# Radiation Oncology/Hodgkin/Early stage

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Early Stage Hodgkin's Disease

## Treatment Overview

* Initially, high cure rate was achieved through prophylactic extended field radiation, to adjacent areas next to involved regions
* Since staging laparotomy showed infradiaphgragmatic occult disease in ~20% patients with supradiaphragmatic disease, prophylactic radiation was extended to para-aortic fields or all lymph node areas. Spleen was either removed or irradiated
* Local and distant relapses continued to occur despite extensive RT; combined chemotherapy (MOPP) and radiation (EFRT) was shown to result in 80-90% 5-year survival. Randomized trials showed that combined chemotherapy + EFRT and combined chemotherapy + IFRT was superior to RT alone
* Because maximal combined treatment resulted in significant toxicity (late sepsis in splenectomy patients, second malignancies, heart and lung disease, and sterility), efforts were undertaken to reduce radiation field size after administration of chemotherapy
* to be continued ...
* German HD8 and EORTC H9 showed ABVD x4 cycles + IFRT 30 Gy as the superior approach for unfavorable disease over chemotherapy + EFRT
* to be continued ...

## RT alone

* Princess Margaret Hospital; 1992 (1978-86) PMID 1555977 — "Analysis of supradiaphragmatic clinical stage I and II Hodgkin's disease treated with radiation alone." Gospodarowicz MK et al. Int J Radiat Oncol Biol Phys. 1992;22(5):859-65.
** Retrospective. 250 patients. Stage cI-II with supradiaphragmatic disease; no adverse prognostic factors. Variety of radiation techniques (involved field, mantle, or extended field).
** 90% cause-specific survival at 8-years with RT alone
* Stanford
** 1973 PMID 4126721 — "Survival and relapse rates in Hodgkin's disease: Stanford experience, 1961-71." (Kaplan HS, Natl Cancer Inst Monogr. 1973 May;36:487-96.)
*** No abstract
** 1968 PMID 4170945 -- "Clinical evaluation and radiotherapeutic management of Hodgkin's disease and the malignant lymphomas." (Kaplan HS, N Engl J Med. 1968 Apr 18;278(16):892-9.)
*** No abstract
** 1962 PMID 14453744 — "The radical radiotherapy of regionally localized Hodgkin's disease." (Kaplan HS, Radiology. 1962 Apr;78:553-61.)
*** No abstract

## RT vs Chemo

* NCI-Canada HD.6
** See results below (at #Chemo vs Chemo+RT)
* NCI
** PMID 2033427, 1991 — "Radiation therapy versus combination chemotherapy in the treatment of early-stage Hodgkin's disease: seven-year results of a prospective randomized trial." Longo DL et al. J Clin Oncol. 1991 Jun;9(6): 906-17.
** Randomized. 136 pts. Stage I,II,and IIIA1. Pts with peripheral IA treated with RT alone (n=30). The rest were randomized to RT alone vs MOPP.
** Median f/u 7.5 yrs. For pts with peripheral IA dz treated with RT alone, all pts cured. For pts randomized to RT, 96% CR, 35% relapsed, 20% died. For MOPP, 96% CR, 13% relapsed, 7% died. 10-yr DFS 60% RT vs 86% (SS). 10-yr OS, 76% vs 92% (p=.05). MOPP superior for the following subgroups: Stage IIIA1, massive mediastinal dz, no B symptoms, ESR >20, 4 or more involved sites, age < 40.
* Italian trial
** PMID 1740677, 1992 (1979-82) — "Extended-field radiotherapy is superior to MOPP chemotherapy for the treatment of pathologic stage I-IIA Hodgkin's disease: eight-year update of an Italian prospective randomized study." Biti GP et al. J Clin Oncol. 1992 Mar;10(3): 378-82.
** 89 pts. Stage pI-IIA. Randomized to mantle field followed by para-aortic vs MOPP x 6 cycles.

## Chemo + RT

* Stanford, 1993 (1980-88) - PMID 7683016 — "Hodgkin's disease with bulky mediastinal involvement: effective management with combined modality therapy." Behar RA et al. Int J Radiat Oncol Biol Phys. 1993 Apr 2;25(5):771-6.
** Retrospective. 48 pts with bulky disease. Chemo followed by mantle field RT.
** 9-yr OS 84%, FFR 88%
** Good results for combined modality treatment.

