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NCCN Clinical Practice Guidelines in Oncology™
Hodgkin Disease/Lymphoma
V.1.2007
www.nccn.org
Hodgkin Disease/Lymphoma
Version 1.2007, 04/23/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Guidelines Index
Hodgkin Disease TOC
Staging, MS, ReferencesNCCN® Practice Guidelines
in Oncology – v.1.2007
NCCN Hodgkin Disease/Lymphoma Panel Members
Richard T. Hoppe, MD/Chair §Stanford
Ranjana Hira Advani, MD †
Stanford Comprehensive Cancer Center
Richard F. Ambinder, PhD, MD
UNMC Eppley Cancer Center at The
Nebraska Medical Center
Clara D. Bloomfield, MDArthur G. James Cancer Hospital &
Richard J. Solove Research Institute at
The Ohio State University
St. Jude Children's Research
Hospital/University of Tennessee Cancer
Institute
Comprehensive Cancer Center
Philip J. Bierman, MD † ‡
†
Francis Buadi, MD † ‡
Benjamin Djulbegovic, MD, PhD † ‡H. Lee Moffitt Cancer Center & Research
Institute at the University of South Florida
†The Sidney Kimmel Comprehensive
Cancer Center at John Hopkins
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Peter M. Mauch, MD §
Russell J. Schilder, MDFox Chase Cancer Center
Lawrence Weiss, MDCity of Hope
Jane N. Winter, MDRobert H. Lurie Comprehensive Cancer
Center of Northwestern University
Joachim Yahalom, MDMemorial Sloan-Kettering Cancer Center
Andrew D. Zelenetz, MD, PhD † ÞMemorial Sloan-Kettering Cancer Center
Dana-Farber/Brigham and Women's
Cancer Center | Massachusetts General
Hospital Cancer Center
Joseph O. Moore, MD †Duke Comprehensive Cancer Center
† ‡
‡
§
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Andres Forero, MD † ‡University of Alabama at Birmingham
Comprehensive Cancer Center
Leo I. Gordon, MD ‡Robert H. Lurie Comprehensive Cancer
Center of Northwestern University
†Roswell Park Cancer Institute
Mark S. Kaminski, MD †University of Michigan Comprehensive
Cancer Center
† ‡
Francisco J. Hernandez-Ilizaliturri, MD
Gena Love ¥New Mexico Department of Health
Comprehensive Cancer Programs
David G. Maloney, MDFred Hutchinson Cancer Research
Center/Seattle Cancer Care Alliance
David Mansur, MDSiteman Cancer Center at Barnes-
Jewish Hospital and Washington
University School of Medicine
* Writing Committee Member
*
§ Radiation oncology
† Medical Oncology
‡ Hematology/Hematology oncology
Bone Marrow Transplantation
Pathology
Þ Internal medicine
¥ Patient Advocacy
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Hodgkin Disease/Lymphoma
Version 1.2007, 04/23/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Guidelines Index
Hodgkin Disease TOC
Staging, MS, ReferencesNCCN® Practice Guidelines
in Oncology – v.1.2007
This manuscript is being
updated to correspond
with the newly updated
algorithm.
These guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinicianseeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances todetermine any patient's care or treatment. The National Comprehensive Cancer Network makes no representations nor warranties of any kindwhatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These guidelines arecopyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced inany form without the express written permission of NCCN. ©2007.
