An increase in second solid tumors has also been observed, especially cancers of the lung, breast, thyroid, bone/soft tissue, stomach, esophagus, colon and rectum, uterine cervix, head and neck, and mesothelioma.[7,10,11,12,13,14,15] These tumors occur primarily after radiation therapy or with combined modality treatment, and approximately 75% occur within radiation ports. At a 15-year follow-up, the risk of second solid tumors is approximately 13%,[7,11] and at a 25-year follow-up the risk is approximately 22%.[10,16] In a cohort of 18,862 5-year survivors from 13 population-based registries, the younger patients had elevated risks for breast, colon, and rectal cancer for 10 to 25 years before the age when routine screening would be recommended in the general population.
Lung cancer is seen with increased frequency, even after chemotherapy alone, and the risk of this cancer is increased with cigarette smoking.[17,18,19,20] Breast cancer is seen with increased frequency after radiation therapy or combined modality therapy.[10,12,14,21,22,23,24] The risk appears greatest for women treated with radiation before age 30 years, and the incidence increases substantially after 15 years of follow-up.[10,13,25,26,27] In a case control study of 106 patients who developed breast cancer after therapy for HL, cumulative absolute risks for developing breast cancer were calculated as a function of radiation therapy dose and the use of chemotherapy. With a 30-year follow-up, cumulative absolute risks of breast cancer with exposure to radiation range from 8.5% to 39.6%, depending on the age at diagnosis. A family history of breast cancer or ovarian cancer does not confer a greater increased risk than that of radiation therapy for this cohort. In a nested case control study and subsequent cohort study, patients who received both chemotherapy and radiation therapy had a statistically significant lower risk of developing breast cancer than those treated with radiation therapy alone.[22,30] Reaching early menopause with less than 10 years of intact ovarian function appeared to account for the reduction in risk among patients who received combined modality therapy. Reduction of radiation volume also decreased the risk of breast cancer after HL. The risk of non-Hodgkin lymphoma is also increased, but this risk is not clearly related to type or extent of treatment.
Several studies suggest that splenic-field radiation therapy and splenectomy increase the risk of a treatment-related second cancer.[31,32,33] Late effects after autologous stem cell transplantation that is given for failure of induction chemotherapy include second malignancies, hypothyroidism, hypogonadism, herpes zoster, depression, and cardiac disease.
Adverse Effects of Therapy
A toxic effect that is primarily related to chemotherapy is infertility, usually after MOPP-containing or BEACOPP-containing regimens;[11,35,36] ABVD appears to spare long-term testicular and ovarian function.[36,37] Late complications primarily related to radiation therapy include hypothyroidism and cardiac disease, which may persist through to 25 years after first treatment.[38,39,40,41,42,43] The absolute excess risk of fatal cardiovascular disease ranges from 11.9 to 48.9 per 10,000 patient years, mostly attributable to fatal myocardial infarction (MI).[39,40,41,43] The use of subcarinal blocking did not reduce the incidence of fatal MI in a retrospective review, perhaps because of the exposure of the proximal coronary arteries to radiation. In a cohort of 7,033 HL patients, MI mortality risk persisted through to 25 years after first treatment with supradiaphragmatic radiation therapy (dependent on the details of treatment planning), doxorubicin, or vincristine. Impairment of pulmonary function may occur as a result of mantle-field radiation therapy; this impairment is not usually clinically evident, and recovery in pulmonary testing often occurs after 2 to 3 years. Pulmonary toxic effects from bleomycin as used in ABVD are seen in older patients (especially those older than 40 years). Avascular necrosis of bone has been observed in patients treated with chemotherapy and is most likely related to corticosteroid therapy. Bacterial sepsis may occur rarely after splenectomy performed during staging laparotomy for HL; it is much more frequent in children than in adults. The Advisory Committee on Immunization Practices recommends that all patients with HL, whether or not they have had a splenectomy, should be immunized with Haemophilusinfluenzae type b conjugate, meningococcal, and pneumococcal vaccines at least 1 week before treatment. Some investigators recommend reimmunization with all three vaccines 2 years after completion of treatment and with pneumococcal vaccine every 6 years thereafter.