Radiation Therapy for Cancer

Key Points
Radiation therapy uses high-energy radiation to
kill cancer cells by damaging their DNA.
Radiation therapy can damage normal cells as
well as cancer cells. Therefore, treatment must be
carefully planned to minimize side effects.
The radiation used for cancer treatment may
come from a machine outside the body, or it may
come from radioactive material placed in the body
near tumor cells or injected into the bloodstream.
A patient may receive radiation therapy before,
during, or after surgery, depending on the type of
cancer being treated.
Some patients receive radiation therapy alone,
and some receive radiation therapy in combination
with chemotherapy.

1. What is radiation therapy?

Radiation therapy uses high-energy radiation

to shrink tumors and kill cancer cells (1). X-
rays,gamma rays, and charged particles are
types of radiation used for cancer treatment.
 The radiation may be delivered by a machine
outside the body (external-beam radiation
therapy), or it may come from radioactive
material placed in the body near cancer cells
(internal radiation therapy, also
called brachytherapy).

Systemic radiation therapy uses radioactive

substances, such as radioactive iodine, that
travel in the blood to kill cancer cells.

About half of all cancer patients receive some

type of radiation therapy sometime during the
course of their treatment.

2. How does radiation therapy kill cancer

cells?

Radiation therapy kills cancer cells by

damaging their DNA (the molecules inside
cells that carrygenetic information and pass it
from one generation to the next) (1). Radiation
therapy can either damage DNA directly or
create charged particles (free radicals) within
the cells that can in turn damage the DNA.

Cancer cells whose DNA is damaged beyond

repair stop dividing or die. When the damaged
 cells die, they are broken down and eliminated
by the bodys natural processes.

3. Does radiation therapy kill only cancer

cells?

No, radiation therapy can also damage normal

cells, leading to side effects (see Question 10).

Doctors take potential damage to normal cells

into account when planning a course of
radiation therapy (see Question 5). The
amount of radiation that normal tissue can
safely receive is known for all parts of the
body. Doctors use this information to help
them decide where to aim radiation during
treatment.

4. Why do patients receive radiation therapy?

Radiation therapy is sometimes given with

curative intent (that is, with the hope that the
treatment will cure a cancer, either by
eliminating a tumor, preventing
cancer recurrence, or both) (1). In such cases,
radiation therapy may be used alone or in
combination with surgery, chemotherapy, or
both.
 Radiation therapy may also be given with
palliative intent. Palliative treatments are not
intended to cure. Instead, they
relieve symptoms and reduce the suffering
caused by cancer.

Some examples of palliative radiation therapy

are:

Radiation given to the brain to shrink tumors

formed from cancer cells that have spread to
the brain from another part of the body
(metastases).
Radiation given to shrink a tumor that is
pressing on the spine or growing within a
bone, which can cause pain.
Radiation given to shrink a tumor near
the esophagus, which can interfere with a
patients ability to eat and drink.
5. How is radiation therapy planned for an
individual patient?

A radiation oncologist develops a patients

treatment plan through a process called
treatment planning, which begins
with simulation.
During simulation, detailed imaging scans
show the location of a patients tumor and the
normal areas around it. These scans are
usually computed tomography (CT) scans, but
they can also include magnetic resonance
imaging (MRI), positron emission
tomography (PET), and ultrasoundscans.

CT scans are often used in treatment planning for

radiation therapy. During CT scanning, pictures of the
inside of the body are created by a computer linked to
an x-ray machine.

Computed Tomography
Scanner

During simulation and daily treatments, it is

necessary to ensure that the patient will be in
exactly the same position every day relative to
the machine delivering the treatment or doing
the imaging. Body molds, head masks, or
other devices may be constructed for an
individual patient to make it easier for a patient
to stay still. Temporary skin marks and even
tattoos are used to help with precise patient
positioning.
 Patients getting radiation to the head may need a mask. The
mask helps keep the head from moving so that the patient is
in the exact same position for each treatment.

Radiation Therapy Head

Mask

After simulation, the radiation oncologist then

determines the exact area that will be treated,
the total radiation dose that will be delivered to
the tumor, how much dose will be allowed for
the normal tissues around the tumor, and the
safest angles (paths) for radiation delivery.

The staff working with the radiation oncologist

(including physicists and dosimetrists) use
sophisticated computers to design the details
of the exact radiation plan that will be used.
After approving the plan, the radiation
oncologist authorizes the start of treatment. On
the first day of treatment, and usually at least
weekly after that, many checks are made to
ensure that the treatments are being delivered
exactly the way they were planned.

Radiation doses for cancer treatment are

measured in a unit called a gray (Gy), which is
a measure of the amount of radiation energy
absorbed by 1 kilogram of human tissue.
Different doses of radiation are needed to kill
different types of cancer cells.

Radiation can damage some types of normal

tissue more easily than others. For example,
thereproductive organs (testicles and ovaries)
are more sensitive to radiation than bones.
The radiation oncologist takes all of this
information into account during treatment
planning.

If an area of the body has previously been

treated with radiation therapy, a patient may
not be able to have radiation therapy to that
area a second time, depending on how much
radiation was given during the initial treatment.
If one area of the body has already received
the maximum safe lifetime dose of radiation,
another area might still be treated with
radiation therapy if the distance between the
two areas is large enough.

The area selected for treatment usually

includes the whole tumor plus a small amount
 of normal tissue surrounding the tumor. The
normal tissue is treated for two main reasons:

To take into account body movement from

breathing and normal movement of the
organs within the body, which can change the
location of a tumor between treatments.
To reduce the likelihood of tumor recurrence
from cancer cells that have spread to the
normal tissue next to the tumor
(called microscopic local spread).
6. How is radiation therapy given to patients?

Radiation can come from a machine outside

the body (external-beam radiation therapy) or
from radioactive material placed in the body
near cancer cells (internal radiation therapy,
more commonly called brachytherapy).
Systemic radiation therapy uses a radioactive
substance, given by mouth or into a vein, that
travels in the blood to tissues throughout the
body.

The type of radiation therapy prescribed by a

radiation oncologist depends on many factors,
including:
 The type of cancer.
The size of the cancer.
The cancers location in the body.
How close the cancer is to normal tissues that
are sensitive to radiation.
How far into the body the radiation needs to
travel.
The patients general health and medical
history.
Whether the patient will have other types of
cancer treatment.
Other factors, such as the patients age and
other medical conditions.

External-beam radiation therapy

External-beam radiation therapy is most often

delivered in the form of photon beams (either
x-rays or gamma rays) (1). A photon is the
basic unit of light and other forms
of electromagnetic radiation. It can be thought
of as a bundle of energy. The amount of
energy in a photon can vary. For example, the
photons in gamma rays have the highest
energy, followed by the photons in x-rays.

Many types of external-beam radiation

Linear Accelerator Used for
External-beam Radiation
Therapy
therapy are delivered using a machine
called a linear accelerator (also called a
LINAC). A LINAC uses electricity to
form a stream of fast-moving subatomic
particles. This creates high-energy
radiation that may be used to treat
cancer.

Patients usually receive external-beam

radiation therapy in daily treatment sessions
over the course of several weeks (see
Question 7). The number of treatment
sessions depends on many factors, including
the total radiation dose that will be given.

One of the most common types of external-

beam radiation therapy is called 3-
dimensional conformal radiation
therapy (3D-CRT). 3D-CRT uses very
sophisticated computer software and
advanced treatment machines to deliver
radiation to very precisely shaped target areas.
 Many other methods of external-beam
radiation therapy are currently being tested
and used in cancer treatment. These methods
include:

Intensity-modulated radiation
therapy (IMRT): IMRT uses hundreds of tiny
radiation beam-shaping devices, called
collimators, to deliver a single dose of
radiation (2). The collimators can be
stationary or can move during treatment,
allowing the intensity of the radiation beams
to change during treatment sessions. This
kind of dose modulation allows different areas
of a tumor or nearby tissues to receive
different doses of radiation.

