hearts, with
normal blood pressures and glucoses, and the risk is probably even
less than 1% per year.
With Coumadin there is an overall 65% reduction in stroke presentations
with atrial fibrillation. Anticoagulation is important in atrial
fibrillation.
There is a significant reduction in the risk of stroke with Coumadin
over platelet inhibitors. So, in the general population, including the
high-risk patients, Coumadin is clearly better than aspirin alone. In
patients that are low-risk, who have essentially structural normal
hearts, that have no hypertension, no LV dysfunction, no prior
embolic events, even if they are older, aspirin is probably better
than warfarin in those patients. High risk patients should be on
Coumadin.
With strong contraindications to warfarin, you need to put them on
aspirin. In patients with lone atrial fibrillation that are relatively
young, either nothing or aspirin is recommended. If it is a male
patient that is 55 years old, having him take an aspirin a day may
have some added benefit in coronary disease, so I like to tell them
to take an aspirin anyway.
Low-risk patients can be treated with aspirin alone. If they have one
or more risk factors, warfarin is recommended with an INR between
2 and 3, usually shooting between 2 to 2.5. Greater than 70 puts
them in high-risk; however, those are the people that have a higher
incidence of bleeding. What I tend to do in people that have relatively
normal hearts even if they are older than 70, I will often use
aspirin alone, or if I do use Coumadin I will tend to shoot on the
lower side of the INR. You have to individualize it for each patient.
7
Treatment Goals
. Alleviate symptoms
. Prevent ischemia
. Improve hemodynamics
. Prolonge life in prevent sequelae
Maintenance of sinus rhythm with an antiarrhythmic has not
been proven to reduce risk of stroke or prolong life
Treatment goals in treating atrial fibrillation include alleviation of
symptoms, prevention of ischemia with high heart rates. Some
patients with atrial fibrillation due to the loss of AV synchrony and
the irregularness of their rate have more CHF and keeping them in
sinus will improve hemodynamics. You would like to prolong life
and prevent sequelae.
There is no data at present that supports reduction in stroke or
prolongation of life with antiarrhythmic maintenance of sinus
rhythm.
Antiarrhythmics in patients that had no history of CHF did not
cause a significant increase in mortality. Patients with a history of
CHF and no antiarrhythmics, clearly they did less well than those
patients that had no history of CHF, but the surprising finding was
that if you looked at the survival curve for the patients that both had
a history of CHF and were receiving antiarrhythmics to maintain
sinus rhythm, their survival is much worse than the other groups.
8
Rate Control
. Pharmacological
Calcium blockers
Beta-blockers
Digitalis
Amiodarone
. Non-pharmacological
AV node modification
AV node ablation plus physiologic pacing
Rate control in chronic atrial fibrillation. There are pharmacologic
agents, digitalis, beta blockers, calcium channel blockers and even
amiodarone for rate control and there are some non-pharmacologic
approaches such as AV node modification or ablation of the AV
node and physiologic pacing.
9
Pharmacologic Rate Control
. Digitalis is indicated if history of CHF
Poor choice in active patients
Excessive slowing during sinus rate or at rest
. Beta-blockers
Excellent in active patients
Using combination with and antiarrhythmics
First choice in thyrotoxicosis
First choice in ischemic patients
May not be tolerated in patients with CHF or lung disease
ISA in patients with tachy-bradycardia syndrome
. Calcium channel blockers
Good in active patients
First choice in patients with lung disease
Acceptable in patients with ischemia
May not be tolerated in patients with CHF
. Amiodarone
May work when nothing else does
Good in patients with enhanced AV conviction
May be beneficial in patients with LV dysfunction
and/or Nonsustained ventricular tachycardia
If you are going to go ahead with pharmacologic rate control it is
important to confirm that the patient is rate controlled. A significant
number of patients who their physicians thought were adequately
rate-controlled were in atrial fibrillation with rates of 140 to 150 at
rest. Before people leave the hospital, I will get them up and put
them on the stairs while they are still on telemetry and see what
their heart rate does. After I send them out, I will either get a treadmill
test, or it is even better to send them home with a Holter monitor
and tell them, "I want you to go do all of the things that you are
normally going to do." You really want to do surveillance Holters
when they are back doing the things that they do because when
these people get active, their heart rates often shoot up much
higher than you thought.
Beta blockers are an excellent choice for active patients. Use in
combination with antiarrhythmics is well tolerated. It is the first
choice in patients with thyrotoxicosis. It is the first choice in patients
with ischemia. It may not be tolerated in patients with moderate
CHF or lung disease, although patients with mild CHF should be
put on beta blockers. A beta blocker like Pindolol, with intrinsic
sympathomimetic activity, may be advantageous in patients with
tachy-bradycardia syndrome, where you could avoid a pacemaker.
But I am not sure how good that is.
Calcium channel blockers, I think, are very good agents for rate
control. They are good in the active patients. They are the first
choice of patients with lung disease who can't use beta blockers. I
think they are the first choice of patients with atrial fibrillation and
LVH because of the beneficial effects of calcium channel blockers
in these patients and the regression of LVH. It may not be tolerated
in patients with CHF. Negative inotropic effects.
Digitalis is only recommended in patients with a history of CHF
because you have the added benefit in those patients. It is very
poor in active patients. The problem with digoxin is that you have
excessive slowing of the sinus rate at rest but not good control
during exertion. So, you push the dig to a point where someone has
a heart rate of 60 at rest and then they get up and start doing things
like climbing stairs and stuff and their heart rate goes up to 170 or
140. Digoxin, especially in the active patient, is not recomended.
Amiodarone may work when nothing else can control the heart rate.
It is good in patients that have enhanced AV nodal conduction is a
very rare entity where people go into atrial fibrillation and go very
rapidly up to 250 or 350 beats per minute. It may be beneficial in
patients with LV dysfunction and/or nonsustained VT where you get
the added benefit of reducing the risk of sudden death.
AV junctional ablation for rate control of atrial fibrillation. The
response of patients is really dramatic, and people do really well
with this procedure. Indications include failure of the multiple AV
nodal blocking drugs. So, patients that you just can't rate control no
matter what you use. Patients in whom even though their rate is
controlled the irregularity of the atrial fibrillation still bothers them.
Drug intolerance. Patients that when they take the drugs that rate
control, they get admitted five times a year with CHF and their heart
rate is 150 because they never take their medications. Also, patient
preference.
What do we do with patients with atrial fibrillation and heart failure?
Twenty five percent of patients with heart failure may also have
atrial fibrillation. These are the patients that are at highest risk of
proarrhythmia from antiarrhythmic drugs. Congestive heart failure
10
Chemical Cardioversion
. Procainamide
15 mg/kg IV over 20-30 minutes (750-1500 mg)
Watch for hypotension, QRS widening, QT prolongation.
can lead to atrial fibrillation, and atrial fibrillation can lead to and
worsen congestive heart failure. Chronic tachycardia is associated
with the development of a cardiomyopathy and it appears to be
reversible.
Ablation and pacing results in an improvement in EF from 25% to
52%. Dramatic increases in injection fraction. With severe LV
dysfunction, after you ablate their AV node and put in a pacemaker;
it is almost back to normal. I think that is a really important point
that people don't fully understand yet. Patients with mean heart
rates of 60 to 100 beats per minute on a Holter that had depressed
LV function underwent AV junctional ablation and showed a significant
improvement in function after this.
Regularization of ventricular response. Even if you have somebody
rate controlled, the ventricle is being activated very irregularly.
Regularization of rhythm provides significant hemodynamic benefits.
In patients with AF, an increase in pulmonary capillary wedge
pressure were seen with irregular rhythm as opposed to regular
rhythm; therefore, both rapid rate and irregularity leads to decreased
LV function.
If you have patients that are difficult to manage and are having
repeated visits to the hospital with CHF and have chronic atrial
fibrillation, AV junctional ablation with pacing is something to
consider. It may help you manage their CHF.
11
Maintenance of Sinus to Rhythm
. Pharmacologic
. Preventive pacing
. Implantable defibrillator
. Ablative therapy
Surgical
Catheter
Maintenance of sinus rhythm. There is a subset of patients in whom
we are going to want to try and maintain sinus rhythm. There are
pharmacologic approaches, preventative pacing, implantable
defibrillators and ablative therapy.
12
Pharmacologic Maintenance of Sinus
to Rhythm
. Class IA
Quinidine: diarrhea
Procainamide: arthritis/rash/lupus
Disopyramide: urinary retention
..Class IC
Flecainide: avoided in ischemia/poor LV function
Propafenone: avoided in ischemia/poor LV function
. Class III
Sotalol: CHF, asthma, bradycardia
. Amiodarone: end organ toxicity
Pharmacologic agents. The class-I agents are sodium channel
blockers. There is quinidine, procainamide, disopyramide.
Quinidine is a drug that has been used for years and years, but 40
to 50% of patients can't take it because of the diarrhea.
Procainamide maintenance is not recommended because of arthritis,
rash, and lupus-like syndromes. Disopyramide (Norpace) is not
good in older men because of urinary retention, but it is very well-
tolerated in younger patients, and in patients with vagally mediated
atrial fibrillation.
