Radiation Oncology/Hodgkin/German

German Hodgkin's Disease Trials


 * HD4 (1988-1994) -- All IFRT 40 Gy, EFRT 40 Gy vs EFRT 30 Gy
 * Randomized. 376 patients, Stage I-II, no risk factors (large mediastinal mass, extranodal lesions, massive splenic disease, elevated ESR, 3+ involved areas). Involved field RT 40 Gy. Arm 1) EFRT 40 Gy vs Arm 2) EFRT 30 Gy. No chemotherapy
 * 2001 PMID 11387364 -- "Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin's disease: long-term results of a randomized trial of radiotherapy alone." (Duhmke E, J Clin Oncol. 2001 Jun 1;19(11):2905-14.) Median F/U 7.2 years
 * Outcome: 7-year RFP 40 Gy 78% vs 30 Gy 83% (NS); 7-year OS 91% vs 96% (NS). Worse outcome (RFS 72% vs 84%) with protocol violations
 * Conclusion: 30 Gy dose adequate for clinically noninvolved areas


 * HD7 (1993-1998)
 * Randomized. 650 patients, Stage IA-IIB without risk factors. Treated with 1) RT alone vs. 2) ABVD x 2 cycles + RT RT same in both arms, given as EFRT 30 Gy + IFRT 10 Gy
 * 2007 PMID 17606976 -- "Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin's lymphoma: final results of the GHSG HD7 trial." (Engert A, J Clin Oncol. 2007 Aug 10;25(23):3495-502.). Median F/U 7.2 years
 * 7-year outcome: no difference in survival (92% vs. 94%, NS), but significant difference in DFS RT alone 67% vs. CRT 88% (SS). Treatment relapse more successful for RT only arm
 * Second malignancies: no difference, 0.8% per year, highest in older patients & B-symptoms
 * Conclusion: Combined modality more effective than EF-RT alone


 * HD8 (1993-98) -- COPP/ABVD x2 cycles plus EFRT vs IFRT
 * Randomized. 1064 patients, with early stage unfavorable HD. Clinical stages I-II with 1 or more risk factors, as well as stage IIIA without risk factors. Risk factors were large mediastinal mass, extranodal, massive splenic involvement, elevated ESR, or more than 2 lymph node groups. IIB may have only elevated ESR or more than 2 lymph node groups but no other risk factors. Treated with COPP / ABVD x 2 cycles, then randomized to Arm 1) EFRT 30 Gy vs. Arm 2) IFRT 30 Gy. A 10 Gy boost to bulky disease. Supradiaphragmatic EF RT was a mantle + PA + splenic hilum / spleen. Subdiaphragmatic EF RT was an inverted Y plus mini-mantle.
 * 2012 PMID 22767583 - "Comparing long-term toxicity and efficacy of combined modality treatment including extended- or involved-field radiotherapy in early-stage Hodgkin's lymphoma."
 * At 10 years, no arm differences were revealed with respect to freedom from treatment failure (FFTF) (79.8% versus 79.7%), progression-free survival (79.8% versus 80.0%), and overall survival (86.4% versus 87.3%).
 * Non-inferiority of IF-RT was demonstrated for the primary end point FFTF (95% confidence interval for hazard ratio 0.72-1.25).
 * Conclusion: "Radiotherapy intensity reduction to IF-RT does not result in poorer long-term outcome but is associated with less acute toxicity and might be associated with less secondary malignancies."
 * 2003 PMID 12913100 &mdash; "Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group." (Engert A, J Clin Oncol. 2003 Oct 1;21(19):3601-8.) Median F/U 4.5 years
 * Outcome: 5-year FFTF EFRT 86% vs. IFRT 84% (NS), 5-year OS EFRT 91% vs. 92% (NS). No difference in CR, PFS, relapse rate, death, and second neoplasm
 * Toxicity: Nause/vomiting, pharyngitis, GI toxicity, leukopenia, and thrombocytopenia worse in EFRT arms
 * Conclusion: RT volume reduction from EFRT to IFRT produces similar results and less toxicity
 * Elderly; 2007 PMID 17071932 -- "Poorer outcome of elderly patients treated with extended-field radiotherapy compared with involved-field radiotherapy after chemotherapy for Hodgkin's lymphoma: an analysis from the German Hodgkin Study Group." (Klimm B, Ann Oncol. 2007 Feb;18(2):357-63. Epub 2006 Oct 27.)
 * Subset analysis. 89 patients age >60. Poorer risk profile
 * Outcome: 5-year FFTF EFRT 58% vs. IFRT 70% (SS), OS 59% vs. 81% (SS)
 * Toxicity: Grade 3-4 EFRT 26% vs. IFRT 9%
 * Conclusion: Treatment with EFRT of elderly patients after chemo has negative impact on survival


