Hodgkin Lymphoma

Technical aspects of radiation therapy

IFRT and involved-node radiotherapy (INRT)

In a combined-modality setting, irradiation of the involved lymph node chain, with or without adjacent sites, and tailoring of the field borders to the postchemotherapy tumor volume (in critical areas such as the mediastinum) are recommended. IFRT is the most appropriate irradiation approach after chemotherapy. IFRT or regional radiotherapy alone is used for lymphocyte-predominant HL. Further reduction of the radiation field has been introduced and implemented in EORTC/GELA studies. The INRT field is limited to the prechemotherapy lymph node(s) volume, and, in the mediastinum, it also accounts for the reduction of mass after chemotherapy.

The transition into INRT fields or reduced IFRT markedly reduces the exposure of normal structures in most cases; the safety of field reduction has recently been reported.

Extended radiation fields

Successful therapy with irradiation alone in classic HL requires treatment of all clinically involved lymph nodes and all nodal and extranodal regions at risk for subclinical involvement (Figure 2). The HL radiation fields were designed to conform to the philosophy of treating regions beyond the immediately involved area while accounting for normal tissue tolerance and the technical constraints of field size. The extended radiation fields are inappropriate when radiation is administered as consolidation following chemotherapy and, thus, they are rarely used today.

FIGURE 2

Extended radiation fields used for treatment of classic Hodgkin lymphoma with irradiation alone.

Dose considerations

When irradiation alone is used to treat HL, the standard total dose to each field is 3,600 cGy, delivered in daily fractions of 180 cGy over 4 weeks. In addition, clinically involved areas are given a boost of 360 to 540 cGy in 2 to 3 fractions to bring the total dose to these areas up to 3,960 to 4,140 cGy. Patients who receive irradiation as consolidation after chemotherapy receive a total dose of 2,000 to 3,600 cGy in 150- to 180-cGy fractions. We normally use opposed anterior and posterior fields that are evenly weighted and treat both fields daily. Three-dimensional conformal radiotherapy and intensity-modulated radiation therapy (IMRT) are employed for selected cases.

Recent studies suggest that a reduction in the size of radiation fields and doses delivered may decrease the risk of breast cancer.

Side effects and complications of radiotherapy

Side effects of radiotherapy depend on the irradiated volume, dose administered, and technique employed. They are also influenced by the extent and type of prior chemotherapy, if any, and by the patient's age.

Acute effects

The potential acute side effects of involved fields in the upper body include mouth dryness, change in taste, pharyngitis, nausea, dry cough, dermatitis, and fatigue. These side effects are usually mild and transient.

The main potential side effects of subdiaphragmatic irradiation are loss of appetite, nausea, and increased bowel movements. These reactions are usually mild and can be minimized with standard antiemetic medications.

Irradiation of more than one field, particularly after chemotherapy, can cause myelosuppression, which may necessitate treatment delays.

The effect of radiation dose and field reduction on the risk of long-term complications was analyzed in two studies. A French collaborative group randomized 188 patients with favorable early-stage HL to receive either ABVDX3 followed by radiotherapy at 40 Gy to the involved sites and 30 Gy to uninvolved sites, including the paraaortic and splenic areas (control arm) or the same chemotherapy followed by 30 Gy to involved areas and 24 Gy to uninvolved sites. While FFTF and overall survival were the same in both arms, long-term severe adverse events, either cardiac or second tumors, at a median follow-up of 10 years were observed only in the control arm with the higher radiation doses. Rates of complications in the control group were similar to those of patients in an older study who were treated with the higher doses of radiation therapy (and ABVDX3) (Arakelyan N et al: Cancer 116:4054–4062, 2010). In another study, researchers from the Netherlands Cancer Institute analyzed 1,122 female 5-year survivors treated for HL between 1965 and 1995; 806 were irradiated (36–44 Gy) to a mantle field that includes the bilateral axillae or axillae alone, while in 126 patients who received radiation only to the mediastinum, the axillae (and thus most of the breast tissue) were spared from radiation. Sparing the axillae markedly reduced the risk of breast cancer (by 2.7-fold) compared with patients who received a full mantle field. Nowadays, in most patients treated with IFRT, the axillae are not included (De Bruin ML et al: J Clin Oncol 27:4239–4246, 2009).

Delayed effects

Delayed side effects may develop anywhere from several weeks to several years after the completion of radiotherapy.

Lhermitte's sign Approximately 15% of patients who received the full dose of radiation to the neck noted an electric shock sensation radiating down the backs of both legs when the head is flexed (Lhermitte's sign) 6 weeks to 3 months after mantle-field radiotherapy. Possibly secondary to transient demyelinization of the spinal cord, Lhermitte's sign resolves spontaneously after a few months and is not associated with late or permanent spinal cord damage. It is rarely seen with modern dose-reduced radiation therapy.

