HODGKIN LYMPHOMA (PEDIATRIC)
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
HODGKIN LYMPHOMA (PEDIATRIC)
Executive Summary
Hodgkin lymphoma (HL) is the most common malignancy among adolescents 15-19 years of
age.1 It is one of the most curable forms of cancer in young people, with estimated 5-year
survival rates exceeding 98%,2 yet long-term overall survival declines primarily from delayed
effects of therapy. This challenge has resulted in the development of various strategies aimed at
identifying the optimal balance between maintaining overall survival and avoidance of long-term
morbidity of therapy, often representing strategies quite different than those used for adults with
HL. The regimens described herein apply to children, adolescents, and young adults. No specific
age categories are given. Please see separate briefing within this application for adults with
Hodgkin Lymphoma.
Pre-treatment evaluation should include plain radiographs of the chest to evaluate for bulky
mediastinal involvement, CT scans of the neck, chest, abdomen and pelvis with IV and oral
contrast, and whole body FDG-PET scan for determination of a clinical stage. Bone marrow
involvement may be ascertained by biopsies or by FDG-PET.
At the core of chemotherapeutic strategies are combinations of vincristine, doxorubicin,
cyclophosphamide and prednisone, with combinations that variably incorporate bleomycin,
etoposide, and dacarbazine across North America and Western Europe.3-12 Assignment of
radiotherapy on the basis of early response to chemotherapy has become a standard across the
different treatment approaches.
For standard risk patients we are recommending AVPC (COG AHOD03P1): (including
doxorubicin, vincristine, prednisone, cyclophosphamide), or OEPA (GPOH 2002): (including
vincristine, etoposide, prednisone, doxorubicin). For patients with intermediate or high-risk
disease we are recommending ABVE-PC (COG AHOD00317; P94255) (including doxorubicin,
bleomycin, vincristine, etoposide, prednisone, cyclophosphamide), or OEPA/COPDac (GPOH
2002)8 (including vincristine, etoposide, prednisone, cyclophosphamide, doxorubicin, and
dacarbazine).
Public Health Relevance
Hodgkin lymphoma (HL) is diagnosed in approximately 1100 children and adolescents under
age 20 years in the USA each year, accounting for 6% of overall childhood cancer diagnoses and
its rank as the most common malignancy among adolescents 15-19 years of age.1
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Requirements for diagnosis, treatment, and monitoring
Diagnostics:
HL is characterized by the presence of multinucleated giant cells (Hodgkin/Reed-Sternberg cells,
H/RS) or large mononuclear cell variants (lymphocytic and histiocytic cells) accounting for
approximately 1% of the cells in a background of inflammatory cells consisting of small
lymphocytes, histiocytes, neutrophils, eosinophils, plasma cells, and fibroblasts. Incisional
lymph node biopsy or several large needle cores are recommended for confirmation of diagnosis,
rather than fine needle aspiration, in order to provide sufficient material for pathologic
interpretation. Use of fine needle aspirates for determination of diagnosis is strongly
discouraged due to the rarity of the H/RS cells and risk of missing the diagnosis. Two broad
pathologic classes exist; classical (cHL) and nodular lymphocyte predominant (NLPHL) and
immunohistochemistry for antigen expression (CD30, CD15, CD20) is used to best distinguish
the types.
Testing:
Physical examination and diagnostic imaging evaluations (upright posteroanterior and lateral
thoracic radiographs; CT of the neck, chest, abdomen, and pelvis with intravenous and oral
contrast; and functional nuclear imaging studies with FDG-PET) are used to designate a clinical
stage. Data from retrospective studies suggests that FDG-PET may replace the need for bone
marrow biopsies in patients with clinical stage III to IV disease or B symptoms, however this has
not been validated prospectively. Staging laparotomy is rarely appropriate with the imaging
modalities available today, but biopsy of specific sites with equivocal findings by clinical staging
should be considered when results will alter therapy. Interim assessment of response by FDGPET is incorporated into contemporary treatment approaches. However, the optimum time point
for assessment and the criteria for response have not been defined. Continued surveillance for
relapse with FDG-PET in the post treatment period is not recommended, due to its low positive
predictive value.