The class 1C agents. Flecainide got a very bad name because of
the excess mortality in patients post MI. But I think in patients with
structurally normal hearts, it is probably one of the most effective
agents that we have for controlling atrial fibrillation. It should be
avoided it in patients with ischemia or poor LV function. The same
thing with propafenone (Rythmol). A newer agent, Sotalol can be
very effective because it offers both rate control and an
antiarrhythmic properties, but the beta blocking properties can
cause problems in patients with CHF, asthma, and it can cause
bradycardia.
Amiodarone is a very good drug for controlling atrial fibrillation, but
the end organ toxicities are something to be concerned about. Over
one year's time on quinidine, about 50% are maintained in sinus
rhythm. Propafenone and Sotalol, 50%. With the exception of
amiodarone, the antiarrhythmic drugs are all about 50% effective at
one year. Amiodarone appears to be the most effective
antiarrhythmic at maintaining sinus rhythm. It is 78% effective at
maintaining sinus rhythm in people who had failed a type-I
antiarrhythmic. Amiodarone versus quinidine, again right around
50% versus 79%. Same thing for amiodarone versus Norpace.
Amiodarone is the best drug available for maintaining sinus rhythm.
We have had a lot of good success with using amiodarone, and we
use it in a lot of patients. Toxicity tends to be dose related. So, in
the doses we use in ventricular tachycardia, 400 to 600 mg/day,
there is a significant incidence of pulmonary fibrosis and other end
organ toxicities. At the dose we use for atrial fibrillation, it is 200
mg/day, which is one pill, or even 200 mg every other day, the
incidence of these side effects are very low. The side effects are
reversible. In patients that have failed other drugs and patients that
have LV dysfunction, amiodarone is the drug of choice.
Amiodarone is a very unique drug. The half-life is one month to five
months. It is a very lipophilic drug so when you give it to people it
immediately gets sucked up into their fat stores. Start with a much
higher dose and then we cut the dose back. Start them on 800
mg/day for about two weeks, then I will put them on 400 mg/day for
about a month, then cut them back down to 200 mg/day. Results
have been very good. Patients have tolerated it well and it clearly
works much better than other agents. Anybody over 70 who presents
with atrial fibrillation or who has any LV dysfunction, should be
started on amiodarone as a first line agent.
13
No Structural Heart Disease
. First-line agents
Class IC (flecainide, propafenone)
Disopyramide (especially if vagally mediated)
. Second-line
Sotalol
. Third line
Amiodarone
If you have a patient that has no structural heart disease with lone
AF, they are very symptomatic, you don't want to leave these
people in AF all the time and make them take aspirin and have
them in atrial fibrillation. You can give them drugs to try to maintain
sinus rhythm. We have had a lot of success with flecainide in this
population. Norpace is very good especially in vagally mediated AF.
There is a group of patients who get atrial fibrillation after they eat
big meals or they wake up in the middle of the night. Vagal surges
change the electrophysiologic properties of the atrium and make it
more susceptible to atrial fibrillation. Norpace has some vagolytic
effects and may be effective in those patients. Second line, Sotalol
is often good in these patients, and you can use amiodarone.
14
Ischemic Heart Disease
. First-line:
Sotalol
. Second-line:
Amiodarone
. Avoid class IC
In patients with ischemic heart disease, the class 1C drugs should
be avoided. Sotalol may be a good drug. The beta blocking properties
are good for the ischemic patient, and amiodarone is a good
agent in those patients.
15
CHF/LV Dysfunction
. First-line:
Amiodarone
. Consider non-pharmacologic approach
. Avoid class IC
In the patients with CHF and LV dysfunction, you have to avoid
those drugs that are proarrhythmic. Amiodarone may be the best
drug in these patients because you get the added protection from
sudden death. You should also consider the non-pharmacologic
approach in these patients because you may see an increase in LV
function after you control their rate with ablation and regularize their
ventricular response with pacing.
16
LVH/HCM
. First-line
Class 1C (flecainide, propafenone)
. Second-line:
Sotalol
Amiodarone
. Consider nonpharmacologic management (HCM)
In patients that have left ventricular hypertrophy or hypertrophic
cardiomyopathy, class 1C agents are also good. Disopyramide is
specifically good in patients with hypertrophic cardiomyopathy
because of the negative inotropic effects. It may decrease the
gradient. Sotalol also is very good in these patients, and
amiodarone is good. In patients with hypertrophic cardiomyopathy,
you should consider non-pharmacologic management, such as
ablation, because dual-chamber pacing will decrease the pressure
gradient so you get the added benefit of those two things.
17
Outpatient loading of antiarrhythmic medications utilizing a monitoring device is probably safe and cost-effective. Patients get their
first dose of the drug in the hospital, and then were sent out with a loop recorder for 10 days. Every day they transmit a tracing of
their heart rate and their QT interval and they also transmit any palpitations or any adverse effects that they had.
Prophylactic pacing for atrial fibrillation. It is thought that atrial fibrillation is due to multiple re-entrant wave fronts throughout the
atria. Excitation and therefore prolongation of the refractoriness of the tissue in the critical regions of the atrium may prevent the
initiation or maintenance of atrial fibrillation. If you stimulate the heart in more than one place, you may be able to prevent these reentrant
wave fronts and prevent atrial fibrillation. There are trials that have looked at patients with sick sinus syndrome that got either
dual chamber pacers or ventricular pacers alone. The studies showed that in patients that had atrial pacing, it was a significantly
much lower incidence of atrial fibrillation that had active atrial pacing suggesting that somehow pacing the atrium will decrease the
incidence of atrial fibrillation.
Implantable ventricular defibrillators. This is a device that goes in the pectoral region, has two leads in the right atrium. One in the
right atrium, one in the coronary sinus and one for R-wave synchronization in the RV apex. It is used to cardiovert people out of atrial
fibrillation. It can be done when you have two leads inside the heart like this and you are not shocking externally and you are not
stimulating skeletal muscle. The amount of energy required is only in some patients 0.5 Joule or 1 or 2 Joule. So, although in some
patients that causes a fair amount of discomfort, in some patients it doesn't and the idea of atrial defibrillators are being tested right
now. The big questions are safety. The first patient that has an atrial defibrillator that gets shocked or it fails and they get put into VF
and then dies, that will be the end of the whole idea.
Surgical treatment of atrial fibrillation. The Maze procedure consists of multiple atriotomies which interrupt all the potential re-entrant
circuits. This will restore control of the heartbeat to the atrial pacemaker, which is the sinus node, and it allows activation of the entire
atrial myocardium. The long term results are unclear.
Atrial flutter. Typical atrial flutter is characterized by the typical saw-tooth flutter wave in the inferior leads beneath the positive flutter
wave in lead V1. It is a macroreentrant electrical rhythm confined to the right atrium. So, the electrical wave front goes around the
right atrium, up the septum, down the lateral wall and through this isthmus of tissue between the opening of the IVC and the tricuspid
annulus and the coronary sinus. If we can create a line of conduction block, the patient should not have atrial flutter anymore.
We are now able to terminate atrial flutter and cure people that have typical atrial flutter in about 95% of cases. Antiarrhythmic drugs
are not very effective for atrial flutter, and rate control is much more difficult in atrial flutter than atrial fibrillation because it is hard to
get a reasonable rate control. When somebody presents with atrial flutter for the first time, cardioversion is recommended, and then
the patients are discharged and observed to determine what the natural history is going to be. If they are not going to have atrial
flutter for the next five years, no treatment is necessary. The first time they return with atrial flutter, if it is early on, the first line of
therapy now is ablative therapy and our success rate is very good and the risk is low.
18
Wednesday, August 18, 2010
Cancer Chemotherapy
Table 4–3. Treatment choices for cancers responsive to systemic agents.
Diagnosis
Acute lymphocytic leukemia
Acute myelocytic and myelomonocytic leukemia
Chronic myelocytic leukemia
Chronic lymphocytic leukemia
Hairy cell leukemia Hodgkin’s disease (stages III and IV)
Non-Hodgkin’s lymphoma
Multiple myeloma
Waldenström’s macroglobulinemia
Polycythemia vera
Carcinoma of lung Small cell Non-small cell3
Carcinoma of the head and neck3 Carcinoma of the esophagus3 Carcinoma of the stomach and pancreas3
Carcinoma of the colon and rectum3
Carcinoma of the kidney3
Carcinoma of the bladder3
Carcinoma of the testis3
Carcinoma of the prostate3
Carcinoma of the uterus3 Carcinoma of the ovary3
Carcinoma of the cervix3
Carcinoma of the breast3
Current Treatment of Choice
Induction: Combination chemotherapy. Adults:
Vincristine, prednisone, daunorubicin, and asparaginase.
Children: Vincristine, prednisone with or without
asparaginase.
Consolidation: Multiagent alternating chemotherapy.
Allogeneic bone marrow transplant for young adults or
high-risk disease or second remission. CNS prophylaxis
with intrathecal methotrexate with or without whole brain
radiation.
Remission maintenance: Methotrexate, thioguanine.
Induction: Combination chemotherapy with cytarabine
and an anthracycline (daunorubicin, idarubicin).
Tretinoin for acute promyelocytic leukemia.
Consolidation: High-dose cytarabine. Autologous
(with or without purging) or allogeneic bone marrow
transplantation for high-risk disease or second remission.
Hydroxyurea, alpha interferon. Allogeneic bone marrow
transplantation for young patients.
Chlorambucil and prednisone or fludarabine (if treatment
is indicated).
