Ionizing Radiation

Radiation has long been associated with the development of primary cancers and, when used as treatment, imparts a risk for the development of a second cancer. Typically, second tumors occur within or at the margin of the radiated field. Bone and soft-tissue sarcomas are the most frequent SMNs following radiation therapy, but skin, brain, thyroid, and breast cancers also can occur.⁷⁰ Radiation doses less than 30 Gy tend to be associated with thyroid and brain tumors, whereas doses greater than 30 Gy can evoke secondary sarcomas.^82–85 In the Late Effects Study Group, the median time to developing SMNs was 10 years following radiation, but some were seen as late as 34 years following exposure.⁶⁰ For many postradiation SMNs, the risk is higher if the radiation exposure occurs earlier in life or during periods of rapid growth of a tissue, such as bone sarcomas during adolescence. This is also seen with thyroid, breast, skin, brain, and stomach cancers. Adolescent girls receiving mediastinal radiation therapy for Hodgkin's disease develop breast cancer more often than do their adult counterparts.^86–90 Cells that have matured and are no longer proliferating appear to be less susceptible to the effects of radiation, although lung cancer has been observed after chest irradiation^91–93 and bladder cancer after pelvic irradiation.^94,95 More recently, an association between radiation and esophageal cancer has been observed.^96,97

Dose-response relationships have been found between radiation dose and sarcomas. A 40-fold increase in risk of bone sarcomas was observed following 60 Gy or more.⁸² Tenfold increases in soft-tissue sarcoma risk were seen in RB patients receiving 60 Gy or more, but even 5 Gy increased the risk twofold for this genetically predisposed group.⁵⁹ High-dose radiation appears not to increase the risk for leukemia or thyroid cancer. This may be a result of cell killing or inactivation, with cells losing their ability to proliferate, and thus their ability to sustain a malignant transformation. As has been observed with other sources of radiation exposure, radiation therapy and cigarette smoking may act in a synergistic fashion.⁹⁸

Chemotherapy

Leukemia as a secondary cancer can occur following treatment with chemotherapy. Although acute myelogenous leukemia is the most common type of therapy-related leukemia, acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) have also been reported.²⁴ Chemotherapy-induced myeloid leukemias are relatively resistant to subsequent therapy and have a cure rate of only 10% to 20%.^25,26

Evidence is accumulating concerning the mechanisms of leukemogenesis DNA topoisomerase-II inhibitors and alkylating agents.^99–101 Table 159-3 summarizes the features of these chemotherapy-related leukemias. Alkylating agents include cyclophosphamide, ifosfamide, cisplatin, carboplatin, chlorambucil, busulfan, melphalan, nitrogen mustard, and procarbazine. Treatment-related myelodysplasia or secondary leukemia following alkylator therapy usually has a latency period of 4 to 7 years. These leukemias demonstrate deletions on chromosomes 5 or 7. Topoisomerase-II inhibitors include the epipodophyllotoxins, etoposide, and teniposide, as well as the anthracycline doxorubicin and, presumptively, epirubicin. Leukemia following epipodophyllotoxin therapy has a shorter latency period (usually 1 to 3 years) and is primarily associated with translocation of the MLL gene at chromosome band 11q23.

Table 159-3

Secondary Acute Myelogenous Leukemia.

Treatment for solid tumors, such as Hodgkin's disease, Ewing sarcoma, and rhabdomyosarcoma, is associated with a dose-response relationship for alkylators and the risk of leukemia. Alkylating agents increase the risk of leukemia almost 5-fold, but that risk increases to almost 24-fold in patients receiving the highest doses. Doxorubicin, together with high-dose alkylating agents, increases that risk further. A similar increase in risk of secondary leukemia has been reported with increasing doses of epipodophyllotoxins. t-AML is reported in fewer than 3% of germ cell tumor patients receiving doses of etoposide less than 2 g/m². This risk increased to more than 11% in patients receiving more than 2 g/m².¹⁰⁰ Using more recent data from the Cancer Therapy Evaluation Program (CTEP), Smith and colleagues found neither a dose-response relationship for epipodophyllotoxin in solid tumors and secondary AML, nor an increasing risk in patients who received up to 5 g/m² of etoposide.¹⁰¹

