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CHAPTER 7 Neoplasia
135
cells can be enhanced by treating the patient with specific growth fac-
tors, such as erythropoietin (Epogen) or granulocyte-stimulating
factors (Neupogen).
Hair loss and the sloughing of mucosal membranes are complica-
tions of radiation therapy and chemotherapy. Treatment is designed to
kill the rapidly proliferating cancer cells, but normal cells with high
growth rates such as mucosal epithelia and hair follicle cells are also
damaged. Damaged mucosa is a primary source of cancer pain and
anorexia, and may provide a portal for the invasion of organisms from
the skin or gastrointestinal tract.
Paraneoplastic syndromes are symptom complexes that cannot be
explained by obvious tumor properties and occur in 10% to 15% of
patients with cancer. Many of the syndromes are associated with
excessive production of hormones or cytokines by the tumor. Com-
mon paraneoplastic syndromes include (1) hypercalcemia, (2) Cushing
syndrome secondary to excess adrenocorticotropic hormone (ACTH)
secretion, and (3) hyponatremia and water overload secondary to
excess antidiuretic hormone (SIADH, syndrome of inappropriate
ADH) secretion. Small cell carcinoma of the lung is commonly the
culprit for excess ACTH and ADH syndromes. Hypercalcemia (ele-
vated concentration of serum calcium) is a paraneoplastic syndrome
associated with abnormal production of parathyroid hormone-
related protein (PTHrP) by the tumor cells. Unexplained hypercalce-
mia is regarded as evidence of cancer until proven otherwise.
Hypercalcemia may be a consequence of metastatic bone cancer, and
in this case it would be an expected finding rather than a paraneoplastic
syndrome.
If left untreated, cancer has the potential to kill the host. The cause of
death is multifactorial. Infection, hemorrhage, and organ failure are the
primary causes of cancer death. The failure of cancer-ridden organs such
as the liver, kidney, brain, and lung results in the loss of life-sustaining
functions. Treatment for cancer can also be detrimental to the host by
contributing to immunosuppression and platelet deficiencies. The
cumulative effects of one or more of these factors may lead to death.
of treatment are not selective for cancer cells and result in unavoidable
damage to normal tissue. The immune system, on the other hand, is
noted for its ability to make subtle distinctions between normal and
abnormal or foreign cells. Recognition of tumor cells as different from
their normal counterparts is the basis of tumor immunology. Recogni-
tion depends on the expression of abnormal molecules or antigens on
the cancer cell surface. Unfortunately, most tumor-associated antigens
are also expressed to some degree on normal cells, which makes it dif-
ficult to develop strategies to target cancer cells selectively.
Transplantation of stem cells from the bone marrow or peripheral
blood is an increasingly important aspect of cancer treatment for leu-
kemia, lymphoma, and some solid tumors. The choice of treatment
depends largely on the results of the staging procedure. A greater
degree of metastasis generally requires a more aggressive therapeutic
approach.
Surgery
The majority of patients with solid tumors are treated surgically, which
can be curative in some localized cancers. The main benefit of surgery
is removal of a tumor with minimal damage to other body cells. The
surgeon generally removes a margin of normal-appearing tissue
around the resected tumor to ensure complete tumor removal. Lymph
nodes are subjected to biopsy and also removed if evidence of metasta-
sis is present. Surgical resection of some tumors can be tricky if vital
structures such as neurons or blood vessels are involved.
Surgery involves risks related to the effects of anesthesia, infection,
and blood loss. The surgical procedure may be disfiguring or may
result in loss of function. Surgical resection as the sole treatment for
solid tumors is curative in a minority of patients because most patients
already have undetectable metastases at the time of diagnosis.25 There-
fore, surgical resection is commonly accompanied by radiation therapy
or chemotherapy. Even one remaining cancer cell could be sufficient to
reinitiate tumor formation.
Radiation Therapy
Ionizing radiation is used for two principal reasons: to kill tumor cells
that are not resectable because of location in a vital or inaccessible area
and to kill tumor cells that may have escaped the surgeon’s scalpel and
remain undetected in the local area. Radiation kills cells by damaging
their nuclear DNA. Cells that are rapidly cycling are more susceptible to
radiation death because there is little time for DNA repair. Radiation
may not kill cells directly; rather, it may initiate apoptosis. The P53
tumor suppressor gene is an important mediator of this response. Many
tumors have mutant P53 and may be less susceptible to radiation-
induced cell death.