## RT vs Chemo+RT

* EORTC H5, 1988 (1977-82)
    See details at #EORTC Hodgkin's trials
* EORTC H8-Favorable (1993-1999) -- 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
* German HD7 (1993-1998) -- EFRT alone vs. ABVD x2 + EFRT
** 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
* SWOG S9133 (1989-2000) -- STNI vs doxorubicin/vinblastine + STNI
** 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 (STNI 36/20 or 40/20) or chemo (doxorubicin/vinblastine x3 cycles) + STNI
** 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. STNI 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 STNI alone
* EORTC H7-Favorable (1988-1993) -- EBVP x6 + IFRT vs STNI
** 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 — "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

## Chemo vs Chemo+RT

Meta-analysis
* Cologne; 2010 PMID 19951972 -- "Combined modality treatment improves tumor control and overall survival in patients with early stage Hodgkin's lymphoma: a systematic review." (Herbst C, Haematologica. 2010 Mar;95(3):494-500. Epub 2009 Nov 30.)
** Meta-analysis. 5 randomized trials of chemo alone vs chemo-RT, 1245 patients, early stage HL
** Outcome: tumor control better with chemo-RT (HR 0.4, SS), OS better with chemo-RT (HR 0.4, SS)
** Conclusion: Adding RT to chemotherapy improves local tumor control and overall survival
Randomized
* EORTC H10(ONGOING) - chemotherapy alone vs chemo-RT (involved nodes - INRT) in pts with PET CR after 2 cycles of chemo
** See details at H10
* EORTC H9-F (1998-2004) - chemo followed by IFRT 36 Gy vs 20 Gy vs observation
** See details at H9F
* Italy; 2007 PMID 17786707 -- "Randomized comparison of consolidation radiation versus observation in bulky Hodgkin's lymphoma with post-chemotherapy negative positron emission tomography scans." (Picardi M, Leuk Lymphoma. 2007 Sep;48(9):1721-7.)
** Randomized. 260 patients with bulky HL, treated with induction chemo. Then if no residual disease on PET, randomized to +/- IFRT 32 Gy. Median F/U 3.3 years
** Outcome: Biopsy malignancy observation 14% vs. RT 4% (SS). All relapses in chemo-only group were in the bulky site/contiguous LNs
** Conclusion: PET accuracy 86% with 14% false-negative rate; addition of RT improves EFS in PET-negative patients
* NCI-Canada HD.6 / ECOG (1994-2002) - ABVD vs RT (or ABVD+RT)
** 405 pts. Stage I-IIA, no bulky disease. Also excluded pts with low risk disease (single node, NS or LP histology, limited to high neck or epitrochlear). Stratified into favorable or unfavorable groups (unfavorable, any of: age >40, ESR > 50, MC or LD histology, 4 or more sites of disease). Staging eval included CT but not PET.
** Randomized to:
*** 1) ABVD alone. All received at least 4 cycles. Restaged after cycles 2 and 4. If achieve CR after 2nd cycle, then had 4 cycles only. If not achieve early CR, then receive a total of 6 cycles.
*** 2) Radiation therapy. Favorable group received RT alone (subtotal nodal). Unfavorable group received 2 cyles ABVD then RT (subtotal nodal). Dose was 35 Gy / 20 fx (175 cGy/fx).