Unlike other types of radiation therapy, IMRT

is planned in reverse (called inverse treatment
planning). In inverse treatment planning, the
radiation oncologist chooses the radiation
doses to different areas of the tumor and
surrounding tissue, and then a high-powered
computer program calculates the required
number of beams and angles of the radiation
treatment (3). In contrast, during traditional
(forward) treatment planning, the radiation
 oncologist chooses the number and angles of
the radiation beams in advance and
computers calculate how much dose will be
delivered from each of the planned beams.

The goal of IMRT is to increase the radiation

dose to the areas that need it and reduce
radiation exposure to specific sensitive areas
of surrounding normal tissue. Compared with
3D-CRT, IMRT can reduce the risk of some
side effects, such as damage to the salivary
glands (which can cause dry mouth,
or xerostomia), when the head and neck are
treated with radiation therapy (4). However,
with IMRT, a larger volume of normal tissue
overall is exposed to radiation. Whether IMRT
leads to improved control of tumor growth and
better survival compared with 3D-CRT is not
yet known (4).

Image-guided radiation therapy (IGRT): In

IGRT, repeated imaging scans (CT, MRI, or
PET) are performed during treatment. These
imaging scans are processed by computers to
identify changes in a tumors size and location
due to treatment and to allow the position of
the patient or the planned radiation dose to be
 adjusted during treatment as needed.
Repeated imaging can increase the accuracy
of radiation treatment and may allow
reductions in the planned volume of tissue to
be treated, thereby decreasing the total
radiation dose to normal tissue (5).
Tomotherapy: Tomotherapy is a type of
image-guided IMRT. A tomotherapy machine
is a hybrid between a CT imaging scanner
and an external-beam radiation therapy
machine (6). The part of the tomotherapy
machine that delivers radiation for both
imaging and treatment can rotate completely
around the patient in the same manner as a
normal CT scanner.

Tomotherapy machines can capture CT

images of the patients tumor immediately
before treatment sessions, to allow for very
precise tumor targeting and sparing of normal
tissue.

Like standard IMRT, tomotherapy may be

better than 3D-CRT at sparing normal tissue
from high radiation doses (7).
However, clinical trials comparing 3D-CRT
with tomotherapy have not been conducted.
 Stereotactic radiosurgery: Stereotactic
radiosurgery (SRS) can deliver one or more
high doses of radiation to a small tumor (5, 8).
SRS uses extremely accurate image-guided
tumor targeting and patient positioning.
Therefore, a high dose of radiation can be
given without excess damage to normal
tissue.

SRS can be used to treat only small tumors

with well-defined edges. It is most commonly
used in the treatment of brain or spinal tumors
and brain metastases from other cancer
types. For the treatment of some brain
metastases, patients may receive radiation
therapy to the entire brain (called whole-brain
radiation therapy) in addition to SRS.

SRS requires the use of a head frame or

other device to immobilize the patient during
treatment to ensure that the high dose of
radiation is delivered accurately.

Stereotactic body radiation

therapy: Stereotactic body radiation therapy
(SBRT) delivers radiation therapy in fewer
sessions, using smaller radiation fields and
 higher doses than 3D-CRT in most cases. By
definition, SBRT treats tumors that lie outside
the brain and spinal cord. Because these
tumors are more likely to move with the
normal motion of the body, and therefore
cannot be targeted as accurately as tumors
within the brain or spine, SBRT is usually
given in more than one dose (8). SBRT can
be used to treat only small, isolated tumors,
including cancers in the lung and liver (8).

Many doctors refer to SBRT systems by their

brand names, such as the CyberKnife.

Proton therapy: External-beam radiation

therapy can be delivered by proton beams as
well as the photon beams described above.
Protons are a type of charged particle.

Proton beams differ from photon beams

mainly in the way they deposit energy in living
tissue. Whereas photons deposit energy in
small packets all along their path through
tissue, protons deposit much of their energy
at the end of their path (called the Bragg
peak) and deposit less energy along the way.
 In theory, use of protons should reduce the
exposure of normal tissue to radiation,
possibly allowing the delivery of higher doses
of radiation to a tumor (9). Proton therapy has
not yet been compared with standard
external-beam radiation therapy in clinical
trials (10, 11).

Other charged particle beams: Electron

beams are used to irradiate superficial
tumors, such as skin cancer or tumors near
the surface of the body, but they cannot travel
very far through tissue (1). Therefore, they
cannot treat tumors deep within the body.

Patients can discuss these different methods

of radiation therapy with their doctors to see if
any is appropriate for their type of cancer and
if it is available in their community or through a
clinical trial (see Question 11).

Internal radiation therapy

Internal radiation therapy (brachytherapy) is

radiation delivered from radiation sources
(radioactive materials) placed inside or on the
body (12). Several brachytherapy techniques
are used in cancer treatment. Interstitial
brachytherapy uses a radiation source placed
within tumor tissue, such as within a prostate
tumor. Intracavitary brachytherapy uses a
source placed within a surgical cavity or a
body cavity, such as the chest cavity, near a
tumor. Episcleral brachytherapy, which is used
to treat melanoma inside the eye, uses a
source that is attached to the eye.

In brachytherapy, radioactive isotopes are

sealed in tiny pellets or seeds. These seeds
are placed in patients using delivery devices,
such as needles, catheters, or some other type
of carrier. As the isotopes decay naturally, they
give off radiation that damages nearby cancer
cells.

If left in place, after a few weeks or months,

the isotopes decay completely and no longer
give off radiation. The seeds will not cause
harm if they are left in the body (see
permanent brachytherapy, described below).

Brachytherapy may be able to deliver higher

doses of radiation to some cancers than
 external-beam radiation therapy while causing
less damage to normal tissue (1, 12).

Brachytherapy can be given as a low-dose-

rate or a high-dose-rate treatment:

In low-dose-rate treatment, cancer cells

receive continuous low-dose radiation from
the source over a period of several days
(1, 12).
In high-dose-rate treatment, a robotic
machine attached to delivery tubes placed
inside the body guides one or more
radioactive sources into or near a tumor, and
then removes the sources at the end of each
treatment session. High-dose-rate treatment
can be given in one or more treatment
sessions.

An example of a high-dose-rate treatment is

the MammoSite system, which is being
studied to treat patients with breast
cancer who have undergone breast-
conserving surgery.

The placement of brachytherapy sources can

be temporary or permanent (1, 12):
 For permament brachytherapy, the sources
are surgically sealed within the body and left
there, even after all of the radiation has been
given off. The remaining material (in which the
radioactive isotopes were sealed) does not
cause any discomfort or harm to the patient.
Permanent brachytherapy is a type of low-
dose-rate brachytherapy.
For temporary brachytherapy, tubes
(catheters) or other carriers are used to
deliver the radiation sources, and both the
carriers and the radiation sources are
removed after treatment. Temporary
brachytherapy can be either low-dose-rate or
high-dose-rate treatment.

Doctors can use brachytherapy alone or in

addition to external-beam radiation therapy to
provide a boost of radiation to a tumor while
sparing surrounding normal tissue (12).

Systemic radiation therapy

In systemic radiation therapy, a patient

swallows or receives an injection of a
radioactive substance, such as radioactive
 iodine or a radioactive substance bound to
a monoclonal antibody.

Radioactive iodine (131I) is a type of systemic

radiation therapy commonly used to help treat
some types of thyroid cancer. Thyroid cells
naturally take up radioactive iodine.

For systemic radiation therapy for some other

types of cancer, a monoclonal antibody helps
target the radioactive substance to the right
place. The antibody joined to the radioactive
substance travels through the blood, locating
and killing tumor cells. For example:

The drug ibritumomab tiuxetan (Zevalin) has

been approved by the Food and Drug
Administration (FDA) for the treatment of
certain types of B-cell non-Hodgkin
lymphoma(NHL). The antibody part of this
drug recognizes and binds to a protein found
on the surface of B lymphocytes.
The combination drug regimen
of tositumomab and iodine I 131
tositumomab (Bexxar) has been approved
for the treatment of certain types of NHL. In
this regimen, nonradioactive tositumomab
 antibodies are given to patients first, followed
by treatment with tositumomab antibodies that
have 131I attached. Tositumomab recognizes
and binds to the same protein on B
lymphocytes as ibritumomab. The
nonradioactive form of the antibody helps
protect normal B lymphocytes from being
damaged by radiation from 131I.