 * HD9 (1993-1998) -- COPP/ABVD vs baseline BEACOPP vs escalated BEACOPP
 * Randomized. COPP/ABVD arm stopped prematurely after being significantly inferior. 1282 patients, advanced stage HL (IIB-IIIA with high risk features, IIIB-IV). Arm 1) COPP/ABVD x8 cycles vs Arm 2) baseline BEACOPP x8 cycles vs Arm 3) escalated BEACOPP x8 cycles
 * 2009 PMID 19704068 -- "Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin's lymphoma: 10 years of follow-up of the GHSG HD9 study." (Engert A, J Clin Oncol. 2009 Sep 20;27(27):4548-54. Epub 2009 Aug 24.) Median F/U 9.2 years
 * Outcome: 10-year FFTF COPP/ABVD 64% vs BEACOPP 70% vs escalated BEACOPP 82% (SS); 10-year OS 75% vs 80% vs 86% (SS)
 * Toxicity: Secondary malignancy 5.7% vs 6.6% vs 6.0%
 * Conclusion: Significant improvement for escalated BEACOPP. Results challenge ABVD as a standard of care


 * HD10 (1998-2002) -- 2x2: ABVD x2 vs ABVD x4; IFRT 30 Gy vs 20 Gy
 * Randomized, 2x2. 1131 patients. Stage I-II without risk factors. Randomization #1) ABVD x4 cycles vs ABVD x2 cycles, and randomization #2) IFRT 30 Gy vs IFRT 20 Gy
 * 2010 PMID 20818855 -- "Reduced Treatment Intensity in Patients with Early-Stage Hodgkin's Lymphoma." (Engert A, N Engl J Med 2010 Aug 12; 363:640-652).
 * Non-inferiority. ABVD x4 = ABVD x2 (FFTF5 93% v 91%; p=0.39; also p=ns: OS5, PFS5). IFRT 30 Gy = 20 Gy (FFTF5 93.4% v 92.9%)
 * Toxicity = G3/4 acute toxicity: ABVD x4 > ABVD x2 (≥1 event: 51.7% v 33.2%); 30 Gy > 20 Gy (8.7% v 2.9%; p<0.001)
 * Caveat = "Although the 5-year estimate for the group difference between the most intensive treatment and the least intensive treatment in this study was only 1.6 percentage points, a potential difference of 6.3 percentage points in favor of the more intensive treatment cannot be excluded."
 * 2009; 5-years ASH Abstract #716 Abstract - No PMID (Abstract only) &mdash; "Two Cycles of ABVD Followed by Involved Field Radiotherapy with 20 Gray (Gy) Is the New Standard of Care in the Treatment of Patients with Early-Stage Hodgkin Lymphoma: Final Analysis of the Randomized German Hodgkin Study Group (GHSG) HD10." (Engert A; Dec 2009) Median F/U 6.6 years
 * ABVD Outcome: No significant difference in 5-year OS, FFTF, or PFS between ABVD x 4 and ABVD x 2 (OS 97% vs 97%; FFTF 93% vs 91%; PFS 93% vs 91%).
 * IFRT Outcome: No significant difference between IFRT 30 Gy vs 20 Gy (OS 98% vs 97%, FFTF 93% vs 93%, PFS 94% vs 93%). No difference when all 4 arms compared.
 * Conclusion: 2 cycles of ABVD followed by 20 Gy IFRT is the new standard for GHSG for early favorable HD