Administration and Care of Patients:
Chemotherapy for HL is given by the IV and oral routes and consists of multiple agents. This
requires careful management of fluid and electrolyte balance as well as prophylactic anti-emetic
therapy and other supportive care measures. All of this is accomplished usually through a central
venous catheter and so should be undertaken only in a specialized cancer center. Radiotherapy
administration also requires special expertise to minimize exposure of normal tissue.
Management of the side effects of chemotherapy in the short term include nausea, vomiting,
mucositis, pancytopenia, and peripheral neuropathy. In the long-term, survivors are at risk for
infertility (notably from cyclophosphamide or procarbazine), cardiomyopathy (especially from
doxorubicin and radiotherapy), restrictive pneumonitis (especially from bleomycin and
radiotherapy), hypothyroidism (from radiotherapy) and second cancers (particularly leukemia
from etoposide and solid tumors in the radiation fields).
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Classical HL. Recent trials (summarized in Tables 1a and 1b) have utilized chemotherapy
regimens of varying dose intensity, and have significant differences in the criteria for omission
of radiotherapy. The European consortium has investigated OEPA (vincristine, etoposide,
prednisone, doxorubicin) for low risk, and OEPA with COPDac (cyclophosphamide, vincristine,
prednisone, dacarbazine) for intermediate and high risk groups. In North America, the Children’s
Oncology Group has primarily evaluated ABVE-PC (doxorubicin, bleomycin, vincristine,
etoposide, prednisone, cyclophosphamide) and its derivatives across the risk groups.5-7,11,12
Radiotherapy usage varies considerably. The Children’s Oncology Group recently reported that
radiotherapy may be safely omitted in intermediate risk patients who have a rapid reduction in
tumor dimensions by CT after 2 cycles of chemotherapy.7 The European consortium has omitted
radiotherapy for low risk patients achieving a CR after 2 cycles of OEPA.8 In general, pediatric
radiotherapy approaches utilize lower doses (15-25Gy) and smaller fields (involved field or
nodes) than in adult patients.3-12
Nodular Lymphocyte Predominant HL. Surgery alone could be considered for completely
resected stage I disease. For stage IIA or incompletely resected stage IA, reduced chemotherapy
with a regimen such as doxorubicin, vincristine, prednisone and cyclophosphamide (AVPC)
could be used based on results from the COG AHOD03P1 trial.12 Radiation can likely be
restricted to only those patients with a less than a complete response after 3 cycles of
chemotherapy. The approach eliminates radiation for >90% of patients. There is an ongoing
EuroNet study evaluating a similar approach with the anthracycline-free regimen of
cyclophosphamide, vinblastine, and prednisone (CVP). As this study is ongoing, we do not yet
have data on this approach.
Overview of Regimens
The following tables include basic information on administration and dosing for the Children’s
Oncology Group and European Consortium regimens, and exclude ancillary medications
pertaining to the management of side effects.