Table of Contents
Primary Treatment
Classical Hodgkin disease:
Nodular Lymphocyte-predominant Hodgkin disease:
NCCN Hodgkin Disease/Lymphoma Panel Members
Principles of Radiation Therapy (HODG-C)
Revised Response Criteria (HODG-D)
Principles of Salvage Chemotherapy (HODG-E)
Guideline Index
Print the Hodgkin Disease/Lymphoma Guidelines
Diagnosis and Workup (HODG-1)
CS IA-IIA (HODG-2)
CS IB-IIB (HODG-3)
CS III-IV (HODG-3)
CS IA-IIA (HODG-4)
CS IB-IIB (HODG-4)
CS IIIA-IVA (HODG-4)
CS IIIB-IVB (HODG-4)
Follow-up After Completion of Treatment and Monitoring For Late Effects (HODG-5)
Relapse (HODG-6)
Unfavorable Factors (localized and advanced disease) (HODG-A)
Principles of Chemotherapy (HODG-B)
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Staging
Manuscript
References
Clinical Trials:
Categories of Consensus:NCCNAll recommendations are Category2A unless otherwise specified.
See
Thebelieves that the best managementfor any cancer patient is in a clinicaltrial. Participation in clinical trials isespecially encouraged.
NCCN
To find clinical trials online at NCCNmember institutions, click here:nccn.org/clinical_trials/physician.html
NCCN Categories of Consensus
Summary of Guidelines Updates
Hodgkin Disease/Lymphoma
Version 1.2007, 04/23/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Guidelines Index
Hodgkin Disease TOC
Staging, MS, ReferencesNCCN® Practice Guidelines
in Oncology – v.1.2007
Summary of the Guidelines updates
UPDATES
Summary of changes in the 1.2007 version of the Hodgkin Disease/Lymphoma guidelines from the 1.2006 version include:
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In the workup of a patient with Hodgkin disease, category 2B was added to PET scan. Fertility counseling was also added
( ).
New treatment algorithms were developed for the management of classical Hodgkin Disease based upon type of chemotherapy
to be administered. The previous "Interim Restaging" pages have been removed. Footnotes g, i, and j are new to these
algorithms ( and ).
Footnote l is new to the page describing chemotherapy for NLPHD ( ).
The following was added to the "Follow-up after Completion of Treatment" - Surveillance PET is not encouraged due to the risk
for false positives. Management decisions should not be based on PET scan alone, clinical or pathological correlation is
needed ( ).
Chest imaging for Monitoring for Late Effects after 5 Years was clarified to "Consider spiral chest CT for patients at increased
risk for lung cancer.” The mammography recommendation was modified to "5"-8 years after initial therapy. The American
Cancer Society recommendation for breast MRI was added ( ).
Consider RT was added as an option after salvage therapy for Initial stage IA-IIA ( ).
Extranodal sites was added as an unfavorable factor for localized presentations.
Footnotes 1 and 4 are new to the page ( ).
The recommended RT dose to bulky sites was changed from 20 to 30 Gy ( ).
Revised Response Criteria for Lymphoma ( ).
HODG-1
HODG-2 HODG-3
HODG-4
HODG-5
HODG-5
HODG-6
HODG-A
HODG-C
HODG-D
Hodgkin Disease/Lymphoma
Version 1.2007, 04/23/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Guidelines Index
Hodgkin Disease TOC
Staging, MS, ReferencesNCCN® Practice Guidelines
in Oncology – v.1.2007
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
DIAGNOSISa WORKUP
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Excisional biopsy
(recommended)
Core needle biopsy may
be adequate if diagnostic
FNA alone is insufficient
Immunohistochemistry
recommended but not
necessary for classical
Hodgkin disease.