 * HD11 (1998-2003)
 * Randomized. 1395 pts. Unfavorable disease (CS I or IIA with at least one of the risk factors: (a) large mediastinal mass, (b) extranodal disease, (c) elevated ESR, or (d) ≥ 3 nodal areas; or IIB with risk factors c and/or d.) BEACOPP x4 cycles vs. ABVD x4 cycles. IFRT 30 Gy or 20 Gy.
 * 2010 PMID 20713848 -- Intensified Chemotherapy and Dose-Reduced Involved-Field Radiotherapy in Patients With Early Unfavorable Hodgkin’s Lymphoma: Final Analysis of the German Hodgkin Study Group HD11 Trial. (Eich HT; J Clin Oncol. 2010 Aug 16. [Epub ahead of print]).
 * ABVD x4 + 30 Gy IFRT (FFTF5 85%, OS5 94%, PFS5 87%) = BEACOPP x4 + either 30 (FFTF5 87%, OS5 ~95%, PFS5 ~88%) or 20 Gy IFRT (FFTF5 ~87%, OS5 ~95%, PFS5 87%).
 * ABVD x4 + 20 Gy IFRT was inferior (FFTF5 81%, OS5 ~94%, PFS5 ~82%).
 * More severe toxicity: BEACOPP > ABVD (WHO 3/4 = 73.8% v 51.5%; P<.001). More severe toxicity: 30 Gy v 20 Gy (CTC 3/4 = 12.0% v 5.7%; P<.001).
 * 2009 ASH Abstract #717 Abstract - No PMID (Abstract only) &mdash; "Combined Modality Treatment with Intensified Chemotherapy and Dose-Reduced Involved Field Radiotherapy in Patients with Early Unfavourable Hodgkin Lymphoma (HL): Final Analysis of the German Hodgkin Study Group (GHSG) HD11 Trial" (Borchmann P, Dec 2009)
 * CR was obtained in 94%, did not differ between arms. 5-yr FFTF estimate 85%. BEACOPP more effective than ABVD if followed by 20 Gy RT (difference in 5-yr FFTF 5.7%). No difference seen between BEACOPP and ABVD when 30 Gy used (1.6%). After BEACOPP, 20 Gy not inferior to 30 Gy; after ABVD, inferiority of 20 Gy could not be excluded (4.0%).
 * Conclusion: "A reduction of RT dose from 30Gy to 20Gy IF-RT seems to be justified only in combination with Bbas [BEACOPP], but not with a less effective chemotherapy such as 4xABVD. Patients will benefit from an intensified CT such as Bbas only in combination with 20Gy IF-RT but not with 30Gy IF-RT."


 * HD13
 * Randomized to 2 cycles of ABVD, ABV, AVD, or AV. All followed by 30 Gy IF-RT.
 * 2015 PMID 25539730: Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial.
 * Of 1502 qualified patients, 566, 198, 571, and 167 were randomly assigned to receive ABVD, ABV, AVD, or AV, respectively.
 * Due to a high event rate, randomization to the dacarbazine deleted arms was closed early.
 * 5 year FFTF was 93.1%, 81.4%, 89.2%, and 77.1% with ABVD, ABV, AVD, and AV, respectively.
 * inferiority of the dacarbazine-deleted variants was detected with 5 year differences of -11.5% (95% CI -18.3 to -4.7; HR 2.06 [1.21 to 3.52]) for ABV and -15.2% (-23.0 to -7.4; HR 2.57 [1.51 to 4.40]) for AV. Non-inferiority of AVD compared with ABVD could also not be detected (5 year difference -3.9%, -7.7 to -0·1; HR 1.50, 1.00 to 2.26).
 * Conclusion: Neither dacarbazine nor bleomycin can be safely omitted from the ABVD regimen for patients with Early Stage, favourable prognosis Hodgkin's lymphoma.


 * HD14 (closed - terminated early)
 * Randomized. Early Unfavorable disease, IA-IIB with at least 1 risk factor. Randomized to: 1) BEACOPP x2 cycles + ABVD x2 cycles ("2 + 2") + IFRT 30 Gy vs. 2) ABVD x4 cycles + IFRT 30 Gy
 * Protocol (PDF)
 * Study terminated early at 3rd interim analysis because of better outcomes seen in the 2+2 arm.
 * 2011 PMID 22271480 (pending) -- "Dose-Intensification in Early Unfavorable Hodgkin's Lymphoma: Final Analysis of the German Hodgkin Study Group HD14 Trial." (von Tresckow B, J Clin Oncol -- online before print Jan 23, 2012)
 * 1525 pts. 5-yr FFTF superior for the 2+2 regimen vs ABVD : difference of 7.2% (HR 0.44), S.S. 5-yr PFS 6.2%. More acute toxicity with 2+2 regimen, but no overall difference in treatment-related mortality or second malignancies.
 * Conclusion: BEACOPP x 2 cycles followed by ABVD significantly improves tumor control in patients with early unfavorable HD.