Combined-Modality Therapy: Optimizing Radiation Therapy
Historically, when radiation therapy was utilized as a single modality it was necessary to treat not only known disease but also possible microscopic disease in high-risk adjacent sites. For patients with supradiaphragmatic Hodgkin lymphoma, this most commonly required treatment of all of the lymph node regions above the diaphragm (mantle field) combined with a field encompassing the para-aortic lymph nodes and spleen. This is referred to as subtotal nodal radiation therapy (Figure 2).
In a combined-modality approach, chemotherapy is relied upon to eradicate microscopic disease. Thus, prophylactic coverage of uninvolved sites becomes unnecessary and radiation fields can be significantly reduced. Several randomized trials have confirmed this premise, showing equivalent control rates when involved-field radiation therapy (ie, treatment of the involved lymph node region only) is utilized in lieu of more extensive fields[18-20] (Figure 3A). Involved-field radiation therapy, which has been extensively studied in Hodgkin lymphoma, consists of treatment of an entire region (ie, entire left neck treated even if disease is confined to left supraclavicular fossa).
Even smaller radiation fields are being explored, including involved-site radiation therapy (Figure 3B) and involved-node radiation therapy (Figure 3C). The former consists of treatment of the original extent of disease with a comfortable margin to account for uncertainties in pre- and post-chemotherapy imaging. A retrospective study from British Columbia suggested equivalent outcomes with this approach compared with the standard involved-field method. Involved-node radiation therapy is even more conformal and is confined to the original extent of disease (Figure 3C). International guidelines suggest that radiation treatment planning with PET and CT should be performed both before and after chemotherapy, with careful review of the imaging studies to ascertain original extent of disease and thereby facilitate accurate treatment when using this approach.[22,23]
While such tight fields may decrease the risk of complications, care and judgment are necessary to avoid making radiation fields too small and exposing a patient to an unnecessary risk of relapse. Further, the current use of low doses of radiation therapy (20 Gy) may mean that complications are not significantly improved by modest reductions in field size. It should also be pointed out that randomized trials have not been completed comparing either involved-site or involved-node radiation therapy with involved-field radiation therapy. Currently, either involved-field or involved-site radiation therapy is used in most instances.
With definitive radiation therapy alone, a dose of 36 to 40 Gy is necessary for clinically evident disease, and a lower dose (26 to 30 Gy) is used for prophylactic treatment areas. After chemotherapy, particularly in the setting of a negative post-treatment PET scan, a much lower dose suffices inasmuch as a dramatically reduced quantity of disease remains. This concept was first proposed by one of us nearly 40 years ago and has subsequently been confirmed by randomized trials.
In a study by the German Hodgkin Study Group (HD1), 20 Gy was compared with 40 Gy in patients with non-bulky presentations after 2 double cycles of chemotherapy (COPP-ABVD). There was no difference in freedom from treatment failure at 4 years (79% vs 80%). A randomized study by the GOELAMS (Groupe Ouest Est d’Étude des Leucénies et Autres Maladies du Sang) Hodgkin Lymphoma Network in France (H97-E) also confirmed that lower doses are sufficient with a combined-modality approach. Final results of the EORTC-GELA H9 trial, which compared no RT (closed early due to an unacceptable failure rate), 20 Gy, and 36 Gy are awaited.
An important recent study from the German Hodgkin Study Group (HD10) randomized 1370 patients with early-stage, favorable Hodgkin lymphoma to 20 Gy vs 30 Gy of radiotherapy after 2 to 4 cycles of ABVD. Favorable disease was defined as two or fewer sites of involvement, nonbulky tumors, no extranodal disease, and a favorable B-symptoms/erythrocyte sedimentation rate (ESR) ratio. There was no difference in the primary endpoint, freedom from treatment failure (92.9% vs 93.4%, P = 1), or in any secondary endpoints, including overall survival, between the two arms (Figure 4). Thus, for patients with early-stage, favorable Hodgkin lymphoma, 20 Gy of radiation therapy after 2 cycles of ABVD is sufficient.
For patients with early-stage, unfavorable Hodgkin lymphoma there remains some uncertainty and practice variability. The German Hodgkin Study Group HD11 study randomized 1395 patients to 4 cycles of either ABVD or non-escalated 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)). A secondary randomization was to 20 Gy or 30 Gy of consolidation radiation therapy. While 20 Gy appeared as effective as 30 Gy with BEACOPP, a clinically relevant inferiority of 20 Gy could not be excluded with ABVD. The authors concluded that 4 cycles of ABVD should be followed by 30 Gy of radiation therapy.
Data from our institution suggest that 20 Gy after 6 cycles of chemotherapy for unfavorable Hodgkin lymphoma is effective and sufficient in the presence of negative post-chemotherapy functional imaging (gallium scans, in this study). These data were obtained principally from patients with large mediastinal adenopathy. The assumption that 6 cycles of ABVD + 20 Gy of radiation therapy is equally effective and less toxic than 4 cycles of ABVD + 30 Gy needs to be further studied.
Smaller fields and lower doses: implications for risk
It is intuitive that treating fewer areas with lower doses of radiation therapy will be associated with fewer long-term risks. The more critical question is the magnitude of the risk using modern radiation techniques. This may take many more years to fully recognize, since some effects are not manifest for many decades after treatment. However, several studies have suggested that risks are significantly less with current treatment approaches.[4,20,30-38]