Alkylating agents may also potentiate the risk of secondary bone cancers when used with radiation therapy. The relative risk of secondary bone sarcomas following radiation therapy was 2.7, but when alkylating agents were used as well, the relative risk rose to 4.7.⁸²

Hodgkin's Disease

Patients with Hodgkin's disease treated with chemotherapy, radiation therapy, or a combination have a relative risk of 2 to 4 of developing SMNs.^{18,86–91,102} The overall cumulative incidence of SMN, the majority of which are solid neoplasms, after treatment for childhood Hodgkin's disease ranges between 2% and 27% by 30 years from diagnosis, and depends primarily on the therapy received. Relative risks, based on comparison with cancer risk in age-matched individuals in the population, ranges from 2 to more than 50, and depends on the tissue of origin of the second cancer, as well as treatment.^87–91

Thyroid cancer is the most common postradiation cancer noted in Hodgkin's disease survivors.¹² Breast cancer is seen in females, with those over the age of 10 years being at greatest risk.^86–90 There is also an increased risk of skin cancer within the radiation field. Recently, many pediatric centers have altered their therapy of Hodgkin's disease to reflect differences in second cancer and gonadal toxicity in girls and boys, girls receiving less chest irradiation and boys receiving less alkylating agent.¹⁰³

Although radiation therapy for Hodgkin's disease is associated with secondary solid tumors, chemotherapy is associated with the development of secondary leukemia. As many as 25% of second malignancies following treatment for Hodgkin's disease are secondary leukemia or lymphoma.^87–91 Because MOPP (Mustargen [mechlorethamine], Oncovin [vincristine], procarbazine, and prednisone) regimens contain nitrogen mustard and procarbazine, they incur a greater risk for secondary leukemia than either combination regimens containing cyclophosphamide or with ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine).^18,103 Higher doses and multiple alkylating agents also increase that risk; hence the incidence of secondary leukemia is higher in patients who suffer a recurrence of Hodgkin's disease and require retreatment. Radiation therapy alone does not appear to increase the secondary leukemia risk.

Retinoblastoma

As discussed in Genetic Risk Factors above, RB patients are at very high risk of developing a second malignancy, primarily because of their genetic predisposition. An interaction with radiation has also been shown. In the largest study of RB survivors, Wong and colleagues reported 190 second cancers for a RR of 30, when compared with age-matched controls.⁵⁹ The cumulative incidence of second cancers for patients with hereditary RB was 51% at 50 years, as compared to 5% in 50 years for the nongenetic form of RB. Two-thirds of the second cancers were osteogenic or soft-tissue sarcomas, and a radiation dose-response relationship was noted for all soft-tissue sarcomas with as little as 5 Gy, increasing the risk of second malignancy twofold. For those patients receiving over 60 Gy, there was a tenfold increase in risk. The recommendation that all survivors of childhood cancer be followed annually by practitioners educated about risks for second malignancies applies especially to survivors of the genetic form of retinoblastoma.

Acute Lymphocytic Leukemia

Several reports have been published analyzing the risk of second malignancies following therapy for childhood ALL.^84,104–107 Children treated on Children's Cancer Group (CCG) protocols, Berlin-Frankfurt-Munster (BFM) protocols, and Dana Farber protocols have estimated the cumulative risk of SMNs at 15 years to be 2.5% to 3.3%.^84,104,105 Patients who received craniospinal radiation were at increased risk of CNS tumors, skin cancer, and thyroid cancer.