For nodular lymphocyte-
predominant Hodgkin
disease, recommend
CD3, CD15, CD20, CD21,
CD30, CD57
For typical classical
Hodgkin disease,
recommend CD3, CD15,
CD20, CD30, CD45
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H&P including:
B symptoms
ETOH intolerance
Pruritus
Fatigue
Performance status
Exam lymphoid regions
Spleen, liver
CBC, differential, platelets
Erythrocyte sedimentation
rate (ESR)
LDH, LFT, albumin
BUN, creatinine
Chest x-ray
Chest/abdominal/pelvic CT
PET scan, especially if
equivocal CT (category 2B)
Adequate bone marrow
biopsy in stage IB-IIB and
stage III-IV
Counseling: Fertility,
smoking cessation,
psychosocial
Pregnancy test: women of
childbearing age
Fertility Counseling
Oophoropexy, if
premenopausal and pelvic
RT contemplated
Semen cryopreservation, if
chemotherapy or pelvic RT
contemplated
Neck CT
Pneumococcal, H-flu,
meningococcal vaccines,
if splenic RT contemplated
HIV, if risk factors, unusual
disease presentations
Evaluation of ejection
fraction (eg, if ABVD or
BEACOPP planned)
Pulmonary functions tests
(PFTs), Diffusion capacity
of the lungs for carbon
monoxide (DLCO) (eg,
ABVD or BEACOPP
planned)
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(
)
Useful in selected cases:
see NCCN Distress
Management Guidelines
HODG-1
a
c
Treatment recommendations for postadolescent Hodgkin disease.
Classical Hodgkin disease (HD) includes nodular sclerosis (NSHD), mixed cellularity (MCHD), lymphocyte-depleted (LDHD) and lymphocyte-rich (LRHD).
bNodular lymphocyte-predominant has a different natural history and response to therapy than does classical Hodgkin disease, especially stages I-II. For thatreason, separate guidelines are presented for NLPHD.
CLINICAL STAGING
See PrimaryTreatment(HODG-2)
See PrimaryTreatment(HODG-4)
Classical
Hodgkin
diseasec
Nodular lymphocyte-
predominant
Hodgkin disease
(NLPHD)b
Stage IA-IIANonbulky
Stage I-II
Bulky
Stage IB-IIB
Nonbulky
and III-IV
See PrimaryTreatment(HODG-2)
See PrimaryTreatment(HODG-3)
Hodgkin Disease/Lymphoma
Version 1.2007, 04/23/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Guidelines Index
Hodgkin Disease TOC
Staging, MS, ReferencesNCCN® Practice Guidelines
in Oncology – v.1.2007
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Chemotherapy + involved-
field RT (category 1)
e
f g
PRIMARY TREATMENThCLINICAL PRESENTATION:Classical Hodgkin diseasec
c
d
e
f
g
i
j
Classical Hodgkin disease (HD) includes nodular sclerosis (NSHD), mixed cellularity(MCHD), lymphocyte-depleted (LDHD) and lymphocyte-rich (LRHD).
Bulky mediastinal disease or mass > 10 cm.
.
ma alonemay be considered for patients not able tolerate chemotherapy chemotherapy alonemay be considered patients .
A corresponding CT scan is always recommended with PET scan.
.Depending upon co-morbidities, subtotal lymphoid irradiation (category 1) or ntleand
for who are not candidates for radiation (category 2B)
hIndividualized treatment may be necessary for older patients and patientswith concomitant disease.
( )see Unfavorable Factors, HODG-A
Principles of Radiation Therapy
See Principles of Chemotherapy (HODG-B)
See (HODG-C).