** Trial closed to accrual early (goal was 450 pts) after results of EORTC trial that showed excellent results for involved field (rather than subtotal nodal) RT in combination with chemotherapy.
** 2005 PMID 15837968 — "Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group." Meyer RM et al. J Clin Oncol. 2005 Jul 20;23(21):4634-42.
*** Median f/u 4.2 yrs. 399 pts evaluated. No difference in EFS (86 v 86%) or OS (96 vs 94%). Benefit for freedom from disease progression for RT arm (87 vs 93%, SS). In unfavorable group, freedom from disease progression was superior in the combined modality arm, but no difference in OS.
*** Note: Compare to preliminary results from H9F (listed above)
** 2012 (12 yrs): PMID 22149921 -- "ABVD Alone versus Radiation-Based Therapy in Limited-Stage Hodgkin's Lymphoma" (Meyer RM, N Engl J Med. 2012 Feb 2;366(5):399-408.) -- Median f/u 11.3 yr
*** 12-yr OS 94% (ABVD alone) vs 87% (STNI), SS. FFDP 87% (ABVD) vs 92% (STNI), SS. EFS 85% vs 80%, NS.
*** In favorable group, no difference in OS, FFDP, EFS at 12 years with ABVD vs STNI
*** In unfavorable group, ABVD+STNI had better 12 yr FFDP (94% vs 86%, SS) but worse 12 yr OS (81% vs 92%, SS) than ABVD alone
*** More secondary cancers (23 vs 10 pts), cardiac events (26 vs 16 pts) with STNI
** Conclusion: ABVD alone was associated with a higher rate of overall survival owing to a lower rate of death from other causes.
** Criticisms: Antiquated RT techniques with large field (STNI) and high dose (35 Gy) may have increased late toxicity, RT group had older patients (45% vs 36% over age 40), 5 of 24 deaths in RT arm from "other causes" including drowning/suicide/Alzheimer's vs. no such deaths in chemo alone arm, ABVD x 2c may be insufficient systemic therapy for unfavorable disease
* Tata Memorial Hospital; India (1993-1996) -- Initial chemotherapy, PET-, then +/- RT
** Randomized. 179 patients (251 enrolled, and 179 achieved CR). Stage I-IV (I-II in ~55%), ABVD x6. If clinical/radiographical CR, then Arm 1) EBRT vs Arm 2) observation. RT given as IFRT 84%, inverted Y 11%, mantle 4%, TNI 1%. Dose 30 Gy with 10 Gy boost to bulky disease
** 2004 PMID 14657226 -- "Consolidation radiation after complete remission in Hodgkin's disease following six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy: is there a need?" (Laskar S, J Clin Oncol. 2004 Jan 1;22(1):62-8. Epub 2003 Dec 2.) Median F/U 5.25 years
*** Outcome: 8-year EFS no RT 76% vs RT 88% (SS), 8-year OS 89% vs 100% (SS). RT improved outcomes for age <15 years, B-symptoms, advanced stage, and bulky disease
*** Conclusion: Addition of consolidation RT improves EFS/OS in patients achieving CR after ABVD
Retrospective
* SEER (1988-2006)
** Adult stage I-II. No chemo information available.
** 2012 PMID 22251881 -- "Declining use of radiotherapy in stage I and II Hodgkin's disease and its effect on survival and secondary malignancies." (Koshy M, Int J Radiat Oncol Biol Phys. 2012 Feb 1;82(2):619-25.) -- Median f/u 4.9 yrs
*** 12,247 pts; 51.5% received RT. Decreasing utilization of RT: 62.9% RT use 1988-91, vs 43.7% in 2004-06.
*** 5-yr OS 76% (RT) vs 87% (no RT); HR 1.72. No increase in secondary malignancies.
*** Conclusion: survival benefit associated with use of RT