Cladribine (2-chlorodeoxyadenosine; CdA).
Combination chemotherapy: doxorubicin (Adriamycin),
bleomycin, vinblastine, dacarbazine (ABVD) or
mechlorethamine, vincristine, prednisone, procarbazine
(MOPP) or alternating MOPP/ABVD or MOPP/ABV,
autologous bone marrow transplant for high-risk patients
or relapsed disease.
Combination therapy depending on histologic classification
but usually including cyclophosphamide, vincristine,
doxorubicin, and prednisone (CHOP) with or without
other agents. Autologous bone marrow transplantation in
high-risk first remission or first relapse.
Combination chemotherapy: melphalan and prednisone
or melphalan, cyclophosphamide, carmustine,
vincristine, doxorubicin, and prednisone. Autologous
bone marrow transplantation in first complete or partial
remission. Allogeneic bone marrow transplantation for
young patients with poor prognosis disease.
Chlorambucil versus combination chemotherapy:
cyclophosphamide, vincristine, prednisone. Allogeneic
bone marrow transplantation for high-risk young patients.
Hydroxyurea, phlebotomy
Combination chemotherapy: cisplatin and etoposide.
Palliative radiation therapy.
Advanced disease: cisplatin, vinorelbine
Localized disease: cisplatin, vinblastine
Combination chemotherapy: cisplatin and fluorouracil
Combination chemotherapy: fluorouracil, cisplatin,
mitomycin
Stomach: etoposide, leucovorin,2 fluorouracil (ELF)
Pancreas: fluorouracil or ELF, gemcitabine
Colon: fluorouracil plus levamisole (adjuvant) or with
leucovorin.2
Rectum: fluorouracil with radiation therapy (adjuvant)
Floxuridine, vinblastine, IL-2, alpha interferon
Intravesical BCG or thiotepa. Combination
chemotherapy: methotrexate, vinblastine, doxorubicin
(Adriamycin), cisplatin (M-VAC) or CMV alone
Combination chemotherapy: etoposide and cisplatin
Autologous bone marrow transplantation for high-risk or
relapsed disease.
Estrogens or LHRH analog (leuprolide) plus an
antiandrogen (flutamide)
Progestins or tamoxifen
Combination chemotherapy: cyclophosphamide and
cisplatin (or carboplatin) or paclitaxel and cisplatin/
carboplatin
Combination chemotherapy: methotrexate,
doxorubicin, cisplatin, and vinblastine; or mitomycin,
bleomycin, vincristine, and cisplatin
Combination chemotherapy: cyclophosphamide,
doxorubicin, fluorouracil, or cyclophosphamide,
methotrexate, fluorouracil. Tamoxifen for estrogen/
progesterone receptor-positive tumors. Adjuvant therapy
for high-risk patients and for limited metastatic disease:
Other Valuable Agents and Procedures
Doxorubicin, cytarabine, cyclophosphamide, etoposide, teniposide (VM-26),1 allopurinol,2 autologous bone marrow transplantation
Mitoxantrone, idarubicin, etoposide,
mercaptopurine, thioguanine,
azacitidine,1 amsacrine,1
methotrexate, doxorubicin, tretinoin,
allopurinol,2 leukapheresis, prednisone
Busulfan, mercaptopurine,
thioguanine, cytarabine, plicamycin, melphalan,
autologous bone marrow transplantation, allopurinol2
Vincristine, cyclophosphamide, doxorubicin,
Cladribine (2-chlorodeoxyadenosine; CdA),
androgens,2 allopurinol2
Pentostatin (deoxycoformycin), alpha interferon
Carmustine, lomustine, etoposide,
thiotepa, autologous bone marrow transplantation
Bleomycin, methotrexate, etoposide,
chlorambucil, fludarabine, lomustine, carmustine,
cytarabine, thiotepa, amsacrine, mitoxantrone,
autologous or allogeneic bone marrow transplantation
Etoposide, cytarabine, alpha interferon,
dexamethasone, autologous bone marrow
transplantation
Etoposide, alpha interferon, doxorubicin,
dexamethasone, plasmapheresis, autologous bone
marrow transplantation
Busulfan, chlorambucil, cyclophosphamide, alpha
interferon, radiophosphorus 32P
Cyclophosphamide, doxorubicin, vincristine
Doxorubicin, etoposide, mitomycin
Methotrexate, bleomycin,
hydroxyurea, doxorubicin, vinblastine
Methotrexate, bleomycin,
doxorubicin, mitomycin
Carmustine, mitomycin, lomustine,
doxorubicin, gemcytidine.
Doxorubicin, methotrexate, cisplatin, combinations
for stomach
Methotrexate, mitomycin, carmustine,
cisplatin, floxuridine
Alpha interferon, progestins, infusional FUDR,
fluorouracil
Cyclophosphamide, fluorouracil
Bleomycin, vinblastine, ifosfamide,
mesna,2 carmustine, carboplatin
Ketoconazole, doxorubicin,
aminoglutethimide, progestins, cyclophosphamide,
cisplatin, estramustine, vinblastine, etoposide,
suramin1
Doxorubicin, cisplatin, fluorouracil, ifosfamide
Docetaxel, topotecan
Carboplatin, ifosfamide, lomustine
Mitoxantrone, vinblastine, paclitaxel,
docetaxel, topotecan, thiotepa, vincristine,
carboplatin, cisplatin/carboplatin, mitomycin,
vinorelbine, progestins, androgens, aminoglutethimide
Choriocarcinoma (trophoblastic neoplasms)3 Dose intensification or autologous bone marrow transplantation. Methotrexate or dactinomycin (or both) plus chlorambucil Vinblastine, cisplatin, mercaptopurine, doxorubicin, bleomycin, etoposide
Carcinoma of the thyroid gland3 Carcinoma of the adrenal Radioiodine (131I) Mitotane Doxorubicin, cisplatin, bleomycin, melphalan Doxorubicin, suramin1
gland3 Carcinoid3 Osteogenic sarcoma3 Soft tissue sarcoma3 Melanoma3 Kaposi’s sarcoma Wilms’ tumor (in children)3 Neuroblastoma3 Fluorouracil plus streptozocin with or without alpha interferon High-dose methotrexate, doxorubicin, vincristine Doxorubicin, dacarbazine Dacarbazine, alpha interferon, IL-2 Vincristine alternating with vinblastine or vincristine alone. Palliative radiation therapy. Combination chemotherapy: vincristine and dactinomycin with or without doxorubicin after surgery and radiation therapy Combination chemotherapy: variations of cyclophosphamide, cisplatin, vincristine, doxorubicin, dacarbazine Doxorubicin, cyclophosphamide, octreotide, cyproheptadine,2 methysergide2 Cyclophosphamide, ifosfamide, bleomycin, dacarbazine, cisplatin, dactinomycin Ifosfamide, cyclophosphamide, etoposide, cisplatin, high-dose methotrexate, vincristine Carmustine, lomustine, melphalan, thiotepa, cisplatin, paclitaxel,1 tamoxifen, vincristine Alpha interferon, bleomycin, etoposide doxorubicin Cyclophosphamide, methotrexate, etoposide, cisplatin Melphalan, ifosfamide, autologous or allogeneic bone marrow transplantation
1Investigational agent. Treatment is available through qualified investigators and centers authorized
by the National Cancer institute and Cooperative Oncology Groups.
2Supportive agent; not oncolytic.
3These tumors are generally managed initially with surgery with or without radiation therapy
with or without adjuvant chemotherapy. For metastatic disease, the role of palliative radiation
therapy is as important as that of chemotherapy.
Table 4–4 sets forth the currently used dosage schedules and toxicities of the most commonly used cancer chemotherapeutic agents.
The dosage schedules given are for single-agent therapy. Combination therapy is used for many diseases, including advanced-stage
Hodgkin's disease, non-Hodgkin's lymphoma, and testicular carcinoma. Hematologic or other toxicity may limit the therapeutic
effectiveness of chemotherapy. It is possible to avoid the need for dose reductions or delay in therapy by using granulocyte
colony-stimulating factor (G-CSF; filgrastim) or granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim).
Scroll right to see more columns.
Table 4–4. Single agent dosage and toxicity of anticancer drugs.
Drug Alkylating agents Dosage Acute Toxicity Delayed Toxicity
Mechlorethamine 6–10 mg/m2 IV every 3 Severe vesicant; severe Moderate suppression of blood counts.
weeks nausea and vomiting Melphalan effect may be delayed 4–6 weeks.
Excessive doses produce severe bone
marrow suppression with leukopenia,
Chlorambucil 0.1–0.2 mg/kg/d orally None thrombocytopenia, and bleeding.
(6–12 mg/d) or 0.4 Alopecia and hemorrhagic cystitis occur with
mg/kg pulse every 4 cyclophosphamide, while busulfan can cause
weeks hyperpigmentation, pulmonary fibrosis, and
weakness (see text). Ifosfamide
Cyclophosphamide 100 mg/m2/d orally for Nausea and vomiting with is always given with mesna to prevent
14 days; 400 mg/m2 higher doses cystitis. Acute leukemia may develop
orally for 5 days; 1–1.5 in 5–10% of patients receiving prolonged
g/m2 IV every 3–4 weeks therapy with melphalan, mechlorethamine, or
chlorambucil; all alkylators probably increase
the risk of secondary malignancies with
prolonged use. Most cause either
Melphalan 0.25 mg/kg/d orally for 4 None temporary or permanent aspermia/
days every 6 weeks amenorrhea.