Many other systemic radiation therapy drugs

are in clinical trials for different cancer types.

Some systemic radiation therapy drugs relieve

pain from cancer that has spread to the bone
(bone metastases). This is a type of palliative
radiation therapy. The radioactive
drugssamarium-153-lexidronam (Quadramet)
and strontium-89 chloride (Metastron) are
examples of radiopharmaceuticals used to
treat pain from bone metastases (13).

7. Why are some types of radiation therapy

given in many small doses?

Patients who receive most types of external-

beam radiation therapy usually have to travel
to the hospital or an outpatient facility up to 5
 days a week for several weeks. One dose (a
single fraction) of the total planned dose of
radiation is given each day. Occasionally, two
treatments a day are given.

Most types of external-beam radiation therapy

are given in once-daily fractions. There are two
main reasons for once-daily treatment:

To minimize the damage to normal tissue.

To increase the likelihood that cancer cells
are exposed to radiation at the points in
the cell cycle when they are most vulnerable
to DNA damage (1, 14).

In recent decades, doctors have tested

whether other fractionation schedules are
helpful (1), including:

Accelerated fractionationtreatment given in

larger daily or weekly doses to reduce the
number of weeks of treatment.
Hyperfractionationsmaller doses of
radiation given more than once a day.
 Hypofractionationlarger doses given once a
day or less often to reduce the number of
treatments.

Researchers hope that different types of

treatment fractionation may either be more
effective than traditional fractionation or be as
effective but more convenient.

8. When will a patient get radiation therapy?

A patient may receive radiation therapy before,

during, or after surgery. Some patients may
receive radiation therapy alone, without
surgery or other treatments. Some patients
may receive radiation therapy and
chemotherapy at the same time. The timing of
radiation therapy depends on the type of
cancer being treated and the goal of treatment
(cure or palliation).

Radiation therapy given before surgery is

called pre-operative or neoadjuvant radiation.
Neoadjuvant radiation may be given to shrink
a tumor so it can be removed by surgery and
be less likely to return after surgery (1).
Radiation therapy given during surgery is
called intraoperative radiation therapy (IORT).
IORT can be external-beam radiation therapy
(with photons or electrons) or brachytherapy.
When radiation is given during surgery, nearby
normal tissues can be physically shielded from
radiation exposure (15). IORT is sometimes
used when normal structures are too close to a
tumor to allow the use of external-beam
radiation therapy.

Radiation therapy given after surgery is called

post-operative or adjuvant radiation therapy.

Radiation therapy given after some types of

complicated surgery (especially in the
abdomen or pelvis) may produce too many
side effects; therefore, it may be safer if given
before surgery in these cases (1).

The combination of chemotherapy and

radiation therapy given at the same time is
sometimes called chemoradiation or
radiochemotherapy. For some types of cancer,
the combination of chemotherapy and
radiation therapy may kill more cancer cells
 (increasing the likelihood of a cure), but it can
also cause more side effects (1, 14).

After cancer treatment, patients receive

regular follow-up care from their oncologists to
monitor their health and to check for possible
cancer recurrence. Detailed information about
follow-up care can be found in the National
Cancer Institute fact sheet Follow-up Care
After Cancer Treatment, which is available
at http://www.cancer.gov/cancertopics/factshe
et/therapy/followupon the Internet.

9. Does radiation therapy make a patient

radioactive?

External-beam radiation does not make a

patient radioactive.

During temporary brachytherapy treatments,

while the radioactive material is inside the
body, the patient is radioactive; however, as
soon as the material is removed, the patient is
no longer radioactive. For temporary
brachytherapy, the patient will usually stay in
the hospital in a special room that shields
other people from the radiation.
During permanent brachytherapy, the
implanted material will be radioactive for
several days, weeks, or months after the
radiation source is put in place. During this
time, the patient is radioactive. However, the
amount of radiation reaching the surface of the
skin is usually very low. Nonetheless, this
radiation can be detected by radiation monitors
and contact with pregnant woman and young
children may be restricted for a few days or
weeks.

Some types of systemic radiation therapy may

temporarily make a patients bodily fluids (such
as saliva, urine, sweat, or stool) emit a low
level of radiation. Patients receiving systemic
radiation therapy may need to limit their
contact with other people during this time, and
especially avoid contact with children younger
than 18 and pregnant women.

A patients doctor or nurse will provide more

information to family members and caretakers
if any of these special precautions are needed.
Over time (usually days or weeks), the
radioactive material retained within the body
 will break down so that no radiation can be
measured outside the patients body.

10. What are the potential side effects of

radiation therapy?

Radiation therapy can cause both early (acute)

and late (chronic) side effects. Acute side
effects occur during treatment, and chronic
side effects occur months or even years after
treatment ends (1). The side effects that
develop depend on the area of the body being
treated, the dose given per day, the total dose
given, the patients general medical condition,
and other treatments given at the same time.

Acute radiation side effects are caused by

damage to rapidly dividing normal cells in the
area being treated. These effects include skin
irritation or damage at regions exposed to the
radiation beams. Examples include damage to
the salivary glands or hair loss when the head
or neck area is treated, or urinary problems
when the lower abdomen is treated.

Most acute effects disappear after treatment

ends, though some (like salivary
 gland damage) can be permanent. The
drug amifostine (Ethyol) can help protect the
salivary glands from radiation damage if it is
given during treatment. Amifostine is the only
drug approved by the FDA to protect normal
tissues from radiation during treatment. This
type of drug is called a radioprotector. Other
potential radioprotectors are being tested in
clinical trials (see Question 11).

Fatigue is a common side effect of radiation

therapy regardless of which part of the body is
treated. Nausea with or without vomiting is
common when the abdomen is treated and
occurs sometimes when the brain is treated.
Medications are available to help prevent or
treat nausea and vomiting during treatment.

Late side effects of radiation therapy may or

may not occur. Depending on the area of the
body treated, late side effects can include (1):

Fibrosis (the replacement of normal tissue

with scar tissue, leading to restricted
movement of the affected area).
Damage to the bowels, causing diarrhea and
bleeding.
 Memory loss.
Infertility (inability to have a child).
Rarely, a second cancer caused by radiation
exposure.

Second cancers that develop after radiation

therapy depend on the part of the body that
was treated (16). For example, girls treated
with radiation to the chest for Hodgkin
lymphoma have an increased risk of
developing breast cancer later in life. In
general, the lifetime risk of a second cancer is
highest in people treated for cancer as children
or adolescents (16).

Whether or not a patient experiences late side

effects depends on other aspects of their
cancer treatment in addition to radiation
therapy, as well as their individual risk factors.
Some chemotherapy drugs, genetic risk
factors, and lifestyle factors (such as smoking)
can also increase the risk of late side effects.

When suggesting radiation therapy as part of a

patients cancer treatment, the radiation
oncologist will carefully weigh the known risks
 of treatment against the potential benefits for
each patient (including relief of symptoms,
shrinking a tumor, or potential cure). The
results of hundreds of clinical trials and
doctors individual experiences help radiation
oncologists decide which patients are likely to
benefit from radiation therapy.

A more comprehensive discussion of acute

and late side effects from radiation therapy, as
well as ways to cope with these side effects,
can be found in the NCI publications Radiation
Therapy and You: Support for People With
Cancer (http://www.cancer.gov/cancertopics/ra
diation-therapy-and-you) and the Radiation
Therapy Side Effects Fact
Sheets(http://www.cancer.gov/cancertopics/wt
k/index).

11. What research is being done to

improve radiation therapy?

