Are event-free survival and freedom-from progression compromised by reduced radiation doses fields? Comparison between the results of the AIEOP (Italian Association of Pediatric Hematology and Oncology) LH-2004 & MH96 Protocols

Introduction Objective To compare the results of the LH2004 protocol with those of the previous MH96 study - already published - after a similar observation time, and to evaluate if reduced RT doses & fields compromise FFP and EFS rates.

Methods GR1: stages I-IIA w/out: M/T ≥0.33 or ≥4 nodal sites or hilar adenopathy; GR2: pts not included in G1 and GR3; GR3: stages IIIB-IV and pts with M/T≥0.33. MH96 therapy GR1: 3 ABVD+IFRT in pts with mediastinal mass and in PR pts after CT. GR2: 4 COPP/ABV+IFRT. GR3: 6 COPP/ABV+ IFRT. RT doses were: 20 Gy if CR or PR≥75%, 30 Gy if PR<75%. LH2004 therapy GR1: 3 ABVD+25,2 Gy only to PR after CT. GR2: 4 COPP/ABV+14,4 Gy if CR achieved; PR pts received 2 cycles of IEP (Ifosfamide, Etoposide and Prednisone) and RT (14,4 Gy if CR, 25,2 if PR). GR3: 4 COPP/ABV and 2 further COPP/ABV+RT if CR was achieved. PR pts: 2 IEP+14,4 Gy if CR was obtained; if not, pts received 2 additional COPP/ABV+RT according to the quality of response. Irradiation fields considered involved nodal regions. Response evaluation was after cycle 2 and 4 and after CT in GR3, by conventional imaging and with PET in pts with mediastinal mass.

Results From June 2004 to July 2017, 1300 pts were enrolled into the LH2004 protocol: 1201 evaluable for the analysis, with a median FUP time of 7,25 yrs. 181 pts were included in GR1, 274 in GR2 and 746 in GR3. The 10yr FFP rates registered in LH2004 GR1, GR2 and GR3 pts are 90.0%, 90.2% and 75.2% respectively and those of MH96 are 92.4%, 84.7% and 78.6%.

RT was spared in 70% of LH2004-GR1 pts, because of CR after CT; the 10yr EFS rates are 90.1% and 76.9% in noRT and irradiated pts respectively. In MH96-GR1 RT was avoided in 57% of pts; the 10yr EFS are 87.1% and 91.2% respectively for noRT and irradiated pts; no significant difference in both comparisons.

With regard to RT doses in the LH2004 study, 77% of GR2 pts received 14,4Gy; the 10yr FFP rate is 91.5% vs 89.5% of pts treated with higher dose because in PR. In GR3, 67% of pts received 14,4Gy; the 10yr FFP is 85.5% vs 66.1% of pts treated with higher dose (p=0.0000).

Conclusion In GR1 the removal of RT for all CR pts did not determine a significant difference with irradiated pts, who showed a lower EFS rate. In GR2 the reduction of RT doses & fields did not compromise the prognosis in pts in CR at the end of chemotherapy. In GR3 additional CT and RT dose did not succeed in overcome the gap between CR and PR patients. The long-term FFP rates of therapeutic groups in the two trials are superimposable.