## Extent of radiation field (RT alone)
### Meta-analysis

* International HD Collaborative Group; 1998 PMID 9508163 -- "Influence of more extensive radiotherapy and adjuvant chemotherapy on long-term outcome of early-stage Hodgkin's disease: a meta-analysis of 23 randomized trials involving 3,888 patients. International Hodgkin's Disease Collaborative Group." (Specht L, J Clin Oncol. 1998 Mar;16(3):830-43.)
** Meta-analysis. 1,974 patients in 8 trials comparing more vs less extensive RT and 1,688 patients in 13 trials comparing RT + chemo vs RT alone
** Outcome: More extensive RT reduces risk of failure (31% vs. 43%, SS), but there was no impact on 10-year OS (77% vs 77%). Addition of chemotherapy reduced risk of failure (15% vs. 33%), with no impact on 10-year OS (79% vs. 76%)
** Conclusion: More extensive RT field or addition of chemo improve disease control, but have no effect on OS due to effective salvage. Less intensive primary treatment appears to achieve similar survival rates as more intensive treatment

## Extent of radiation field (with chemotherapy)

Please see HD radiation fields for overview

### STNI vs. IFRT

* EORTC H8-U (1993-1999) -- 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
* Milan (Italy)(1990-96) - ABVD x 4 cycles plus subtotal nodal vs involved field RT
** Randomized. 136 patients. Stage I (unfavorable) or IIA (favorable or unfavorable), clinical staging. ABVD x4 cycles. Arm 1) subtotal nodal irradiation vs. Arm 2) involved field RT. RT began 4 weeks after chemo and restaging. Dose for CR 36 Gy, for PR/unconfirmed CR 40 Gy. For STNI, 30.6 Gy to uninvolved mantle + para-aortic + spleen. Treated postchemotherapy volumes
** 2004 PMID 15199092 (2004) - "ABVD plus subtotal nodal vs involved-field radiotherapy in early-stage Hodgkin's disease: long-term results." (Bonadonna G, J Clin Oncol. 2004 Jul 15;22(14):2835-41.) Median F/U 9.7 years
*** Outcome: CR STNI 100% vs. IFRT 97%. 12-year FFP 93% vs. 94% (NS); 12-year OS 96% vs. 94% (NS)
*** Conclusion: ABVD + IFRT is feasible to use involved-field instead of more extensive RT

### EFRT vs. IFRT

* German 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.
** 5-years; 2003 PMID 12913100 — "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
* GPMC (Groupe Pierre-et-Marie-Curie, France)(1976-81) -- MOPP x3 plus EFRT vs IFRT
** Randomized. 335 patients, Stage I-IIIA. No staging laparotomy or splenectomy. MOPP x3 cycles. Then randomized to Arm 1)EFRT vs Arm 2) IFRT. Supradiaphragmatic disease = mantle + para-aortic field. Infradiaphragmatic disease = inverted Y + supraclavicular fields. Stage III = total nodal irradiation. Dose 40 Gy @ 2-2.5 Gy/fx. For unfavorable prognosis patients, additional MOPP x3 given
** 1985 PMID 3838188 — "Extended versus involved fields irradiation combined with MOPP chemotherapy in early clinical stages of Hodgkin's disease." (Zittoun R, J Clin Oncol. 1985 Feb;3(2):207-14.) Median F/U 3.5 years
*** Outcome: 6-year DFS EFRT 90% vs. IFRT 86% (NS), OS 93% vs. 90% (NS). Relapse in nonirradiated areas EFRT 3/11 (27%) vs IFRT 12/18 (67%)
*** Conclusion: Combined chemotherapy and EFRT did not result in definite advantage and may represent overtreatment for many patients

### INRT

* British Columbia; 2008 (1989-2005) PMID 18838714 -- "Involved-nodal radiation therapy as a component of combination therapy for limited-stage Hodgkin's lymphoma: a question of field size." (Campbell BA, J Clin Oncol. 2008 Nov 10;26(32):5170-4. Epub 2008 Oct 6.)
** Retrospective. 325 patients with limited-stage HD Stage (IA 29%, IIA 71%), treated with chemotherapy + RT. EFRT used 1989-1996 (39%), IFRT used 1996-2001 (30%), INRT used 2001-2005 (31%). INRT defined as prechemo nodal volume with margin <=5 cm. No PET. Median F/U of living patients 6.7 years
** Outcome: Relapse rate EFRT 3% vs. IFRT 5% vs. INRT 3% (NS). No marginal recurrences after INRT. 5-year PFS 97% and OS 95%. 10-year PFS 95% and OS 90%
** Conclusion: Reduction in field size to involved nodes + 5cm appears safe, without increased risk of recurrence