Doctors and other scientists are conducting

research studies called clinical trials to learn
how to use radiation therapy to treat cancer
more safely and effectively. Clinical trials allow
researchers to examine the effectiveness of
 new treatments in comparison with standard
ones, as well as to compare the side effects of
the treatments.

Researchers are working on improving image-

guided radiation so that it provides real-time
imaging of the tumor target during treatment.
Real-time imaging could help compensate for
normal movement of the internal organs from
breathing and for changes in tumor size during
treatment.

Researchers are also

studying radiosensitizers and radioprotectors,
chemicals that modify a cell's response to
radiation:

Radiosensitizers are drugs that make cancer

cells more sensitive to the effects of radiation
therapy. Several agents are under study as
radiosensitizers. In addition, some anticancer
drugs, such as 5-fluorouracil and cisplatin,
make cancer cells more sensitive to radiation
therapy.
Radioprotectors (also called radioprotectants)
are drugs that protect normal cells from
damage caused by radiation therapy. These
drugs promote the repair of normal cells
exposed to radiation. Many agents are
currently being studied as potential
radioprotectors.

The use of carbon ion beams in radiation

therapy is being investigated by researchers,
but, at this time, the use of these beams
remains experimental. Carbon ion beams are
available at only a few medical centers around
the world. They are not currently available in
the United States. Researchers hope that
carbon ion beams may be effective in treating
some tumors that are resistant to traditional
radiation therapy.

People with cancer who are interested in

taking part in a clinical trial should talk with
their doctor. A comprehensive list of current
clinical trials is available on NCIs Web site
athttp://www.cancer.gov/clinicaltrials on the
Internet.

NCI's Cancer Information Service (CIS) can

also provide information about clinical trials
and help with clinical trial searches. Call the
CIS at 18004CANCER (18004226237)
Diabetes and cancer
The U.S. incidence of both diabetes mellitus and
cancer is increasing. Approximately 1.6 million new
cases of diabetes mellitus and 1.4 million of cancer are
diagnosed every year.

Pankaj Shah, M.D., of the Division of Endocrinology,

Diabetes, Metabolism, & Nutrition at Mayo Clinic, says:
"Evidence suggests that these 2 common conditions
coexist more often than would be expected to occur by
chance.

"Large cohort studies show that pancreatic, colorectal,

breast, hepatobiliary, bladder, and endometrial cancers
occur more frequently in people with type 2 diabetes.
Potential reasons behind this association include
common causality (shared risk factors), hyperglycemia,
and other metabolic abnormalities of type 2 diabetes
that cause cancer, and cancer that causes
hyperglycemia."

Older age, male sex, obesity, diminished physical

activity, a diet high in calories and glycemic index,
excessive alcohol intake, and tobacco smoking are
associated with increased risk of diabetes, as well as
many cancers.
Mechanisms linking cancer and diabetes mellitus

Enlarge

Dr. Shah explains: "A common thread for many of

these risk factors is hyperinsulinemia. Insulin induces
cell proliferation. Hyperinsulinemia, insulin resistance,
and obesity are associated with increased estrogens,
endometrial hyperplasia, and breast and endometrial
cancers.

"Obesity is also associated with increased insulinlike

growth factor 1 (IGF-1) activity due to reduced levels of
insulinlike growth factor binding proteins 1 and 2. Most
malignant cells express IGF-1 receptors. Activation of
IGF-1 receptors by IGF-1 or insulin, or both, is thought
to have an important role in carcinogenesis. Whether
exogenously administered insulin used to control
hyperglycemia promotes cancer growth in vivo is still an
open question."

In 1956, Otto Warburg proposed that cancer cells

preferentially use large amounts of glucose through
glycolysis to produce lactate, whereas most
nonmalignant cells completely oxidize glucose through
the citric acid cycle. Potential mechanisms linking
cancer and type 2 diabetes include the following:

Glycolysis upregulation may support

carcinogenesis. Cancer cells may have a defective
mitochondrial metabolism and may have
overexpression of the glucose transporter GLUT-1.
Hyperglycemia may be responsible for excess
glucose supply to these glucose-hungry cells,
resistance to apoptosis, oncogenesis, and tumor
cell resistance to therapy. However, hyperglycemia
associated with type 1 diabetes is not associated
with these cancers. Moreover, hyperglycemia
correction has yet to show reduction in cancer
incidence in people with type 2 diabetes.
Hyperglycemia and hyperinsulinemia are associated
with endothelial proliferation and neovascularization
(in the retina). Vascular growth is essential to the
fuel supply required for malignancy maintenance.
Therefore, it is conceivable that vascular growth is
stimulated in people with type 2 diabetes, thus
promoting cancers.
Some cancers (such as pancreatic cancer) are
associated with newly diagnosed diabetes.
Cytokines and other substances released from
cancers can cause hyperglycemia by inducing
insulin resistance.
 Cancer-related decreased physical activity can
reduce insulin sensitivity.
Cancers are associated with varying degrees of
cachexia, and cachexia-associated muscle wasting
leads to insulin resistance.

Managing diabetes in patients with

cancer
Treating diabetes in a person with active cancer is often
complicated by the cancer, cancer therapies, and the
adverse effects of treatment (such as anorexia, nausea,
weight loss). Acute diabetes complications and the
urgency of treating severe hyperglycemia may delay
cancer treatment.

Dr. Shah advises: "Tight glycemic control carries

clinically important risks without clear benefits in
patients with cancer. The goals of therapy should be to
prevent marked hyperglycemia (>180 mg/dL) and the
adverse effects of treatment (eg, hypoglycemia,
anemia, increased risk of fractures).

"Hyperglycemia first recognized during cancer therapy

should not be neglected, and the patient and the family
should be taught to monitor blood glucose
concentrations. Hyperglycemia can and possibly will
occur again during subsequent treatment cycles. If
hyperglycemia is recognized and appropriately treated,
severe acute hyperglycemic complications can be
prevented.

"The health care provider must understand the patient's

distressing situation. We take special care to share with
the patient and the family that we understand their
difficult situation. We tell them that we know that they
are likely overwhelmed by the complexity of their
multiple therapies and the adverse effects emanating
from cancer and cancer therapies.

"Usually, this conversation is followed with clarification

of the purpose of home glucose monitoring and
hyperglycemia therapy. We stress that our goal is to
prevent severe acute hyperglycemic and infective
complications while avoiding complications from
hyperglycemia therapies and ensuring timely optimal
cancer therapy. Patients often participate in the
decision making about the goals and modes of
hyperglycemia therapies."

Choosing antidiabetic agents

Marked hyperglycemia is associated with poor
outcomes in cancer patients. Thus, most experts
recommend treatment of severe hyperglycemia.

Growing evidence shows that metformin use is

associated with lower cancer incidence and lower
cancer mortality rate than is treatment with
sulfonylureas or insulin. The adenosine
monophosphate-activated protein kinase (AMPK)
pathway is involved in cancer growth, and metformin
activates AMPK.

Currently, 10 studies registered at clinicaltrials.gov are

investigating possible benefits of metformin in cancer
patients. These studies include patients with advanced
cancers and patients with breast, pancreatic, and
prostate cancers.

Mutation of peroxisome proliferator-activated receptor g

(PPAR-g) is involved in carcinogenesis.
Thiazolidinediones are PPAR-g agonists and are being
investigated to see whether they enhance outcomes
from anticancer therapy in patients with breast, lung,
prostate, and head and neck carcinomas; sarcoma; and
premalignant conditions.

Clinical use of antidiabetic agents

Dr. Shah recommends: "If tolerated and not
contraindicated, metformin is the first line oral agent.
Metformin may cause nausea and diarrhea, which can
be confused with complications of cancer or its
therapies.

"Insulin is usually effective in controlling severe

hyperglycemia. In our experience, intensive insulin
therapy using multiple insulin injections may be easier,
providing the patient with freedom of time and amount
of food.

