Radiation Therapy
Second Malignancies
Adverse Effects of Therapy

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Drug combinations described in this section:

• ABVD: doxorubicin plus bleomycin plus vinblastine plus dacarbazine.
• BEACOPP: bleomycin plus etoposide plus doxorubicin plus cyclophosphamide plus vincristine plus procarbazine plus prednisone.
• MOPP: mechlorethamine plus vincristine plus procarbazine plus prednisone.

After initial clinical staging for Hodgkin lymphoma (HL), patients with obvious stage III or IV disease, bulky disease (defined as a 10 cm mass or mediastinal disease with a transverse diameter exceeding 33% of the transthoracic diameter), or the presence of B symptoms will require combination chemotherapy with or without additional radiation therapy.

Patients with nonbulky stage IA or IIA disease are considered to have clinical early-stage disease. These patients are candidates for chemotherapy, combined modality therapy, or radiation therapy alone. Staging laparotomy is no longer recommended because it may not alter management and does not enhance ultimate outcome.[1] When chemotherapy alone or combined modality therapy is applied, laparotomy is not required.

In adult HL, the appropriate dose of radiation alone is 25 Gy to 30 Gy to clinically uninvolved sites, and 35 Gy to 44 Gy to regions of initial nodal involvement.[2-5] These recommendations are often modified in pediatric or advanced-staged adult patients who also receive chemotherapy. Treatment is usually delivered to the neck, chest, and axilla (mantle field) and then to an abdominal field to treat para-aortic nodes and the spleen (splenic pedicle). In some patients, pelvic nodes are treated with a third field. The three fields constitute total nodal radiation therapy. In some cases, the pelvic and para-aortic nodes are treated in a single field called an inverted Y. In patients with a favorable prognosis, treatment of the pelvic lymph nodes is frequently omitted, since fertility can be preserved without affecting relapse-free survival. (For more information on fertility, refer to the Sexuality and Reproductive Issues summary.)

Acute nonlymphocytic leukemia may occur in patients treated with combined modality therapy or with combination chemotherapy alone.[6-8] At 10 years following therapy with regimens containing MOPP, the risk of acute myelogenous leukemia (AML) is approximately 3%, with the peak incidence occurring 5 to 9 years after therapy. The risk of acute leukemia at 10 years following therapy with ABVD appears to be less than 1%.[6] A population-based study of more than 35,000 survivors during a 30-year time span identified 217 patients who developed AML; the excess absolute risk is significantly higher (9.9 vs. 4.2 after 1984, P < .001) for older patients (i.e., older than 35 years at diagnosis) versus younger survivors.[9]

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.[7,10-15] 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.[15]

Lung cancer is seen with increased frequency, even after chemotherapy alone, and the risk of this cancer is increased with cigarette smoking.[17-20] Breast cancer is seen with increased frequency after radiation therapy or combined modality therapy.[10,12,14,21-24] 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] 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.[27] 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.[28] In a nested case control 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] Reaching menopause before age 36 years appeared to account for the reduction in risk among patients who received combined modality therapy. The risk of non-Hodgkin lymphoma is also increased, but this risk is not clearly related to type or extent of treatment.[11]

Several studies suggest that splenic-field radiation therapy and splenectomy increase the risk of a treatment-related second cancer.[29-31] 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.[32]

A toxic effect that is primarily related to chemotherapy is infertility, usually after MOPP-containing or BEACOPP-containing regimens;[11,33,34] ABVD appears to spare long-term testicular and ovarian function.[34,35] Late complications primarily related to radiation therapy include hypothyroidism and cardiac disease, which may persist through to 25 years after first treatment.[36-41] 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).[37-39,41] 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.[38] 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.[41] 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.[42] Pulmonary toxic effects from bleomycin as used in ABVD are seen in older patients (especially those older than 40 years).[43] Avascular necrosis of bone has been observed in patients treated with chemotherapy and is most likely related to corticosteroid therapy.[44] Bacterial sepsis may occur rarely after splenectomy performed during staging laparotomy for HL;[45] 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.[46] Some investigators recommend reimmunization with all three vaccines 2 years after completion of treatment and with pneumococcal vaccine every 6 years thereafter.[47]

Fatigue is a commonly reported symptom of patients who have completed chemotherapy. In a case control study design, a majority of HL survivors reported significant fatigue lasting for more than 6 months after therapy compared to age-matched controls.[48]

Patients older than 60 years with HL experience more treatment-related morbidity and mortality and typically receive a lower dose intensity of chemotherapy because of poorer tolerance of treatment than comparably staged younger patients.[49,50]

References

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