Radiation Oncology/Hodgkin/EORTC

EORTC Hodgkin's Disease Trials

H1 (1964-71)

 * Purpose: can Velban improve on RT alone?
 * 288 pts (mostly supradiaphragmatic, but a few infradiaphragmatic). Stage I-II. No laparotomy. All pts received mantle field (if supradiaph.) or inverted Y (if infra).
 * Randomized to 1) no further treatment, or 2) weekly Velban x 2 years
 * Results:
 * Preliminary: PMID 5074778, 1972 (No abstract) &mdash; "A randomized study of irradiation and vinblastine in stages I and II of Hodgkin's disease. Preliminary results." Eur J Cancer. 1972 Jun;8(3):353-62.
 * PMID 116855, 1979 (No abstract) &mdash; "Long-term results of the E.O.R.T.C. randomized study of irradiation and vinblastine in clinical stages I and II of Hodgkin's disease." Tubiana M et al. Eur J Cancer. 1979 May;15(5):645-57.
 * PMID 2462943, 1989 &mdash; "Toward comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin's disease. The EORTC Lymphoma Group controlled clinical trials: 1964-1987." Tubiana M et al. Blood. 1989 Jan;73(1):47-56.
 * At 15 yrs, DFS 60% (RT+VLB) vs 38% (RT alone). OS 65% vs 58%, N.S.
 * Comments: Suggests that salvage treatment was more efficient in the RT alone group. High incidence of relapse in the para-aortic region suggests a need to explore or treat this area.

H2 (1972-76)

 * Purpose: compare splenectomy and spleen irradiation
 * 300 pts. Stage I-II (supradiaphragmatic). Based on prelim. results of H1.
 * Randomized to 1) staging laparotomy + splenectomy, followed by mantle field RT and para-aortic RT, 2) mantle + PA + spleen (i.e. subtotal nodal irradiation).
 * Pts with MC or LD histologies randomized to 1) Velban alone, or 2) Velban + procarbazine for 2 yrs.
 * Results:
 * PMID 7021162, 1981 (No abstract) &mdash; "Five-year results of the E.O.R.T.C. randomized study of splenectomy and spleen irradiation in clinical stages I and II of Hodgkin's disease." Tubiana M et al. Eur J Cancer. 1981 Mar;17(3):355-63.
 * PMID 2462943, 1989 &mdash; "Toward comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin's disease. The EORTC Lymphoma Group controlled clinical trials: 1964-1987." Tubiana M et al. Blood. 1989 Jan;73(1):47-56.
 * At 12 yrs, DFS 68% (STNI) vs 76% (lap-STNI). OS 77% vs 79%. With positive staging lap, DFS 56% vs 83% for negative lap. However, no difference in OS according to staging lap, 80% vs 76%.  Pts with MC and LD histology who received chemo had DFS 85% vs 65%, but OS not different, 75% vs 80%.
 * Comments: Effective salvage treatment makes survival equivalent. Showed that laparotomy had no therapeutic benefit.

H5 (1977-82)