"The so-called sliding scale insulin regimen is

associated with the worst glycemic extremes and
should be avoided. If diabetes is treated with agents
that predispose to hypoglycemia (eg, sulfonylureas,
other insulin secretagogues, intermediate-acting or
mixed insulin), meals should be timed throughout the
day.

"When life expectancy with terminal cancer is brief,

blood glucose monitoring is performed only when
symptom control requires it, with the sole aim of making
the person comfortable."

http://www.ncbi.nlm.nih.gov/pubmed/11961197

Another factor that complicates the relationship is the

treatments given to patients. Diabetes drugs can have an
impact on cancer prognosis and vice versa. Type 2
diabetics treated with the drug metformin, for
example,develop cancer less frequently than diabetics
given other medications. A number of clinical trials are
now under way to see how well the drug performs as a
cancer treatment.
Drugs used against cancer, on the other hand, tend to
worsen diabetes. Chemotherapy can wreak havoc
on blood sugar levels, and glucocorticoids, which are
 widely prescribed to alleviate nausea in cancer patients,
promote insulin resistance, said Dr. Lorraine L.
Lipscombe of Womens College Hospital in Toronto.

Chemotherapy and Nutrition

Chemotherapy affects cells all
through the body.
Chemotherapy affects fast-growing cells and is
used to treat cancer because cancer cells grow
and divide quickly. Healthy cells that normally grow
and divide quickly may also be killed. These
include cells in the mouth, digestive tract, and hair
follicles.

Chemotherapy may affect nutrition.

Chemotherapy may cause side effects that cause
problems with eating and digestion. When more
than one anticancer drug is given, more side
effects may occur or they may be more severe.
The following side effects are common:

Loss of appetite.
Inflammation and sores in the mouth.
 Changes in the way food tastes.
Feeling full after only a small amount of food.
Nausea.
Vomiting.
Diarrhea.
Constipation. (See the Constipation section for
more information.)

Nutrition therapy can help relieve

nutrition problems caused by
chemotherapy.
Patients who have side effects from chemotherapy
may not be able to eat normally and get all the
nutrients they need to restore healthy blood
counts between treatments. Nutrition therapy can
help relieve these side effects, help patients
recover from chemotherapy, prevent delays in
treatment, prevent weight loss, and maintain
general health. Nutrition therapy may include the
following:

Nutrition supplement drinks between meals.

Enteral nutrition (tube feedings).
 Changes in the diet, such as eating small meals
throughout the day.

Radiation Therapy and Nutrition

Radiation therapy can affect cancer
cells and healthy cells in the
treatment area.
Radiation therapy can kill cancer cells and healthy
cells in the treatment area. The amount of damage
depends on the following:

The part of the body that is treated.

The total dose of radiation and how it is given.

Radiation therapy may affect

nutrition.
Radiation therapy to any part of the digestive
system often has side effects that cause nutrition
problems. Most of the side effects begin a few
weeks after radiation therapy begins and go away
a few weeks after it is finished. Some side effects
can continue for months or years after treatment
ends.
 The following are some of the more common side
effects:

For radiation therapy to the head and neck

o Loss of appetite.
o Changes in the way food tastes.
o Pain when swallowing.
o Dry mouth or thick saliva.
o Sore mouth and gums.
o Narrowing of the upper esophagus, which can
cause choking, breathing, and swallowing
problems.
For radiation therapy to the chest
o Infection of the esophagus.
o Trouble swallowing.
o Esophageal reflux (a backward flow of the
stomach contents into the esophagus).
For radiation therapy to the abdomen or pelvis
o Diarrhea.
o Nausea.
o Vomiting.
o Inflamed intestines or rectum.
o A decrease in the amount of nutrients absorbed
by the intestines.

Radiation therapy may also cause tiredness, which

can lead to a decrease in appetite.

Nutrition therapy can help relieve the

nutrition problems caused by
radiation therapy.
Nutrition therapy during radiation treatment can
help the patient get enough protein and calories to
get through treatment, prevent weight loss,
help wound and skin healing, and maintain general
health. Nutrition therapy may include the following:

Nutritional supplement drinks between meals.

Enteral nutrition (tube feedings).
Changes in the diet, such as eating small meals
throughout the day.

Patients who receive high-dose radiation therapy to

prepare for a bone marrow transplant may have
 many nutrition problems and should see
a dietitian for nutrition support.

See the Stem Cell Transplant and Nutrition section

for more information.

The Effect of Nonmalignant Systemic

Disease on Tolerance to Radiation
Therapy
1. Brian H. Chon and
2. Jay S. Loeffler
+ Author Affiliations
1. Department of Radiation Oncology,
Massachusetts General Hospital, Harvard
Medical School, Boston, Massachusetts,
USA
1. Jay S. Loeffler, M.D., Massachusetts General Hospital,
Department of Radiation Oncology, 100 Blossom Street,
Boston, Massachusetts 02114, USA. Telephone: 617-726-
8653; Fax: 617-726-3603; e-mail: jloeffler@partners.org
Received November 5, 2001.

Accepted March 4, 2002.

Next Section
Abstract
Purpose. Some patients with nonmalignant systemic
diseases, like collagen vascular disease (CVD), hypertension,
diabetes mellitus, and inflammatory bowel disease (IBD),
tolerate radiation therapy poorly. Although the mechanisms
of each of these disease processes are different, they share a
common microvessel pathology that is potentially
exacerbated by radiotherapy. This article reviews and
evaluates available data examining the effects of these
benign disease processes on radiation tolerance.
Methods. We conducted a thorough review of the Anglo-
American medical literature from 1960 to 2001 on the effects
of radiotherapy on CVD, hypertension, diabetes mellitus, and
IBD.
Results. Fifteen studies were identified that examined the
effects of radiation therapy for cancer in patients with CVDs.
Thirteen of 15 studies documented greater occurrences of
acute and late toxicities (range 7%-100%). Higher rates of
complications were noted especially for nonrheumatoid
arthritis CVDs. Nine studies evaluated the effects of
hypertension and diabetes on radiation tolerance. All nine
studies documented higher rates of late toxicities than in a
control group (range 34%-100%). When patients had both
diabetes and hypertension, the risk of late toxicities was even
higher. Six studies examined radiation tolerance of patients
with IBD irradiated to the abdomen and pelvis. Five of these
six studies showed greater occurrences of acute and late
toxicities for patients with IBD, even with precautionary
measures like reduced fraction size and volume and patient
immobilization (13%-29%).
Conclusion. The majority of published studies documented
lower radiation tolerance for patients who have CVD,
diabetes mellitus, hypertension, and IBD. This may reflect a
publication bias, as the majority of these studies are
retrospective with small numbers of patients and use
different scoring scales for complications. These factors may
contribute to an overestimation of true radiation-induced
morbidity. Although the paucity of data makes precise
estimates difficult, a subset of patients, in particular, those
with active CVD, IBD, or a combination of uncontrolled
hypertension with type I diabetes, is likely to be at higher
risk. Future prospective trials need to document these disease
entities when reporting treatment-related complications and
also must monitor toxicities associated with quiescent versus
active IBD and CVD, type I versus type II diabetes, and
levels of hypertension (controlled versus uncontrolled)
matched for radiation-specific treatment sites, field size,
fractionation, and total dose.
Collagen vascular disease

Hypertension

Diabetes

Inflammatory bowel disease

Radiation therapy
Previous SectionNext Section
INTRODUCTION
Collagen vascular disease (CVD) and inflammatory bowel
disease (IBD) are considered relative contraindications for
radiotherapy. Common diseases, like diabetes mellitus and
hypertension, also represent management quandaries
inasmuch as some reports also implicate these prevalent
diseases with reduced tolerance to radiotherapy. This report
reviews the relevant clinical literature published in the last 40
years and outlines the potential mechanisms for radiation-
induced morbidity with the aforementioned diseases.