See Revised Response Criteria for Lymphoma (HODG-D)
CS IA-IIANonbulkyd
HODG-2
2 additional
cycles
Positive
or PR by
PET/CT
j
Negative
or CR by
PET/CT
j
2 additional
cycles
Stage I-II
Bulkyd
Stanford Ve 3 cycles or
12 weeks
If initial disease > 5
cm or spleen
positive, RT (36 Gy
begins optimally
within 3 weeks)
Restage with
PET/CT after
3 months
Progressive
disease or
no change in
PET/CT
j
Follow-up, if
progressive disease,
see belowRestage
with
PET/CTi
Biopsy
Autologous
hematopoietic stem cell
transplant (AHSCT)orIFRTf
Restage
with
PET/CTi
or
See Follow-up HODG-5
ABVD x
4 cycles
e
Restage
with
PET/CTi
Consolidative
RTNegative
PositiveAHSCTorIFRTf
Biopsy
Restage
with
PET/CTi
Negative
or CR by
PET/CT
j Observe
Progressive
diseasejSee Progressive Disease
or Relapse HODG-6
See Follow-up HODG-5
Involved-
field RTfSee Follow-upHODG-5
< CR (not
progressive)
j Observe 2-3
months then
repeat PET PET negative
PET positive See HODG-6
See HODG-5
Negative
or CR by
PET/CT
j
Hodgkin Disease/Lymphoma
Version 1.2007, 04/23/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Guidelines Index
Hodgkin Disease TOC
Staging, MS, ReferencesNCCN® Practice Guidelines
in Oncology – v.1.2007
ABVD x
4 cycles
e Restage
with
PET/CTiPET Positive
Progressive
diseasej
2 additional
cycles
2 more cycles
or
ObserveAdd IFRT for stage I-IIf
BiopsyorIFRTf
2 additional
cycles
ObserveorIFRT (especially for stage I-II
unless contraindicated)
f
Restage
with
PET/CTi
c
e
f
h
i
j
k
Classical Hodgkin disease (HD) includes nodular sclerosis (NSHD), mixedcellularity (MCHD), lymphocyte-depleted (LDHD) and lymphocyte-rich (LRHD).
.
Individualized treatment may be necessary for older patients and patients withconcomitant disease.
A corresponding CT scan is always recommended with PET scan.
.
If there is bulky mediastinal disease on CT after 6 cycles of ABVD,consolidative RT to mediastinum recommended. It is not known in the contextof PET negative whether the outcomes will be altered.
See Principles of Chemotherapy (HODG-B)
See (HODG-C).
See Revised Response Criteria for Lymphoma (HODG-D)
Principles of Radiation Therapy
Stage IB-IIB
Nonbulky
and Stage
IIIA, IIIB and
IV Nonbulky
and Bulky
Stanford Ve 3 cycles or
12 weeks
CR or PRj jRestage with
PET/CT after
3 months
Progressive
disease or
no change in
PET/CT scan
j
Follow-up, if
progressive
disease, see
below
Negativek
Positivek
IFRT to initial sites
> 5 cm or involved
spleen (36 Gy
begins optimally
within 3 weeks)
f
Biopsy
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
CR or
PET negative
j
Restage
with
PET/CTi
Restage
with
PET/CTi
Biopsy AHSCT
or
PRIMARY TREATMENThCLINICAL PRESENTATION:Classical Hodgkin diseasec
HODG-3
AHSCT
AHSCT
See Follow-up HODG-5
Hodgkin Disease/Lymphoma
Version 1.2007, 04/23/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Guidelines Index
Hodgkin Disease TOC
Staging, MS, ReferencesNCCN® Practice Guidelines
in Oncology – v.1.2007
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Involved-field or regional RTorObservation (if patient cannot tolerate RT)
f
PRIMARY TREATMENTCLINICAL PRESENTATION:Nodular lymphocyte-predominant Hodgkin Diseaseb
CS IIA
CS IA
Involved-field or regional RT
Observation (if patient cannot tolerate RT)
f
orChemotherapy + involved-field RT (category 2B)or
l,m f
b
i
j
l
m
Nodular lymphocyte-predominant has a different natural history and responseto therapy than does classical Hodgkin disease, especially stages I-II. For thatreason, separate guidelines are presented for NLPHD.
A corresponding CT scan is always recommended with PET scan.
.
Chemotherapy may be different for NLPHD than for Classical HD. Alkylatingagent based regimens may be preferred.
f .
There are only limited data for combined modality or chemotherapy alone inearly stage LPHD.