Busulfan 2–8 mg/d orally; None
150–250 mg/course
Carmustine (BCNU) 200 mg/m2 IV every 6 Local irritant Prolonged leukopenia and thrombocytopenia .
weeks Rarely hepatitis. Acute leukemia has been
observed to occur in some patients
Lomustine (CCNU) 100–130 mg orally Nausea and vomiting receiving nitrosoureas. Nitrosoureas can
every 6–8 weeks cause delayed pulmonary fibrosis with
prolonged use.
Procarbazine 100 mg/m2/d orally for Nausea and vomiting Bone marrow suppression, mental
14 days every 4 weeks suppression, MAO inhibition, disulfiram-like
effect
Dacarbazine 250 mg/m2/d IV for 5 Severe nausea and Bone marrow suppression; flu-like syndrome
days every 3 weeks; vomiting; anorexia
1500 mg/m2 IV as
single dose
Cisplatin 50–100 mg/m2 IV every Severe nausea and vomiting
3 weeks; 20 mg/m2 IV
for 5 days every 4 weeks
Carboplatin 360 mg/m2 IV every 4 Severe nausea and vomiting
weeks
Structural analogs or antimetabolites
Methotrexate 2.5–5 mg/d orally; None
20–25 mg IM twice
weekly; high-dose:
500–1000 mg/m2 IV
every 2–3 weeks;
12–15 mg intrathecally
every week for 4–6
doses
Mercaptopurine 2.5 mg/kg/d orally; 100 None
mg/m2/d orally for 5
days for induction
Thioguanine 2 mg/kg/d orally; 100 Mild nausea, diarrhea
mg/m2/d IV for 7 days
for induction
Fluorouracil 15 mg/kg/d IV for 3–5 None
days every 3 weeks; 15
mg/kg weekly as
tolerated; 500–1000
mg/m2 IV every 4 weeks
Cytarabine 100–200 mg/m2/d for High-dose: nausea,
5–10 days by vomiting, diarrhea, anorexia
continuous IV infusion;
2–3 g/m2 IV every 12
hours for 3–7 days; 20
mg/m2 SC daily in
divided doses
Hormonal agents
Testosterone 100 mg IM 3 times None
propionate weekly
Fluoxymesterone 20–40 mg/d orally None
Flutamide 250 mg 3 times a day None
orally
Diethylstilbestrol 1–5 mg/d orally in Occasional nausea and
divided doses vomiting
Ethinyl estradiol 3 mg/d orally None
Tamoxifen 20 mg/d orally in 2 Transient flare of bone pain
divided doses
Megestrol acetate 40 mg orally 4 times daily None
Anastrazole 1 mg orally daily None
Hydroxyproges1 g IM twice weekly None
terone caproate
Medroxyproges100–200 mg/d orally; None
terone 200–600 mg orally twice
weekly
Adrenocorticosteroid
Prednisone 20–100 mg/d orally or Alteration in mood
50–100 mg every other
day orally with systemic
chemotherapy
Aromatase inhibitor
Aminoglutethimide 500 mg/d orally, along Initial drowsiness
with hydrocortisone, 40
mg/d orally
GnRH analogs
Leuprolide 7.5 mg IM (depot) once Local irritation, transient
a month; 1 mg/d SC flare of symptoms
Goserelin acetate 3.6 mg SC monthly Transient flare of symptoms
Biologic response modifiers
Interferon alfa-2a 3–5 million units Fever, chills, fatigue,
Interferon alfa-2b SC 3 times weekly or anorexia
daily
Aldesleukin (IL-2) 600,000 IU/kg IV over Hypotension, fever, chills,
15 minutes every 8 rigors, diarrhea, nausea,
hours for 14 doses, vomiting, pruritus, liver,
repeated after 9-day kidney, and CNS toxicity,
rest period. Some capillary leak (primarily at
doses may be withheld high doses), pruritic skin
or interrupted because rash, infections (can be
of toxicity. Caution: severe)
High doses must be
administered in an ICU
setting by experienced
Nephrotoxicity, mild otic and bone marrow
toxicity, neurotoxicity.
Bone marrow suppression, prolonged
anemia; same as cisplatin but milder.
Bone marrow suppression, oral and
gastrointestinal ulceration, acute renal failure;
hepatotoxicity, rash, increased toxicity when
effusions are present. Note: Citrovorum
factor (leucovorin) rescue for doses over 100
mg/m2.
Well tolerated. Larger doses cause bone
marrow suppression
Well tolerated. Larger doses cause bone
marrow suppression
Nausea, diarrhea, oral and gastrointestinal
ulceration, bone marrow suppression,
dacryocystitis.
Nausea and vomiting; cystitis; severe bone
marrow suppression; megaloblastosis; CNS
toxicity with high-dose cytarabine.
Fluid retention, masculinization, leg cramps.
Cholestatic jaundice in some patients
receiving fluoxymesterone.
Gynecomastia, hot flushes, decreased libido,
mild gastrointestinal side effects.
Fluid retention, feminization, uterine bleeding,
exacerbation of cardiovascular disease,
painful gynecomastia,
thromboembolic disease.
?Increased risk of venous thrombosis;
anovulation
Occasional fluid retention; rare thrombosis,
weight gain.
Fluid retention, hypertension, diabetes,
increased susceptibility to infection, "moon
facies," osteoporosis, electrolyte
abnormalities, gastritis.
Transient skin rash, which usually subsides
with continued therapy; weight gain, fluid
retention, leg cramps; cholestatic jaundice.
Hot flushes, decreased libido, impotence,
gynecomastia, mild gastrointestinal side effects
.
General malaise, weight loss, confusion
Hypoglycemia, anemia
personnel.
Peptide hormone inhibitor
Octreotide acetate 100–600 mg/d SC in 2 Local irritant; nausea and Diarrhea, abdominal pain, hypoglycemia.
divided doses vomiting
Natural products and miscellaneous agents
Vinblastine 0.1–0.2 mg/kg or 6 Mild nausea and vomiting; Alopecia, peripheral neuropathy, bone
mg/m2 IV weekly severe vesicant marrow suppression, constipation, SIADH,
areflexia.
Vincristine 1.5 mg/m2 (maximum: 2 Severe vesicant Areflexia, muscle weakness, peripheral
mg weekly) neuropathy, paralytic ileus, alopecia (see
text), SIADH.
Vinorelbine 30 mg/m2 IV weekly Mild nausea and vomiting, Granulocytopenia, constipation, peripheral
fatigue, severe vesicant neuropathy, alopecia
Paclitaxel 135 mg/m2 by Hypersensitivity reaction Peripheral neuropathy, bone marrow
continuous infusion over (premedicate with suppression, fluid retention.
24 hours every 3 weeks diphenhydramine and
dexamethasone), mild
Docetaxel 60–100 mg/m2 IV every nausea and vomiting
3 weeks
Dactinomycin 0.04 mg/kg IV weekly Nausea and vomiting; Alopecia, stomatitis, diarrhea, bone marrow
severe vesicant suppression.
Daunorubicin 30–60 mg/m2 daily IV Nausea, fever, red urine Alopecia, stomatitis, bone marrow
for 3 days, or 30–60 (not hematuria); severe suppression, late cardiotoxicity. Risk of
mg/m2 IV weekly vesicant; acute cardiotoxicity cardiotoxicity increases with radiation,
cyclophosphamide.
Idarubicin 12 mg/m2 daily IV for 3
days
Doxorubicin 60 mg/m2 IV every 3
weeks to a maximum
total dose of 550 mg/m2
Liposomal 20 mg/m2 IV every 3
Doxorubicin weeks
Daunorubicin 40 mg/m2 IV every 2
weeks
Etoposide 100 mg/m2/d IV for 5 Nausea and vomiting; Alopecia, bone marrow suppression.
days or 50–150 mg/d occasionally hypotension
orally
Plicamycin 25–50 mg/kg IV every Nausea and vomiting Thrombocytopenia, diarrhea, hepatotoxicity,
(mithramycin) other day for up to 8 nephrotoxicity, stomatitis.
doses
Mitomycin 10–20 mg/m2 every 6–8 Severe vesicant; nausea Prolonged bone marrow suppression, rare
weeks hemolytic-uremic syndrome.
Mitoxantrone 12–15 mg/m2/d IV for 3 Mild nausea and vomiting Alopecia, mild mucositis, bone marrow
days with cytarabine; suppression.
8–12 mg/m2 IV every 3
weeks
Bleomycin Up to 15 units/m2 IM, Allergic reactions, fever, Fever, dermatitis, pulmonary fibrosis.
IV, or SC twice weekly hypotension
to a total dose of 200
units/m2
Hydroxyurea 500–1500 mg/d orally Mild nausea and vomiting Hyperpigmentation, bone marrow
suppression.
Mitotane 6–12 g/d orally Nausea and vomiting Dermatitis, diarrhea, mental suppression,
muscle tremors.
Fludarabine 25 mg/m2/d IV for 5 Nausea and vomiting Bone marrow suppression, diarrhea, mild
days every 4 weeks hepatotoxicity, immune suppression.