It is difficult to kill all the cells of a large tumor by irradiation
because they are heterogeneous—they are in different phases of mito-
sis and are cycling at different rates. A single radiation dose large
enough to kill all the tumor cells would be sufficient to kill the normal
cells as well. Radiation is often administered in smaller doses over sev-
eral treatments and is most effective at eradicating small groups of
tumor cells. It is often used in combination with surgery. Radiation is
also useful for palliative reductions in tumor size. Pain from bone and
brain tumors may be effectively managed with radiation therapy that
shrinks the tumor. Tumors with bleeding surfaces may be coagulated
with radiation to decrease blood loss.
A certain degree of destruction of normal cells in the irradiated field
is expected with radiation therapy. Radiation is best used when tumor
cells are regionally located. Total-body irradiation to kill tumor cells in
disseminated locations is not recommended because of the likelihood
of life-threatening tissue damage, although it may be used in prepara-
tion for bone marrow or peripheral stem cell transplantation.
.
KEY POINTS
Regardless of the type of malignancy, affected individuals exhibit charac-
teristic signs and symptoms, including pain, cachexia, bone marrow sup-
pression, and infection.
Bone marrow suppression is manifested as anemia, leukopenia, and
thrombocytopenia.
Immunosuppression with consequent infection is a primary cause of
cancer-associated death.
CANCER THERAPY
The overall 5-year survival rate for patients with cancer is approxi-
mately 68%, with some types of cancer having much higher or lower
rates. Early detection of cancer, while it remains localized in the tissue
of origin, is associated with the best prognosis for cure. Cure implies
eradication of all cancer cells in the body and is different than the
5-year survival rate. Patients with metastatic invasion of regional
lymph nodes still have a good opportunity for cure with appropriate
therapy. Widespread invasion of multiple tissues and organs is associ-
ated with a poor prognosis, and therapy may be aimed at remission or
palliation of symptoms rather than cure. The mainstays of cancer ther-
apy are surgery, radiation therapy, and drug therapy. In some hor-
mone-sensitive tumors (breast, prostate), hormonal blocking drugs
may be used.
Immunotherapy and targeted molecular therapies have begun to
emerge as important treatments for specific cancers. Traditional forms
136
UNIT II Cellular Function
Drug Therapy
Chemotherapy generally refers to the systemic administration of anti-
cancer chemicals as treatment for cancers that are known or suspected
to be disseminated in the body. Unlike surgery or radiation therapy,
which is locally or regionally applied, parenterally administered che-
motherapeutic drugs can find their cancer cell targets in areas through-
out the entire body.
Most chemotherapeutic agents are cytotoxic because they interfere
with some aspect of cell division. The more rapidly dividing cells are
more susceptible to the killing effects of chemotherapeutic agents. In a
large tumor mass, the rates of cell division are very diverse, with many
slowly dividing cells. At any one time, only a portion of the tumor cells
are in a cell cycle stage that is susceptible to chemotherapy. Several
courses of chemotherapy are generally necessary to ensure that all
tumor cells have been killed. It is difficult to kill slowly cycling tumor
cells without also killing normal cells that are cycling at approximately
the same rate. Small tumors are easier to eradicate because rates of cell
division are generally faster. To prevent relapse, the “stem” cells that
develop into clones of malignant cells must be destroyed. Unfortu-
nately, stem cells may not divide as rapidly as other cells. Resection or
irradiation to reduce tumor size may prompt the stem cells to divide,
thus making them more susceptible to chemotherapy. Tumor cells
with mutations of the P53 gene may be resistant to chemotherapeutic
agents that work by damaging DNA, so drugs that act by interfering
with the cancer cell cycle in other ways may be more effective.
Chemotherapeutic agents are not selective for tumor cells, and a
certain amount of normal cell death also occurs. Rapidly dividing cells,
particularly those of the bone marrow, intestinal epithelia, and hair
follicles, are most affected. Bone marrow depression is a most serious
side effect inasmuch as it predisposes the patient to anemia, bleeding,
and infection.
New approaches to cancer drug therapy have emerged that indi-
rectly inhibit tumors rather than seeking to eradicate tumor cells
directly. A promising approach is to interrupt the tumor’s blood supply.