Secondary brain tumors occurred after cranial radiation therapy for ALL in the CCG and at the St. Jude Children's Research Hospital.^84,106 In the latter report, the overall cumulative incidence was 1.4%; a statistically significant increase in risk with increasing cranial radiation dose was noted, with patients receiving > 30 Gy having a 3.23% cumulative incidence of brain tumors at 20 years. Younger age increased the risk of secondary CNS tumors. Fortunately, in more recent pediatric ALL protocols, cranial radiation has been replaced by intensive intrathecal chemotherapy for children younger than age 10 years who have no evidence of CNS disease at diagnosis.

The risk for t-AML in patients treated for ALL varies with the original protocol used and the dose and schedule of epipodophyllotoxins. Children receiving weekly or twice weekly epipodophyllotoxins had a cumulative incidence of 12% of secondary AML.¹⁰⁷ In the BFM study the development of t-AML was not associated with the use of any specific cytotoxic agent and 12 of 16 t-AMLs had not received epipodophyllotoxins.¹⁰⁵

Wilms Tumor

The data from the National Wilms Tumor Study Group found an eightfold increase in SMNs in children treated for Wilms tumor between 1969 and 1991.¹⁰⁸ There was an excess of leukemia as well as lymphomas and solid tumors. The secondary leukemias were primarily t-AML and were diagnosed 1 to 6 years after original therapy. Similar latency periods were seen for lymphomas. Secondary solid tumors following treatment for Wilms tumor had a much longer latent period of 3 to 21 years. The solid tumors were primarily sarcomas and carcinomas (breast, thyroid, colon, hepatocellular, parotid), but there was also an increased incidence of brain tumors. Patients who had received abdominal radiation had twice the risk of second cancers, compared with those who did not. The report also suggested that doxorubicin potentiated the radiation effect.

Pediatric Sarcomas

Recent studies show a consistent rate of second malignancies in patients treated with intensive chemotherapy for soft-tissue and bone sarcomas. The cumulative risk of SMNs after therapy for Ewing sarcoma ranged from 3% at 10 years to more than 20% at 20 years.^60,82,85,109 Patients developed AML, ALL, and MDS from 1 to 8 years after diagnosis. Secondary sarcomas, related to radiation therapy in a dose-dependent manner, were noted 7 to 11 years after diagnosis. Rhabdomyosarcoma survivors similar to the Ewing sarcoma cohorts, developed SMNs with an identical latency period, and a similar cumulative risk.^60,64 The rates were highest for patients who received both alkylating agents and radiation therapy.⁶⁴

Upper Aerodigestive Tract Cancers

The risk of esophageal cancer following lung cancer is increased by treatment of the initial lung cancer with radiation, strongly suggesting a carcinogenic effect of radiation in its etiology. Nonetheless, the risk of esophageal carcinoma is elevated following lung cancer even in the absence of radiation therapy.^33,35,70

Schottenfeld and colleagues, as well as others, demonstrated that tobacco cessation following the diagnosis of the initial primary cancer leads to a reduction in subsequent risk for other tobacco-related malignancies, and thus, in most instances, it remains a reasonable strategy to decrease risk.¹¹⁰

It is essential to perform a work-up for multiple primaries at presentation, particularly for an initial head and neck cancer, including malignancies of the oropharynx, tongue, and larynx. If a lung nodule or nodules in the other areas of the head and neck appear, it is essential to rule out the possibility that this represents a second primary malignancy.³⁴ If a lung nodule is a metastasis from an initial oropharyngeal primary, then the prognosis is poor. However, if a lung nodule represents a second primary lung cancer and is operable, cure is still a possibility. Every effort should be made to make this distinction. New molecular genetic approaches may play a role in the future in making this distinction.

