Recent results of treatment of early stage Hodgkin lymphoma: risk-adapted approaches

Excellent results have been reported recently for the treatment of patients with stages I and II Hodgkin lymphoma (HL) with combined modality treatment (CMT) with a limited number of cycles of chemotherapy and involved field radiation therapy (IF RT). It is important to have an understanding of the subgroups of early stage patients that are included in these recent reports. Whether or not the results of treatment for the entire group of patients with stages I and II HL have improved over the past few years is unclear.

In the HD10 trial of the German Hodgkin Study Group (GHSG), freedom from treatment failure rate at 5 years was 90–93% for two or four cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) with either 20 or 30 Gy IF RT for patients with favorable stages I and II HL (one or two sites without bulk, extranodal extension, or elevated erythrocyte sedimentation rate [ESR]) [1]. Excellent results in early stage unfavorable HL (stages IA, IB, and IIA with one or more of these risk factors: ≥3 lymph node sites, bulky mediastinal mass, extranodal extension, and/or elevated ESR or stage IIB with ≥3 nodal sites and/or elevated ESR) with CMT were also reported in the GHSG HD11 study, which compared four cycles of ABVD with four cycles of standard-dose BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and subsequently either 30 Gy or 20 Gy IF RT. The best 5-year freedom from treatment failure (FFTF) was similar in three of the four arms (4 × ABVD + 30 Gy IF RT, 4 × standard BEACOPP + 30 Gy IF RT, and 4 × standard BEACOPP + 20 Gy IF RT). For the entire trial at 5 years, FFTF was 85.0%, overall survival (OS) 94.5%, and progression-free survival (PFS) 86% [2,3]. These studies provide benchmarks for current CMT trials in stages I and II HL.

In this issue of Leukemia and Lymphoma, Wirth and colleagues also report results of a trial of CMT in stages I and II HL with IF RT, with the number of cycles of chemotherapy (ABVD) determined by risk group [4]. Patients without any risk factors of the GHSG (group 1) received three cycles of ABVD and IF RT. Patients with stages IA and IIA disease with any risk factors (group 2) received four cycles of ABVD and IF RT. Patients with IB and IIB HL (group 3) also received four cycles of ABVD and IF RT. It is noteworthy that patients with stage IIB and bulky nodal disease were included in the current trial, although not in the HD10 or HD11 trials. Five-year freedom from progression (FFP) and OS were comparable to those reported in the HD10 and HD11 trials for groups 1 and 2, although for group 3, 5-year FFP was 73% and OS 85%, probably reflecting the inclusion of IIBX disease (44% of the patients). This trial illustrates again that the best results are seen in the most favorable subgroups of patients with stages I and II disease.

A major concern with the use of RT alone or in CMT are the late effects of treatment, in particular increased risks of second malignancies and cardiovascular events including carotid stenosis and stroke, coronary artery disease, heart valve fibrosis, and conduction abnormalities [3,5]. An excess of deaths due to causes other than HL was not seen in the trial of Wirth and colleagues at a median follow-up time of 5.9 years, but it was a small trial with a total accrual of 150 patients, and follow-up time for late effects is short. In the HD10 study with 1370 patients accrued, it is noteworthy that the rate of secondary neoplasia at a median follow-up of 7.5 years is 4.6%, similar in all four arms of the trial, and it may increase with further follow-up. Also, of 57 deaths (4.8%) in the HD10 trial, 10 were due to HL while 11 were due to secondary neoplasias, nine due to cardiovascular events, seven to acute toxicity of treatment, and five to salvage therapy. In the HD11 trial of 1395 patients at a median follow-up time of 6.8 years, there have been 52 second cancers (3.7%). At a median follow-up time for survival of 7.6 years, 105 patients have died (7.5%). Cause of death was HL in 36% and other causes in 64% (18% second malignancies, 13% cardiovascular events).

Excellent results have also been produced with the use of ABVD alone for non-bulky early stage HL [6–8 ]. Although there may be up to a 6% excess of relapses with this approach as compared to CMT, there does not appear to be a difference in relatively short-term survival as compared with CMT trials [9]. Currently a number of trials are in progress, including Cancer and Leukemia Group B (CALGB) 50801 (NCT01118026) for patients with stage I and II and bulky mediastinal disease and CALGB 50604 (NCT01132807) for patients with stage I and II disease without tumor bulk, conducted in the US Intergroup, that are attempting to limit intensive chemotherapy and IF RT only to the minority of patients who are interim positron emission tomography positive (PET+) after two cycles of ABVD.

Reduction of overall long-term morbidity and mortality is at least as important a goal as the achievement of excellent short-term treatment results. A more clear definition of which patients require RT and/or more intensive chemotherapy will be an important step in achieving this goal.

Potential conflict of interest: A disclosure form provided by the author is available with the full text of this article at www.informahealthcare.com/lal .