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Second Cancers Caused by Cancer Treatment

Current treatments of radiation and chemotherapy have increased the survival of people with cancer. As people with cancer are living longer, it becomes more important to study the long-term effects of cancer treatment. Of all the late complications of cancer treatment, developing a second cancer is one of the most serious.

It is possible that people can have more than one cancer in their lifetime because cancer is a very common disease. But 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, exposure to certain cancer causing substances like tobacco smoke can put a person at risk for several different cancers such as lung cancer as well as cancers of the larynx, throat, or mouth.

Several clinical studies sponsored by the National Cancer Institute and related to the long-term effects of cancer treatment are helping us to better understand the effect of cancer treatment on the development of second cancers.

Radiation Therapy

The potential of radiation therapy to cause cancer was recognized many years ago. In fact, much of what we know about radiation therapy has come from the study of survivors of the atomic bomb in Japan, exposure of workers in certain occupations, and patients treated with radiation therapy for malignant and nonmalignant diseases.

Some types of leukemia occur as a result of radiation exposure. Most cases usually develop within a few years of exposure, peaking at 5 to 9 years then slowly declining. Increased risk of cancers other than leukemia has been shown to take much longer to occur. Most of these cancers do not occur until 10 years after radiation exposure and some cancers are diagnosed even 15 or more years later. Radiation-related leukemia risk depends on a number of factors, such as radiation dose to the bone marrow and how much of the marrow is exposed. The person’s age at the time of therapy does not seem to be a risk factor in general.

In contrast, studies of radiation-related breast cancer have found the greatest risk in those who received radiation as children and adolescents. Most studies have found no increased breast cancer risk among women who receive radiation after the age of 44.

The risk of lung cancer rises with both lower doses and higher doses of radiation, as does the risk of thyroid cancer. For smokers, exposure to radiation increases the risk of lung cancer even more. Children are also at greater risk than adults for developing solid tumors other than breast cancer due to radiation exposure. The same is true for lung cancer, thyroid cancer, bone sarcoma, and gastrointestinal or stomach cancers.

More research will likely be done in the future on the interaction of genetics and radiation therapy and its link to other cancer-causing agents.

Chemotherapy

The cancer most often associated with chemotherapy as the cause is 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 following the use of certain types of chemotherapies called alkylating agents in treating such cancers as Hodgkin disease, non-Hodgkin lymphoma (NHL), ovarian, lung and breast cancer. Alkylating agents known to cause leukemia include mechlorethamine, chlorambucil, cyclophosphamide, melphalan, semustine, lomustine (CCNU), carmustine (BCNU), prednimustine, busulfan, and dihydroxybusulfan. The risk has been shown to increase with a higher dose given, a longer treatment time, and with more drug given over a short period of time. In most studies, the risk for leukemia is highest between 3 to 9 years after chemotherapy, then the risk declines.

In recent years drugs called epipodophyllotoxins have also been thought to cause leukemia. One of these drugs, etoposide, is used in patients treated for non-small cell lung cancer, testicular cancer, and acute lymphocytic leukemia, and is associated with an increased risk of developing AML. Teniposide, another one of these types of drugs used to treat ALL, is also thought to increase the risk for a second cancer.

More recently, evidence has suggested that the chemotherapies called anthracyclines, such as doxorubicin and epirubicin, may also cause AML. But in these studies the anthracyclines were given along with alkylating agents, so it was unclear whether the anthracyclines were the source of any increased risk of leukemia.

Hodgkin Disease

Survivors of Hodgkin disease who have been treated with allkylating agents are at an increased risk for developing second cancers. The risk is highest for AML, followed by an increased risk of NHL. Radiation therapy is associated with little or no increased risk of leukemia, but it is associated with an increased risk of developing solid tumor cancers. These cancers include lung, breast, gastrointestinal (stomach), thyroid, and sarcoma.

Women who have been treated with mantle field irradiation (mantle field refers to the neck, chest, and lymph nodes under the arms) before age 35 are at an increased risk for breast cancer.

Follow-Up Care

Since there is an increased risk for a second cancer following treatment for Hodgkin Disease (HD), survivors of HD should receive careful follow-up. Your doctors should be looking for the development of solid tumors, leukemia, and non-Hodgkin Lymphoma along with recurrence of Hodgkin disease.

All patients should be encouraged to not smoke. Patients with a history of mantle field radiation therapy, especially before the age of 35, should have regular breast exams and yearly breast mammograms at least up to 8 years after radiation treatments.

In patients who received radiation to their abdomen, pay special attention to any complaints you may have of symptoms in your abdomen and report them to your doctor.

