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Advances in radiation therapy and chemotherapy have increased
the chances of survival for people with cancer today. People with
cancer are living longer, so it's becoming more important to study the
long-term effects of cancer treatment. Of all the possible late
complications of cancer treatment, developing a second cancer is one of
the most serious.
People can have more than one cancer in their lifetime. Cancer
is a very common disease, and not all second cancers are due to cancer
treatment. For example, certain inherited gene changes can increase a
woman's risk for both breast and ovarian cancer. Also, being exposed to
certain cancer- causing substances, like tobacco smoke, can put a
person at higher risk for several different cancers, such as cancers of
the lung, larynx, throat, or mouth. Even though it is hard to separate
out the exact cause of any one person's cancer, here we will try to
focus on the risk of second cancers that may be linked to past cancer
treatment.
The National Cancer Institute has sponsored several clinical
trials related to the long-term effects of cancer treatment. These are
helping us to better understand how cancer treatments can affect the
development of second cancers.
Treatments linked to the development of
second cancers
Radiation therapy
Radiation therapy was recognized as a potential cause of
cancer many years ago. In fact, much of what we know about radiation
therapy has come from studying survivors of atomic bomb blasts in
Japan. We also have learned from workers in certain jobs that included
radiation exposure, and patients treated with radiation therapy for
cancer and other diseases.
Acute myelogenous leukemia (AML), chronic myelogenous leukemia
(CML), and acute lymphoblastic leukemia (ALL) have been linked to past
radiation exposure. The risk of leukemia after radiation treatment
depends on a number of factors such as:
- how much of the bone marrow was exposed to radiation
- the amount of radiation that reached active bone marrow
- the radiation dose rate
The person's age when they were treated with radiation does
not seem to be a risk factor. Most cases usually develop within a few
years of radiation treatment, peaking at 5 to 9 years after exposure.
Then the number of cases developing slowly declines over the following
years.
In contrast, other cancers, which are mostly solid tumors,
have been shown to take much longer to develop. Most of these cancers
are not seen for 10 years after radiation therapy and some are
diagnosed even more than 15 years later. The effect of radiation on the
risk of developing a solid tumor cancer depends on such factors as:
- the dose of radiation
- the area treated
- the age of the patient when they were treated with
radiation
In general, the risk of developing a solid tumor after
radiation treatment goes up as the dose of radiation increases. Some
cancers require larger doses of radiation than others, and certain
techniques require more radiation. For example, intensity modulated
radiation therapy (IMRT) helps to protect tissues that are more easily
injured by radiation, but a larger dose of radiation overall must be
used.
The area treated is also important, since these cancers tend
to develop in or near the area that was treated with radiation. Certain
organs, such as the breast and thyroid, seem to be more likely to
develop cancers after radiation than others.
Age at the time of treatment also affects risk. For example,
the risk of developing breast cancer after radiation is higher in those
who were treated when they were young compared with those given
radiation as adults. The chance of developing breast cancer after
radiation seems to be highest in those exposed as children. Risk
decreases as the age at the time of radiation increases, with little or
no increase in breast cancer risk among women who had radiation after
the age of 40. Age at the time of radiation treatment has a similar
effect on the development of other solid tumors, including lung cancer,
thyroid cancer, bone sarcoma, and gastrointestinal or stomach cancers.
Other factors can also affect the risk of radiation-related
cancers. Smoking, for example, increases the risk of lung cancer after
radiation even more. Early menopause can lower the risk of
radiation-related breast cancer. For some cancers, the risk is higher
if chemotherapy was given along with radiation.
More research will probably be done in the future to look at
how genetics and radiation therapy interact, as well as the link
between radiation therapy and other cancer-causing agents.
Chemotherapy
The cancer most often linked to chemotherapy as the cause is a
type of leukemia called acute myelogenous leukemia (AML). Acute
lymphocytic leukemia (ALL) is also a chemotherapy-related cancer and
may make up about 5% to 10% of acute leukemias caused by chemotherapy.
