Surgery

Surgical procedures can increase the risk of subsequent malignancy. Adenocarcinoma of the colon was reported in several patients following ureterosigmoidostomy. The incidence rate of adenocarcinoma in these patients was approximately 9.9 per 1,000, as compared to an incidence rate of 9.9 per 100,000 in the general population.¹⁷⁸ The median number of years between ureterosigmoidostomy and the diagnosis of colon carcinoma was 22.¹⁷⁹ Carcinoma may develop at the uretero-colonic suture line following temporary ureterosigmoidostomy despite rediversion of urine away from the colonic mucosa,¹⁸⁰ and was reported in one patient with ileal loop urinary diversion,¹⁸¹ suggesting that the complication may not be avoided by the use of a different surgical procedure.

Radiation Therapy

Patients who received neck irradiation for malignant diseases were at risk for the subsequent occurrence of thyroid malignancies. The incidence of thyroid cancer in survivors of Hodgkin disease was 0.8% among 119 children treated at Stanford University.¹¹²

Central nervous system tumors, including meningiomas and gliomas, have been reported with increasing frequency following direct or incidental irradiation of the brain.^182–187 Neglia and his colleagues reported that the relative risk of a secondary central nervous system malignancy among children treated for acute lymphoblastic leukemia was 21.7. The most significant factors for the occurrence of these tumors were previous prophylactic cranial irradiation and age younger than 6 years at diagnosis.¹⁸⁸

Sarcomas of bone have been reported both in patients with hereditary retinoblastoma, and those surviving other types of childhood cancer. The cumulative risk of an SMN in bone was estimated to be 2.8% among 9,170 patients evaluated, but was 14.1% among those with retinoblastoma and 22.1% among those treated for Ewing sarcoma.¹⁸⁹ The relative risk was 2.7 among patients whose treatment had included radiation therapy, with the relative risk increasing with increasing radiation therapy dose and more intensive use of alkylating agents.¹⁸⁹ The dramatic risk of sarcoma of bone following treatment of Ewing sarcoma, reported earlier from several single institutions.^190,191 was confirmed in a multiinstitutional review. The cumulative frequency of an SMN in successfully treated patients was 9.2% at 20 years after diagnosis, and that of a secondary sarcoma was 6.5%. No secondary sarcomas developed in patients who had received less than 4,800 cGy.¹⁹²

The evolution of radiation therapy technique from the use of orthovoltage radiation apparatus which produce a higher absorbed dose in bone to the use of megavoltage radiation apparatus which does not have this characteristic should result in a lower frequency of SMNs in irradiated bones.^193,194 However when this question was addressed in a case-control study of bone sarcoma as an SMN, no difference in the relative risk for patients treated with orthovoltage, as compared to megavoltage, radiation therapy could be demonstrated.¹⁸⁹

Successfully treated patients are at risk of developing carcinomas within prior radiation therapy treatment volumes at a very early age (eg, the skin).¹⁹⁵ Breast cancer occurs with a relative risk of 17 to 136 among irradiated survivors of pediatric Hodgkin disease.^196–199 Adenocarcinoma of the colon occurred within the volume of irradiation in three patients at the ages of 12, 27, and 27 years.^200–202

Total-body irradiation, a component of most preparative regimens for allogeneic bone marrow transplantation for malignant diseases, is associated with a cumulative risk for the occurrence of a second solid neoplasm of 8.3% at 13 years after treatment.²⁰³

Chemotherapy

The significance of prior treatment with chemotherapy in the pathogenesis of SMNs was first evaluated in detail in cohorts of adults treated successfully for Hodgkin disease. The risk factors for the occurrence of SMNs in pediatric patients following treatment for Hodgkin disease have been less thoroughly evaluated.

Bhatia and colleagues reported that the cumulative risk of developing any SMN following treatment for Hodgkin disease in childhood was 7% at 15 years after diagnosis. The risk of developing non-Hodgkin lymphoma was 1.1%, and of any type of leukemia was 2.8% at 15 years after diagnosis.¹⁹⁷ The actuarial risk of developing acute myelogenous leukemia 10 years after diagnosis was 11% (± 7%) among pediatric patients treated at Stanford University with low-dose (2,500 cGy) radiation therapy and MOPP chemotherapy.²⁰⁴ Prior treatment with an alkylating agent has been shown to modify the risk of developing bone cancer¹⁸⁹ or leukemia²⁰⁵ as an SMN.

The epipodophyllotoxins have been identified as important leukemogens. The risk of secondary AML (acute myelogenous leukemia) depends upon the cumulative dose of drug administered, as well as the schedule of administration, with the frequency reported to be 0% among germ cell tumor patients treated with less than 2,000 mg/m²,²⁰⁶ 5.9% among childhood acute lymphoblastic leukemia patients treated with 1,800 to 9,900 mg/m²,²⁰⁷ 11.3% among germ cell tumor patients who received more than 2,000 mg/m²,²⁰⁷ and 18.4% among pediatric non-Hodgkin lymphoma patients who received 4,200 to 5,600 mg/m².²⁰⁸

The carcinogenic potential of the anthracycline doxorubicin was suggested by the results of a case-control study of risk factors for leukemia as an SMN, in which increasing doxorubicin dose was associated with an increasing relative risk of leukemia as an SMN after adjustment for the ackylating agent dose score.²⁰⁵ An analysis of risk factors for any SMN in a large cohort of childhood cancer patients demonstrated that treatment with doxorubicin was the only factor identified, in addition to treatment with BCNU, which increased the risk of an SMN,¹⁶⁵ a finding apparently extending the earlier suggestion that doxorubicin was leukemogenic. Breslow and his colleagues demonstrated that treatment with doxorubicin increased the risk of an SMN among Wilms tumor patients who were treated with radiation therapy.²⁰⁹

Immune Suppression

Immune suppression is a component of allogeneic bone marrow transplantation. To prevent graft versus host disease, antithymocyte globulin (ATG) may be administered to the recipient or the bone marrow may be manipulated to remove T cells. These manipulations and bone marrow transplantation from an unrelated bone marrow donor increase the risk of Epstein-Barr virus associated B-cell lymphoproliferative disorder. The cumulative incidence rates at 10 years after bone marrow transplantation were 11.3% among those treated with ATG, 11.4% among those who received T-cell-depleted bone marrow, and 2.3% among those who received bone marrow from unrelated donors.²⁰³