Radiation Oncology/Hodgkin/Early stage favorable

Hodgkin's Lymphoma: Early Stage Favorable

Guidelines

 * American College of Radiology; 2008 PMID 18812149 -- "ACR Appropriateness Criteria on Hodgkin's lymphoma: favorable prognosis stage I and II." (Das P, J Am Coll Radiol. 2008 Oct;5(10):1054-66.)
 * Guideline link

Favorable prognostic factors

 * NCCN guidelines : no bulky disease, 1-3 involved regions, 1 extranodal site, no B symptoms, ESR <50
 * ACR appropriateness criteria : no bulky mediastinal disease, 1-3 involved regions, no B symptoms
 * EORTC : age <=50, no bulky mediastinal adenopathy, 1-3 involved regions, no B symptoms and ESR <50, B symptoms and ESR <30

RT Alone: Field Size

 * If patients negative subdiaphragmatic disease by staging laparotomy, Mantle field alone sufficient compared with STNI
 * If patients clinically negative, Mantle field alone insufficient, however, STNI sufficient without requiring surgical staging


 * EORTC H7-Very Favorable -- no staging laparoscopy + Mantle RT
 * 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 subset (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 with Mantle RT only; arm closed


 * 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 H5-Favorable (1977-82) -- Mantle 40 Gy vs STNI 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

RT Alone: Dose

 * German 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

 * German HD7 (1993-1998) -- ABVD x2 + EFRT vs EFRT alone
 * 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


 * EORTC H8-Favorable (1993-1999) -- MOPP-ABV x3 + IFRT vs STNI alone
 * Randomized. 542 patients, Stage I-II supradiaphragmatic HD, favorable (Prognostic score using EORTC H7 criteria 1-5). Arm 1) MOPP-ABV x3 cycles + IFRT (36 Gy if CR, 40-44 Gy if PR) vs. Arm 2) STNI alone (36 Gy + 4 Gy boost to involved fields)
 * 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 H7-Favorable (1988-1993) -- EBVP x6 + IFRT vs STNI alone
 * Randomized. 333 patients with Stage I supradiaphragmatic HL, favorable (prognostic score 1-5). No staging laparotomy. Arm 1) STNI alone (36 Gy + 4Gy boost to 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 EBVP x6 + IFRT is superior STNI alone

Chemo-RT: RT Dose

 * EORTC H9-Favorable (1998-2004) -- EBVP x6 followed 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


 * HD10 (1998-2002) -- 2x2: ABVD x2 vs ABVD x4; IFRT 30 Gy vs 20 Gy
 * Randomized, 2x2. 1370 pts. Stage IA, IB, IIA, IIB (Note only ~7% of patients had B Symptoms) without risk factors (ie, large mediastinal mass, size >1/3 of the maximum thorax diameter, extranodal disease, 3 or more nodal areas, or elevated erythrocyte sedimentation rate (> 50 mm/h for stages IA, IIA and > 30 mm/h for stages IB, IIB). 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) &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
 * 2010; 5-years PMID 20818855 -- "Reduced Treatment Intensity in Patients with Early-Stage Hodgkin's Lymphoma" (Engert A, N Engl J Med 2010 Aug 12;363(7):640-652.)
 * For comparison of ABVD 2 cycles vs 4 cycles, no difference in FFTF or OS -- 5-yr FFTF 93.0% (ABVD x 4) vs 91.1% (ABVD x 2). For comparison of RT dose, no differences. Percent of grade 3/4 toxicities higher in group of ABVD x 4 vs ABVD x 2, 55% vs 33 % p=sig and XRT 30 Gy vs 20 Gy, 8.7% vs 2.9% p=sig.  6 treatment related deaths occured in ABVD x 4 vs 1 death in ABVD x 2.
 * Conclusion: ABVD x 2 + 20 Gy IFRT is as effective as ABVD x 4 + 30 Gy.

Chemo-RT vs Chemo Alone

 * EORTC H10 -- PET scan guided early treatment adaptation (omission of RT)
 * See details at: H10
 * Conclusion: "combined-modality treatment resulted in fewer early progressions in clinical stage I/II HL"


 * EORTC H9-Favorable (1998-2004) -- EBVP x6 followed 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