See Principles of Radiation Therapy (HODG-C)
See Revised Response Criteria for Lymphoma (HODG-D)
HODG-4
CS I-IIB
CS III-IVA
CS III-IVB
Chemotherapy + involved-field RT (category 2B)m f
Chemotherapy ± RTorRituximab (in selected symptomatic patients who
are not candidates for chemotherapy) (category 2B)
m f
Chemotherapy ± RT
orRituximab (in selected symptomatic patients who are not
candidates for chemotherapy or observation) (category 2B)
m f
orObservation (category 2B)orLocal RT (palliation only)
CR or
PET/CT
negative
j
Observe
Restage
with
PET/CTi
Restage
with
PET/CTi
< CRj
Observe, if
asymptomaticorChemotherapyorRT( )See also HODG-6
CR or
PET/CT
negative
j
Observe
< CRj
Observe, if
asymptomaticorChemotherapyorRT( )See also HODG-6
Hodgkin Disease/Lymphoma
Version 1.2007, 04/23/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Guidelines Index
Hodgkin Disease TOC
Staging, MS, ReferencesNCCN® Practice Guidelines
in Oncology – v.1.2007
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
FOLLOW-UP AFTER COMPLETION OF TREATMENT AND MONITORING FOR LATE EFFECTSn
Follow-up with an oncologist is recommended especially during the first 5 y interval to detect recurrence,
then annually due to the risk of late complications including second cancers and cardiovascular disease.o,p
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Interim H&P:
Every 2-4 mo for 1-2 y, then every 3-6 mo for next 3-5 yConsider annual influenza vaccine especially in high risk
patients (eg, treated with chest RT, bleomycin)
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Laboratory studies:CBC, platelets, ESR, chemistry profile every 2-4 mo for 1-2 y,
then every 3-6 mo for next 3-5 yTSH at least annually if RT to neck
Chest imaging:
Chest x-ray or CT (category 2B for CT) every 3-6 mo during
first 2-3 y, then annually thereafter depending on clinical
circumstancesq
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Abdominal/pelvic CT (category 2B):
Every 3-12 mo for first 2-3 y, then annually up to 5 y
Annual mammographic screening:
Initiate 5-8 y post-therapy, or at age 40, whichever comes first, if
RT above diaphragm
Counseling:
Reproduction, health habits, psychosocial, cardiovascular,
breast self-exam, skin cancer risk, end-of-treatment discussion.
Surveillance PET is not encouraged due to risk for false
positives. Management decisions should not be based on PET
scan alone, clinical or pathological correlation is needed.
See Recurrence(HODG-6)
HODG-5
n
oThe frequency and types of tests may vary depending on clinical circumstances; age and stage at diagnosis, social habits, treatment modality, etc.
Mauch P, Ng A, Aleman B, et al. Report from the Rockefellar Foundation sponsored International Workshop on reducing mortality and improving quality of life in long-term survivors of Hodgkin's disease: July 9-16, 2003, Bellagio, Italy. Eur J Haematol 2005;75(s66).
p
qAppropriate medical management should be instituted for any abnormalities.
Chest imaging optional after 5 y if patient treated with a non-alkylating agent, no RT to the chest and no other risk factors are present.
Follow-up after completion of treatment
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Interim H&P: Annually
Pneumococcal revaccination every 5-7 y, if patient treated
with splenic RT or previous splenectomyMeningococcal + H-flu in selected casesConsider annual influenza vaccine especially in high risk
patients (eg, treated with chest RT, bleomycin)
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Annual blood pressure, serum glucose and lipid screeningBaseline stress test/echocardiogram at 10 y
Laboratory studies:CBC, platelets, ESR, chemistry profile annuallyTSH at least annually if RT to neck
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Chest imaging:
Consider spiral chest CT for patients at increased risk for lung
cancer
Annual mammographic/breast MRI screening:
Initiate 5-8 y post-therapy, or at age 40, whichever comes first, if
RT above diaphragm. The American Cancer Society recommends
breast MRI in addition to mammography.