Standard Regimens for Standard Risk Patients
AVPC (COG AHOD03P1): three 21 day cycles12
Doxorubicin
Vincristine
Prednisone
Cyclophosphamide
IV infusion
IV push
PO BID
IV infusion
50 mg/m2
1.4 mg/m2 (maximum 2.8 mg)
20 mg/m2 Days 1-7
800 mg/m2
OR
OEPA (GPOH 2002): two 28 day cycles8
Vincristine
IV push
1.5 mg/m2 (maximum 2 mg) Days 1, 8, 15
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Etoposide
Prednisone
Doxorubicin
IV infusion
PO BID
IV infusion
125 mg/m2 Days 2-6
30 mg/m2 Days 1-15
40 mg/m2 Days 1, 15
Standard Regimens for Intermediate or High Risk Patients
ABVE-PC (COG AHOD00317; P94255):
Four (intermediate risk) or five (high risk) 21 day cycles:
Doxorubicin
IV infusion
25 mg/m2 Days 1,2
Bleomycin
IV infusion
5 units/m2 Day 1
10 units/m2 Day 8
Vincristine
IV push
1.4 mg/m2 (maximum 2.8 mg) Days 1, 8
Etoposide
IV infusion
125 mg/m2 Days 1, 2, 3
Prednisone
PO BID
20 mg/m2 Days 1-7
Cyclophosphamide
IV infusion
800 mg/m2 Day 1
OR
OEPA/COPDac (GPOH 2002)8:
Two 28 day cycles:
Vincristine
Etoposide
Prednisone
Doxorubicin
IV push
IV infusion
BID PO BID
IV infusion
1.5 mg/m2 (maximum 2 mg) Days 1, 8, 15
125 mg/m2 Days 2-6
30 mg/m2 Days 1-15
40 mg/m2 Days 1, 15
Two (intermediate risk) or four (high risk) 28 day cycles:
Cyclophosphamide
IV infusion
500 mg/m2 Days 1 and 8
Vincristine
IV push
1.5 mg/m2 Days 1 and 8 (maximum 2 mg)
Prednisone
PO
40mg/m2
Days 1 to 15
2
Dacarbazine
IV infusion
250 mg/m Days 1 to 3
Review of Benefits and Harms
Survival Benefits
The overall 5 years relative survival for 2002–2008 from the SEER database was 84.7%.
Children and adolescents have significantly better HL-specific survival than adults (5 years
survival rate, 96%±0.4% vs. 88% ± 0.3%, P < 0.001).2 P 4 HODGKIN LYMPHOMA (PEDIATRIC)
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Harms and Toxicity Considerations
Common
Pediatric patients receiving combination chemotherapy for HL will experience significant
hematotoxicity including severe neutropenia increasing risk of infection, as well as high
incidences of anemia and thrombocytopenia. The incidence of serious infection including sepsis
is relatively high, occuring in 8-17% of patients.5,7 Many patients also experience stomatitis and
mucositis from combined therapy.
Vincristine commonly causes neurotoxicity, including sensory and motor neuropathies, which is
typically dose-related. Neurotoxicity is usually reversible, and in the regimens above is typically
mild. A small percentage (up to 2%) of patients receiving intravenous etoposide experience
hypersensitivity reactions, which may include angioedema, bronchospasm, and/or chest
discomfort.13
Serious
Patients should be monitored for symptoms indicating the existence of long-term toxicity,
particularly of heart and lung as well as secondary malignancy. Treatment with bleomycin may
result in late bleomycin-related pulmonary toxicity, therefore, a high index of suspicion is
warranted to allow omission of the bleomycin as early as possible when toxicity occurs.
Doxorubicin is associated with a risk of cardiotoxicity. Development of severe heart failure is
uncommon, however myocardial dysfunction may appear in long-term follow up. In pediatric
patients, the risk of heart failure and pericardial disease increases with cumulative doses
≥250mg/m2.14
Survivors are also at risk of secondary malignancy, associated most commonly with etoposide
and dacarbazine in the regimens above. Though the risk remains small (<3% in pediatric HL
trials listed), patients should be closely monitored for this development.5,7 Survivors are also at
risk for infertility, most notably from cyclosphosphamide.
Systematic Reviews
•
Kelly KM. Management of children with high-risk Hodgkin lymphoma. British Journal of
Haematology, 2012 ;157:3-13.
o Abstract: This review summarizes recent clinical trials in pediatric high risk HL,
along with key findings from studies in adults with high risk HL that are applicable to
the pediatric population. New directions in prognostic classification and targeted
therapies are reviewed. Considerations for clinical practice at the current time outside
the clinical trial setting are provided.