Cladribine (CdA) 0.09 mg/kg/d by Mild nausea, rash, fatigue Bone marrow suppression, fever, immune
continuous IV infusion suppression.
for 7 days
Topotecan 1.5 mg/kg IV daily for 5 Nausea, vomiting, diarrhea, Alopecia, bone marrow suppression.
days every 3 weeks headache, dyspnea
Tretinoin 45 g/m2 by mouth until Retinoic acid syndrome (fever, dyspnea, pleural or pericardial effusion)
remission or for 90 days must be treated emergently with dexamethasone; headache, dry skin rash,
flushing.
Gemcitabine 1000 mg/m2 every week Nausea, vomiting, diarrhea, Bone marrow suppression, rash, fluid
up to 7 weeks, then 1 fever, dyspnea retention, mouth sores, flu-like symptoms,
week off, then weekly paresthesias.
for 3 out of 4 weeks
Supportive agents
Allopurinol 300–900 mg/d orally for None Rash, Stevens-Johnson syndrome; enhances
prevention or relief of effects and toxicity of mercaptopurine when
hyperuricemia used in combination.
Mesna 20% of ifosfamide Nausea, vomiting, diarrhea None
dosage at the time of
ifosfamide
administration, then 4
and 8 hours after each
dose of chemotherapy
to prevent hemorrhagic
cystitis
Leucovorin 10 mg/m2 every 6 hours None Enhances toxic effects of fluorouracil.
IV or orally until serum
methotrexate levels are
below 5 ´ 10–8 mol/L
with hydration and
urinary alkalinization
(about 72 hours)
Amifostine 910 mg/m2 IV daily, 30 Hypotension, nausea, Decrease in serum calcium.
minutes prior to vomiting, flushing
chemotherapy
Dexrazoxane 10:1 ratio of Pain on injection Increased bone marrow suppression.
anthracycline IV, before
(within 30 minutes of)
chemotherapy infusion
Pilocarpine 5–10 mg orally 3 times Sweating, headache, flushing; nausea, chills, rhinitis, dizziness, and
hydrochloride daily urinary frequency at high dosage
Pamidronate 90 mg IV every month Symptomatic hypoglycemia None
(rare), flare of bone pain,
local irritation
Epoetin alfa 100–300 units/kg IV or Skin irritation or pain at Hypertension, headache, seizures in
(erythropoietin) SC 3 times a week injection site patients on dialysis (rare).
Filgrastim (G-CSF) 5 mg/kg/d SC or IV Mild to moderate bone pain, ?Unknown risk of tumor cell stimulation.
mild hypotension (rare),
irritation at injection sites
(rare)
Sargramostim 250 mg/kg/d as a 2-hour Fluid retention, dyspnea,
(GM-CSF) IV infusion (can be capillary leak (rare),
given SC) supraventricular tachycardia
(rare), mild to moderate
bone pain, irritation at
injection sites
Hormonal therapy also plays an important role in cancer management. Hormonal therapy or ablation is important in treatment and palliation of breast and prostatic carcinoma, while added progestins are useful in suppression of endometrial carcinoma. Women with metastatic breast cancer who show objective improvement with hormonal therapy have tumors that contain cytoplasmic estrogen and progesterone receptors. Antiestrogens (eg, tamoxifen) and aromatase inhibitors (eg, anastrazole or megestrol acetate) that block peripheral conversion of adrenal androgens into estrogens have substantial additive effects to—or may obviate the need for—oophorectomy in premenopausal women whose tumors are estrogen- or progesterone receptor-positive. Hormonal approaches are also available to treat prostate cancer, though androgen receptors remain difficult to measure. These include the use of estrogen therapy, gonadotropin-releasing hormone agonists (eg, leuprolide), aromatase inhibitors (eg, aminoglutethimide), and antiandrogens (eg, flutamide). The use of leuprolide plus flutamide can be considered as an alternative to orchiectomy but also causes impotence. High-dose ketoconazole has been used to rapidly suppress adrenal production of steroids in crises such as cord compression. Use of this agent requires hydrocortisone supplementation. Several recombinant growth factors have been shown to be effective in the treatment of malignancy. Recombinant alpha interferon has marked antitumor effects in hairy cell leukemia and chronic myelogenous leukemia, moderate effects in lymphomas, in the epidemic (AIDS-associated) form of Kaposi's sarcoma, in multiple myeloma, and as adjuvant therapy for malignant melanoma. Alpha interferon has some utility also in metastatic melanoma, renal cell carcinoma, and carcinoid syndrome. Patients with chronic myelogenous leukemia may benefit from treatment with alpha interferon and achieve both a hematologic and cytogenetic remission. Patients with a cytogenetic response to interferon (about 30% of treated patients) have longer survival than patients treated with standard oral chemotherapy. The addition of alpha interferon to systemic chemotherapy for multiple myeloma appears to enhance the degree of cytoreduction achieved as compared with chemotherapy alone; toxicity is additive. Use of alpha interferon for myeloma following chemotherapy or autologous bone marrow transplant has prolonged remission duration, though overall survival may not be altered. Another cytokine, interleukin-2, when administered alone or in combination with lymphocyte-activated killer cells or tumor-infiltrating lymphocytes, exhibits marked antitumor activity in a minority of patients with melanoma or renal cancer, though its use is associated with marked toxicity. In addition to cytokines, other agents have recently been shown to be efficacious in the treatment of some tumors. For chronic lymphocytic leukemia and low-grade lymphomas, fludarabine phosphate, cladribine (2-chlorodeoxyadenosine; CdA), and pentostatin (2-deoxycoformycin) are effective. Studies using cladribine to treat hairy cell leukemia have resulted in a high remission rate that is durable with tolerable toxicities after a 1-week course of therapy. Pentostatin has been approved for use in hairy cell leukemia. Paclitaxel is a novel agent isolated from the Pacific yew tree that has been found to be effective in reducing tumor size in 20–35% of patients with refractory metastatic ovarian cancer, though most patients experienced rapid disease progression after an initial response; paclitaxel combined with carboplatin appears to be more effective than cyclophosphamide plus carboplatin in the adjuvant setting. Dose intensification as well as intraperitoneal instillation may also be helpful. The toxicity of paclitaxel is primarily hematologic and neurologic. The hematologic toxicity is dose-dependent and can be ameliorated by the use of myeloid growth factors. Effectiveness has been demonstrated in metastatic carcinoma of the breast as well as in other cancers. Docetaxel, a synthetic analog of paclitaxel, has recently been approved and is effective also in the treatment of advanced malignancies, especially breast cancer. Toxicities are similar to those of paclitaxel. Vinorelbine, a semisynthetic vinca alkaloid, has recently been approved for use in treating advanced non-small-cell lung cancer. Response rates of 30% have been observed when vinorelbine is used as a single agent in this poorly responsive tumor. Current studies are evaluating combination chemotherapy, including vinorelbine, in the treatment of metastatic breast cancer and other tumors. Newer experimental cancer therapies are discussed briefly at the end of this chapter.
10040:7:1 Berkowitz RS, Goldstein DP: Chorionic tumors. N Engl J Med 1996;335:1740. (Review of the clinical presentation and treatment of this curable tumor.)
10040:7:2 Chabner BA: Biological basis for cancer treatment. Ann Intern Med 1993;118:633. (A discussion of cancer biology as the basis of drug discovery research and a review of novel cancer therapies.)
10040:7:3 O'Brien S, del Giglio A, Keating M: Advances in the biology and treatment of B-cell chronic lymphocytic leukemia. Blood 1995;85:307. (Fludarabine treatment results in high complete remission rates and may allow more aggressive subsequent therapy.)
10040:7:4 Philip T et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 1995;333:1540. (Bone marrow transplantation for chemotherapy-sensitive relapsed lymphoma markedly improves event-free survival over standard salvage chemotherapy [46% versus 12% at 5 years].)
10040:7:5 Pritchard RS, Anthony SP: Chemotherapy plus radiotherapy alone in the treatment of locally advanced, unresectable, non-small-cell lung cancer: A meta-analysis. Ann Intern Med 1996;125:723. (Fourteen articles with 2589 patients suggested a 2-month mean gain in life expectancy when chemotherapy was added to radiation therapy.)
10040:7:6 Rowinsky EK, Donehower RC: Paclitaxel (Taxol). N Engl J Med 1995;332:1004. (A thorough review, including mechanisms of action, toxicity, and antitumor effects.)
10040:7:7 Saven A, Piro LD: Treatment of hairy cell leukemia. Blood 1992;79:1111. (Current and investigational treatments of hairy cell leukemia, including interferon, deoxycoformycin, and cladribine.)
10040:7:8 Yuen A, Sikic BI: Multidrug resistance in lymphomas. J Clin Oncol 1994;12:2453. (Review of multidrug resistance in lymphomas and status of ongoing trials using modulating agents.)