CVDs constitute a heterogeneous consortium of ailments

highlighted by alterations in immunoregulation. Although the
precise mechanism and pathogenesis of immunological
dysfunction remain an enigma, the resulting clinical entities,
known as rheumatoid arthritis, systemic lupus erythematosus
(SLE), polymyositis, systemic sclerosis, and mixed
connective tissue disease, are characterized by a combination
of periarticular, perimuscular, and perivascular inflammation
[1, 2]. In some institutions, CVDs are considered relative
contraindications for radiotherapy for fear of greater risks of
acute and late complications [3,6].
Mechanistically, diabetes and hypertension have similar
vascular pathologies as CVDs, albeit without the
autoimmune etiology [1, 2, 7]. Von Lothar et al. [8]
described marked medial hypertrophy with luminal
narrowing in the arterioles of patients with hypertension.
Similarly, chronic diabetes can cause microvascular
occlusive changes leading to capillary hyalinization,
arteriolar obliteration, and atherosclerosis with resultant
tissue hypoxia [1]. Diabetics also have increased blood
viscosity, which can lead to further tissue ischemia [1, 2].
IBD, comprised of ulcerative colitis and Crohn's disease, is a
disease marked by inflammation of the bowel, a pattern of
familial occurrence, and systemic manifestation [1, 2]. Much
like the CVD publications, the literature on IBD treated with
external beam radiation has been limited to case reports
detailing one to five patients [9, 10]. In general, these reports
emphasize the marked intolerance to radiation of patients
with IBD.
Mechanistically, IBD shares similar characteristics with the
previously described CVD. The microscopic hallmark of
Crohn's disease is transmural nodular lymphoid aggregates,
accompanied by proliferative changes of the muscularis
mucosa, vessels, and nerves of the myenteric plexus [1, 2].
Endothelial edema in small blood vessels, transmural
fibrosis, and excess collagen deposition are prominent. In
ulcerative colitis, highly vascular granulation tissue develops
in denuded mucosal areas. Although the level of fibrosis is
usually less than that seen with Crohn's disease, chronic
perivascular inflammatory infiltrate in the mucosa and
submucosa is appreciable. Consequently, the potential for
radiotherapy to add to this milieu of inflammatory vascular
changes is certainly plausible.
Previous SectionNext Section
METHODS

We performed a systematic review of published Anglo-

American literature that examined the effects of CVD,
diabetes, hypertension, and IBD on radiation tolerance.
Computer searches were conducted with the key words and
synonyms for CVD, lupus, scleroderma, polyarteritis,
hypertension, diabetes, IBD, radiation tolerance, and
morbidity. MEDLINE (U.S. National Library of Medicine)
and CANCERLIT (U.S. National Cancer Institute)
databases were used in the search, which included a time
period of 1960 through 2001. This selection procedure
resulted in the identification of 42 studies. The published
studies were examined for information regarding radiation
tolerance. The numbers and characteristics of patients, years
of follow-up, institutional settings, tumor types, radiation
dose, radiation fractionation, and acute and late toxicities
were recorded.

Previous SectionNext Section

RESULTS
CVDs
In all, over 300 reported cases examined the potential risks
associated with radiotherapy in patients with CVDs. This
review primarily focuses on studies reporting on a substantial
number of patients with adequate follow-up (Table 1).
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Table 1.

Trials correlating severe acute and late toxicities (RTOG

Grade 3) of radiation therapy and CVD
The largest and perhaps the most cited study on this subject
was published byMorris and Powell in 1997 [11]. Their
study retrospectively reviewed 209 patients with CVDs
treated between 1960 and 1995 at Massachusetts General
Hospital (MGH). Sixty-four percent of these patients had
rheumatoid arthritis, 12% had lupus, 8% had scleroderma,
8% had dermatomyositis/polmyositis, and 2% had mixed
connective tissue disorder. The median dose of radiation was
45 Gy (range 13 to 82.1 Gy). With a median follow-up of 6
years, the authors noted 12.4% and 11.7% risks of significant
acute toxicity (defined as Radiation Therapy Oncology
Group/Eastern Cooperative Oncology Group [RTOG/ECOG]
Early Morbidity Scoring Scale >3) in nonrheumatoid and
rheumatoid arthritis patients, respectively. They also reported
a 6% risk of significant late morbidity (defined as
RTOG/ECOG Late Morbidity Scoring Scale >3) for
rheumatoid arthritis patients and a 21% risk for
nonrheumatoid arthritis patients at 5 years. Although no
control arm was included in this study, the authors concluded
that rheumatoid arthritis patients had an equal risk of
significant acute and late toxicities compared with patients
without collagen vascular disorder, while patients with
nonrheumatoid arthritis had a significantly higher risk of late
toxicity from radiation therapy. This study, however, did not
correlate dose, fraction size, and irradiated volume with late
effects.
Another large series that implicated radiotherapy with
significant morbidity in patients with collagen vascular
disorder was published by Teo et al. [12]. When compared
with other nasopharyngeal carcinoma patients diagnosed and
treated in the same hospital, those with dermatomyositis had
a higher rate of late toxicities. Two out of 10 patients
developed chronic skin necrosis 7-9 months postradiation,
and all 10 patients developed chronic indurated subcutaneous
fibrosis in the treatment field. All 10 patients were treated to
a median dose of 70 Gy at 1.8-2.0 Gy per fraction (fx).
A 1993 study by Ross et al. [13], had the strength of a
matched-pair case-control study design. Sixty-one patients
with CVD were compared with a matched control group of
61 patients without CVD. These patients were matched for
age, stage, and treatment sites. The CVD population had very
similar proportions of the different CVDs as the previous
MGH study, with 64% rheumatoid arthritis, 21% lupus, 8%
dermatomyositis, and 7% scleroderma. Sixty percent of these
patients were treated with curative doses, exceeding 40 Gy.
The remaining patients were treated with palliative doses
of less than 40 Gy. With a median follow-up period of 18
months, Ross et al. reported 11% and 7% rates of acute
toxicities (RTOG > Grade 3) for CVD and non-CVD
patients, respectively and 10% and 7% late toxicity (RTOG >
grade 3) for CVD and non-CVD patients, respectively. In
both the acute and late toxicity comparisons, there was not a
statistically significant difference between the CVD and non-
CVD arms. In addition, this analysis could not correlate the
risk of radiation effects with anatomical sites of irradiation.
When the data were analyzed according to specific CVDs,
patients with rheumatoid arthritis had a trend toward higher
risk for late toxicity than patients in the control arm, at 24%
and 5%, respectively (p = 0.125). Interestingly, patients with
lupus had a higher risk for acute reactions compared with
patients in the control arm, at 36% and 18%, respectively,
although this also was statistically nonsignificant (p = 0.5).
Overall, this study did not show greater risks for acute and
late toxicities for patients with CVD when matched with a
control group. Unlike the MGH study, nonrheumatoid
patients in this trial did not fair worse than rheumatoid
arthritis patients.
Two publications reported the effects of total lymphoid
irradiation for refractory rheumatoid arthritis. Trentham et al.
[14] reported on 10 patients who were treated with 30 Gy of
radiation at 1.8-2.0 Gy/fx. Even with these modest doses,
20% of patients experienced acute diarrhea and 10% had
chronic, persistent radiation enteritis. The second publication
from Kotzin et al. [15] reported on Stanford University
Medical Center's experience with total lymphoid irradiation
for rheumatoid patients. Eleven patients were treated with 20
Gy of radiation at 1.5-2.2 Gy/fx. One patient developed
pulmonary fibrosis, and two patients developed pericarditis
requiring steroid therapy. Although the number of cases was
small, there was a trend among the refractory rheumatoid
patients toward a greater sensitivity to even the modest doses
of radiation used in this treatment protocol.
Rakfal and Deutsch documented six patients with SLE
treated with radiotherapy [16]. The doses utilized ranged
from 25.4-60 Gy. Although the number of patients was
small, this report represents the fourth largest publication of
CVD patients treated with radiotherapy. None of the patients
treated with radiotherapy developed unexpected acute or late
complications. The authors consequently concluded that
CVDs are not contraindications for radiation.
A study by Fleck et al. [17] revealed no complications
among five patients whose CVD was diagnosed after
radiation therapy, whereas three of four patients whose
disease was diagnosed before radiation therapy had
complications. In addition, Varga et al. [18] described one
patient who received two courses of radiation therapy, one
before the onset of scleroderma and the other 4 years later.
The first course of radiation therapy was well tolerated, but
the patient had severe complications after the second course
delivered to a different anatomical site. Therefore, these
studies suggest that the toxicities associated with radiation
therapy in patients with CVD exist only if the CVD is
present or active at the time of radiation delivery.
Significant systemic exacerbation of the CVD process after
localized radiation therapy has also been described in the
literature. Robertson et al. [19] described two patients, one
with rheumatoid arthritis and the other with scleroderma,
who were treated with breast irradiation and subsequently
developed diffuse activation of inflammation and fibrosis.
The rheumatoid arthritis patient developed progressive joint
inflammation outside the radiation port that required gold,
nonsteroidal anti-inflammatory drugs, and intraarticular
aspirations for symptomatic relief. The patient's rheumatoid
arthritis had been quiescent prior to her irradiation, requiring
no immunoregulatory drugs. The second patient, with
scleroderma, developed severe fibrosis of the esophagus,
which was in the radiation port, 27 months post radiation
therapy.
Delanian et al. [20] attempted to ameliorate the effects of
curative doses of radiotherapy in patients with CVD by
significantly reducing the dose. In three patients with
diagnosis of quiescent scleroderma, doses were dropped,
from 65 Gy typically used, to 40-45 Gy at 1.8 Gy/fx. Two of
the three patients developed significant late toxicities even
with reduced doses. One patient developed fatal hemorrhagic
alveolitis, and the other developed femoral artery thrombosis
and skin necrosis. The authors concluded that both
significant doses and volumes must be reduced for radiation
to be safely utilized in patients with CVD.
Diabetes and Hypertension
There is a paucity of published literature documenting late
effects of radiation therapy for patients with underlying
diabetes mellitus or hypertension (Table 2). van Nagell et
al. [21] reported on 271 patients treated with definitive
radiotherapy (paracervical dose range 70-90 Gy) for locally
advanced cervical cancer. Their study reported 11 cases of
rectovaginal/vesicovaginal fistulas, with a median follow-up
of 5 years. Five of the 11 fistulas were due to tumor
progression, and six were free of local disease. When
examining these six cases, all six fistulas occurred in patients
with diabetes or hypertension. In fact, 3 out of 6 patients had
diabetes, and the other 3 patients had chronic hypertension.
Two of the 6 cases had both diseases.
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Table 2.