•
Allen CE, Kelly KM, Bollard CM. Pediatric lymphomas and histiocytic disorders of
childhood. Pediatr Clin North Am. 2015 ;62:139-165.
P 5 HODGKIN LYMPHOMA (PEDIATRIC)
Union for International Cancer Control
2014 Review of Cancer Medicines on the WHO List of Essential Medicines
o Abstract: Although there have been dramatic improvements in the treatment of
children with Non-Hodgkin lymphoma, Hodgkin lymphoma and Histiocytic disorders
over the past 3 decades, many still relapse or are refractory to primary therapy. In
addition, late effects such as 2nd malignancies, cardiomyopathy and infertility remain
a major concern. Thus, this review focuses on the current state of the science and, in
particular, novel treatment strategies that are aimed at improving outcomes for all
pediatric patients with lymphoma and histiocytic disorders while reducing treatment
related morbidity.
•
Terezakis SA, Metzger ML, Hodgson DC et al. ACR Appropriateness criteria pediatric
Hodgkin lymphoma. Pediatr Blood Cancer. 2014 ;61:1305-1312.
o Abstract: Pediatric Hodgkin lymphoma is a highly curable malignancy and potential
long-term effects of therapy need to be considered in optimizing clinical care. An
expert panel was convened to reach consensus on the most appropriate approach to
evaluation and treatment of pediatric Hodgkin lymphoma. The American College of
Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical
conditions that are reviewed every 2 years by a multidisciplinary expert panel. The
guideline development and review include an extensive analysis of current medical
literature from peer reviewed journals and the application of a well-established
consensus methodology (modified Delphi) to rate the appropriateness of imaging and
treatment procedures by the panel. In those instances where evidence is lacking or not
definitive, expert opinion may be used to recommend imaging or treatment. Four
clinical variants were developed to assess common clinical scenarios and render
recommendations for evaluation and treatment approaches to pediatric Hodgkin
lymphoma. We provide a summary of the literature as well as numerical ratings with
commentary. By combining available data in published literature and expert medical
opinion, we present a consensus to the approach for management of pediatric
Hodgkin lymphoma.
Recommendations
The reviewers recommend the incorporation of pediatric Hodgkin lymphoma treatment options
into the WHO Model List of Essential Medicines, and recommend specifically that etoposide and
dacarbazine be added for pediatric indications to the core Essential Medicines List.
Medicines proposed for Section 8.2 of the Child EML
Etoposide
Dacarbazine
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References
1. Howlader NNA, Krapcho M, Neyman N, et al. editors. Surveillance Epidemiology and
End Results (SEER) cancer statistics review, 1975–2009 (Vintage 2009 Populations).
Bethesda, MD: National Cancer Institute.
2. Bazzeh F, Rihani R, Howard S, et al. Comparing adult and pediatric Hodgkin lymphoma
in the Surveillance, Epidemiology and End Results program, 1988–2005: An analysis of
21,734 cases. Leuk Lymphoma 2010;51:2198–2207.
3. Wolden SL, Chen L, Kelly KM, et al. Long-term results of CCG 5942: A randomized
comparison of chemotherapy with, without radiotherapy for children with Hodgkin
lymphoma. J Clin Oncol 2012;30:3174–3180.
4. Kelly KM, Sposto R, Hutchinson R, et al. BEACOPP chemotherapy is a highly effective
regimen in children and adolescents with high risk Hodgkin lymphoma: A report from
the Children’s Oncology Group CCG-59704 clinical trial. Blood 2011;117:2596–2603.
5. Schwartz CL, Constine LS, Villaluna D, et al. A risk-adapted, response-based approach
using ABVEPC for children and adolescents with intermediate- and high-risk Hodgkin
lymphoma: The results of P9425. Blood 2009;114:2051–2059.
6. Keller FG, Nachman J, Constine L, et al. A phase III study for the treatment of children
and adolescents with newly diagnosed low risk Hodgkin lymphoma (HL) [abstract]. ASH
Annual Meeting Abstracts 2010; 116: p. 767.