Adjuvant Chemotherapy for Micrometastases
One of the most important roles of cancer chemotherapy is as adjuvant therapy to eradicate or suppress minimal residual disease after primary field treatment with surgery or irradiation. Failure of primary field therapy to eradicate tumor is due principally to occult micrometastases of tumor stem cells outside the primary field. These distant micrometastases are more likely to be present in patients with positive lymph nodes at the time of surgery (eg, breast cancer), in patients with tumors known to have a propensity for early hematogenous spread (eg, osteogenic sarcoma, Wilms' tumor), and in patients with certain pathologic or molecular risk factors (eg, high proliferative index, vascular invasion, oncogene amplification). Given specific risk factors, the risk of recurrent or metastatic disease can be extremely high (> 80%). Only systemic therapy can adequately prevent micrometastases. Chemotherapeutic regimens that have been shown to be effective in inducing regression of advanced cancers may be curative when combined with surgery for high-risk "early" cancer. More data are now available to support the use of adjuvant therapy in several neoplasms. Prolongation of survival times has been shown for women (especially premenopausal women) with breast cancer and positive or negative axillary lymph nodes (stages I, II, and III) from combination chemotherapy following surgical resection; there are several useful regimens. Node-negative patients are treated with CMF (cyclophosphamide, methotrexate, and fluorouracil) or variants, whereas high-risk, node-positive patients are generally treated with regimens that include doxorubicin. Neoadjuvant (preoperative) and perioperative chemotherapy are also used and may improve surgical resectability or time to disease progression. The antiestrogen tamoxifen is used routinely either with or without antecedent chemotherapy if receptors for estrogen and progesterone are present. The role of amplification of the c-erbB-2 or Her-2/neu oncogene in tamoxifen-resistant breast cancer is a subject of current research. In postmenopausal women, tamoxifen alone may be used. The main challenge in treating women with node-negative (stage I) breast cancer is to identify prognostic factors to determine which patients are at higher risk and therefore more likely to benefit from adjuvant therapy. Adjuvant chemotherapy with fluorouracil plus levamisole is now indicated in Dukes C (node-positive) colon cancer and has been shown to reduce the risk of cancer recurrence. Earlier clinical trials employing semustine (methyl-CCNU) appeared to result in an increased risk of both leukemia and renal insufficiency. The omission of semustine from combination regimens still results in enhanced cure rates with decreased local and overall tumor recurrence. Other tumors that have been shown to respond to adjuvant therapy include osteogenic sarcoma, ovarian cancer, and malignant melanoma. Adjuvant therapy remains investigational and unproved for a number of common tumors, including non-small-cell lung cancer and pancreatic cancer. Patients with Hodgkin's disease or testicular carcinoma do not benefit from adjuvant therapy. Although adjuvant therapy has been shown to reduce the rate of recurrence for some cancers, there is still a high failure rate (up to 80% in high-risk breast cancer despite adjuvant therapy). In most cases, tumor recurrence signifies incurability. There is clear evidence of a dose-response effect of adjuvant chemotherapy in some cancers; however, doses have been limited by bone marrow toxicity. Current studies are investigating the use of dose-intense chemotherapy regimens with or without autologous bone marrow or peripheral blood progenitor cell rescue in the high-risk adjuvant setting for patients with carcinoma of the breast, testis, and ovaries. Otherwise incurable patients with testicular cancer have been cured by this intensive treatment approach. Nonrandomized studies suggest efficacy with tolerable side effects of high-dose chemotherapy with stem cell support in the setting of high-risk breast cancer (more than ten positive lymph nodes). Multicenter trials are now in progress comparing aggressive adjuvant chemotherapy with autologous bone marrow transplantation for high-risk breast cancer. The use of marrow transplantation for high-risk ovarian cancer remains controversial, though long-lived responses in otherwise incurable patients have been documented. Patients with advanced ovarian cancer at high risk for recurrence may now be considered for treatment in a multicenter randomized study comparing transplantation with standard adjuvant chemotherapy. Young patients with high-risk malignancies should be considered for entry into clinical trials investigating this aggressive, potentially curable therapy. 10040:8:1 [Physicians' Data query: Information on cancer treatment] http://cancernet.nci.nih.gov/h_treat.htm
10040:8:2 Bonadonna G et al: Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: The results of 20 years of follow-up. N Engl J Med 1995;332:901. (Long-term improvement in survival in patients with node-positive breast cancer randomized to receive adjuvant chemotherapy following mastectomy.)
10040:8:3 Cannistra SA: Cancer of the ovary. N Engl J Med 1993;329:1550. (A review of risk factors, presentation, staging, surgical treatment and chemotherapy, and prognosis.)
10040:8:4 Gradishar WJ, Tallman MF, Abrams JS: High-dose chemotherapy for breast cancer. Ann Intern Med 1996;125:599. (A review of this controversial but widely used therapy.)
10040:8:5 Moertel CG: Chemotherapy for colorectal cancer. N Engl J Med 1994;330:1136.
10040:8:6 Trimble EL et al: Neoadjuvant therapy in cancer treatment. Cancer 1993;72:3515. (Increasing indications.)
Toxicity and Dose Modification of Chemotherapeutic Agents
A number of cancer chemotherapeutic agents have cytotoxic effects on rapidly proliferating normal cells in bone marrow, mucosa, and skin. Still other drugs such as the vinca alkaloids produce neuropathy, and hormones often have psychologic effects. Acute and chronic toxicities of the various drugs are summarized in Table 4–4. Appropriate dose modification usually minimizes these side effects, so that therapy can be continued with relative safety.
Bone Marrow Toxicity
Depression of bone marrow is usually the most serious limiting toxicity of cancer chemotherapy. Autologous bone marrow or peripheral blood progenitor cell transplantation or rescue can reduce the myelosuppressive toxicity of high-dose chemotherapy; however, cost and toxicity limit its general use. Growth factors that stimulate myeloid proliferation (eg, granulocyte colony-stimulating factor [G-CSF; filgrastim] and granulocyte-macrophage stimulating factor [GM-CSF]; sargramostim) or erythroid proliferation (erythropoietin [epoetin alfa]) are now used to ameliorate bone marrow toxicity. G-CSF and GM-CSF have been shown to shorten the period of neutropenia following both standard and high-dose chemotherapy. Mucosal toxicity is also reduced. The myeloid growth factors are also used to stimulate circulation of progenitor cells in the peripheral blood either at steady state or during white blood cell recovery following myelosuppressive chemotherapy. These cells are then harvested using an apheresis machine and frozen for later use. When stimulated peripheral blood progenitor cells are used instead of or in conjunction with bone marrow for autologous transplantation following high-dose chemotherapy and radiotherapy, recovery of both neutrophils and platelets may be hastened by as much as 7–10 days as opposed to the use of bone marrow alone. Epoetin alfa (erythropoietin) has been shown to improve anemia associated with malignancy. Patients must have adequate iron stores to respond to this agent, and even patients with marrow infiltration with tumor may benefit. Higher doses are necessary for patients with cancer than for patients with renal failure (100–150 units/kg compared with 50 units/kg). It is useful to check the level of erythropoietin before instituting therapy. Very high levels (> 500 ng/mL) predict a poor response. Erythropoietin is usually given by subcutaneous injection three times a week. Thrombocytopenia remains a problem with high doses of or prolonged exposure to chemotherapeutic agents and may limit therapy. Several agents may help with this problem. Interleukin-3 stimulates myeloid growth and, to a lesser extent, platelet recovery. The megakaryocyte growth factor thrombopoietin has been cloned and is the subject of intense study. Clinical trials using thrombopoietin in a variety of circumstances are under way. Commonly used short-acting drugs that affect the bone marrow are the alkylating agents (eg, cyclophosphamide, melphalan, chlorambucil), procarbazine, mercaptopurine, methotrexate, vinblastine, fluorouracil, dactinomycin, and doxorubicin. In general, it is preferable to use alkylating agents in intensive "pulse" courses every 3–4 weeks rather than to administer the drugs in continuous daily schedules. This allows for complete hematologic (and immunologic) recovery between courses rather than continuously suppressing the bone marrow with a cytotoxic agent. Pulse therapy reduces side effects to some degree but does not reduce therapeutic efficacy. The standard dosage schedules required to produce tumor responses with these agents often induce bone marrow depression. Continuing some drugs in the face of falling blood counts may result in severe bone marrow aplasia with pancytopenia, bleeding, or infection. Simple guidelines for treatment and follow-up can usually prevent severe marrow depression. With long-term chemotherapy, counts should be obtained initially at weekly intervals; the frequency of counts may be reduced only after the patient's sensitivity to the drug can be well predicted (eg, 3–4 months) and cumulative toxicity excluded. In patients with normal blood counts as well as normal liver and kidney function, drugs should be started in full dosages. Bone marrow toxicity is cumulative over time, and this must be anticipated during follow-up. Patients with bone marrow involvement may tolerate chemotherapy poorly initially, with improved counts on future cycles as the tumor burden is reduced. Drug dosage can usually be modified as a function of the peripheral white blood count or platelet count (or both). These modifications assume that the blood counts are checked shortly before the next course of chemotherapy is to be administered. Dosage modifications are used primarily for repeated courses of oral alkylator or antimetabolite therapy but should be avoided when possible if treatment is given with curative intent. A scheme for dosage modification is presented in Table 4–5. Alternatively, the interval between drug courses can be lengthened, thereby permitting more complete hematologic recovery and repetition of full-dose chemotherapy. Both dosage modification and delay of chemotherapy limit the efficacy of treatment.
Table 4–5. A common scheme for dose modification of cancer chemotherapeutic agents.1
Granulocyte Suggested Drug
Count Platelet Count (/mL) Dosage (% of full dose)
> 2000/µL > 100,000/µL 100%
1000–2000/µL 75,000–100,000/µL 50%
< 1000/µL < 50,000/µL 0% 1In general, dose modification should be avoided if full recovery is expected within 1–2 weeks. Chemotherapy can be delayed and given after recovery at full dosage to maintain therapeutic efficacy.