Breast Cancer

Breast cancer is the most common malignancy diagnosed in women in the United States. Women with an initial breast cancer are at significantly elevated risk for cancer in the contralateral breast. Antiestrogens can reduce the incidence of second malignancies, as well as improve survival.^111,112 Disciplined systematic screening can identify a contralateral breast cancer at an early stage. Breast cancer survivors are also at elevated risk for cancers of the ovary, endometrium, and colon/rectum, independent of the treatment administered for the breast cancer,^14,15,17 although these risks may not always be very large.¹¹³ This suggests that these organs share risk factors with cancer of the breast, including obesity, diet, and reproductive hormonal status. New discoveries in breast cancer genetics also implicate mutations in BRCA1 and BRCA2 as risk factors for ovarian as well as breast cancer. Screening for ovarian and endometrial cancer as well as colorectal cancer should be done regularly in women with a history of breast cancer.^114,115

The treatment used for breast cancer may also impact on the subsequent risk of second malignancies. Studies show that postmastectomy radiation can elevate the subsequent risk of lung cancer, particularly in smokers.^93,98 If alkylating agents are used as adjuvant therapy, the risk of acute leukemia will also be increased, particularly if patients have also received postmastectomy radiation.¹¹⁶ Postirradiation sarcomas may also occur in the treatment field, especially angiosarcomas.^117,118 Although tamoxifen acts as an antiestrogen with regard to breast cancer and significantly reduces the occurrence of contralateral breast cancer, it acts as a weak estrogenic agent elsewhere, raising the risk for endometrial cancer.¹¹¹ Thus, patients who have received long-term adjuvant hormonal therapy should have regular endometrial screening by a gynecologist. Radiation therapy for an initial breast cancer does not appear to elevate the risk for contralateral breast cancer.¹¹⁹

Prostate Cancer

It was recently reported that radiotherapy for prostate cancer slightly elevates the risk for bladder cancer after many years.⁹⁴ As described earlier, an association between prostate cancer and other malignancies has occasionally been found, for example, lung cancer or colorectal cancer, but these have usually been unidirectional, and thus probably represent detection bias rather than some shared risk factor.

Testicular Cancer

Testicular cancer is one of the most curable solid tumors, whether it occurs unilaterally or bilaterally.^42,120 Because etoposide is used as a major treatment modality in this disease, and this chemotherapeutic agent is associated with acute leukemia, there may be some elevation in risk of leukemia following successful therapy.^42,99 Furthermore, when radiation therapy is used in the primary management of testicular cancer, there may be elevated risks for other neoplasms in the pelvis.

Pancreas/Gastric Cancer

Because both pancreatic and gastric cancer have a poor outlook with few long-term survivors, it is difficult to know what second malignancies would be associated with these neoplasms. Both are associated with cigarette smoking, however, and thus, one could speculate that when successful treatments are developed, other tobacco-related malignancies might be observed. Pancreatic cancer has occurred as a second malignancy in individuals with other smoking-related neoplasms.⁴³ No significant associations with gastric cancer were found in a recent report.¹²¹

Colorectal Cancer

Survivors of colorectal cancer are at elevated risk for second malignancies within the colon and rectum, as well as in the breast, uterus, and ovary.¹¹⁵ In those patients with HNPCC, there is an elevated risk of small bowel and endometrial cancers.

Endometrial/Ovarian Cancer

Survivors of endometrial cancer are at elevated risk for ovarian and colorectal cancers as well as breast cancer.^{14,15,17,115,122} As a result, appropriate surveillance and screening should be performed in women with any of these neoplasms. If appropriate, bilateral oophorectomy should be considered at the time of hysterectomy in order to reduce the subsequent risk for ovarian cancer.

Skin Cancer

It has long been recognized that basal cell carcinomas and squamous cell carcinomas (nonmelanotic skin cancer) tend to occur in the same individuals.¹²³ This represents the impact of sun exposure, a shared risk factor. Thus, those who have nonmelanotic skin cancer should undergo regular surveillance for further skin malignancies and should avoid further sun exposure. Individuals with dysplastic nevi may develop multiple cutaneous melanomas and should undergo regular evaluations by experienced clinicians.¹²⁴ Certainly those who survive an initial melanoma are also at elevated risk (> 30-fold according to a recent report) for a second melanoma.¹²⁵