Chemotherapy is known to be a higher risk factor than
radiation therapy in causing leukemia. Studies of patients treated in
the 1970s and 1980s have shown an increased risk of AML after certain
types of chemotherapy drugs called alkylating agents were used to treat
cancers like Hodgkin disease, non-Hodgkin lymphoma (NHL), ovarian,
lung, and breast cancer.
Alkylating agents known to cause leukemia include:
- mechlorethamine
- chlorambucil
- cyclophosphamide (Cytoxan®)
- melphalan,
- semustine,
- lomustine (CCNU),
- carmustine (BCNU),
- prednimustine,
- busulfan,
- dihydroxybusulfan.
The risk gets higher with higher drug doses, longer treatment
time, and higher dose-intensity (meaning that more drug is given over a
short period of time). Studies have shown that leukemia risk begins to
rise about 2 years after treatment with alkylating agents, becomes
highest after 5 to 10 years, and then the risk decreases. Leukemia that
develops after treatment with alkylating agents can be hard to treat
and tends to have a poor outcome.
The chemotherapy drug cisplatin is not an alkylating agent,
but it attacks cancer cells in much the same way. Cisplatin seems to
increase the risk of leukemia, too. This leukemia is hard to treat and
tends to have a poor outcome, much like the leukemia linked to the
alkylating agents. But the risk of developing leukemia after treatment
with cisplatin is not as great as with the alkylating agents. Cisplatin
is used to treat a lot of different cancers, including lung,
testicular, and ovarian cancer. The risk of leukemia rises as the
amount of drug used gets higher. The risk of developing leukemia
increases even more if radiation is given along with the cisplatin.
In more recent years, drugs that are topoisomerase II
inhibitors have also been found to cause leukemia, mainly
AML. Drugs in
this class include etoposide, teniposide, and mitoxantrone. Leukemia
develops sooner after treatment with these drugs, than the leukemia
from alkylating agents. Most cases are found within 2 or 3 years of
treatment. Etoposide (VP-16, Etopophos®,
or Vepesid®)
is used to treat patients with non-small cell lung cancer, testicular
cancer, and ALL, and is linked with an increased risk of developing
AML. Treatment of childhood ALL with teniposide is also thought to
increase the risk of AML. Mitoxantrone (Novantrone®),
used to
treat breast cancer and lymphoma, can also cause acute leukemia.
Leukemia from these drugs acts differently from the leukemia from
alkylating agents -- it responds to treatment better and has a better
outlook.
More recently, evidence has suggested that the class of
chemotherapy drugs called anthracyclines may also cause AML. Examples
of anthracyclines
include the drugs doxorubicin (Adriamycin®),
daunorubicin, and epirubicin (Ellence®).
These drugs are also
topoisomerase II inhibitors, but are less likely to cause leukemia than
etoposide, teniposide, and mitoxantrone.
Cancers linked to the development of second
cancers
No matter what type of cancer is treated, treatments such as
radiation and chemotherapy can lead to a second cancer in the long run.
Because it can take many years for treatment-related cancers to
develop, they have been studied best in those who have lived a long
time after being treated. Successfully treating a first cancer gives a
second cancer the time (and the chance) to develop. The cancers
discussed in this section were some of the first cancers in which
treatment led to long-term survival. It is likely that we will see
second cancers developing after some other cancers as treatment and
survival improves.
Hodgkin disease
Survivors of Hodgkin disease (HD) have a risk of developing
another cancer that is more than 3 times that of people who didn't have
HD (the general population). Overall, the risk of a second cancer is
more than 20% (1 in 5) in the first 20 years after treatment.
An increased risk of acute leukemia has been seen in HD
patients treated with chemotherapy. This is especially true if an
alkylating agent was used, for example, in the combination of drugs
known as MOPP [mechlorethamine, vincristine (Oncovin®),
prednisone, and procarbazine]. Leukemia is much less common in people
treated with the combination known as ABVD [doxorubicin
(Adriamycin®), bleomycin,
vinblastine, and dacarbazine].
