# Radiation Oncology/Hodgkin/Advanced stage

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Advanced Stage Hodgkin's Lymphoma

## Chemo +/- RT
### Randomized

* EORTC 20884 (1989-2000) -- MOPP-ABV, if CR -> RT vs. observation
** Randomized. 739 patients. Stage III-IV. MOPP-ABV x 6-8 cycles depending on response. If CR after 4 cycles (early CR), received 6 cycles total. If CR at 6 cycles, received 8 cycles total. If early or late CR, randomized after completing all chemo. Arm 1) IFRT 24 Gy vs Arm 2) observation. If PR after 6 cycles, no further chemo and IFRT (not randomized) 30 Gy to nodal sites or 18-24 Gy to extranodal sites plus optional 4-10 Gy boost. CR in 57% (n=421), of these 333 (79%) were randomized.
** Overall; 2003 PMID 12802025, 2003 — "Involved-field radiotherapy for advanced Hodgkin's lymphoma." (Aleman BM et al. N Engl J Med. 2003 Jun 12;348(24):2396-406.) Median F/U 6.6 years
*** Outcome: Randomized (n=333): 5-year EFS observation 84% vs. RT 79% (NS); 5-year OS 91% vs. 85% (NS). Local relapse RT 46% vs. 27%. Partial response cohort (n=250): 5-year EFS 79%, 5-year OS 87%
*** Second cancers: 5-year rate observation 4% vs. RT 8% (p=0.05)
*** Conclusion: No need for IFRT in patients who are in CR after MOPP-ABV; only patients in PR after chemo benefit
** RT QC; 2005 PMID 15936157 -- "Quality control of involved-field radiotherapy in patients with advanced Hodgkin's lymphoma (EORTC 20884)." (Aleman BM, Int J Radiat Oncol Biol Phys. 2005 Nov 15;63(4):1184-90. Epub 2005 Jun 2.)
*** Major violation rate 47% (predominately target volumes). Dose correct in 81%. However, no difference in cumulative failure rate between with or without major violations
*** Conclusion: Outcome was not influenced by violations of the RT protocol
** Partial Response; 2007 PMID 17097834 — "Involved-field radiotherapy for patients in partial remission after chemotherapy for advanced Hodgkin's lymphoma." Median F/U 7.8 years
*** Outcome (all IFRT): 8-year EFS 76% and OS 84% not significantly different from those with CR +/- RT (73-77% and 78-85%).
*** Second cancers: Comparable to non-irradiated patients
*** Conclusion: Outcomes suggest a definitive role for RT in patients with PR
*** Other publications: PMID 15936157, 2005 (Quality control)
* SWOG 7808 (1978-88)
** Randomized. 530 patients entered, 322 achieved CR after MOP-BAP, 278 pts randomized. Stage III-IV. Randomized to low-dose RT (10-20 Gy at 1.5 Gy/fx) to all initially involved sites vs observation. RT: 135 randomized, 104 received it, 18 major protocol violations
** 1994 PMID 8172436, 1994 — "Low-dose involved field radiation after chemotherapy in advanced Hodgkin disease. A Southwest Oncology Group randomized study." Fabian CJ et al. Ann Intern Med. 1994 Jun 1;120(11):903-12.
*** 5-year outcomes: RFS and OS similar between the two arms. RT improved RFS for pts with NS histology (82% vs. 60%, SS) or bulky disease (75% vs. 57%, SS)
*** RT subanalysis: Relapse rate: 8% in correctly delivered RT, 16% in as-treated with RT, 23% in as-assigned to RT, 32% in CT alone
** Conclusion: RT benefits pts with bulky disease (>6cm) or nodular sclerosing HD who achieve CR after chemo.
* HD1 (German Hodgkins Study Group)
** PMID 8624293 — "Further chemotherapy versus low-dose involved-field radiotherapy as consolidation of complete remission after six cycles of alternating chemotherapy in patients with advanced Hodgkin's disease. German Hodgkins' Study Group (GHSG)." Diehl V et al. Ann Oncol. 1995 Nov;6(9):901-10.
** 288 pts. Stages IIIB-IV. Induction with 3 cycles COPP/ABVD. If CR, then randomized to 20 Gy to involved fields (IF) or 1 additional cycle of COPP/ABVD. Pts with nodal PR received more RT: 20 Gy IF with 40 Gy to persistent disease.
** 59% had CR after induction. No difference in relapses between those randomized to the 2 arms. 3-fold higher risk of relapse for those receiving no additional therapy (refused).