 * Purpose: Risk-adapted therapy. Based on prior studies (H1 + H2) it was known that pts with favorable risk factors could receive RT alone. Staging lap was used to confirm this favorable risk group who would receive RT alone. It was not known if mantle alone or mantle + PA should be given. Pts with unfavorable risk factors, despite a negative staging lap, were at high risk for relapse, and would be randomized between RT alone and combination therapy.
 * CS I-II supradiaphragmatic. 494 total pts. Divided into two groups based on prognostic indicators (based on analysis of H1 and H2 trials). Favorable group included all of the following: age <= 40, ESR <= 70, LP or NS histology, CS II (without mediastinal involvement) or CS I.
 * Favorable group, H5F (n=237): Underwent staging laparatomy. If negative lap (n=198;84%) received RT alone, randomized to mantle vs mantle+PA, 40 Gy each. If Lap+ (n=39) randomized similarly as H5U.
 * Unfavorable group, H5U (n=257+39): No staging lap. Randomized to total/subtotal nodal irradiation (TNI/STNI) vs. mantle + chemo sandwich therapy: MOPPx3 -> mantle RT 35 Gy -> MOPP x 3.
 * H5-Favorable -- Mantle 40 Gy vs Mantle + PA 40 Gy
 * Randomized. 198 patients, favorable (age <=40, ESR <=70, LP/NS, Stage I or Stage II without mediastinal involvement), negative staging laparotomy. Arm 1) Mantle RT 40 Gy vs Arm 2) Mantle RT + PA RT (T11-L4) 40 Gy
 * 1988 PMID 2578012 -- "Clinical stages I and II Hodgkin's disease: a specifically tailored therapy according to prognostic factors." (Carde P, J Clin Oncol. 1988 Feb;6(2):239-52.) Median F/U 5.3 years
 * Outcome: 6-year RFS mantle 74% vs mantle+PA 72% (NS); 6-year OS 96% vs 89% (NS)
 * Conclusion: In surgically staged patients, more limited RT (mantle alone) is sufficient
 * H5-Unfavorable -- TNI/STNI 40 Gy vs MOPP-Mantle RT 35 Gy-MOPP
 * Randomized. Two subsets of patients. H5F lap+: 39 patients, favorable, but positive staging laparotomy. H5U: 257, unfavorable profile (at least one unfavorable characteristic age >40, ESR >70, LP/NS, STage II bulky), but no staging laparotomy. Arm 1) Total Nodal Irradiation 40 Gy with 2-3 week rest; STNI allowed in female <40 vs Arm 2) MOPP x3 -> mantle RT 35 Gy -> MOPP x3
 * 1988 PMID 2578012 -- "Clinical stages I and II Hodgkin's disease: a specifically tailored therapy according to prognostic factors." (Carde P, J Clin Oncol. 1988 Feb;6(2):239-52.) Median F/U 5.3 years
 * Outcome (H5F lap+): 6-year RFS TNI/STNI 53% vs chemo-RT 100% (SS); 6-year OS 95% vs 88% (NS)
 * Outcome (H5U): 6-year OS TNI/STNI 82% vs chemo-RT 89% (SS)
 * Conclusion: Improved outcome with combined chemo-RT over comprehensive RT alone

H6 (1982-88)

 * Purpose: Is laparotomy necessary? Compare ABVD vs MOPP for unfavorable.
 * EORTC H6-Favorable (1982-1988) -- staging laparoscopy + Mantle RT vs clinical staging + STNI
 * Randomized. 262 patients, favorable prognosis (1-2 nodal areas, no bulky disease, no B symptoms and ESR <50, B symptoms and ESR <30). Arm 1) No staging laparotomy, Mantle + PA RT 40 Gy vs Arm 2) Staging laparotomy (-), Mantle RT 40 Gy
 * 1993 PMID 7693881 -- ""Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage Hodgkin's disease: the H6 twin randomized trials from the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group." (Carde P, J Clin Oncol. 1993 Nov;11(11):2258-72.) Median F/U 5.3 years
 * Outcome: In patients undergoing lap, 33% found lap (+). 6-year FFP laparoscopy + Mantle 83% vs Mantle + PA 78% (NS); 6-year OS 89% vs 93% (NS)
 * Conclusion: No difference between surgical staging + mantle vs clinical staging + STNI
 * EORTC H6-Unfavorable (1982-1988) -- MOPP x6 + Mantle RT vs ABVD x6 + Mantle RT
 * Randomized. 316 patients, unfavorable prognosis (at least one of: >2 nodal areas, bulky, B-symptoms, elevated ESR). No surgical staging. Arm 1) MOPP x6 + Mantle RT vs Arm 2) ABVD x6 + Mantle RT
 * 1993 PMID 7693881 -- ""Clinical staging versus laparotomy and combined modality with MOPP versus ABVD in early-stage Hodgkin's disease: the H6 twin randomized trials from the European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group." (Carde P, J Clin Oncol. 1993 Nov;11(11):2258-72.) Median F/U 5.3 years
 * Outcome: 6-year FFP MOPP 76% vs ABVD 88% (SS); 6-year OS 85% vs 91% (NS)
 * Toxicity: Less fertility problems for ABVD (in both men and women).
 * Conclusion: In combination with mantle RT, ABVD superior to MOPP

H7 (1988-93)