Treating HD with radiation alone has little effect on leukemia risk,
but adding radiation to MOPP chemotherapy increases the risk further.
The chance of getting leukemia after HD is related to the patient's age
when they were treated, with the highest risk seen in those treated
after age 40. The risk also seems to go up as the amount of
chemotherapy used increases.
The risk of non-Hodgkin lymphoma (NHL) is also higher in those
who survive HD. Because this risk does not seem to change based on the
type of treatment used, many experts do not think that NHL seen after
HD is caused by cancer treatments.
Radiation therapy for HD has been linked to an increased risk
of developing solid tumor cancers. The risk is highest in the areas
that were in the path of the radiation beam. The most common second
cancer in female survivors of HD is breast cancer. The risk is highest
in those who had radiation to an area in the center of the chest called
the mediastinum
before age 30. (The mediastinum is the area between the
lungs where the heart and its vessels, the trachea, the esophagus, the
thymus, and some lymph nodes are found.) Early in the treatment of HD,
many patients got radiation to the mediastinum as a part of mantle
field radiation. (Mantle field radiation covers the area
of the neck,
chest, and armpits.) Some patients also went into early menopause from
radiation or alkylating agent chemotherapy. In women who went through
menopause before age 40 because of HD treatment, the risk of breast
cancer went down.
Lung cancer risk is also higher after treatment for HD. This
higher risk is related to chest radiation treatments as well as
chemotherapy with alkylating agents. Patients who have both
chemotherapy and radiation are even more likely to develop lung cancer.
Smoking further increases the risk. The risk of lung cancer goes up if
the patient smoked before treatment, but the risk gets even higher if
the patient keeps on smoking after radiation therapy.
The risk of thyroid cancer is also increased in HD patients
who were treated with radiation to the neck. Other cancers that are
seen after radiation include gastrointestinal (stomach) cancer and
sarcoma.
Over time, treatment for HD has changed. Chemotherapy with
alkylating agents has become much less common, and when radiation is
needed, lower doses are used. These changes seem to have helped lower
the cancer risks after treatment, but long-term follow-up studies are
still needed.
Follow-up care
Since there is an increased risk for a second cancer following
treatment for Hodgkin disease, survivors of HD should be carefully
followed up. Your doctors should look for the development of solid
tumors, leukemia, and non-Hodgkin lymphoma along with recurrence of
Hodgkin disease.
All patients should be encouraged to reduce their risk of lung
cancer by avoiding tobacco smoke. Women who were treated with radiation
to the chest (such as mantle field radiation therapy) before age 35
should start breast cancer screening early. There are no standard
guidelines, but many experts recommend that patients treated with this
type of radiation start screening 5 to 8 years after finishing their HD
treatment. This screening should include regular breast exams and
mammograms. Breast MRI (magnetic resonance imaging) could also be
helpful.
Patients who had radiation to their abdomen (belly) should pay
special attention to any abdominal problems and report them to the
doctor right away. Problems like unplanned weight loss, ongoing
diarrhea, or other bowel problems could be a sign of a serious
condition.
Non-Hodgkin lymphoma
Survivors of non-Hodgkin lymphoma (NHL) are at increased risk
of developing some second cancers, but less so than patients who were
treated for Hodgkin disease. Overall, NHL survivors get new cancers
about 15% more often than most people (the general population).
Increased risks of malignant melanoma, lung cancer, and kidney cancer
have been seen in patients who had been treated for NHL.
Survivors of NHL are also at risk for several other cancers
such as:
- Kaposi sarcoma
- cancers of the head/neck area (this includes the
tongue, floor of the mouth, throat, and voice box)
- colon cancer
- thyroid cancer
- bone and soft tissue cancer
- bladder cancer
- leukemia
- Hodgkin disease
Radiation therapy increases the risk of breast cancer in women
who were treated before age 25. Mesothelioma, a rare cancer of the
outer lining of the lung, is also increased in those who were treated
with radiation.
