Radiotherapy in Pediatric
Hodgkin Lymphoma
TASHA MCDONALD, MD
DEPARTMENT OF RADIATION
MEDICINE
JUNE 18, 2008
OVERVIEW
 Case presentation
 Risk-groups
 Early/favorable risk
 Unfavorable risk
 Toxicities
 Future directions
Case presentation
 L.S.: 18 yo girl presented in 1/08 with 2 months of
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fatigue, fever, chills, sweats and 10 lb weight loss
Developed difficulty swallowing and enlarged neck
nodes and SOB when lying down
On exam: palpable cervical LAD
Underwent US of the neck 1/3/08: irregular 2.3x2.3
x3.4cm nodule in right neck.
LN biopsy on 1/4/08 at Kaiser: nodular sclerosing
Hodgkin disease
Outside PET 1/22/08
Outside CT Chest 1/22/08
Case presentation
 Stage IIB NSHD
 No subdiaphragmatic disease
 Bone marrow bx was negative
 Started on COG AHOD 0031 protocol and received 2
cycles of ABVE-PC
 Re-imaged on 3/7/08 and determined to be a slow
early responder per protocol
OHSU PET 3/7/08
OHSU CT Chest 3/7/08
Case presentation
 Randomized to the augmented therapy arm to
receive DECA x 2 followed by 2 more cycles of
ABVE-PC
 CT and PET on 4/28/08 (before the ABVE-PC)
showed a 66% reduction tumor size
 Finished chemotherapy and scheduled to start RT on
5/23/08.
OHSU PET 4/28/08
OHSU CT Chest 4/28/08
RT Guidelines for AHOD0031 Protocol
 IFRT for all pts except those who achieve rapid early
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response after 2 cycles of chemo AND CR after 4
cycles of chemo.
IFRT with 21 Gy in 14 fxs given with AP:PA fields
RT to start w/in 4 weeks of last chemo cycle
GTV = LN>1.5 cm; CTV = anatomical compartment
of LN; PTV = 1.0 cm margin to CTV
RT fields adapted to response of chemo are not
permitted except if treating the mediastinum
RT Plan evaluation
RT field with pre-chemo volume shown
RT AP field with post-chemo volume
History
 Treated with full-dose (35-45 Gy) extended-field RT
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w/ excellent disease control but significant late toxicity
Chemotherapy (MOPP or ABVD) was shown to salvage
relapsed disease after RT and improve DFS when used
as part of initial therapy1,2
Low-dose RT (15-25 Gy) following chemotherapy was
shown to produce excellent EFS and OS3-5
Chemotherapy followed by low-dose RT became the
standard therapy
The most recent trials use risk-adapted and/or
response-adapted therapy
Risk groups
 Division into groups based on factors shown
to influence outcome
 Histology
 Clinical
stage
 B symptoms
 Bulky disease
Risk groups
 Prognostic stratification (not uniformly agreed on):
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Low-risk/favorable: Stage I or II, no B symptoms, no bulky
disease and disease in fewer than 3 nodal regions
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Intermediate-risk: Stage IB, IIB (or bulky disease and
extranodal involvement) and sometimes IIIA
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High-risk: Stage IIIB, IVA/B
Early stage/favorable risk
 Goal = limit treatment-related toxicity and maintain
success of therapy
 Efficacy of various strategies is relatively equivalent
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~90% or better EFS or PFS
~95% OS
 Treatment: 2-4 cycles of chemotherapy +/- involved
field RT
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Response-adapted approach: Response to the first cycles of
chemotherapy determines inclusion of additional chemo or
dose of RT
Treatment and outcomes in early stage
pediatric Hodgkin disease
Early stage/favorable risk
Response-adapted approach
 SDS group study6,7: single arm study; 4 cycles of VAMP followed
by IFRT with RT dose determined by response to first 2 cycles
 PR (53%): 25 .5 Gy IFRT
15 Gy IFRT
 German HD958,9: OPPA or OEPA for two cycles
 CR (47%):
 CR (27%): observation
 PR with >75% reduction (53%): 25 Gy IFRT
 <75% reduction (~5%): 20-30 Gy IFRT + 5 Gy boost to >50 ml residual
 French MDH9010: 4 cycles of VBVP
 >70% response (85%): 20 Gy IFRT
 <70% response: 1 or 2 more cycles of OPPA and 20 or 40 Gy IFRT
 Despite the differences in treatment, all these studies had a EFS or PFS
of 93% or better
Early stage/favorable risk
Exclusion of RT
 POG 862511: Laparotomy-staged IA-IIIA disease