7. Friedman DL, Wolden S, Constine L, et al. Dose-intensive response-based chemotherapy
and radiation therapy for children and adolescents with newly diagnosed intermediate
risk Hodgkin lymphoma: AHOD0031 – A report from the Children’s Oncology Group. J
Clin Oncol. 2014 ;32:3651-3658.
8. Mauz-Ko¨rholz C, Hasenclever D, Do¨rffel W, et al. Procarbazine-free OEPA-COPDAC
chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness
in pediatric Hodgkin’s lymphoma: The GPOH-HD-2002 study. J Clin Oncol
2010;28:3680–3686.
9. Metzger ML, Weinstein HJ, Hudson MM, et al. Association between radiotherapy vs no
radiotherapy based on early response to VAMP chemotherapy, survival among children
with favorable-risk Hodgkin lymphoma. JAMA 2012;307:2609–2616.
10. Metzger M, Billett A, Friedmann AM, et al. Stanford V chemotherapy and involved field
radiotherapy for children and adolescents with unfavorable risk Hodgkin lymphoma:
Results of a multi-institutional prospective clinical trial. J Clin Oncol 2012;30:9502.
11. Tebbi CK, Mendenhall NP, London WB, et al. Response-dependent and reduced
treatment in lower risk Hodgkin lymphoma in children and adolescents, results of P9426:
A report from the Children’s Oncology Group. Pediatr Blood Cancer 2012;59:1259–1265.
12. Appel, B., Chen, L., Hutchinson, R.J., et al. (2014) Treatment of Pediatric Lymphocyte
Predominant Hodgkin Lymphoma (LPHL): A Report from the Children's Oncology
Group. Klin Padiatr, 226, Oral Presentation O-10.
13. Etoposide. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc.
Greenwood Village, CO.
14. Floyd J, Morgan JP. Cardiotoxicity of anthracycline-like chemotherapy agents. In:
UpToDate, Post TW (Ed), UpToDate, Waltham, MA, 2014.
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Table 1a. Results of Recent Trials for Pediatric low-risk HL.
Group
Europe
French
Society of
Pediatric
Oncology
German
Society of
Pediatric
Oncology and
Hematology
Study
n
LR
Definition
Chemotherapy
RT (dose, field)
EFS or DFS,
OS (yr)
MDH90
202
IA, IB, IIA,
IIB
VBVP x 4
(+ OPPA x 1-2 if
PR after cycle 4)
20-40Gy IF
91.1%,
97.5%
(5yr)
GPOH-HD-95
328
IA, IB, IIA
OPPA (female);
OEPA (male) x 2.
CR after cycle 2: no RT
PR after cycle 2: 2030Gy IF
93.2%,
98.8%
(10yr)
GPOH-HD-2002
195
IA, IB, IIA
OPPA (female);
OEPA (male) x 2
CR after cycle 2: no RT
PR after cycle 2: 2030Gy IF
92%,
99.5%
(5yr)
110
IA, IB, IIA,
IIB no
bulk, no E
IA, IIA, <3
nodal
sites, no
bulk, no E
IA, IB, IIA
without
adverse
+
features
VAMP x 4
15 -22.5 Gy IF
VAMP x4
CR after cycle 2: no RT
PR after cycle 2:
25.5Gy IF
89.4%,
96.1%
(10yr)
EFS:
90.8%
(2yr)
COPP/ABV x 4
CR after cycle 4:
randomized to 21Gy
IFRT vs. no RT
PR: 21Gy IF
DBVE x 2-4
(based on
response after
cycle 2)
AV-PC x 3
25.5 Gy IF
North
America
Stanford,
Dana Farber,
St. Jude
consortium
CCG, POG,
and COG
88
CCG 5942
294
P9426
294
IA, IB, IIA,
IIIA
AHOD0431
287
IA, IIA, no
bulk
CR after cycle 3: no RT
PR after cycle 3: 21 Gy
IF
10 yr EFS
IFRT: 100%
no RT: 89.1%
(p=.001)
10 yr OS:
RT: 97.1%
no RT: 95.9%
(p=0.5)
86.2%
97.4%
(8yr)
79.8%
99.6%
(4yr)
P 8 HODGKIN LYMPHOMA (PEDIATRIC)
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Table 1b. Results of Recent Trials for Pediatric Intermediate and High risk HL.
