Radiation Oncology/Hodgkin/Randomized

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Hodgkin's Lymphoma Randomized Evidence

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Early Stage

RT Alone: Dose

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

RT vs. Chemo-RT

SWOG S9133 (1989-2000)
- Randomized. Closed after 2nd analysis due to superior outcome of CMT arm. 348 patients with clinical Stage IA-IIA, supradiaphragmatic HD, no staging laparotomy. Arm 1) subtotal lymphoid irradiation (STLI 36/20 or 40/20) or chemo (doxorubicin/vinblastine x3 cycles) + STLI
- 2001 PMID 11709567 — "Phase III randomized intergroup trial of subtotal lymphoid irradiation versus doxorubicin, vinblastine, and subtotal lymphoid irradiation for stage IA to IIA Hodgkin's disease." (Press OW et al. J Clin Oncol. 2001 Nov 15;19(22):4238-44.) Median F/U 3.3 years
  - Outcome: FFS CMT 94% vs. STLI only 81% (SS); only 3 and 7 deaths in the arms
  - Toxicity: well tolerated
- Conclusion: Good outcome possible without staging laparotomy; combined modality superior to STLI alone

EORTC H8 (1993-1999)
- Two randomized trials:
  - H8-F (favorable): Arm 1) MOPP-ABV x3 cycles + IFRT vs. Arm 2) STNI alone
  - H8-U (unfavorable): Arm 1) MOPP-ABV x6 cycles + IFRT vs. Arm 2) MOPP-ABV x4 cycles + IFRT vs. Arm 3) MOPP-ABV x4 cycles + STNI
- 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)
  - H8-U Outcome: 5-year EFS similar 84% vs. 88% vs. 87% (NS); 10-year OS 88% vs. 85% vs. 84%
  - Conclusion: Favorable disease chemo x3 + IFRT best, unfavorable disease chemo x4 + IFRT best

German 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

Chemo-RT: Chemotherapy Regimens

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; 5 years - PMID 20818855 — "Reduced Treatment Intensity in Patients with Early-Stage Hodgkin's Lymphoma." (Engert A et al; NEJM 2010) Median F/U 7.5 years
  - ABVD Outcome: No significant difference in 5-year OS, FFTF, or PFS between ABVD x 4 and ABVD x 2 (OS 97.1% vs 96.6%; FFTF 93% vs 91.1%; PFS 93.5% vs 91.2%).
  - 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.
  - Toxicity: Acute toxicity during chemotherapy was more frequent with four cycles of ABVD: 51.7% of the patients who received four cycles of ABVD had at least one instance of severe toxicity (grade III or IV) as compared with 33.2% of those who received two cycles (P<0.001). Severe toxicity (grade III or IV) was observed more often among the patients treated with 30 Gy of involved-field radiation therapy than among those who received 20 Gy (8.7% vs. 2.9%, P<0.001).
  - Conclusion: 2 cycles of ABVD followed by 20 Gy IFRT is the new standard for GHSG for early favorable HD
- 2009; 5-years ASH Abstract #716 Abstract - No PMID (Abstract only) — "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

Italian IIL (1997-2001) -- ABVD + IFRT vs. EVE + IFRT
- Randomized. 181 patients, age <65, with unfavorable Stage IA-IIA (bulky, subdiaphragmatic, ESR >40, Extranodal, hilar, or >3 LN areas). Arm 1) doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) + IFRT vs. Arm 2) epirubicin, vinblastine, etoposide (EVE) + IFRT. RT 36/20, postchemo volumes, to all initially involved regions
- 5-years; 2008 PMID 18180244 -- "ABVD plus radiotherapy versus EVE plus radiotherapy in unfavorable stage IA and IIA Hodgkin's lymphoma: results from an Intergruppo Italiano Linfomi randomized study." (Pavone V, Ann Oncol. 2008 Apr;19(4):763-8. Epub 2008 Jan 6.)
  - Outcome: 5-year RFS ABVD 95% vs. EVE 78% (SS); OS 95% vs. 92% (NS)
  - Conclusion: EVE chemotherapy significantly worse than ABVD

Chemo-RT: RT Dose

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
- 2009; 5-years ASH Abstract #716 Abstract - No PMID (Abstract only) — "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

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