### Retrospective

* NCI, 1991 - PMID 1988570 — "Treatment of advanced-stage massive mediastinal Hodgkin's disease: the case for combined modality treatment." Longo DL et al. J Clin Oncol. 1991 Feb;9(2):227-35.
** Retrospective. 49 pts with bulky disease (most were Stage III-IV). 10 pts received mantle field RT after MOPP, the rest received MOPP alone. Tumor mortality 80% vs 44% (nearly SS, p=0.055). OS not S.S.
* Yale, 1995 (1969-89)
** PMID 9166487 — "Combined Modality Therapy in Previously Untreated Patients With Advanced Hodgkin's Disease: A 24-Year Follow-Up Study." Salloum E et al. Cancer J Sci Am. 1995 Nov;1(4):267.
** Retrospective. 186 pts. Stages IIB,III,IV. Pts received 6 months of chemotherapy (MVVPP, MOPP, MOPP/ABVD, or ABVD) followed by RT.
** FFS was 63% @ 5 yrs, 56% / 10 y, and 40% / 23.5 y.
** Comment: Better results than CALGB 8251 trial with MOPP alone but similar to those using MOPP/ABVD or ABVD.
* ECOG E1492 - phase II, Stanford V chemotherapy
** Stage I/II bulky and Stage III/IV. Stanford V x 12 weeks followed by 36 Gy RT to nodes > 5 cm.
** PMID 10694546 (2000) — "Assessment of the stanford V regimen and consolidative radiotherapy for bulky and advanced Hodgkin's disease: Eastern Cooperative Oncology Group pilot study E1492." Horning SJ et al. J Clin Oncol. 2000 Mar;18(5):972-80.
To add:
* German HD
* SWOG
* EORTC-GPMC
Meta-analysis
* 1998 PMID 9508162 -- "Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin's disease. International Database on Hodgkin's Disease Overview Study Group." (Loeffler M J Clin Oncol. 1998 Mar;16(3):818-29.)
** 14 trials, 1740 patients. 8 comparisons of CT +/- RT, 8 comparisons of CT1 vs CT2+RT
** 10-years: addition of RT shows 11% benefit in tumor control (SS), no difference in OS. However, in CT1 vs. CT2+RT comparisons, no difference in tumor control, but OS better 8% if no RT but more chemo. Also significantly fewer fatal events in chemo only group in CR
** Conclusion: Combined modality significantly inferior survival, if adequate chemo given
** 2003 Comment: PMID 12788163 -- "Consolidation radiotherapy in the treatment of advanced Hodgkin's disease: is it dead?" (Prosnitz LR, Int J Radiat Oncol Biol Phys. 2003 Jul 1;56(3):605-8.)
*** Good review of literature. Several issues with analysis, only 6 of the 14 studies actually published as full manuscripts. Conclusion: "Targeted low-dose consolidation RT, skillfully administered, probably does some good."

### Non-randomized

* MRC UKLG LY09 - IF-RT for incomplete response to chemo or bulky disease presentation
** 807 pts. Prospective, randomized (chemo, not +/- RT). Randomized to ABVD or 1 of 2 multidrug combinations x 6 cycles (up to 8). IF-RT recommended for incomplete response to chemo or bulky disease presentation
** 2010 PMID 20498402 -- "Consolidation Radiotherapy in Patients With Advanced Hodgkin's Lymphoma: Survival Data From the UKLG LY09 Randomized Controlled Trial" (Johnson PW, J Clin Oncol. 2010 July 10;28(20):3352-59.) - Median f/u 6.9 yrs
*** 702 of 807 achieved objective response. Postchemo RT given in 300 (43% of responders). ; 5-yr PFS 86% (RT) vs 71% (no RT);(HR 0.43). Overall survival, HR = 0.47.
** Conclusion: Patients who received consolidation RT apparently had better outcomes.
* Stanford
** PMID 11821442, 2002 — "Stanford V and radiotherapy for locally extensive and advanced Hodgkin's disease: mature results of a prospective clinical trial." Horning SJ et al. J Clin Oncol. 2002 Feb 1;20(3):630-7.
** Prospective. 142 pts. Stage III-IV (or Stage I-II if bulky). Treated with Stanford V x 12 wks followed by 36 Gy to initial sites of bulky (>5cm) or macroscopic splenic dz. Most pts received modified mantle field.
** Median f/u 5.4 yrs. FFP 89%, OS 96%. FFP 94% (for prognostic score 0-2) vs 75% (for 3 or more).

## Chemotherapy alone

* CALGB 8251
** PMID 1383821, 1992 — "Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD." Canellos GP et al. N Engl J Med. 1992 Nov 19;327(21):1478-84.
** Both ABVD and MOPP/ABVD were superior to MOPP alone. ABVD less toxic than MOPP/ABVD.
* CALGB 8952
** PMID 12586796, 2003 — "Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup trial." Duggan DB et al. J Clin Oncol. 2003 Feb 15;21(4):607-14.
** 76% CR, 63% FFP, 81% OS at 5-yrs, no difference between arms. Worse pulmonary and hematologic toxicity and more 2nd malignancies with MOPP/ABV.
** No benefit for MOPP/ABV vs ABVD. ABVD should be considered standard regimen.