Pneumonitis and pericarditis During the same period, radiation pneumonitis and/or acute pericarditis may occur in < 5% of patients who receive large fields of radiation to the mediastinum; these side effects occur more often in those who have extensive mediastinal disease. Both inflammatory processes have become rare with modern radiation techniques.

Herpes zoster infection Patients with HL, regardless of treatment type, have a propensity to develop herpes zoster infection within 2 years after therapy. Usually, the infection is confined to a single dermatome and is self-limited. If the cutaneous eruption is identified promptly, treatment with systemic acyclovir will limit its duration and intensity.

Subclinical hypothyroidism

Radiotherapy of the neck can induce subclinical hypothyroidism in about one-third of patients. This condition is detected by elevation of thyroid-stimulating hormone. Thyroid replacement with levothyroxine is recommended, even in asymptomatic patients, to prevent overt hypothyroidism and decrease the risk of benign thyroid nodules.

Infertility

Irradiation of the pelvis may have deleterious effects on fertility. In most patients, this problem can be avoided by appropriate gonadal shielding. In females, the ovaries can be moved into a shielded area laterally or inferomedially near the uterine cervix. Irradiation fields that spare the pelvis do not increase the risk of sterility.

Secondary malignancies

The rate of second malignancies following radiation therapy with or without chemotherapy for HL is approximately 1% per year. The most common second malignancies were breast cancer, gastrointestinal cancers, lung cancer, thyroid cancer, soft tissue and bone sarcomas, and acute leukemias, which are associated with chemotherapy as mentioned below in this chapter. The risk of developing breast cancer following radiation therapy increases with length of follow-up. Addition of alkylating agent–containing chemotherapy of the MOPP type seems to reduce this risk, probably because of effects on the ovaries that reduce estrogen production. The risk is increased with larger fields and higher doses of radiation therapy.

Lung cancer Patients who are smokers should be strongly encouraged to quit the habit because the increase in lung cancer that occurs after irradiation or chemotherapy with alkylating agents has been detected mostly in smokers. Alkylating agents (such as in the MOPP regimen) and radiation therapy were associated with an increased risk of lung cancer in an additive and dose-dependent fashion. These effects were multiplied by tobacco use. Among solid tumors (see sidebar), only alkylating agent–based regimens of the MOPP type are associated with an increased risk of lung cancer. Second malignancies are the leading cause of late morbidity and mortality in early-stage patients cured of HL.

Breast cancer The increase in breast cancer risk is inversely related to the patient's age at HL treatment; no increased risk has been found in women irradiated after 30 years of age. The risk of breast cancer is increased with higher radiation breast dose and is reduced in patients who received chemotherapy or ovarian irradiation that induced early menopause.

In most situations, modern IFRT should spare the breast. Breast cancer is curable in its early stages, and early detection has a significant impact on survival. Breast examination should be part of the routine follow-up for women cured of HL, and routine mammography should begin about 8 years after treatment.

Cardiovascular disease

An increased risk of cardiovascular morbidity has been reported among patients who have received mediastinal irradiation. In a retrospective study evaluating the cardiac risks of 450 patients cured of HL with radiotherapy alone or in combination, 42 patients (10%) developed coronary artery disease (CAD) at a median of 9 years after treatment, 30 patients (7%) developed carotid and/or subclavian artery disease at a median of 17 years after treatment, and 25 patients (6%) developed clinically significant valvular dysfunction at a median of 22 years after treatment. The most common valve lesion was aortic stenosis, which occurred in 14 cases. At least 1 cardiac risk factor was present in all patients who developed CAD. The only treatment-related factor associated with the development of CAD was use of a radiation technique that resulted in a higher total dose to a portion of the heart (relative risk [RR] = 7.8; 95% CI = 1.1–53.2; P =.04). No specific treatment-related factor was associated with carotid or subclavian artery disease or valvular dysfunction. Freedom from cardiovascular morbidity was 88% at 15 years and 84% at 20 years.

In a cohort of 2,201 people who were 5-year survivors of Hodgkin lymphoma treated between 1965 and 1995 with full dose large-field irradiation, irradiation of the neck and mediastinum was associated with a 2.55 increased risk of ischemic cerebrovascular disease. Yet, currently used doses of radiation are markedly smaller than those practiced during the study era.

To reduce this hazard, radiation fields should conform to the involved postchemotherapy volume, and the dose should be reduced to 20 to 30 Gy, if possible. Patients who have received radiation to the mediastinum should be monitored and advised about other established CAD risk factors, such as smoking, hyperlipidemia, hypertension, and poor dietary and exercise habits. Cholesterol levels should be monitored and treated if elevated.

The risk of late mortality from myocardial infarction is increased with use of supradiaphramatic radiotherapy, especially total nodal radiation therapy. The risk also was higher in patients given various chemotherapy regimens (particularly ABVD) with, and even without, supradiaphragmatic radiotherapy.

Effects on bone and muscle growth

In children, high-dose irradiation will affect bone and muscle growth and may result in deformities. Current treatment programs for pediatric HL are chemotherapy-based; radiotherapy is limited to low doses.