10040:9:1 ASCO Ad Hoc Colony-Stimulating Factor Guideline Expert Panel: American Society of Clinical Oncology recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based clinical practice guidelines. J Clin Oncol 1994;12:2471. (Standard practice guidelines.)
10040:9:2 Kaushansky K: Thrombopoietin: The primary regulator of megakaryocyte and platelet production. Thromb Haemost 1995;74:521. (A review of current preclinical data.)
10040:9:3 Vose JM, Armitage JO: Clinical applications of hematopoietic growth factors. J Clin Oncol 1995;13:1023.
Chemotherapy-Induced Nausea & Vomiting
A number of cytotoxic anticancer drugs induce nausea and vomiting. In general, these symptoms are thought to originate in the central nervous system rather than peripherally. Parenteral administration of agents such as doxorubicin, etoposide, or cyclophosphamide frequently is associated with mild to moderate nausea and vomiting, whereas nitrosoureas, dacarbazine, and particularly cisplatin usually cause severe symptoms. Combination chemotherapy can also cause severe symptoms. Antiemetics clearly reduce and often eliminate nausea and vomiting associated with these drugs and are especially useful in conjunction with cisplatin. Metoclopramide is a particularly useful agent, especially when administered parenterally at a dosage of 1–2 mg/kg both 30 minutes before and again 30 minutes after the administration of chemotherapy. Extrapyramidal signs may be induced with this drug but frequently can be suppressed with 25–50 mg of oral or parenteral diphenhydramine. Dexamethasone has antiemetic effects when administered at a dosage of 6–10 mg either as a single dose prior to or both prior to and every 6 hours following the administration of chemotherapy for two to four total doses. Both of these drugs are more potent than conventional agents such as prochlorperazine, diphenhydramine, and thiethylperazine. Prochlorperazine is given at a dose of 10 mg orally or intravenously every 6 hours. The total dose given over 24 hours should not exceed 40 mg. A 25 mg rectal suppository is available and may be useful for patients who are too nauseated to swallow pills without experiencing further emesis. Unfortunately, all phenothiazines can induce extrapyramidal side effects. Thiethylperazine is given at a dose of 10 mg every 8 hours by mouth and is also available at the same dose in a rectal suppository. Lorazepam has both antiemetic and sedating effects and is administered at a dose of 0.5–1 mg every 4–6 hours by the sublingual route, making it particularly useful in the outpatient setting. Older patients may have intolerable psychologic side effects. Combinations of antiemetics (eg, metoclopramide with dexamethasone and lorazepam) are often more effective than maximal doses of any one agent for blocking cisplatin-induced vomiting. 5-Hydroxytryptamine-3 receptor antagonists (ondansetron, granisetron) have now replaced high-dose metoclopramide in the treatment and prevention of emesis. A new and very potent class of antiemetics, these drugs are serotonin receptor-blocking agents that have few side effects. They are both more effective and less toxic than metoclopramide in cisplatin-treated patients. They are also effective against radiation-induced and postanesthetic vomiting as well as for patients with refractory nausea and vomiting following administration of other chemotherapeutic agents. Ondansetron is administered by the parenteral route at a dose of 0.15 mg/kg for three doses or orally at a dose of 8 mg every 8 hours. The first dose is given 30 minutes before the start of chemotherapy; subsequent doses are given 4 and 8 hours after the first dose. A typical antiemetic regimen might include ondansetron combined with 0.5–1 mg of lorazepam (sublingual) or 10 mg of prochlorperazine orally or intravenously and dexamethasone (10 mg orally), omitting both metoclopramide and diphenhydramine. For less emetogenic regimens, ondansetron alone may be no more effective than metoclopramide and dexamethasone and is usually used only for failure to control nausea with less expensive combination regimens. Granisetron is a long-acting serotonin receptor antagonist that is given as a single dose of 10 mg/kg intravenously 30 minutes before chemotherapy or orally at a dosage of 1–2 mg/d. The half-life of granisetron is 9 hours, and 24-hour dosing is recommended by the manufacturer. Ondansetron may also be effective in a single daily parenteral dose of 32 mg. Both agents appear to be more effective when given in conjunction with dexamethasone. Dronabinol (D9-tetrahydrocannabinol) is effective in some patients at a dose of 5 mg/m2 prior to and then every 2–4 hours following chemotherapy for a total of four to six doses a day. Dronabinol may cause undesirable side effects such as dysphoria, and it is available only for oral administration. A patient receiving antiemetics (eg, lorazepam, prochlorperazine, metoclopramide) along with chemotherapy on an outpatient basis must be escorted to and from the clinic, since the antiemetics often induce marked sedation and transient impairment of balance and reflexes. Antiemetics are more effective when given prophylactically. Therefore, regular dosing of an agent such as lorazepam or prochlorperazine is recommended after chemotherapy until the emetogenic effects have dissipated. This is dependent on the patient as well as on the type of chemotherapy administered. One problem with all combinations of antiemetic agents is the development of tachyphylaxis over 4–5 days with continuing highly emetogenic chemotherapy. This limits the effectiveness of any regimen.
10040:10:1 Grunberg SM et al: Control of chemotherapy-induced emesis. N Engl J Med 1993;329:1790. (Mechanisms and treatment.)
10040:10:2 Perez EA: Review of the preclinical pharmacology and comparative efficacy of 5-hydroxytryptamine-3 receptor antagonists for chemotherapy-induced emesis. J Clin Oncol 1995;13:1036. (This is a highly effective class of antiemetic agents, and all three studied appear to be relatively equivalent.)
Gastrointestinal & Skin Toxicity
Since antimetabolites such as methotrexate and fluorouracil act only on rapidly proliferating cells, they damage the cells of mucosal surfaces such as the gastrointestinal tract. Methotrexate has similar effects on the skin. These toxicities are at times more serious than bone marrow suppression, and they should be looked for routinely when these agents are used. Erythema of the buccal mucosa is an early sign of mucosal toxicity. If therapy is continued beyond this point, oral ulceration will develop. In general, it is wise to discontinue therapy at the time of appearance of early oral ulceration. This finding usually heralds the appearance of similar but potentially more serious ulceration at other sites lower in the gastrointestinal tract. Therapy can usually be reinstituted when the oral ulcer heals (7–10 days). The dose of drug used may need to be modified downward at this point, with titration to an acceptable level of mucosal toxicity. Adequate mouth care with antimicrobial mouthwashes and attention to dental hygiene are essential and may prevent severe toxicity. Common mouthwashes include the microbicidal oral rinse chlorhexidine and a mixture of salt and bicarbonate of soda in warm water, which aids in debridement of dead mucosa. A prophylactic antifungal mouthwash such as nystatin oral suspension may also be used. High doses of methotrexate require special consideration as noted in the following section. Radiation therapy may cause xerostomia, which can lead to difficulty in swallowing, discomfort, and gum disease. Pilocarpine hydrochloride, 5–10 mg orally three times a day, can relieve symptoms of dry mouth but must be used regularly.
Miscellaneous Drug-Specific Toxicities
The toxicities of individual drugs have been summarized in Table 4–4. Several of these warrant additional mention, since they occur with commonly administered agents, and special preventive measures are often indicated.
A. Hemorrhagic Cystitis Induced by Cyclophosphamide or Ifosfamide: Metabolic products of cyclophosphamide that retain cytotoxic activity are excreted into the urine. Some patients appear to metabolize more of the drug to these active excretory products. If their urine is concentrated, the toxic metabolite may cause severe bladder damage. Patients receiving cyclophosphamide must be advised to maintain a high fluid intake. Early symptoms of bladder toxicity include dysuria and frequency despite the absence of bacteriuria. Such symptoms develop in about 20% of patients who receive the drug chronically. If microscopic hematuria develops, it is advisable to stop the drug temporarily or switch to a different alkylating agent, increase fluid intake, and administer a urinary analgesic such as phenazopyridine. With severe cystitis, large segments of bladder mucosa may be shed and the patient may have prolonged gross hematuria. Such patients should be observed for signs of urinary obstruction and may require cystoscopy for removal of obstructing blood clots. The risk of developing hemorrhagic cystitis is dose-related. For high doses of cyclophosphamide, preventive continuous bladder irrigation with 0.9% saline solution is used during the period of drug administration and for the following 24 hours. The cyclophosphamide analog ifosfamide can cause severe hemorrhagic cystitis when used alone. However, when it is used in conjunction with a series of doses of the neutralizing agent mesna, bladder toxicity can be prevented. Mesna can also be used to prevent cystitis in patients receiving cyclophosphamide in high doses.
