It has been conclusively demonstrated that patients treated for Hodgkin lymphoma are at higher risk for the development of second cancers compared with an age-matched healthy population. The most common second malignancies include female breast cancer and lung cancer. The risk of breast cancer is elevated many years before routine screening is recommended in the general population, which has implications for post-treatment surveillance. Although factors such as genetic predisposition and immunodeficiency may be contributing, the majority of excess second cancers are thought to be treatment-related.
Most studies have shown lower rates of second cancers with combined-modality therapy compared with definitive radiation therapy. Koontz et al evaluated 111 patients from Duke Cancer Institute treated with either definitive radiation therapy (subtotal nodal fields; median dose, 38 Gy) or combined modality therapy (involved fields; median dose, 26 Gy). The 20-year actuarial risk of developing a second cancer was 16% with definitive radiation therapy alone and 0% with combined-modality therapy. A similar decline in the incidence of secondary malignancies with low-dose, involved-field radiation therapy was observed in a study by investigators from Yale University School of Medicine.
Specifically evaluating radiation field size, the German Hodgkin Study Group trial HD8 randomized early-stage favorable patients following chemotherapy to consolidation radiation therapy using either an extended-field or an involved-field approach. As referenced previously, there was no difference in outcomes with smaller radiation fields. Long-term follow-up did demonstrate a decline in all intercurrent illness mortality (12.2% vs 15%). Further, there was a reduction in the number of deaths due to secondary malignancies (45 vs 58), particularly acute myeloid leukemia and myelodysplasia (4 vs 11). Long-term results of a randomized study from Milan comparing subtotal nodal vs involved-field radiation therapy after ABVD also showed fewer secondary malignancies with smaller radiation fields (0 vs 3). Finally, De Bruin et al from the Netherlands observed a significantly lower risk of breast cancer in female patients treated with radiation to the mediastinum alone as opposed to a full mantle field (which includes the axillary regions and necessarily more breast tissue).
In the pediatric literature, lower doses have also been associated with a lower risk of second cancers in some,[30,34] but not all, studies. In the study from Stanford, the 20-year actuarial risk of developing a secondary cancer was 17%, similar to historical values, with breast cancer and thyroid cancers being most common. Thyroid cancers are known to be associated with low radiation doses in the pediatric population. Longer follow-up is necessary, both in the adult and pediatric populations, to ascertain risks associated with smaller radiation fields and lower doses.
Cardiac disease is the second most prevalent late effect, behind secondary malignancies, in Hodgkin survivors. Since radiation therapy can affect all of the structures of the heart, the complications that have been observed include coronary artery disease leading to myocardial infarction, valvular disease, pericardial disease, conduction abnormalities, and cardiomyopathies. Pericarditis was a common complication in the early days of radiation therapy when the entire heart was treated with relatively high doses, but it is rarely observed today.
While mediastinal radiation therapy clearly increases the risk of developing heart disease, anthracyclines appear to compound this risk, particularly for congestive heart failure and valvular disorders.[41,42] Thus, minimizing both radiation and chemotherapy exposure is important. Further, patients with known cardiac risk factors (eg, diabetes, hypertension, hyperlipidemia, smoking) appear to be at much higher risk for the development of cardiac complications compared with patients with no cardiac risk factors.[33,43] Thus, mediastinal radiation therapy can be considered a cardiac risk factor, which when compounded by diabetes or other cardiac comorbidities, begins to increase the risk of an adverse event. Follow-up appointments should emphasize regular exercise, a balanced diet, maintaining a healthy weight, tobacco avoidance, and other lifestyle measures that will decrease the risk of cardiac disease in the ensuing decades.
Cardiac complications are clearly related to the dose and field of radiation. Many studies have shown that lower radiation doses are associated with a lower risk of cardiac disease.[32,33,35] In a study of 1132 Hodgkin survivors treated before they were 18 years of age, the 25-year actuarial risk of cardiac disease was 21% after they had received a mediastinal dose of 36 Gy compared with 3% when 20 Gy was utilized (P < .001). Radiation fields that are more conformal to the disease in the mediastinum are able to avoid the valves and coronary arteries in many patients with Hodgkin lymphoma. Geographic avoidance is the best way to decrease the risk of complications.
Combined-Modality Therapy: Optimizing Chemotherapy
Acute and long-term toxicity of chemotherapy is less commonly discussed in the context of optimizing treatment for Hodgkin lymphoma. Just as radiation therapy carries inherent risks, cytotoxic drugs do as well. Intensive multi-agent chemotherapy regimens increase the risk of cardiac dysfunction, pulmonary complications, neuropathy, infertility, and secondary cancers. Arguably, late effects of radiation therapy have been more comprehensively studied than late effects from chemotherapy. The optimal number of cycles and the best chemotherapeutic regimen are areas of active investigation, with the goal of maximizing the chance of cure while minimizing side effects.