Counseling:
Reproduction, health habits, psychosocial, cardiovascular, breast
self-exam, skin cancer risk, end-of-treatment discussion.
q
Monitoring for Late Effects after 5 Yearso,p
Hodgkin Disease/Lymphoma
Version 1.2007, 04/23/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Guidelines Index
Hodgkin Disease TOC
Staging, MS, ReferencesNCCN® Practice Guidelines
in Oncology – v.1.2007
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
SALVAGE THERAPY
If primary therapy
was RT alone
Chemotherapy: ABVD
Treat to complete
response + 2 cycles
(6-8 cycles) ±
involved-field RT
(category 2B for RT),
if relapse is outside
original field
If primary therapy
was chemotherapy
aloneor combination
chemotherapy/RTAHSCT (category 1) ±
locoregional RTorCombined modality therapyorChemotherapy
u,v,w
x
x
If initial stage was IA-
IIA:
No prior RT and
failure in initial sites
only
s,t
�
�
�
Appropriate treatment in
this setting has not been
identified, individualized
treatment is recommendedu
Consider RT
Less than
complete
response
Complete
responseFollow-up
AHSCTu,v
r
s
t
u
Patients with NLPHD may be managed according to the same algorithm; however, some patients with NLPHD have a chronic indolent course that may not requireaggressive retreatment. These asymptomatic patients may be observed.
There are no data to support a superior outcome with any modalities.
This applies to patients with relapse, not those with progressive disease.
.
Response is not essential to proceed to AHSCT.
v
w
x
Biopsy especially if plan to treat with high-dose therapy.
Conventional-dose chemotherapy may precede high-dose therapy. Timing of RT may vary.
For select patients with long disease-free interval and other favorable features; selection of chemotherapy should be individualized.
See Principles of Salvage Chemotherapy (HODG-E)
CLASSICAL HODGKIN DISEASE
PROGRESSIVE DISEASE OR RELAPSE
r
Progressive
disease or
Relapse
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Rebiopsy
Restaging (same as
initial work-up,
including bone
marrow biopsy)
Consider cytogenetics
prior to transplant
HODG-6
All others
Hodgkin Disease/Lymphoma
Version 1.2007, 04/23/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Guidelines Index
Hodgkin Disease TOC
Staging, MS, ReferencesNCCN® Practice Guidelines
in Oncology – v.1.2007
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
UNFAVORABLE FACTORS
(advanced disease)2,3,4
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Albumin < 4 g/dL
Hemoglobin < 10.5 g/dL
Male
Age 45 years
Stage IV disease
Leukocytosis (white blood cell
count at least 15,000/mm
Lymphocytopenia (lymphocyte
count less than 8% of white blood
cell count, and/or lymphocyte
count less than 600/mm )
� �
3)
3
1
2
2
4
Only bulky disease is incorporated into the guideline algorithm for localized presentations, however the other factors are considered for assignment into some clinicaltrials.
Derived from Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease: International Prognostic Factors Project on Advanced Hodgkin’s Disease. NEngl J Med 1998;339:1506-1514.
Consider use of dose-escalated BEACOPP if patient has 4 or more risk factors.
The unfavorable factors for advanced disease are not incorporated into the guideline algorithm for stage III-IV, however these factors are considered for assignment intosome clinical trials.
UNFAVORABLE FACTORS
(localized presentations)
1
�
� �
�
�
�
Bulky disease:Mediastinal mass (chest x-ray):
Mediastinal mass greater than 35% of
the thoracic diameter at T5-6
Erythrocyte sedimentation rate 50, if
asymptomatic
> 3 sites
B symptoms
Extranodal sites
�
�
� Any other mass > 10 cm (CT)
Maximum mass width
Maximum intrathoracic
diameter
1
3
HODG-A
Hodgkin Disease/Lymphoma
Version 1.2007, 04/23/07 © 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
Guidelines Index
Hodgkin Disease TOC
Staging, MS, ReferencesNCCN® Practice Guidelines
in Oncology – v.1.2007
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
HODG-B
PRINCIPLES OF CHEMOTHERAPY1
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The most common variants of chemotherapy used at NCCN member institutions include ABVD and Stanford V. Some institutions
will use dose-escalated BEACOPP as an alternative regimen in selected cases for highly unfavorable, high-risk patients, usually
with an International Prognostic Score (IPS) 4.