 * Purpose: can involved field radiotherapy + chemo give equivalent results to STNI + chemo? Goal of reducing treatment toxicity
 * Two randomized trials: favorable disease (prognostic score 1-5) and unfavorable disease (prognostic score >=9). Please see Overview for further information
 * EORTC H7-Favorable -- STNI vs EBVP x6 + IFRT
 * Randomized. 333 patients with Stage I supradiaphragmatic HL, favorable (prognostic score 1-5). No staging laparotomy. Arm 1) STNI alone (36 Gy uninvoled, 40 Gy involved fields) vs. Arm 2) EBVP x6 cycles + IFRT (36-40 Gy)
 * 2006 PMID 16754934 &mdash; "Combined-modality therapy for clinical stage I or II Hodgkin's lymphoma: long-term results of the European Organisation for Research and Treatment of Cancer H7 randomized controlled trials." (Noordijk EM, J Clin Oncol. 2006 Jul 1;24(19):3128-35.) Median F/U 8.7 years
 * Outcome: 10-yr EFS STNI 78% vs. EBVP+IF 88% (SS). OS similar at 92%.
 * Conclusion: Combined chemo + IFRT is superior STNI alone
 * 1997 ASTRO Abstract -- "Combination of radiotherapy and chemotherapy is advisable in all patients with clinical stage I-II Hodgkin's disease. Six-year results of the EORTC-GPMC controlled clinical trials 'H7-VF', 'H7-F' and 'H7-U'." (Noordijk EM, Int J Radiat Oncol Biol Phys 1997; 39(2):S173
 * Very favorable group (female, age <40, stage IA, NS/LP histology, ESR <50) treated with Mantle only, without PA field
 * Outcome: 6-year RFS 73%, OS 96%
 * Conclusion: Relapse rate unacceptably high in these clinically staged patients; arm closed
 * EORTC H7-Unfavorable -- EBVP x6 + IFRT vs MOPP/ABV + IFRT
 * Randomized. Stopped early due to worse outcome in EBVP arm. 389 patients with Stage I supradiaphragmatic HL, unfavorable (prognostic score >=9). No staging laparotomy. Arm 1) EBVP x6 + IFRT 36-40 Gy vs. Arm 2) MOPP/ABV x6 + IFRT 36-40 Gy
 * 2006 PMID 16754934 &mdash; "Combined-modality therapy for clinical stage I or II Hodgkin's lymphoma: long-term results of the European Organisation for Research and Treatment of Cancer H7 randomized controlled trials." (Noordijk EM, J Clin Oncol. 2006 Jul 1;24(19):3128-35.) Median F/U 8.7 years
 * Outcome: 10-yr EFS EBVP 68% vs. MOPP/ABV 88% (SS). OS 79% vs 87% (SS). Low control rate in irradiated areas
 * Conclusion: EBVP is inferior to MOPP/ABV, IFRT with poor chemo not sufficient in these patients with high tumor burden
 * Comment (PMID 17989384): Three major conclusion: 1) clinical staging is sufficient for stratifying early stage disease, 2) chemotherapy followed by IFRT should be standard treatment, and 3) duration of chemotherapy should be adapted to severity of the disease

H8 (1993-1999)

 * Two randomized trials: favorable disease (risk score 1-5) and unfavorable disease (risk score >=9)
 * EORTC H8-Favorable -- MOPP-ABV x3 + IFRT vs STNI
 * Randomized. 542 patients, Stage I-II supradiaphragmatic HD, favorable (Prognostic score using EORTC H7 criteria 1-5). Arm 1) MOPP-ABV x3 cycles + IFRT vs. Arm 2) STNI alone
 * 2007 PMID 17989384 -- "Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease." (Ferme C, N Engl J Med. 2007 Nov 8;357(19):1916-27.). Median F/U 7.7 years
 * H8-F Outcome: 5-year EFS MOPP-ABV + IFRT 98% vs. STNI 74% (SS); 10-year OS 97% vs. 92% (SS)
 * Conclusion: For favorable disease, MOPP-ABV x3 cycles + IFRT is superior to STNI
 * EORTC H8-Unfavorable -- MOPP-ABV x6 + IFRT vs MOPP-ABV x4 + IFRT vs MOPP-ABV x4 + STNI
 * Randomized, 3 arms. 996 patients, Stage I-II supradiaphragmatic HD, unfavorable (Prognostic score using EORTC H7 criteria >=9). Arm 1) MOPP-ABV x6 cycles + IFRT vs. Arm 2) MOPP-ABV x4 cycles + IFRT vs. Arm 3) MOPP-ABV x4 cycles + STNI. RT dose CR 36 Gy, PR 40 Gy
 * 2007 PMID 17989384 -- "Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease." (Ferme C, N Engl J Med. 2007 Nov 8;357(19):1916-27.). Median F/U 7.7 years
 * Outcome: 5-year EFS 84% vs. 88% vs. 87% (NS); 10-year OS 88% vs. 85% vs. 84% (NS)
 * Conclusion: Best strategy for unfavorable disease is MOPP-ABV x4 cycles + IFRT

H9 (1998-2004)