Non-Hodgkin Lymphoma

Survivors of non-Hodgkin lymphoma (NHL) are at increased risk for a number of second cancers, but much less so than patients with Hodgkin disease. The risks of increased second cancers have been observed for malignant melanoma, cancer of the lung and kidney cancer. Also, survivors of NHL are at risk for several rare cancers such as Kaposi sarcoma; cancers of the lip and salivary gland, gum, and floor of the mouth; vaginal cancer; thyroid cancer; bone cancer; and soft tissue cancer. For 20-year cancer survivors, there is a higher risk of cancers of the colon, rectum, and bladder.

Patients who received cyclophosphamide as part of their treatment, especially in higher doses, are at risk for bladder cancer. Low-dose total body irradiation (TBI), which was used to treat NHL in the past, has also been associated with an increased risk of leukemia. Patients who undergo autologous bone marrow transplant (meaning the patient’s own -- instead of someone else’s) are also at increased risk for developing acute myelogenous leukemia and an early form of leukemia called myelodysplastic syndrome.

Follow-Up

Since there is an increased risk for a second cancer following treatment for NHL, survivors should receive 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 not smoke.

Testicular Cancer

Increased risks in testicular cancer survivors have been reported for cancer involving the other testicle, but this is probably due to risk factors common to both testicles rather than just the effects of treatment. Patients treated for testicular cancer have less than one-third the risks of second cancers than those treated for Hodgkin Disease. There is an increased risk of stomach cancer in patients who received radiation therapy to the lymph nodes in the chest and abdomen area. Usually the risks are greater with higher radiation doses. Chemotherapy that includes platinum based products also is linked with a small, but increased risk of leukemia. High doses of etoposide chemotherapy are associated with a moderately increased leukemia risk. In recent years, radiation therapy regimens have been changed to lower the doses and narrow the field of treatment and preventive treatment to the mediastinum (the middle part of the chest cavity which contains the heart and the lung sacs, but not the lungs) has been discontinued. Long term follow up studies are needed to see if these changes have lowered the cancer risks.

Ovarian Cancer

The risk of second cancers in ovarian cancer survivors includes melanoma of the eye, cancer of the colon, rectum, breast , bladder, and leukemia. Radiation therapy is associated with cancers of connective tissues, bladder, and possibly pancreas cancer. Chemotherapy is associated with an increased risk for leukemia. Reproductive and genetic factors that may have caused ovarian cancer in the first place may also have added to the risk of breast and colorectal cancers and possibly ocular melanoma. The risk of solid tumors was increased 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.

Breast Cancer

Numerous studies have shown that women with breast cancer are at a three-to four-fold increased risk of developing a new primary cancer in the opposite breast. Increased risk is also seen for ovary, uterus, lung, colon and rectum, connective tissue, melanoma, and leukemia. For some of these cancers, however, such as cancer of the opposite breast, ovary, and uterus, the second cancer may be related to a common cancer causing factor, such as a genetic factor or hormonal risk factor.

Radiation therapy does not seem to increase the risk of cancer in the opposite breast when the survivor is past the age of 45. But the risk is increased for women who received radiation therapy before the age of 45 and who have survived for 10 years. Radiation treatment also increases the risk for lung cancer in women who have had a mastectomy after 10 years. This increased risk is not seen in women who received radiation therapy with lumpectomy.

Radiation therapy to the breast increases the risk of soft tissue sarcomas, such as angiosarcomas in the conserved breast area,chest wall,and arm that has been treated with the radiation therapy. This risk is highest 5 to 10 years after diagnosis.

Taking tamoxifen for five years 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 and 10 year survivors. But the benefits of treatment for breast cancer treatment may exceed the risk of a second cancer.

There is some risk of developing leukemia after treatment for breast cancer. The risk is highest when both chemotherapy radiation therapy.are given,.especially if the chemotherapy includes an alkylating agent. Studies have shown that a total dose of 20 or more grams of cyclophosphamide increases the risk of developing AML. The standard chemotherapy dose of CMF (cyclophosphosphamide, methotrexate and 5-FU) is linked with a low risk of leukemia, but the chemotherapy regimen of FAC (5-FU, adriamycin, and cytoxan) has a slightly higher risk for developing leukemia.

Follow-Up

Follow-up care for the remaining breast tissue, as well as good gynecologic care, is important to watch for the development of endometrial cancer. Anyone who smokes should stop.

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 the American Cancer Society publication, “Childhood Cancer: Late Effects of Cancer Treatment.” If you’d like this information, please call the 24-hour number 1-800-ACS-2345, or search for it on at: www.cancer.org.

The risk of second cancers must always be weighed against the sometimes dramatic benefits gained with treatment. The risks of treatments should always be compared carefully against the costs 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 essential so that we can better understand the long-term effects of cancer treatments as they evolve.

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