## Chemotherapy comparisons

* ABVD is currently the standard regimen (Nov 2012)
* Stanford V is much shorter, and has lower risk of pulmonary toxicity. However, it was designed with consolidative RT, and elimination of RT does not appear feasible. When RT is given appropriately, outcomes are comparable to ABVD
* BEACOPP may be associated with improved PFS, but has greater toxicity. Given good salvage regimens, the improved PFS may not translate into improved OS
* Intergroup E2496 -- ABVD vs Stanford V
** 2012 PMID 23182987 -- "Randomized Phase III Trial of ABVD Versus Stanford V With or Without Radiation Therapy in Locally Extensive and Advanced-Stage Hodgkin Lymphoma: An Intergroup Study Coordinated by the Eastern Cooperative Oncology Group (E2496)." (Gordon LI, J Clin Oncol -- online before print, November 26, 2012.) -- Median f/u 6.4 yr
*** 5-yr FFS 74% (ABVD) vs 71% (Stanford V), NS. No difference in CR rate (73% vs 69%).
*** Conclusion: "ABVD remains the standard of care for patients with advanced Hodgkin lymphoma."
* UK ISRCTN 64141244 (1998-2006) -- Stanford V vs ABVD
** Randomized. Trial stopped early due to problems with mechlorethamine supply. 520 of target 580 patients with Stage IIB-IV, or bulky (>5cm) Stage I-IIA. Arm 1) Stanford V x12 weeks vs. Arm 2) ABVD 6-8 cycles. RT in both arms 34-36 Gy to site of bulky disease and splenic deposits; later in the trial RT in ABVD arm only if not CR. RT given in 73% of SV arm and 53% of ABVD arm
** 2009 PMID 19738111 -- "Randomized comparison of the stanford V regimen and ABVD in the treatment of advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244." (Hoskin PJ, J Clin Oncol. 2009 Nov 10;27(32):5390-6. Epub 2009 Sep 8.) Median F/U 4.3 years
*** Outcome: 5-year PFS SV 74% vs. ABVD 76% (NS); 5-year OS 92% vs. 90% (NS).
*** Toxicity: Acute toxicity comparable; late pulmonary toxicity worse with ABVD
*** Conclusion: Efficacy of Stanford V and ABVD comparable when given in combination with appropriate RT
* Intergruppo Italiano Linfomi (1996-2000) -- modified Stanford V vs MOPPEBVCAD vs ABVD
** Randomized. 334 patients with Stage IIB-IV. Arm 1) ABVD x6 cycles vs. Arm 2) Stanford V x3 cycles vs. Arm 3) MOPPEBVCAD x6 cycles. Goal to decrease RT. RT given to previous bulky sites or PR but not more than 2 sites; dose 36 Gy if uCR or 42 Gy if PR. RT given in 76%, 71% and 50%.
** 2005 PMID 16172458 -- "ABVD versus modified stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced-stage Hodgkin's lymphoma: final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi." (Gobbi PG, J Clin Oncol. 2005 Dec 20;23(36):9198-207. Epub 2005 Sep 19.)
*** Outcome: 5-year PFS ABVD 85% vs. Stanford V 73% vs. MOPPEBVCAD 94% (SS worse for Stanford V); 5-year OS 90% vs. 82% vs 89%.
*** Toxicity: Myelotoxicity MOPPEBVCAD > STanford V > ABVD
*** Conclusion: ABVD best choice when combined with optional limited RT. Stanford V (as originally designed) is unlikely to allow reduction in subsequent RT
* EORTC/GPMC
** PMID 7509381, 1994 — "A randomized study in stage IIIB and IV Hodgkin's disease comparing eight courses of MOPP versus an alteration of MOPP with ABVD: a European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group and Groupe Pierre-et-Marie-Curie controlled clinical trial." Somers R et al. J Clin Oncol. 1994 Feb;12(2):279-87.
** Randomized to MOPP x 8 or alternating MOPPx2/ABVDx2/MOPPx2/ABVDx2. Rt was given to bulky disease (>5cm) or residual areas.
** MOPP/ABVD led to improved response rate and failure-free survival (FFS) but no difference in relapse-free survival or OS. Early CR (CR4) is associated with final remission.
* EORTC 20012 (ongoing) - ABVD vs BEACOPP

## Patterns of failure

* PMID 688174, 1978 — "Patterns of relapse in advanced Hodgkin's disease treated with combination chemotherapy." Young RC et al. Cancer. 1978 Aug;42(2 Suppl):1001-7.
** 161 pts with advanced stage disease achieved CR after chemo. 32% have relapsed. Pts with higher stage, systemic symptoms, and nodular sclerosing histology most likely to relapse. 92% relapse in sites of prior disease. RT did not alter the pattern of sites of relapse.

## Radiation doses

* EORTC 20884(PMID 17097834)
** Nodal areas - 24 Gy (if CR), 30 Gy (if PR), boost 4-10 Gy
** Lung - 16 Gy (18 Gy if PR), boost 4-10 Gy
** Liver - 20 Gy
** Bone - 24 Gy, boost 10 Gy