You may wonder whether you are at increased risk of developing a second cancer. For most survivors, the answer is no. But the risk is not the same for everyone. Factors that determine risk include your genetic predisposition and whether or not you received radiation and/or certain chemotherapy drugs. Your lifestyle and health behaviors can minimize or increase your risk, just as they can for people who never had cancer. For instance, if you had radiation to your chest, you have a small risk for developing throat and/or lung cancers. If you smoke, your chances of developing those cancers dramatically increase. If you don’t smoke, don’t drink alcohol, and eat a healthy diet, your risk decreases.

Although more is being discovered about the genetics of cancer, the relationship between genetic predisposition and the effects from chemotherapy drugs and/or radiation on developing second cancers is only partially understood. The lifetime risk of developing another cancer hasn’t been determined, as most of the survivors studied are just reaching their second or third decade after cure.

Much research is being done to maintain cure rates while lowering the toxicity of treatments to lessen the risk of second cancers. Research is also being done to identify those survivors most at risk so they can be followed appropriately. To find out your individual risk, talk to your healthcare provider during a follow-up visit. She will consider your original disease, the treatments you had, your age when treated, and your family history before discussing your unique situation.

Genetic predisposition

Cancers with known genetic causes sometimes carry a greater risk of second cancers. For instance, survivors of the genetic form of retinoblastoma should be evaluated regularly for the rest of their lives, because they have a much higher chance of developing second tumors than do other survivors.

Some types of cancer (colon, breast, and ovarian) run in families, so it is important to discuss your family history with your healthcare provider. Knowing your risk factors tells you a bit about the chance that you might develop that cancer. It does not determine whether or not you will get cancer again, because not all individuals with the predisposing gene get cancer. Survivors with many risk factors may live long and healthy lives and never get cancer again, while some people at low risk will get cancer. The facts your healthcare provider discusses with you are probabilities for large groups of people; no one can predict what will happen to you.

Survivors at highest risk for second cancers are those who:

• Were treated with radiation.

• Received high doses of alkylating agents: mechlorethamine (nitrogen mustard), cyclophosphamide (Cytoxan ^® ), procarbazine, ifosfamide, melphalan, nitrosoureas (carmustine, lomustine), and/or epipodophylloxins (VP-16, VM-26).

• Have genetic diseases that carry an increased risk of cancer, such as, xeroderma pigmentosum, Klinefelter syndrome, Bloom’s syndrome, Li-Fraumeni, von Recklinghausen’s neurofibromatosis, or the genetic form of retinoblastoma.

If you are in one of the above groups, your follow-up care should be especially vigilant. This allows for earlier detection and treatment should you develop another cancer, increasing your chance for cure. It also gives you the opportunity to discuss ways of lowering your risks by making healthy lifestyle and behavior choices.

Wendy Harpham, a physician and cancer survivor, wrote in After Cancer: A Guide to Your New Life :

Treatment

Radiation and some types of chemotherapy can increase the risk of second cancers. Combined radiotherapy and chemotherapy may play an additive role in the development of second cancers. Some types of second cancers are very easy to cure; these include skin cancers and thyroid cancers. Second cancers that require more intensive therapies are bone and soft tissue sarcomas, non-Hodgkin lymphoma, brain tumors, and acute myelogenous leukemia (AML).

Radiation

In general, higher doses of radiation increase the risk of developing a second cancer. The radiation technology in the 1950s, 1960s, and 1970s delivered a lot of radiation to normal tissues around the tumor. More recent protocols have used lower radiation doses (in some cases), more precise techniques, and radiation given in smaller fractions, allowing the healthy tissue to repair itself. It is hoped that the use of the new proton therapy will significantly decrease the risk of damage to healthy tissue.

Radiation kills cancer cells and may also cause changes in normal cells that are exposed to the radiation. In some cases, second cancers develop in the irradiated areas. For instance, female survivors of Hodgkin lymphoma (formerly called Hodgkin’s disease) treated in the 1970s and 1980s who had more than 3600 centigrays (cGy) of mantle (chest) radiation have a markedly increased risk of developing breast cancer, often at an early age.

Some radiation (called “scatter”) escapes into the areas surrounding the radiation field. Survivors who had radiation to the head or chest can develop late effects in the thyroid gland or salivary glands from scatter radiation. These areas, as well as the radiation field, should be routinely evaluated during follow-up appointments.

Thyroid tumors are a common second tumor following radiation delivered to the cranial/spinal region, head and neck, chest, or total body radiation given before a stem cell transplant. Younger children at time of treatment are at greater risk for thyroid tumors. Thyroid tumors can be either benign or malignant, and the malignant tumors are very treatable.

Radiation to the pelvis or abdomen (more than 3000 cGy) is associated with an increased risk of colon cancer. The current recommendation for follow up is to have a colonoscopy at age 35 or 10 years after the radiation, whichever occurs last. ¹

Chemotherapy

Several chemotherapy drugs are associated with second cancers in some survivors. Examples of these are:

• Alkylating agents: procarbazine, nitrogen mustard, cyclophosphamide (Cytoxan ^® ), ifosfamide, melphalan, and nitrosoureas. High doses of these drugs can cause myelodysplastic syndromes (bone marrow abnormalities that are similar to leukemia) as well as AML. The peak incidence occurs 4 to 6 years after the drugs are given and gradually tapers off until 10 to 15 years have passed. ²

• Epipodophyllotoxins: VP-16 (etoposide), VM-26 (teniposide). These drugs have been associated with AML that usually occurs within 3 years of treatment. ³

• Platinum analogs: cisplatin, carboplatin. Research has not clarified the risk of second cancers after treatment with plantinum analogs such as cisplatin or carboplatin. Most AML or myelodysplastic syndromes occur when these drugs are given in conjunction with alkylating agents or epipodophyllotoxins.