 4 cycles of MOPP/ABVD OR 2 cycles of MOPP/ABVD plus
25.5 Gy IFRT
 EFS (83% vs 91%) and OS (94% vs 97%) were statistically
equivalent
 CCG 594212: Clinically staged I-II disease
 4 cycles of COPP/ABV
 CRs randomized to observation vs. 21 Gy IFRT
 Stopped early after interim analysis indicated superiority of RT
arm (EFS 85% vs 93%) but OS was 100% in both arms
Intermediate and advanced stage disease
 More intensified regimens with a combination of
diverse chemotherapeutic agents
 Goal of minimizing treatment-related toxicity is still
important but studies that reduced alkylating agents
and anthracyclines with limited IFRT lead to
decreased EFS13,14
 RT continues to be standard therapy in this risk
group (unless on protocol)
Treatment and outcomes in intermediate/advanced
stage pediatric Hodgkin disease
Intermediate and advanced stage disease
 POG15: 8 cycles of MOPP/ABVD +/- total-nodal
irradiation
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No diff by intent-to-treat analysis
 CCG 52116: 6 cycles MOPP alternating with 6 cycles of
ABVD vs 6 cycles of ABVD with 21 Gy extended-field RT
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Equivalent outcome
EFS 77% vs 87%, P = .09; OS 84% vs 90%, P=.45
 German HD-958,9: 2 cycles of OPPA or OEPA +2-4 cycles
of COPP
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>70% reduction in tumor volume: No RT
<70% reduction: IFRT
OS equivalent but EFS with RT =92% vs with chemo alone = 69%
RT Planning
 Historical mantle field and total nodal irradiation
RT Fields
IFRT
 IFRT requires careful evaluation of pre- and post
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chemotherapy volumes
CTV encompasses post-chemo mediastianal width
laterally and pre-chemo extent in sup/inf direction
An anterior laryngeal block can be used if it does not
shield involved nodes
If the axillae are to be treated humeral head blocks
are used
CT based planning allows evaluation of adequate
CTV coverage and normal tissue dose
IFRT
 Whole-heart irradiation indications: pericardial
involvement/invasion
 Splenic irradiation is indicated in pts with splenic
involvement but renal dose must be limited to mean
<10.5 Gy or keep 2/3rds of the kidney to <15 Gy
 If the pelvis needs to be treated the ovaries should be
relocated and the dose should be limited to <3 Gy
 When treating a male, ensure on a daily basis that
the scrotum is not in the pelvic field
Late Toxicity of Radiotherapy
 Growth abnormalities17
 Bone and soft-tissue hypoplasia in prepubertal children
 Thyroid sequela18,19
 Hypothyroidism
 Hyperthyroidism
 Benign and malignant thyroid nodules
 17% of children treated with RT dose <26 Gy had thyroid
abnormalities compared to 78% with >26 Gy
Late Toxicity
 Cardiovascular disease20,21
 Atherosclerotic heart disease
 Valvular dysfunction
 Pericardial disease
 Pulmonary toxicity22
 Decrease in pulmonary function tests
 Sterility/Infertility: limit dose to ovaries to 3Gy
 Increase incidence of secondary cancers23-25
 Late effects study group: 30 yr cumulative incidence of SC =
26.3% in pts dx’ed before age 16
 Breast cancer was most elevated solid cancer
Late Toxicity
 Toxicities of higher dose RT are well documented but
it is less clear what toxicities will exist with 15-25 Gy
bc many toxicities are dose and volume dependent
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Second solid cancer risk appears to be dose dependent with
patients w/ <23 Gy mediastinal RT with lower risk of
developing breast cancer26
Future Directions
 Improve the technique of response-adapted therapy
 Incorporate functional imaging into evaluating
treatment response and RT planning
 Improve upon late toxicities AND determine the
effects of decreased dose IFRT on late toxicities
 Refine risk categories
 Improve treatment regimen for high-risk disease
References
1.
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4.
5.
6.
7.
Devita VT Jr et al. Combination chemotherapy in the treatment of advanced HD.
Ann Intern Med 73: 881-95. 1970
Bonadonna G et al. Combination chemotherapy of HD with adriamycin,
bleomycin,vinblastine,and imidazole vs MOPP. Cancer 36: 252-9, 1975.
Donaldson SS et al. HD: Treatment with low dose radiation and chemotherapy.