### Field Guidelines

* German GHSG; 2008 PMID 18956517 -- "Involved-node radiotherapy in early-stage Hodgkin's lymphoma. Definition and guidelines of the German Hodgkin Study Group (GHSG)." (Eich HT, Strahlenther Onkol. 2008 Aug;184(8):406-10.)
** CTV encompasses initial location and extent of disease, taking displacement of normal tissue into account. Margin 2 cm axial and 3cm craniocaudal; can be reduced to 1-1.5 cm. Mediastinum is different
** Conclusion: Concept of INRT has been proposed; field sizes will further decrease compared to IFRT
* EORTC-GELA
** 2008 PMID 18555548 -- "The conundrum of Hodgkin lymphoma nodes: to be or not to be included in the involved node radiation fields. The EORTC-GELA lymphoma group guidelines." (Girinsky T, Radiother Oncol. 2008 Aug;88(2):202-10. Epub 2008 Jun 12.)
*** Three step process in treatment position: 1) PET scan review, 2) CT scan review, 3) prechemo vs postchemo changes used as surrogate of initial involvement
*** Conclusion: Guidelines developed for cervical and axillary lymph nodes. This manuscript is considered an addendum to prior publication
** 2006 PMID 16797755 -- "Involved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: concepts and guidelines." (Girinsky T, Radiother Oncol. 2006 Jun;79(3):270-7. Epub 2006 Jun 22.)
*** New concepts for RT fields in patients with early stage HD after chemotherapy
*** Conclusion: First attempt at concept of involved-node radiotherapy (INRT) guidelines
*** Comment (PMID 17125861): Implementing INRT requires using 4DCT to ensure appropriate margins for motion
*** Author response (PMID 17125861): Goal is to propose easy reasonable guidelines, emphasis on pretreatment volumes
* Memorial Sloan-Kettering; 2002 PMID 12078908 -- "The involved field is back: issues in delineating the radiation field in Hodgkin's disease." (Yahalom J, Ann Oncol. 2002;13 Suppl 1:79-83.)
** Design guidelines and field border recommendations

## RT dose

* Meta-analysis in 1966 (PMID 5947345) suggested a continuous reduction in recurrence rates with RT alone up to 40 Gy, after which toxicity became excessive
* Subsequent dose-response analyses (PMID 1620882, PMID 10348284) suggested a plateau between 30 - 40 Gy for subclinical disease, but reduction in control for bulky disease below 40 Gy
* German HD4 randomized trial showed that 30 Gy was adequate compared to 40 Gy
* Both German HD10 and EORTC H9 suggest (reported as abstract only; 4/2010) that 20 Gy after chemo CR may be sufficient as a consolidation dose
* Please also see the Early Stage Favorable page for more trials
* German Hodgkin Lymphoma Study Group; 1997 (1983-93)
** Review of pts from randomized trials HD1 and HD5. Pts were treated with COPP/ABVD followed by RT. Randomized to 20 vs 40 Gy extended field in HD1; received 30 Gy in HD5. Bulky dz always received 40 Gy.
** No difference in freedom from failure or survival in the different dose arms, supporting that 20 Gy is acceptable for nonbulky disease. Bulky disease should receive 40 Gy.

## Chemotherapy Regimens

* HD13 (ongoing trial)
** Randomized to 2 cycles of ABVD, ABV, AVD, or AV. All followed by 30 Gy IF-RT.
* 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
* EORTC H7-Unfavorable (1988-1993) -- 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 1675493 — "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

## Toxicity

Gonadal function
* EORTC/GELA, 2007 PMID 17515571 -- "Gonadal function in males after chemotherapy for early-stage Hodgkin's lymphoma treated in four subsequent trials by the European Organisation for Research and Treatment of Cancer: EORTC Lymphoma Group and the Groupe d'Etude des Lymphomes de l'Adulte." (van der Kaaij, J Clin Oncol. 2007 Jul 1;25(19):2825-32.)
** Prospective. FSH levels measured in 4 EORTC trials (H6-H9). 355 patients with FSH >1 year for fertility; 349 patients with FSH <1 years for fertility recovery. Median F/U 2.7 years
** Elevated FSH: RT 3% vs. non-alkylating chemo (ABVD or EBVP) 8% vs. alkylating chemo (MOPP, MOPP/ABV, BEACOPP) 60% (SS). Recovery of fertility at 19 months: non-alkylating 82% vs. alkylating 52% (SS). Dose-dependent.
** Conclusion: Fertility ok after non-alkylating chemo; alkylating chemo has dismal effect, even after limited cycles