A higher risk of bladder cancer has only been seen in those
who were treated with chemotherapy. The drug cyclophosphamide
(Cytoxan®), especially if used in
higher doses, is linked to
bladder cancer.
Low-dose total body irradiation (TBI), which was once used to
treat NHL, has been linked to an increased risk of leukemia. The risk
of leukemia is also higher in those treated with chemotherapy, with the
highest risk seen in those treated with both radiation and
chemotherapy.
Patients who had autologous bone marrow transplants (meaning
the patient's own bone marrow was used -- not someone else's) are also
at increased risk for developing acute myelogenous leukemia (AML) and
an early form of leukemia called myelodysplastic
syndrome (MDS).
Treatment-related second cancer risk lasts a long time after
NHL, up to 30 years after diagnosis. Those who were diagnosed and
treated at younger ages (20 years old and younger) have a higher risk
than those who were older (70 or older) when they were found to have
NHL.
Follow-up care
Since there is an increased risk for a second cancer following
treatment for NHL, survivors should get careful follow-up. Your doctors
should be looking for the development of any of the above mentioned
cancers as well as the recurrence of NHL.
All patients should be encouraged to avoid tobacco smoke.
Prostate cancer
Men who are treated for prostate cancer with surgery or
radiation therapy actually have a lower risk of cancer as they get
older because prostate cancer is so common in older men. Men whose
prostates have been removed or destroyed with radiation can no longer
get a new case of prostate cancer, but they can get recurrence of the
original prostate cancer if any of the prostate tissue remains.
But men who are treated with radiation therapy, either with
seed implants (brachytherapy) or external beam radiation therapy, have
a higher risk of bladder cancer later on than men who had surgery to
remove their prostates. They may also have a higher risk for rectal
cancer. Men who had seed implants without external radiation have a
slightly lower risk than those who had external beam radiation. The
risk is likely related to the dose of radiation, as it is with other
cancers. Men who get seed implants typically get less radiation to
nearby organs than those who get EBRT, either by itself or along with
seeds. Risk can continue for more than 10 years after treatment.
Follow-up care
Survivors who are treated with radiation have an increased
risk of certain second cancers, so they should get careful follow-up.
There are no special recommendations for watching for second cancers
after prostate treatment at this time. Still, your doctor will be
watching for recurrence of the prostate cancer. Men who have had
radiation to treat prostate cancer should be careful to follow
screening recommendations for colorectal cancer to improve the chance
of early detection. You should also report blood in your urine, rectal
pain, or rectal bleeding to your doctor right away.
All patients should be encouraged to avoid tobacco smoke. Men
who smoke may further increase their risk of bladder cancer after
prostate radiation, since smoking is a known risk factor for bladder
cancer.
Testicular cancer
The most common cancer seen in testicular cancer survivors is
a second testicular cancer. Overall, 2% to 5% of men who have had
cancer in 1 testicle will eventually have it in the other testicle. The
second cancer is not from treating the first cancer with radiation or
chemotherapy. In fact, those treated with surgery alone still have an
increased risk of a second testicular cancer. Also, the chance of
getting a second testicular cancer is actually lower in men who were
treated with chemotherapy. The rest of this section is about second
cancers other than testicular cancer.
Patients treated for testicular cancer have less than one-half
the risk of second cancers than those treated for Hodgkin disease.
Compared with most people (the general population), testicular cancer
survivors are up to twice as likely to develop a new cancer outside the
testicle. The chance of a second cancer goes up over time and also
depends on which treatments were used.