Trials correlating severe acute and late toxicities (RTOG

Grade 3) of radiation therapy and diabetes/hypertension

A second part of that study examined 15 cases where pelvic

exenterations were performed for gynecological
malignancies. None of these patients received radiotherapy
prior to surgery. Six of 15 cases were from patients with
histories of diabetes and/or hypertension. When their surgical
specimens were pathologically examined, 80% revealed
significant arteriolar thickening and luminal narrowing,
defined as a vessel to lumen diameter ratio exceeding 2:1
[21]. None of the nine other surgical specimens from
nondiabetic and normotensive patients showed any evidence
of significant vascular changes.
Maruyama et al. [22] also reported on 270 cervical cancer
patients treated with at least 40 Gy of radiation. With a
median observation period of 60 months, this study
documented 9 out of 270 cases of small bowel obstruction
unrelated to tumor progression. When examined further for
other medical comorbidities, the authors discovered that four
of these nine patients had diabetes and another three had both
hypertension and diabetes. They consequently concluded that
patients with diabetes and hypertension, especially in
combination, were at higher risk of late radiation-induced
toxicities.
One published study looking exclusively at the effects of
diabetes in irradiated patients comes from Herold et al. [23].
This study examined 944 prostate cancer patients treated
with definitive radiation therapy, 121 of whom had a history
of type I or II diabetes. An average dose of 72 Gy of
radiation at 1.8 Gy/fx was delivered utilizing three-
dimensional conformal therapy. With a median follow-up of
36 months, they reported significantly higher rates of late
genitourinary/gastrointestinal (GU/GI) toxicities in the
diabetic population than in the nondiabetic control arm, at
34% and 23%, respectively (p = 0.01). In addition, the
diabetic group also developed their complications earlier than
the control group, at 10 months and 24 months, respectively.
The authors attributed the higher rate of late morbidities to
altered microvasculature in these diabetic patients. With an
already impaired ability to repair tissue damage due to
microvascular occlusive changes, the additional radiation
insult and its documented affect on vascular integrity seem to
lessen their already precarious ability to heal and perfuse
normal tissue.
A study by Goldstein et al. [24] linked radiation-induced
vascular changes with impotence, especially in smokers. The
authors tested the erectile function in 23 patients who
received radiation therapy for prostate cancer. Vascular
testing revealed abnormalities in 15 of 23 patients. In two of
these patients, arteriography revealed bilateral occlusive
disease in the internal pudendal and penile arteries. Cigarette
smoking was found among the 15 men whose erectile
capacity was decreased. The authors concluded that
vasculogenic impotence was the primary cause for erectile
abnormality after radiation therapy.
Eifel et al. [25] published on 3,495 patients treated with
radiation therapy for Stage I or II carcinomas of the cervix.
The authors observed that late GI complications of 1,172
smokers were more than twice that of 2,143 nonsmokers
(11.6% versus 5.4% at 10 years; p = 0.0001). The authors
also noted that the risk of GU complications was
significantly higher for diabetics (5.5%) than for
nondiabetics (3.8%) (p = 0.04). Microvascular change from
smoking, diabetes, and radiation was postulated as the
potential etiology for the observed greater morbidity.
Harwood and Tierie [26] published a series from Holland
documenting the effects of diabetes, hypertension, or both
diabetes and hypertension on head and neck radiotherapy. A
total of 204 localized glottic cancer patients were treated with
definitive radiotherapy to a mean dose of 62 Gy in 30
fractions. The authors noted that diabetes and/or
hypertension significantly contributed to subsequent risk for
major complications. These major late complications
included severe edema requiring tracheotomy, necrosis of the
larynx, or laryngeal stenosis. When patients were both
hypertensive (defined as having >100 mm Hg diastolic blood
pressure or on antihypertensive medication) and diabetic
(type I or II), the risk of major chronic complication was
67% versus 5% for nondiabetic, normotensive patients (p =
0.01). When diabetics were compared with nondiabetics, the
risk for major complications was 30% versus 6% (p = 0.024).
When hypertensive patients were compared with
normotensive patients, there was a trend toward a higher
major complication rate in the former group at 15% and
5.6%, respectively (p = 0.08). Although this study included
only 39 patients with diabetes and/or hypertension, it further
documents the potential greater toxicities associated with
these comorbidities.
Interestingly, a series of articles relating central nervous
system (CNS) toxicities with diabetes has been
published. Smith et al. [27] reported on a 33-year-old male
with a history of poorly controlled type I diabetes treated
with definitive radiation therapy for localized
nasopharyngeal carcinoma. The patient received 65 Gy in 30
fractions to the nasopharynx with 45 Gy to the spinal cord.
The patient subsequently expired with the diagnosis of brain
stem necrosis. On postmortem exam, foci of edema,
demyelination, and infarction were noted along the brain
stem. The small- and medium-sized vessels revealed hyaline
deposition, endothelial edema, necrosis, and perivascular
lymphocytic infiltration. Although these are typical findings
associated with high-dose radiotherapy, the authors speculate
that microvascular damage already induced by the patient's
prior diabetes mellitus was responsible for his severe
complications following standard-dose radiation therapy.
Correlating this pathological finding with clinical
data, Debus et al. [28] published on brain stem tolerance to
conformal radiotherapy for skull-based tumors. They
examined 367 patients treated at MGH with combined
photon/proton beam therapy. Seventeen of these patients
developed brain stem toxicity. The mean dose to the surface
of the brain stem was 64 cGy at 1.8 Gy/fx. Multivariate
analysis identified three independent factors as important
prognosticators, one of which was the prevalence of diabetes
(p < 0.01).
In view of the published literature, diabetes and
hypertension, especially in combination, appear to be
associated with higher toxicity to radiotherapy. Potential
watershed regions of perfusion, like the brain stem and the
retina, may be at additional risk for injury [7, 26].
IBD
Apart from the anecdotal case reports, there are two large
retrospective analyses evaluating the tolerance to radiation in
patients with IBD (Table 3). The largest of these reported
28 patients with histories of IBD and pelvic/abdominal
tumors treated with >40-Gy radiotherapy [29]. With a
median follow-up of 32 months, severe acute and late effects
were 21% and 29%, respectively. The risk for severe late
effects was significantly higher for patients treated without
precautionary measures (such as lateral decubitus position,
proton beam therapy where available, smaller fields, and
scheduled rest periods). The risk of late effects at 5 years was
reduced by 50% by using some or all of the aforementioned
precautionary measures (p = 0.01). The authors did not find a
poorer prognosis for patients with Crohn's disease versus
ulcerative colitis or active versus quiescent IBD.
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Table 3.

