Complications from Therapy

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The modern treatment of HD, consisting of greater reliance on chemotherapy, reduced doses of radiation, and not doing staging laparotomy as standard care, has resulted in fewer complications from therapy compared to historic regimens of HD treatment.

1. Pulmonary damage (radiation induced and/or chemotherapy [bleomycin] induced): These complications consist of a. Pneumonitis b. Pulmonary fibrosis c. Decreased pulmonary function (as many as 40% of patients)

d. Increased mediastinal width e. Infiltrates extending beyond radiation port f. Spontaneous pneumothorax g. Pleural effusion.

2. Cardiac damage (radiation induced and/or chemotherapy [doxorubicin] induced): These complications (about 13% of patients) consist of a. Cardiomyopathy, resulting in congestive heart failure b. Cardiac arrhythmias with conduction defects c. Pericarditis, resulting in pericardial effusion and cardiac tamponade d. Valvular damage to aorta and pulmonary artery e. Coronary artery disease and myocardial infarction.

3. Spinal cord damage: These complications consist of a. Lhermitte sign—a postradiation syndrome of numbness, tingling, and "electric shock" in extremities; self-limiting, subsiding within 10 months b. Radiation-induced transverse myelitis—more severe.

4. Radiation nephritis

5. Azoospermia: The quality of sperm may be poor in many patients with HD because of the disease itself before exposure to any therapy. Azoospermia induced by alkylating agents such as nitrogen mustard is almost always permanent in postpubertal patients. However, the prognosis of this complication in prepubertal patients is unknown. Many adolescent boys with HD are azoospermic prior to initiation of therapy; thus, sperm banking itself is not always a suitable strategy to guarantee future reproduction among these patients. However, patients should be given the option for bank-cryopre-served sperm. Emerging data now suggest that recovery of spermatogenesis has been seen after three or fewer cycles of MOPP.

6. Amenorrhea: Radiation-induced ovarian damage can be avoided by performing oophoropexy during laparotomy. Among this group, a number of normal pregnancies and normal offspring have been observed. There has been no increase in fetal wastage or abortions. Chemotherapy (MOPP)-induced ovarian dysfunction and amenorrhea occur in 13% of patients under 25 years of age. The younger the patient is when treated, the higher the probability of maintaining regular menses following treatment. The younger the patient, the greater the complement of oocytes at the time of treatment and, hence, the greater the likelihood of maintaining fertility.

7. Hypothyroidism: This results from radiation therapy. Among children who receive neck radiation in doses of 2600 cGy or less, there is a 17% incidence of thyroid dysfunction as compared to a 78% incidence among patients who receive doses in excess of 2600 cGy. Surveillance studies, including tri-iodothy-ronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) levels and neck examination for thyroid swelling, are important in recognizing this complication. Euthyroid patients with high TSH (biochemical hypothyroidism) are treated with T4 to prevent the development of thyroid adenoma.

8. Damage to soft tissue and bone growth: High doses (more than 3500 cGy) and large-volume irradiation administered to the axial skeleton result in a disproportionate alteration in sitting height as compared with standing height and a small thorax. The risk of this complication is particularly high in children under 6 years of age or in adolescence (11-13 years of age) when bone growth is very active at the time of treatment. Shortening of the interclavicular distance (small clavicles as well as atrophy of soft tissues of the neck) often occurs following high doses of radiation in children.

Doses less than 2500 cGy have resulted in no standing height abnormalities greater than one standard deviation from the mean; thus, 2000-2500 cGy appears to be the threshold beyond which growth abnormalities are more likely to occur.

With the use of radiotherapy, slipped femoral capital epiphysis may also occur. This can be minimized when routine humeral and femoral head blocks are used and when low radiation doses are administered.

9. Postsplenectomy infection: The incidence of significant infections and mortality in children splenectomized as part of a staging laparotomy for HD is 8.0% and 4.0%, respectively. The organisms reported to produce overwhelming sepsis in splenectomized children with HD are Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. The risk of these infections can be decreased with the use of pneumococcal vaccine and HIB vaccine before splenectomy and with the use of penicillin prophylaxis after splenectomy for several years. Compliance with penicillin prophylaxis is of crucial importance.

10. Secondary malignant neoplasms: The risk of secondary malignancies is a problem of major concern in selecting therapy for children with HD. Overall, the risk of developing a secondary neoplasm is 2% at 5 years, 5% at 10 years, and 9% at 15 years; the probability of developing s-AML or a secondary non-Hodgkin lymphoma is reported as 1%, 3%, and 4% at 5, 10, and 15 years, respectively; and the probability of developing a solid tumor is reported as 0.4%, 2%, and

6% at 5, 10, and 15 years, respectively. The median time to development of s-AML after chemotherapy and solid tumors after radiotherapy is about 5 and 12 years, respectively. The risk increases among those who have had a relapse. A relationship between leukemia and prior splenectomy has been suggested in the past. Alkylating agent therapy is strongly associated with subsequent development of s-AML with a significant dose-response relationship. Among the agents most often linked to leukemia are nitrogen mustard (mechlorethamine), cyclophosphamide, chlorambucil, and procarbazine. s-AML is almost always refractory to treatment, whereas secondary lymphomas and sarcomas respond better to therapy, and about 50% may attain cures. The actuarial risk of breast cancer at 20 years is 9.2%. The other secondary neoplasms associated with treatment of HD are thyroid carcinoma, skin carcinomas, brain tumor, malignant fibrous histiocytoma, and breast cancer.

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