The risk of a solid tumor cancer starts going up within 5
years and doubles after 10 years in those men who were treated with
radiation alone. This risk remains high for more than 35 years after
treatment. The most common cancers seen after abdominal radiation for
testicular cancer are cancers of the bladder, colon, pancreas, and
stomach. Radiation to the abdomen also increases the risk of cancers of
the rectum, kidney, and prostate. If the radiation field includes the
chest (or the part called the mediastinum), the risks of lung cancer
and thyroid cancer are increased. (The mediastinum is the middle part
of the chest, which contains the heart and its vessels, the trachea,
the esophagus, the thymus, and some lymph nodes.) Radiation treatments
also increase the risk of melanoma skin cancer and connective tissue
cancer (sarcoma). The risks are generally greater with higher radiation
doses or if the patient got both chemotherapy and radiation.
In recent years, radiation therapy for testicular cancer has
changed. Lower doses of radiation are used, and preventive treatment to
the mediastinum has been stopped. Long-term follow-up studies are
needed to see if these changes have lowered the cancer risks.
Chemotherapy is linked with an 80% increased risk of solid
tumor cancers -- slightly less than what is seen after radiation. The
risk of leukemia after treatment for testicular cancer is also
increased. Most cases are linked to the chemotherapy drugs cisplatin
and etoposide (VP-16, Etopophos®, or
Vepesid®). Higher
doses of these drugs have a higher risk of leukemia. Leukemia is
normally a rare cancer, so even though the risk of leukemia after
testicular cancer is higher than average, very few patients develop
leukemia from their treatment.
Follow-up care
Because the most common cancer seen is a second testicular
cancer, survivors should perform regular testicular self-exams. They
should see a doctor at least once a year or sooner if any problems
develop.
All patients should be encouraged to avoid tobacco smoke.
Ovarian cancer
The risk of second cancers in ovarian cancer survivors
includes melanoma of the eye; cancers of the colon, rectum, breast, and
bladder; and leukemia. Radiation therapy is linked with cancers of
connective tissues, bladder, and possibly pancreas cancer. Chemotherapy
is linked with an increased risk for leukemia. Reproductive and genetic
factors that may have caused ovarian cancer in the first place may also
add to the risk of breast and colorectal cancers and possibly ocular
melanoma. Studies have shown that the risk of developing solid tumors
was higher during all follow-up periods, including 10 to 14 years after
ovarian cancer. Fifteen-year survivors had significant increases in
cancer of the pancreas, bladder, and connective tissue.
Follow-up care
Women who have had ovarian cancer will be watched closely for
signs that the cancer has come back with regular physical exams, blood
tests, and, sometimes, CT scans. These women have an increased risk of
breast and colorectal cancers and should have regular screening for
these cancers.
All patients should be encouraged to avoid tobacco smoke.
Breast cancer
Many studies have shown that women with breast cancer are at a
3-to 4-fold increased risk of developing a new primary cancer in the
opposite breast. Increased risk is also seen for cancers of the ovary,
uterus, lung, colon, rectum, and connective tissue, as well as melanoma
and leukemia. But for some of these cancers, such as cancer of the
opposite breast, ovary, and uterus, the second cancer may be linked to
the same thing that caused the first cancer, like genetics or a
hormonal risk factor.
The most common second cancer seen in survivors of breast
cancer is a new cancer in the other breast. The risk of a second breast
cancer is high no matter what treatment is used for the first cancer.
Even people who receive no radiation or chemotherapy have an increased
risk of cancer in the opposite breast. This increase in risk also shows
up in close relatives of women with breast cancer, so there may be a
shared pre-existing factor causing the first and second breast cancers
in many of these women. Still, depending on the patient's age when they
were treated, radiation therapy can increase the risk even more.
Radiation therapy does not seem to increase the risk of cancer in the
opposite breast if the patient is past the age of 45 at the time of
treatment. But in women who had radiation therapy before the age of 45,
an increased risk is seen 10 years after treatment.
The risk of lung cancer is also increased in women who had
radiation therapy for breast cancer. The higher lung cancer risk is
first seen 10 years after radiation, and gets higher over time. The
risk of lung cancer after radiation is even higher in women who smoke.