 * Two randomized trials: favorable disease and unfavorable disease
 * EORTC H9-Favorable (1998-2004) -- IFRT 36 Gy vs IFRT 20 Gy vs No RT
 * Randomized. Arm 3 stopped early due to >20% of failure. 783 favorable Stage I-II patients enrolled, 619 achieved CR(u) on EBVP x6 and were randomized. Arm 1) 36 Gy IF-RT Arm vs. 2) 20 Gy IF-RT vs. 3) no RT. Arm 3 stopped early due to high recurrence (>20%).
 * 2005 ASCO abstract -- "First results of the EORTC-GELA H9 randomized trials: the H9-F trial (comparing 3 radiation dose levels) and H9-U trial (comparing 3 chemotherapy schemes) in patients with favorable or unfavorable early stage Hodgkin’s lymphoma (HL)." (Noordijk, EM ASCO 2005). Median F/U 2.7 years
 * Outcome: 4-year EFS 36 Gy 87% vs 20 Gy 84% vs. no RT 70% (SS). 4 yr OS 98% in all arms.
 * Conclusion: In favorable patients in CR after 6 cycles of EBVP, omission of IFRT leads to unacceptable failure rate; 20 Gy provides comparable control as 36 Gy
 * EORTC H9-Unfavorable (1998-2002) -- ABVD x6 vs ABVD x4 vs BEACOPP x4
 * Randomized. 808 patients, unfavorable Stage I-II. Arm 1) ABVD x 6 vs. 2)ABVD x 4 vs. 3) BEACOPP x 4 followed by 30 Gy IF-RT in all arms.
 * 2005 ASCO abstract -- "First results of the EORTC-GELA H9 randomized trials: the H9-F trial (comparing 3 radiation dose levels) and H9-U trial (comparing 3 chemotherapy schemes) in patients with favorable or unfavorable early stage Hodgkin’s lymphoma (HL)." (Noordijk, EM ASCO 2005). Median F/U 2.7 years
 * Outcome: 4-year EFS ABVD x6 94% vs ABVD x4 89% vs BEACOPP x4 91% (NS); 4-year OS 96% vs 95% vs 93% (NS).
 * Toxicity: Higher with BEACOPP
 * Conclusion: Similar early EFS with reduction of ABVD cycles to 4; BEACOPP similar but more toxic

H10 (ongoing)
H10 Protocol - "The H10 EORTC/GELA randomized Intergroup trial on early FDG-PET scan guided treatment adaptation versus standard combined modality treatment in patients with supradiaphragmatic stage I/II Hodgkin's lymphoma."
 * Favorable: randomized to:
 * Standard arm: ABVD x 3 + INRT 30 Gy (+6 Gy boost for residual lesions). PET after 2 cycles.
 * Experimental: ABVD x 2, then PET. If PET negative, then ABVD x 2 additional cycles (total 4) without RT. If PET positive, switch to escalated BEACOPP x 2 + INRT 30 Gy (+6 Gy boost for residual)
 * Unfavorable: randomized to:
 * Standard arm: ABVD x 4 + INRT 30 Gy (w/wo 6 Gy boost). PET after 2 cycles.
 * Experimental: ABVD x 2, then PET. If PET negative, then ABVD x 4 additional (total 6) without RT. If PET positive, BEACOPP x 2 + INRT 30 Gy (w/wo 6 Gy boost)


 * Interim results; 2014 PMID 24637998 -- "Omitting Radiotherapy in Early Positron Emission Tomography-Negative Stage I/II Hodgkin Lymphoma Is Associated With an Increased Risk of Early Relapse: Clinical Results of the Preplanned Interim Analysis of the Randomized EORTC/LYSA/FIL H10 Trial." (Raemaekers JM, J Clin Oncol. 2014 Mar 17. [Epub ahead of print])
 * ASCO Post
 * 1137 pts. Favorable pts (441): 85.8% had negative early PET. 9 events (Experimental group) vs 1 event (Standard). 1-yr PFS 94.9% vs 100% (SS).
 * Unfavorable pts (683): 74.8% had negative early PET. 16 events vs 9. 1-yr PFS 94.7% vs 97.3% (SS).
 * "Concluded it was unlikely that we would show noninferiority in the final results for the experimental arm and advised stopping random assignment for early PET–negative patients."
 * Conclusion: "On the basis of this analysis, combined-modality treatment resulted in fewer early progressions in clinical stage I/II HL, although early outcome was excellent in both arms. The final analysis will reveal whether this finding is maintained over time."