Group
Europe
German
Society of
Pediatric
Oncology and
Hematology
North
America
CCG, POG,
and COG
Study
n
Definition
Chemotherapy
RT (dose, field)
EFS or DFS, OS
(yr)
GPOH-HD95
341
2 OPPA/OEPA + 4
COPP .
CR after cycle 2: no
RT
PR after cycle 2:
20-35Gy IF
84.5%, 93.2%
(10yr)
GPOH-HD2002
Intermediate:
139
High: 239
Intermediate:
IEA/B; IIEA;
IIB; IIIA
High: IIEB;
IIIEA/B; IIIB;
IV
Intermediate:
IEA/B; IIEA;
IIB; IIIA
High: IIEB;
IIIEA/B; IIIB;
IV
OPPA (female);
OEPA (male) x 2
Intermediate:
COPDAC x 2
High:
COPDAC x 4
19.8-35 Gy IF
Intermediate:
88.3%, 99.5%
High:
86.9%, 94.9%
(5yr)
CCG 5942
Intermediate:
394
High: 141
Intermediate;
IA, IB, IIA
with adverse
+
features ; IIB,
III
High: IV
Intermediate:
COPP/ABV x 6
High:
COPP/ABV,
CHOP, Etoposide
/Cytarabine x 2
CR after cycle 6:
randomized to
21Gy IFRT vs. no
RT
PR: 21Gy IF
P9425
Intermediate:
53
High: 163
Intermediate:
IB, IIALMA, IIIA
High: IIB, IIIB,
IV
DBVE-PC x 3-5
(based on
response after
cycle 3)
25.5 Gy IF
Intermediate:
RT: 87%, 95%
No RT: 83%, 100%;
High:
RT: 90%, 100%
No RT: 81%, 94%
(EFS p<.05)
Intermediate:
84%, OS NR
High: 85%, OS NR
(5yr)
C59704
99
IIB/IIIB + bulk,
IV
M RER: 21 Gy IF
F RER: No RT
SER: 21 Gy IF
94%, 97%
(5 yr)
AHOD0031
1712
IA, IIA + bulk,
IB, IIB, IIIA,
IVA
BEACOPPx 4
M RER: ABVD x 2
F RER :
COPP/ABV x 4
SER: BEACOPP x
4
ABVE-PC x 4
SER: Randomized
DECA x 2
Randomized RER
after cycle 2 and
CR after cycle 4: no
RT
All others: 21 Gy IF
85.6%, 98.2% (3 yr)
VBVP: vinblastine, bleomycin, etoposide, prednisone
OPPA: vincristine, procarbazine, prednisone, doxorubicin
OEPA: vincristine, etoposide, prednisone, doxorubicin
VAMP: vinblastine, doxorubicin, methotrexate, prednisone
COPP/ABV: cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine
DBVE: doxorubicin, bleomycin, vincristine, etoposide
AV-PC: doxorubicin, vincristine, prednisone, cyclophosphamide
COPDac: cyclophosphamide, vincristine, prednisone, dacarbazine
CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone
DBVE-PC: doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide
BEACOPP: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, procarbazine
ABVE-PC: doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide
DECA: dexamethasone, etoposide, cisplatin, cytarabine
IF: involved field
RT: radiation therapy
M: male
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F: female
RER: rapid early responder
SER: slow early responder
CR: complete response
PR: partial response
+
adverse features = hilar disease, bulk, ≥4 nodal regions, mediastinal tumor
P 10