Radiation therapy to the breast also increases the risk of sarcomas of
blood vessels (angiosarcomas),
connective tissue, and bone
(osteosarcomas).
These cancers are most often seen in the remaining
breast area, chest wall, and the arm that had been treated with the
radiation therapy. This risk remains high even 30 years after
treatment.
Taking tamoxifen for 5 years not only makes it less likely
that the first cancer will come back, it also helps to lower the risk
of cancer in the opposite breast by 50%.This appears to be true for
women who have been followed for 10 years after their first treatment.
But tamoxifen increases the risk for endometrial cancer in 5-year and
10-year survivors. Still, the benefits of treatment for breast cancer
are greater than the risk of a second cancer.
There is a small risk of developing leukemia after treatment
for breast cancer. The risk is highest when both chemotherapy and
radiation therapy are given, especially if the chemotherapy includes an
alkylating agent (see the list of alkylating agents above).
Cyclophosphamide (Cytoxan®), an
alkylating agent, has been used
for over 30 years to treat breast cancer. It is a part of the regimen
CMF [cyclophosphamide, methotrexate, and 5-FU], and is also included in
the regimens AC [Adriamycin®
(doxorubicin) and
cyclophosphamide] and FAC (adds 5-fluorouracil or 5-FU to the drugs in
AC). Studies have shown that higher doses of cyclophosphamide
(Cytoxan®) increase the risk of
developing AML. The dose of
cyclophosphamide that is now used in standard CMF and AC is linked with
a low risk of leukemia, but higher doses increase the leukemia risk.
The risk also goes up with dose intensity (when a higher amount of drug
is given over a shorter amount of time). Still, even with a risk of
leukemia that is several times higher than what is usually seen, those
who received 4 times the regular dose of cyclophosphamide had a risk of
leukemia that was only about 1%.
Follow-up care
Even women who were not treated with radiation have an
increased risk of a second cancer in the opposite breast. Follow-up
care should include annual screening for breast cancer (if there is any
remaining breast tissue). Good gynecologic care is also important to
watch for endometrial cancer.
All patients should be encouraged to avoid tobacco smoke.
Cervical cancer
Cervical cancer is often caused by infection with human
papilloma virus (HPV). Survivors of cervical cancer have an increased
risk for other HPV-related cancers, including cancers of the throat,
anus, vulva, and vagina. Survivors of cervical cancer also have an
increased risk of some cancers linked to smoking, such as lung cancer,
bladder cancer, and pancreatic cancer. The risks of bladder and lung
cancer are even higher in those women who were treated with radiation.
Radiation for cervical cancer also increases the risk of cancers of the
colon, rectum, soft tissue, and stomach. Radiation is also linked to a
higher risk of acute leukemia and non-Hodgkin lymphoma.
Follow-up care
Survivors of cervical cancer need good gynecologic care to
watch for signs of a new cancer in the vulva or vagina, as well as to
watch for relapse.
All patients should be encouraged to avoid tobacco smoke.
Childhood cancers
Researchers have learned that the effects of childhood cancer
treatment may affect that child's health later in life. This result is
known as a "late effect." For more information about this topic, see
our document, Childhood Cancer: Late Effects
of Cancer Treatment.
Summary
The risk of second cancers must always be weighed against the
benefits gained with treatment. The risks of treatments should always
be compared carefully against the cost of not using such treatments.
For many new cancer treatments, the long-term effects that cause second
cancers are not yet known. The need for ongoing follow-up of cancer
survivors is important so that we can better understand the long-term
effects of cancer treatments.
Additional resources
More information from your American Cancer
Society
We have selected some related information that may also be
helpful to you. These materials may be ordered from our toll-free
number, 1-800-227-2345.
- Surgery
(also available in Spanish)
No matter who you are, we can help. Contact us anytime, day or
night, for cancer-related information and support. Call us at
1-800-227-2345 or
visit cancer.org.
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Last Medical Review: 07/24/2009
Last Revised: 07/24/2009
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