Front Radiat Ther Oncol 16: 122-33, 1981.
Hunger SP et al. ABVD/MOPP and low-dose IFRT in pediatric HD. J Clin Oncol
12:2160-6, 1994.
Weiner MA et al. Intensive chemotherapy and low-dose RT for the treatment of
advanced-stage HD in pediatric patients: A POG study. J Clin Oncol 9: 1591-98,
1991.
Donaldson SS et al. VAMP and low-dose, IFRT for children and adolescents with
favorable, early-stage HD: results of a prospective clinical trial. J Clin Oncol
20:3081–3087, 2002.
Donaldson SS et al. Final results of a prospective clinical trial with VAMP and
low-dose IFRT for children with low-risk HD. J Clin Oncol 25:332–337, 2007 .
References
8.
9.
10.
11.
12.
13.
14.
Ruhl U et al. Response adapted RT in the treatment of pediatric HD: an interim
report at 5 years of the German GPOH-HD 95 trial. IJROBP, 51: 1209–1218, 2001.
Ruhl U et al. Abstract at ASTRO, 46th annual meeting: German GPOH-HD 95 trial:
Treatment results and analysis of failures in pediatric HD using combination
chemotherapy with and without RT. IJROBP 60:S131, 2004.
Landman-Parker Jet al. Localized childhood HD: response-adapted chemotherapy
with etoposide, bleomycin, vinblastine, and prednisone before low-dose RT-results
of the French MDH90. J Clin Oncol 18:1500–1507, 2000.
Kung FH et al. POG 8625: a randomized trial comparing chemotherapy with
chemoradiotherapy for children and adolescents with stages I, IIA, IIIA1 HD: a
report from the COG. J Pediatr Hematol Oncol 28:362–368, 2006.
Nachman JB et al. Randomized comparison of IFRT and no RT for children with
HD who achieve a complete response to chemotherapy. J Clin Oncol 20(18):3765–
3771, 2002.
Hudson MM et al. Risk-adapted, combined-modality therapy with VAMP/COP and
response-based, IFRT for unfavorable pediatric HD. J Clin Oncol 22:4541–4550,
2004.
Friedmann AM et al. Treatment of unfavorable childhood HD with VEPA and lowdose, involved-field radiation. J Clin Oncol 20:3088–3094, 2002.
References
15.
16.
17.
18.
19.
20.
21.
22.
Weiner MA et al. Randomized study of intensive MOPP-ABVD with or without lowdose total-nodal RT in the treatment of HD in pediatric patients: a POG study. J Clin
Oncol 15:2769–79, 1997.
Fryer CJ et al. Efficacy and toxicity of 12 courses of ABVD chemotherapy followed by
low-dose regional RT in advanced HD in children: a report from the Children’s Cancer
Study Group. J Clin Oncol 8(12):1971–1980, 1990.
Willman KY, Cox RS, Donaldson SS: Radiation induced height impairment in pediatric
HD. IJROBP 28(1): 85–92, 1994.
Constine LS ,et al. Thyroid dysfunction after radiotherapy in children with Hodgkin’s
disease. Cancer 53:878-883, 1984.
Sklar C, et al. Abnormalities of the thyroid in survivors of HD: Data from the
Childhood Cancer Survivor Study. J Clin Endocrinol Metab 85:3227-3232, 2000.
Hancock SL, et al. Factors affecting late mortality from heart disease after
treatment of Hodgkin’s disease. JAMA 270: 1949-1955, 1993.
Hull MC, et al. Valvular dysfunction and carotid, subclavian, and coronary artery
disease in survivors of HD treated with RT. JAMA 290:2831-2837, 2003.
Villani F, et al. Late pulmonary effects in favorable stage I and IIA HD treated
with radiotherapy alone. Am J Clin Oncol 23:18-21, 2000.
References
23. Bhatia S et al. Second cancers after pediatric Hodgkin’s disease. J Clin Oncol
16(7):2570–2572, 1998.
24. Bhatia S, et al. High risk of subsequent neoplasms continues with extended followup of childhood HD: Report from the Late Effects Study Group. J Clin Oncol
21:4386-4394, 2003.
25. Metayer C, et al. Second cancers among long-termsurvivors of Hodgkin’s disease
diagnosed in childhood and adolescence. J Clin Oncol 18:2435-2443, 2000.
26. Travis LB,et al. Cumulative absolute breast cancer risk for young women treated for
Hodgkin lymphoma. J Natl CancerInst 97:1428-1437, 2005.