Secondary leukemia in survivors treated with alkylating agents and/or epipodophyllotoxins usually occur in the first 10 years after treatment. Solid tumors tend to occur many years or decades after treatment ends.

Children and teens who were treated with an immunosuppressant (e.g., cyclosporine or FK 506) have a small chance of developing disorders of the lymph system, including lymphoma. These disorders sometimes resolve without treatment when the immune system is no longer suppressed.

Risks following treatment for specific cancers

The information in this section describes risks for groups of survivors (not individuals). Some of the treatment-related second cancers discussed in the following list are attributed to treatments that are not considered the standard of care today. Many current clinical trials are focusing on maintaining cure rates while using less toxic treatments. Thus, in the future, it is hoped that cures will continue to increase while treatment-related second cancers decrease. All survivors, however, need lifelong surveillance for second cancers, either to provide reassurance that they are in the large majority of survivors who have no second cancers or to diagnose any problems early.

• Hodgkin lymphoma.  Survivors of Hodgkin lymphoma have been studied extensively for many years. The treatments for Hodgkin lymphoma are very effective and have changed dramatically over the last 3 decades. The following information is about long-term survivors of Hodgkin lymphoma. Because treatments have improved, it is hoped that people treated on current protocols will have fewer second cancers. Researchers have found that breast cancer is the most common second cancer after treatment for Hodgkin lymphoma, and it accounts for 65 percent of second cancers in female Hodgkin lymphoma survivors. ⁴ Females treated between the ages of 10 and 16 and those who received more than 4000 cGy of mantle radiation have the highest risk of developing breast cancer. ⁵ Risk factors for developing leukemia are older age at diagnosis, treatment with alkylating agents, recurrence of Hodgkin lymphoma, and a late stage of disease at diagnosis.

• Retinoblastoma.  Researchers at several institutions studied 1,604 survivors of retinoblastoma and found a substantial risk for second cancers in those who had the genetic form of retinoblastoma and had been treated with radiation. ⁶ All survivors who had tumors in both eyes (bilateral) have the genetic form. The second cancers that develop most often in retinoblastoma survivors are bone and soft tissue sarcomas. Bone sarcomas occur equally in and out of the radiation field, while soft tissue sarcomas mostly occur in the radiation field. Retinoblastoma survivors with the genetic form should be followed closely throughout their lives for second cancers.

• Wilms tumor.  The National Wilms Tumor Study enrolled 5,278 survivors and found 43 who developed a second cancer. Fifteen years after diagnosis, the incidence of second cancers was 1.6 percent. Survivors who received more than 3500 cGy of abdominal radiation, were treated with doxorubicin, or were treated for a relapse had the highest risk. ⁷ These doses of radiation are no longer used to treat children newly diagnosed with Wilms tumor.

• Brain and spinal cord tumors.   Children treated with radiation to the brain and/or spinal cord are at risk for development of both benign and malignant tumors. Meningiomas (tumors of the membranes that surround the brain) are the most common benign tumors and, depending on the location and symptoms, can either be followed with MRIs or be surgically removed. Malignant tumors usually require more intensive therapy. Children who received more than 3000 cGy and were younger than age 5 at time of diagnosis are at greatest risk. ⁸

• Ewing sarcoma.  Leukemia, sarcomas, and carcinomas can develop after treatment for Ewing sarcoma. Alkylating agents (e.g., cyclophosphamide, 5FU) and topoisomerase inhibitors (doxorubicin, VP-16) contribute to the risk of leukemia, and high-dose radiation increases the risk of solid tumors.

• Rhabdomyosarcoma.  High-dose radiation and high doses of chemotherapy appear to increase the risk for developing a second cancer in survivors of rhabdomyosarcoma. Children who received radiation and dactinomycin have a higher rate of second tumors.

• Acute lymphoblastic leukemia (ALL).  Several studies have found second cancers to be an uncommon late effect of treatment for childhood ALL. Second cancers very occasionally occur in the brains of survivors treated with cranial radiation when they were younger than age 5. ^{9 , 10}

• Stem cell transplantation.  Child and teen survivors of stem cell transplants have usually received radiation and a variety of chemotherapy drugs. There are different risks for second cancers depending on previous treatment, cumulative doses of drugs, age at transplant, and other factors. Leukemia, thyroid cancer, skin cancer, and solid tumors sometimes develop after a stem cell transplant. ^{11 , 12}

One way to cope with the information your healthcare provider gives you about your risk for developing second cancers is to think in terms of the chance that you will not get a second cancer. For instance, if you have a 3 percent chance of getting a brain tumor because you had cranial radiation at a young age, turn that statistic around and focus on the 97 percent chance that you will not get another cancer. This change in perspective may help you file the information away in your mind and allow you to think of risk in a different way.