The German Hodgkin Lymphoma Group HD10 study clearly shows that, when followed by radiation therapy, 2 cycles of ABVD are as effective as 4 cycles in patients with early-stage, favorable Hodgkin lymphoma. Two cycles of ABVD were less toxic than 4 cycles, with grade 3/4 adverse events occurring in 33% vs 52% of patients, respectively (P < .001). Fewer infections (10 vs 30), respiratory tract disorders (2 vs 12), deaths due to ABVD toxicity (0 vs 6), and deaths due to cardiovascular events (3 vs 6) were observed. No difference in development of secondary cancers has been reported (4.5% vs 4.7%), but follow-up is short.
More intense combined modality therapy may be required to effectively treat patients with early-stage, unfavorable Hodgkin lymphoma. Whether optimal chemotherapy in this high-risk group should be ABVD or BEACOPP (bleomycin, etoposide(Drug information on etoposide), doxorubicin(Drug information on doxorubicin), cyclophosphamide(Drug information on cyclophosphamide), vincristine, procarbazine(Drug information on procarbazine), prednisone(Drug information on prednisone)), is under debate.
As previously mentioned, the HD11 trial had a 2 × 2 factorial design that compared 20 Gy vs 30 Gy of radiation therapy and 4 cycles of ABVD vs 4 cycles of standard BEACOPP. BEACOPP did not improve clinical outcomes but was associated with more toxicity. Grade 3/4 toxicity occurred in 74% vs 52% (P < .001) of patients treated with BEACOPP vs ABVD, respectively, leading to a higher rate of hospitalization (59% vs 43%, respectively). Therefore, the conclusion of this study was that 4 cycles of ABVD plus 30 Gy of radiation therapy should be the standard of care for early-stage, unfavorable Hodgkin lymphoma.
In an attempt to further improve long-term control of Hodgkin lymphoma in patients with early-stage, unfavorable disease, the German Hodgkin Study Group HD14 trial was developed. This was a randomized study of 4 cycles of ABVD vs 2 cycles of escalated BEACOPP + 2 cycles of ABVD with radiation therapy (at 30 Gy) administered in both arms. The 5-year progression-free survival was statistically significantly higher in the BEACOPP arm (at 95.4% vs 89.1% with ABVD plus radiotherapy, (P < .001) but the 5-year overall survival was 97% in both arms. Grade 3/4 hematologic adverse events were more frequent with BEACOPP (87% vs 51%, respectively). No increased incidence of secondary malignancy or long-term toxicity has been demonstrated thus far, but follow-up is short.
The longer progression-free survival seen with the addition of escalated BEACOPP to ABVD has led the German Hodgkin Study Group to recommend this as standard therapy for early-stage, unfavorable Hodgkin lymphoma. However, the overall survival is identical with ABVD and BEACOPP chemotherapy regimens, likely due to the efficacy of salvage regimens for relapsed disease. For now, ABVD continues to be the standard of care in the United States.
Future areas of investigation involve the incorporation of new drugs into the standard chemotherapy regimens, such as the use of the anti-CD30 monoclonal antibody brentuximab vedotin (Adcetris) as a substitute for bleomycin(Drug information on bleomycin) in an ABVD-like regimen; the study of 6 cycles of ABVD in combination with 20 Gy of radiation therapy for early-stage unfavorable disease; and investigation of whether mid-treatment PET scans can risk-stratify patients and determine which patients, if any, can stop treatment after fewer cycles of chemotherapy.
Combined-Modality Therapy: An Optimal Balance
A combination of chemotherapy and radiation therapy provides optimal disease control in early-stage Hodgkin lymphoma. The risks of treatment will continue to decline as both modalities are refined. While results with chemotherapy alone are good, they remain inferior to a combined modality approach. Administering more-intense chemotherapy in an attempt to avoid radiation therapy may prove counterproductive from the perspectives of both disease control and late toxicity. High-dose chemotherapy and stem cell transplant can salvage some patients who relapse after receiving chemotherapy alone. However, this is successful in only a fraction of patients, and long-term morbidity from high-dose chemotherapy must also be considered. As the disciplines of both radiation and medical oncology work together to optimize their individual contributions to the management of early-stage Hodgkin lymphoma, high cure rates will be maintained and long-term morbidity will be minimized.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.