To proliferate, solid tumors must be supplied by a progressively expand-
ing network of capillaries. The development of new capillaries, called
angiogenesis, is accomplished by migration and growth of endothelial
cells. Antiangiogenic drugs block the development of new capillaries.
Immunotherapy
Harnessing the power of the immune system to fight cancer is a par-
ticularly appealing idea because of the potential for specificity. Current
modes of immunomodulation primarily involve the use of interferons,
interleukins, and monoclonal antibodies. These therapies are generally
used as adjuncts to surgery, irradiation, and chemotherapy.
Interferons are glycoproteins produced by immune cells in response
to viral infection. Interferons inhibit cell proliferation and are stimula-
tory to NK cells, T cells, and macrophages. Interferon-a has been used
successfully to treat hairy cell leukemia (a rare B cell malignancy),
chronic myelogenous leukemia, and multiple myeloma. Interferon
therapy produces symptoms similar to those of a viral infection: fever,
chills, and muscle aches.
Interleukins are peptides produced and secreted by white blood
cells. They are also called lymphokines or cytokines. Interleukin-2 (IL-2)
is an important cytokine secreted by activated T helper cells. It stimu-
lates the proliferation of T cells, NK cells, and macrophages. IL-2 can
be used to stimulate the growth of these immune cells in culture.
Immune cells taken from a patient’s blood can be grown in culture in
the presence of IL-2. Then the greatly expanded number of immune
cells can be given back to the patient, along with intravenous infusions
of IL-2. Such treatment has been associated with regression of some
tumors (melanoma, renal cell carcinoma). Because IL-2 toxicity is high
and many individuals have severe allergic reactions, the benefit of ther-
apy must be weighed against the risks for each individual situation.
The use of monoclonal antibodies (antibodies having identical struc-
ture) in cancer therapy is currently the subject of intense investigation.
Monoclonal antibodies specifically bind with target antigens and can
therefore be used in several ways as treatment for cancer. Antibodies can
be used to deliver a cytotoxic drug preferentially to the cancer cell and thus
minimize drug interactions with normal cells. Similarly, antibodies can be
used to direct other cytotoxic cells, such as NK and T cells, to tumor cells
lurking in the body. Antibodies can be attached to a radioactive label and
injected into a patient to screen for recurrence of tumor growth. Antibod-
ies can also be directed against cells that support tumor growth.
Monoclonal antibodies have been developed for management of
several cancers. For example, nearly 25% of breast cancers have overex-
pression of the HER2 receptor on the surface of malignant cells. The
monoclonal antibody trastuzumab specifically binds to this HER2 pro-
tein and helps immune cells to find and kill the tumor cells. A summary
of monoclonal antibody agents and their main tumor protein targets is
shown in Figure 7-19.
Gene and Molecular Therapy
Because cancer is fundamentally a disorder of gene function, the use of
gene therapy to alter the malignant behavior of cells may have high
therapeutic potential.26 As specific gene derangements are identified
for particular tumors, gene therapy may be used to suppress overactive
oncogenes or replenish missing tumor suppressor function. Current
uses of gene therapy for cancer include genetic alteration of tumor cells
to make them more susceptible to cytotoxic agents or immune recog-
nition, and genetic alteration of immune cells to make them more effi-
cient killers of tumor cells.
Tumor cells can also be made more recognizable to immune cells
by insertion of genes that cause the tumor cells to express “foreign”
proteins on their cell surface. This type of gene therapy has shown
some benefit in melanoma and renal carcinoma. Replacement of genes
for P53 is an attractive therapy because tumor cells would be more
susceptible to apoptosis. Gene replacement of other tumor suppressors
such as pRb or APC in those tumors that are deficient could help
inhibit tumor proliferation.
Gene therapy can be directed at cells other than tumor cells to
enhance the body’s cancer defenses. One such approach involves har-
vesting immune cells from the cancer patient, inserting IL-2 genes, and
then returning the genetically enhanced immune cells to the patient.
The enhanced immune cells attack the tumor cells more vigorously
than normal immune cells do and have been shown to persist in the
body for 6 months or longer.
At present, gene therapy is limited by difficulty in delivering the new
genes to the target cells. As methods improve, gene therapy will become
an increasingly important part of cancer prevention and management.
