LONG-TERM Risk of Late Effects After Treatment for EARLY-STAGE HODGKIN'S Lymphoma (HL).

Currently the vast majority of patients (pts) with early-stage HL can be cured. However they still face the lifetime risks of late secondary events, mainly secondary malignancies (SM) and cardiovascular complications (CV). To assess the impact of late events on Overall Survival (OS), we evaluated the incidence of SM and CV in pts with early-stage HL (I A, B, II A), enrolled in a prospective randomized trial comparing 4 cycles of ABVD followed by subtotal nodal irradiation (STNI, arm A) with 4 cycles of ABVD followed by involved field irradiation (IFRT, arm B).

From 1990 to 1995, pts with early stage, defined as stage I A and B and II A, ± bulky disease were randomized. After 4 cycles ABVD, RT was STNI (36 Gy on involved sites and 30 Gy on uninvolved sites) were delivered in arm A and IFRT (36 Gy) in arm B. As previously reported (Bonadonna G, J Clin Oncol 2004;15:2835), no significant survival difference was documented between the two arms. We extended follow-up to evaluate the incidence of late secondary events.

140 pts were randomized, 68 to arm A and 72 to arm B. Median follow-up is 210 months (range:1–264). At 20 years, freedom from progression (FFP) is 95% for arm A and 90% for arm B (p=ns). Eight deaths occurred in arm A and 6 in arm B for a 20-yr OS of 84% for ABVD-STNI and 92% for ABVD-IFRT (p=ns).Cutaneous basal cell carcinoma excluded, a total of 13 SM were documented in arm A (1 MDS after 18 mos from treatment start, and 13 solid tumors after a median of 172 mos (range, 22–237): 7 breast, 2 prostate, 1 ovarian, 1 sigma, 1 cutaneous squamous cell) whereas only 3 SM (3 breast) occurred in arm B after a median fu of 170 mos (range, 160–198). The cumulative incidence of SM at 20 yr is 38% in arm A and 7% in arm B. Overall fatal myocardial infarction was documented in one pt in arm A and in two in arm B; fatal stroke occurred in 1 pt in arm A. Thirty-seven pregnancies occurred in 29 out of 70 premenopausal females (41%) after a mendian of 74 mos from treatment start; 35 males consented to have semen analysis: 63% were normospermic and 37% had some semen abnormality (oligo- ± astheno-± teratospermia) after a median of 42 mos; overall 10 pts fathered.

These findings confirm that ABVD given for 4 cycles followed by reduced extent of irradiation (IFRT) resulted in excellent long-term OS and FFP with an important decrease in the incidence of malignant secondary event. This manageable treatment strategy can still be considered standard treatment for early-stage HL. Long-term follow-up of current combined modality therapy, where lower doses of RT and shorter courses of chemotherapy are applied in favorable presentations, and more intensive chemotherapy regimens like BEACOPP in unfavorable presentations, should lead to even less late secondary events and mortality.

Gianni:Hoffman-La Roche: Consultancy, Honoraria.