B. Vincristine-Induced Neuropathy: Neuropathy is a toxic side effect that is peculiar to the vinca alkaloid drugs, especially vincristine. The peripheral neuropathy can be sensory, motor, autonomic, or a combination of these effects. In its mildest form, it consists of paresthesias of the fingers and toes. Occasional patients develop acute jaw or throat pain after vincristine therapy. This may be a form of trigeminal or glossopharyngeal neuralgia. With continued vincristine therapy, the paresthesias may extend to the proximal interphalangeal joints, hyporeflexia can appear in the lower extremities, and weakness may develop in the quadriceps muscle group. At this point, it is wise to discontinue vincristine therapy until the neuropathy has subsided. A useful means of judging whether peripheral motor neuropathy is severe enough to warrant stopping treatment is to have the patient attempt to do deep knee bends or rise from a chair without using the arm muscles. Constipation is the most common symptom of autonomic neuropathy associated with vincristine therapy. Patients receiving vincristine should be started on stool softeners and mild cathartics when therapy is begun; otherwise, severe impaction may result along with an atonic bowel. More serious autonomic involvement can lead to acute intestinal ileus with signs indistinguishable from those of an acute abdomen. Bladder neuropathies are uncommon but may be severe. These two complications are absolute contraindications to continued vincristine therapy. The majority of symptoms from vincristine are mild and resolve slowly after therapy has been completed. Paclitaxel, cisplatin, carboplatin, and vinorelbine can also cause peripheral neuropathy, though as a rule symptoms improve gradually after treatment is stopped.
C. Methotrexate Toxicity and Citrovorum Rescue: In addition to standard uses of methotrexate for cancer chemotherapy, this drug is also used in very high doses that could lead to fatal bone marrow toxicity if given without an antidote. High-dose methotrexate therapy with leucovorin rescue is routinely used to treat osteogenic sarcoma, acute lymphocytic leukemia, and some cases of non-Hodgkin's lymphoma. The bone marrow and mucosal toxicity of methotrexate can be prevented by early administration of leucovorin. Serum levels of methotrexate are usually monitored and doses of leucovorin adjusted accordingly. Rescue is required for methotrexate doses over 80 mg/m2 and is usually begun within 4 hours after completing treatment. Up to 100 mg/m2 of leucovorin is given initially every 6 hours, with further doses adjusted for the serum methotrexate level. Rescue is usually continued orally for 3 days or longer until the serum methotrexate level is below 0.05 mmol/L. If an overdose of methotrexate is administered accidentally, leucovorin therapy should be initiated as soon as possible, preferably within 1 hour. Intravenous infusion should be employed for larger overdosages to ensure adequate drug delivery. It is generally advisable to give leucovorin repeatedly in this situation. Vigorous hydration and bicarbonate loading also appear to be important in preventing crystallization of high-dose methotrexate in the renal tubular epithelium. Serum creatinine is determined before beginning therapy and daily thereafter, since methotrexate excretion is slowed by renal insufficiency and toxicity will be enhanced. In high doses, methotrexate can itself cause renal injury. Methotrexate doses are reduced in renal insufficiency. Concomitant use of certain drugs will slow methotrexate excretion, and they are avoided during therapy. These drugs include aspirin, NSAIDs, penicillins, sulfonamides, and probenecid.
D. Busulfan Toxicity: The alkylating agent busulfan, occasionally used for the treatment of chronic myelogenous leukemia, has curious delayed toxicities, including increased skin pigmentation, a wasting syndrome similar to that seen in adrenal insufficiency, and progressive pulmonary fibrosis. Patients who develop either of the latter two problems should be switched to a different drug (eg, melphalan) when further therapy is needed. The pigmentary changes are innocuous and will usually regress slowly after treatment is discontinued. Long-term treatment with busulfan also results in an increased risk of secondary leukemias.
E. Bleomycin Toxicity: This antibiotic has found increasing application in cancer chemotherapy in view of its activity in squamous cell carcinomas, Hodgkin's disease, non-Hodgkin's lymphomas, and testicular tumors. Bleomycin can produce edema of the interphalangeal joints and hardening of the palmar and plantar skin. More serious toxicities include an anaphylactic or serum sickness-like reaction and a potentially fatal pulmonary fibrotic reaction (seen especially in elderly patients receiving a total dose of over 300 units). If a nonproductive cough, dyspnea, and pulmonary infiltrates develop, the drug is discontinued, and high-dose corticosteroids are instituted as well as empiric antibiotics pending cultures. Fever alone or with chills is an occasional complication of bleomycin treatment and is not an absolute contraindication to continued treatment. The fever may be avoided by hydrocortisone administration just prior to the injection. Fever alone is not predictive of pulmonary toxicity. About 1% of patients (especially those with lymphoma) may have a severe or even fatal hypotensive reaction after the initial dose of bleomycin. In order to identify and treat such patients, it is wise to administer a test dose of 5 units of bleomycin first and to have adequate monitoring and emergency facilities available. Patients exhibiting a hypotensive reaction should not receive further bleomycin therapy.
F. Doxorubicin-Induced Cardiomyopathy: The anthracycline antibiotics doxorubicin and daunomycin both have acute and delayed cardiac toxicity. The problem is greater with doxorubicin because it has a major role and is used in repeated doses in the treatment of sarcomas, breast cancer, lymphomas, acute leukemia, and certain other solid tumors. Studies of left ventricular function and endomyocardial biopsies indicate that some changes in cardiac dynamics occur in most patients by the time they have received 300 mg/m2 of doxorubicin. The multiple-gated ("MUGA") radionuclide cardiac scan is the most useful noninvasive test for assessing toxicity. Doxorubicin should not be used in elderly patients with intrinsic cardiac disease. In general, patients should not receive a total dose in excess of 550 mg/m2, and 1–10% of patients who receive this dose develop cardiomyopathy. Patients who have had prior chest or mediastinal radiotherapy may develop doxorubicin heart disease at lower total doses. The appearance of a high resting pulse may herald the appearance of cardiac toxicity. Unfortunately, the toxicity may be irreversible and frequently fatal at dosage levels above 550 mg/m2. At lower doses (eg, 350 mg/m2), the symptoms and signs of cardiac failure generally respond well to digitalis, diuretics, and cessation of doxorubicin therapy. Recent evidence suggests that cardiac toxicity can be correlated with high peak plasma levels obtained with intermittent high-dose bolus therapy (eg, every 3–4 weeks). Use of weekly injections or low-dose continuous infusion schedules appears to delay the occurrence of cardiac toxicity. Current laboratory studies suggest that cardiac toxicity may be due to a mechanism involving the formation of intracellular free radicals in cardiac muscle. Pretreatment with dexrazoxane, an iron chelator that decreases free radical formation, appears to protect the myocardium from anthracycline-induced injury but may also reduce the anticancer efficacy of the anthracycline. Dexrazoxane is now approved for the prevention of cardiomyopathy in women with metastatic breast cancer receiving cumulative doxorubicin doses > 300 mg/m2. Liposomally encapsulated doxorubicin and daunorubicin have been FDA-approved and appear to have minimal cardiac toxicity. Their main use to date has been to treat Kaposi's sarcoma. Newer anthracycline analogs include idarubicin, which has shown efficacy against acute nonlymphocytic leukemia and breast cancer when used in combination with other agents. Idarubicin appears to have a similar potential for causing cardiotoxicity when compared with other anthracyclines, though a maximum lifetime dosage recommendation has not yet been made.
G. Cisplatin Nephrotoxicity and Neurotoxicity: Cisplatin is effective in the treatment of testicular, bladder, and ovarian cancer as well as in several other types of tumor. Nausea and vomiting are common, but nephrotoxicity and neurotoxicity are more serious. Vigorous hydration with or without mannitol diuresis may substantially reduce nephrotoxicity. Renal function must be carefully monitored during cisplatin therapy, as should serum magnesium, which may fall during therapy with this agent. Ototoxicity is a potentially serious neurotoxicity that can result in deafness. The neurotoxicity of this drug is delayed and is more common after a total dose of 300 mg/m2. Other manifestations include peripheral neuropathy of mixed sensorimotor type that may be associated with painful paresthesias. These supportive measures do not appear to reduce the therapeutic effectiveness of cisplatin. The second-generation platinum analog carboplatin is now available and has been shown to be as effective as cisplatin in ovarian cancer. Carboplatin is less nephrotoxic and causes less severe nausea or vomiting, but it does induce myelosuppression. Amifostine, an organic thiophosphate initially developed as a radioprotective agent, has efficacy in preventing renal toxicity from cisplatin. It has recently been approved to reduce cumulative renal toxicity associated with repeat administration of cisplatin in advanced ovarian cancer. In addition, amifostine may reduce cytotoxic chemotherapy-induced hematologic toxicity and neurotoxicity. Glutathione also appears to be a promising agent in preventing cisplatin neurotoxicity. Glutathione was given at a dose of 1.5 g/m2 intravenously before cisplatin administration, then at a dose of 600 mg by intramuscular injection on days 2–5.
H. Alpha Interferon Toxicities: While alpha interferon is generally tolerated in the standard doses listed in Table 4–4, it has increasing toxicity with increasing doses and is more toxic in elderly patients. Even standard doses may be intolerable to some patients. Fever and chills are initial side effects but are infrequent after continued treatment. These symptoms may be ameliorated or prevented by premedication with acetaminophen and bedtime dosing. However, anorexia, fatigue, and weight loss can be cumulative and with time may become severe. These symptoms may be dose- or treatment-limiting. Thirty percent or more of patients are intolerant of interferon therapy even at low doses. In some patients, central nervous system symptoms develop, usually manifested as confusion or somnolence. Reduction in peripheral blood counts can develop, but this abnormality is usually not clinically important and may even be a desired effect in the treatment of chronic myelogenous leukemia. These interferon-induced side effects are sometimes confused with the symptoms of progressive cancer. The side effects usually clear within 1 week after cessation of interferon therapy.
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