Molecular therapies that target cytoplasmic signaling pathways
have also been developed. For example, in chronic myelogenous leuke-
mia a chromosomal rearrangement results in the abnormal produc-
tion of an enzyme, BCR/ABL. This enzyme stimulates cell proliferation
and contributes to the overproduction of leukemic cells. An agent that
specifically inhibits this enzyme (Gleevec) has dramatically improved
the management of this disease. Other drugs that specifically target
abnormal tumor products are under development.
Stem Cell Transplantation
Transplantation of hematologic stem cells is used to manage life-
threatening disorders in which the patient’s bone marrow is incapable
of manufacturing white blood cells, red blood cells, or platelets. Most
often, nonfunctional marrow is a consequence of the high-dose
CHAPTER 7 Neoplasia
137
Hematologic malignancies
Rituximab
90Y-Ibritumomab tiuxetan
131|-Tositumomab
CD20
Gemtuzumab ozogamicin
CD33
Alemtuzumab
CD52
Imatinib
Dasatinib
BCR-ABL
Solid tumors
HER2/neu
Trastuzumab
Lapatinib
EGFR
Cetuximab
Panitumumab
Erlotinib
Gefitinib
VEGFR
Bevacizumab
Rece
Sorafenib
Sunitinib
VEGF
FIGURE 7-19 Cancer cells express abnormal antigens (tumor-associated antigens) on their cell surface
that can activate immune cells or be used as targets for monoclonal antibodies. Numerous medications
are now available that use monoclonal antibodies to target cellular proteins relevant to several different
types of cancer.
chemotherapy and radiation used to manage hematologic malignancies
such as leukemia and lymphoma. Stem cell transplantation also has
KEY POINTS
been applied to other malignancies (e.g., breast cancer) and to nonma-
• Early detection of cancer while it remains localized is associated with the
lignant disorders (e.g., aplastic anemia, sickle cell anemia, and thalas- best prognosis for cure. The overall 5-year survival rate for patients with
semia). Stem cells can be harvested from aspirates of bone marrow or
cancer is about 68%.
from the donor’s peripheral bloodstream. Bone marrow is rich in stem • The mainstays of cancer therapy are surgery, radiation therapy, and
cells, but the peripheral blood is poor. The stem cell donor can be a
chemotherapy. Surgery and radiation therapy are effective for cancers that
tissue-matched individual (allogeneic), an identical twin (syngeneic),
are localized. Chemotherapy is usually the treatment of choice for cancers
or the patient in question (autologous). A closer match between donor known or suspected to be disseminated in the body.
and recipient is associated with a better outcome.
• Cells that divide rapidly are the most susceptible to damage from radiation
Before infusion of donor stem cells, the patient’s own immune cells
therapy or chemotherapy. However, in addition to cancer cells, rapidly
must be suppressed to prevent transplant rejection. It is also necessary
dividing normal cells may be killed. Cells of the bone marrow, hair follicles,
to eliminate any residual malignant cells from the body to avoid relapse and gastrointestinal mucosa are particularly susceptible.
of the cancer. Both of these objectives are accomplished through high-
• Immunotherapy has the potential to specifically target cancer cells. At
dose chemotherapy and total-body irradiation regimens, which leave present, interferon, IL-2, and numerous monoclonal antibodies are being
the patient susceptible to severe anemia, infection, and bleeding. The
used to boost the immune system’s ability to locate and destroy cancer cells.
therapeutic goal of stem cell transplantation is to restore immune and
• Gene and molecular therapy may be used to alter cancer cells to suppress
hematopoietic function. It may take weeks to months for the infused oncogenes, enhance tumor suppressor genes, make tumor cells more
stem cells to reestablish themselves and begin to proliferate in their susceptible to cytotoxic agents, or interfere with the function of cancer
new host. During this time, the transplant recipient requires intensive
gene products.
monitoring and management of complications.
• Transplantation of hematopoietic stem cells is an important adjunct to
The success of stem cell transplantation depends on a number of cancer therapy that provides a method to restore bone marrow function
factors, including the age of the patient, closeness of tissue matching, after high-dose irradiation or chemotherapy.
stage of cancer, and general health status of the patient before trans-
plantation. Transplantation is an expensive undertaking but may sig-
nificantly improve disease survival rates in some malignancies.27

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