Trials correlating severe acute and late toxicities (RTOG

Grade 3) of IBD and radiation therapy

Green et al. [30] have also retrospectively analyzed their data

from Mount Sinai Medical Center in New York City. Fifteen
patients with histories of IBD and rectal cancer were treated
with radiotherapy (with or without 5-fluorouracil
chemotherapy) to a median dose of 50.4 Gy of radiation at
1.8 Gy/fx. With a follow-up of 5 years, the risk of severe
acute toxicity was 20%, with one patient having a Grade 4 GI
toxicity. In terms of late effects, 2 of 15 patients developed
small bowel obstruction at 2 and 4 months postirradiation.
Previous SectionNext Section
DISCUSSION

Taken as a whole, CVDs share a common pathological theme

of vascular obliteration and fibrosis via heightened
inflammation, and a clinical theme of potential systemic,
visceral involvement. In light of such observations, the
potential for radiotherapy to augment these pathological
changes becomes significant.
Acutely, radiation therapy affects early responding tissues,
like basal dermis and oral/gastric mucosa, by denuding and
stunting their ability to proliferate. This acute effect of
radiotherapy may also act in conjunction with the already
targeted basal layer filled with immune complex and
inflammatory cells. Such common targeting may be additive
to the typical radiation-induced moist desquamation [13].
In the same manner, the additive injury induced by both
radiation and the preexisting CVD process also may help to
explain potentially exaggerated late effects seen in some
patients following radiotherapy. In the connective tissues,
perivascular infiltrates, resulting in immune complex
vasculitis (typical of lupus, mixed connective tissue disorder,
and diabetes mellitus), and vessel obliteration, via excessive
fibroblast proliferation of the dermal connective tissue
(typical of scleroderma and rheumatoid arthritis), are nearly
universally observed [18]. In a similar manner, late radiation
injury affects the same target structures as CVDs. For
instance, cultured fibroblasts from animals treated with
experimental radiation proliferate at an accelerated rate and
produce excessive amounts of collagen in vitro compared
with fibroblasts from matched nonirradiated animals
[31, 32]. Furthermore, radiation-induced obliteration of
capillaries and small vessels is well documented. This
principle underlies the routine use of radiation to obliterate
arteriovascular malformations in the CNS and capillary
bleeding of tumors. Glomus jugulare tumors, which are
typically benign outgrowths of jugular vasculature, are
routinely controlled with relatively low-dose radiation
therapy. In summary, the local effects of radiation therapy on
fibroblasts and blood vessels may potentiate the natural
progression of CVD.
The intriguing issue of radiation therapy activating a
quiescent state of CVD also remains. Several regulatory
peptides have been shown to stimulate fibroblast growth,
chemotaxis, and connective tissue macromolecule
production. Transforming growth factor- (TGF-) is a
cytokine produced by inflammatory cells known to stimulate
collagen synthesis [33, 34]. Ionizing radiation may be
capable of inducing the production or release of fibroblast-
triggering signals from inflammatory cells, endothelial cells,
and fibroblasts. In fact, TGF- was found to be markedly
elevated in irradiated tissue from patients with GI cancer up
to 40 weeks following radiation, suggesting that TGF- may
be implicated in postirradiation fibrosis [33,35].
Furthermore,Rube and colleagues [36,38] correlated acute
and long-lasting increases in the expression of TGF- in lung
tissue with thoracic irradiation. Another potential mechanism
for systemic activation is through radiation-induced
basement membrane damage to capillary endothelial cells.
This could potentially expose antigens to distant parts of the
body for targeting by the preexisting autoimmune process. In
this manner, the release of other potential cytokines from
localized radiation therapy may induce a systemic flair in
nonirradiated tissue by heightening an already hyperactive
immunoregulated milieu. These potential mechanisms of
radiation-induced acute and late effects are diagramed in
Figure 1.
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Figure 1.
Potential mechanism for radiation-induced toxicity in
collagen vascular disorder, diabetes mellitus, and
hypertension.
With active CVD, immunomodulating drugs should be
initiated to bring the disease into clinical remission prior to
commencing radiation therapy. The literature shows a trend
toward better tolerance of radiotherapy when the disease
process is indolent [19, 20]. A reduction in total dose, dose
per fraction, and treatment field size should all be seriously
considered on a case-by-case basis. Careful consideration
should also be given to the integral dose to the skin, and an
attempt should be made to minimize unnecessary hot spots.
The effect of diabetes and chronic hypertension on radiation
tolerance is better understood. Of paramount importance is to
correct the underlying metabolic and autonomic disease.
Clearly, not all patients with diabetes are at equal risk. The
review of literature shows, specifically, that patients with
uncontrolled hypertension in addition to type I diabetes may
be at the highest risk for radiation-induced morbidity [21
,23]. Once again, reduction in dose, dose per fraction, and
treatment field size are practical options for patients with
suspected vascular disease.
IBD patients have a higher incidence of late morbidities with
radiation therapy. However, an encouraging study
from Willett et al. [29] showed the value of specialized
techniques and precautions in delivering the radiation to
minimize bowel toxicity. Patients with longer courses of
indolent IBD, quiescent disease at the time of radiation
delivery, or on prophylactic anti-inflammatory medication
are less likely to develop radiation complications than their
counterparts.

In light of these findings, a limitation of this literature review

needs to be highlighted. The data obtained for this review
were largely gathered, via computer retrieval, from published
retrospective data, which did not report associated
comorbidities in detail. For instance, reports examining the
effects of radiation therapy on diabetes did not distinguish
between type I and type II. Published reports on CVDs did
not routinely distinguish between active and quiescent
disease. Consequently, future studies will need to document
the comorbidities in more detail to better illuminate the
effects of radiotherapy on nonmalignant diseases.

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FUTURE DIRECTIONS FOR INVESTIGATIONS
The presence of nonmalignant systemic diseases like
diabetes, hypertension, CVD, and IBD is associated with
reduced radiation tolerance. Although the literature is sparse
and retrospective in nature, the association of these diseases
with radiation tolerance should no longer be regarded as
anecdotal. The challenge for the future will be to identify
which subset of patients with these common diseases will
tolerate radiation poorly. Furthermore, the exact amount of
risk associated with such high-risk patients also needs to
be quantified. Future prospective trials need to document
these disease entities and their severity when reporting
treatment complications. For instance, active versus
quiescent IBD and collagen vascular disorder and type I
versus type II diabetes require separate assessments. Prior
history of disease control, defined by the number of
surgeries, the types of medication required, and the length of
quiescent periods, may help identify those at higher risk.
Regarding hypertension, future studies that examine specific
vascular pressure in addition to overall blood pressure may
also provide new insights.

Radiation protectors and modifiers might also be helpful for

these patients. The application of such therapy to these
patients should also be actively researched [38, 39].