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 the possible health effects of 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.
Leukemia

Acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and acute lymphoblastic leukemia (ALL) have been linked to past radiation exposure. Myelodysplastic syndrome (MDS), a bone marrow disorder that can turn into acute leukemia, has also been linked to past radiation exposure. The risk of these diseases 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 (how much was given in each dose, how long it took to give the dose, and how often it was given)

The person’s age when they were treated with radiation does not seem to be a risk factor. Most cases usually develop within several years of radiation treatment, peaking at 5 to 9 years after exposure. Then the number of cases developing slowly declines over the following years.
Solid tumors

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 at least 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 the risk of solid tumors. 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 (chemo) as the cause is acute myelogenous leukemia (AML). In many cases, myelodysplastic syndrome (MDS), a bone marrow problem that is sometimes called a type of cancer, occurs first, then turns into AML. Acute lymphocytic leukemia (ALL) has also been linked to chemo. Chemo is known to be a higher risk factor than radiation therapy in causing leukemia.

Some solid tumor cancers have also been linked to chemo treatment for certain cancers, such as testicular cancer.
Alkylating agents

Certain types of chemo drugs called alkylating agents have been shown to increase the risk of AML when used to treat certain 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 declines. Alkylating agents often cause MDS first, which then progresses into an acute leukemia.

MDS and leukemia that develop after treatment with alkylating agents can be hard to treat and tends to have a poor outcome. Often,
Cisplatin

The chemo 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.
Topoisomerase II inhibitors

In more recent years, a class of chemo drugs called 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 lung cancer, testicular cancer, ALL, and other cancers, 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, lymphoma, and other cancers, can also cause acute leukemia.

Leukemia from these drugs acts differently from the leukemia from alkylating agents – it tends to respond to treatment better and has a better outlook. Also, these drugs don’t often cause MDS first.
Anthracyclines

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.

Cancer.org