Stage IA-IIA non-bulky diseaseABVD is generally administered for 4 cycles. Complete restaging takes place at completion of chemotherapy. Consolidative
irradiation follows. If no irradiation is given, but the patient has achieved a CR, two additional cycles of chemotherapy should be
administered.
Stage I-II bulky disease ( )ABVD is generally administered for 4-6 cycles. Complete restaging takes place either after 4 cycles or at the completion of
chemotherapy. Consolidative irradiation follows the completion of chemotherapy.
Stage IB-IIB non-bulky, Stage III-IVABVD is generally administered for 6-8 cycles. Complete restaging takes place after 4-6 cycles of chemotherapy following which
two additional cycles of chemotherapy are administered to patients who have achieved a CR. Patients with bulky disease may
have consolidative RT.
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Stanford V chemotherapy for Stage I-II non-bulky disease is administered for 8 weeks (2 cycles). Complete restaging takes place
at the completion of chemotherapy. Consolidative irradiation is optimally instituted within 3 wks (30 Gy to all involved fields).
Stanford V chemotherapy is administered for 12 weeks (3 cycles). Complete restaging takes place at the completion of
chemotherapy. Consolidative irradiation is optimally instituted within 3 wks (36 Gy to initial sites > 5 cm).
Stanford V chemotherapy is administered for 12 weeks (3 cycles). Complete restaging takes place at the completion of
chemotherapy. Consolidative irradiation is optimally instituted within 3 wks (36 Gy to initial sites > 5 cm and spleen if focal
nodules are present initially).BEACOPP (escalated dose) is administered every 3 weeks. Complete restaging takes place at the end of 4 cycles and at the end
of 8 cycles (completion of chemotherapy). This is followed by 30-40 Gy irradiation to initial sites > 5 cm.
See HODG-A
1Diehl V, Franklin J, Pfreundschuh M et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's Disease.N Engl J Med 2003;348(24):2386-95.
See Principles of Salvage Chemotherapy page HODG-E
Hodgkin Disease/Lymphoma
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Staging, MS, ReferencesNCCN® Practice Guidelines
in Oncology – v.1.2007
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
PRINCIPLES OF RADIATION THERAPY
COMBINED MODALITY-RT DOSES:
�
�
Bulky disease sites (all stages)
If treated with ABVD: 30-36 Gy
If treated with Stanford V: 36 Gy
Nonbulky disease (stage I-II)
If treated with ABVD: 20-30 Gy
If treated with Stanford V: 30 Gy
RT-ALONE DOSES (uncommon scenario):
�
�
Involved regions: 30-44 Gy
Uninvolved regions: 30-36 Gy
1
� When possible, the high cervical regions (all patients) and axillae
(women) should be excluded from the radiation fields.Involved-field:Regional-field:
involved lymphoid region(s) onlyinvolved and immediately adjacent lymphoid regions
RADIATION FIELDS
HODG-C
1The dose of 30 Gy is mainly used for excised NLPHD.
Hodgkin Disease/Lymphoma
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Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
HODG-D
REVISED RESPONSE CRITERIA FOR LYMPHOMA(including PET)
Response Definition
CR
PR
SD
Relapsed
disease or PD
Source: Table 2 from Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J of Clin Oncol 2007;25(5):579-586.Reprinted with permission from the American Society of Clinical Oncology.
Nodal Masses Spleen, Liver Bone Marrow
Disappearance
of all evidence
of disease
Regression of
measurable
disease and no
new sites
Failure to attain
CR/PR or PD
Any new lesion
or increase by
50% of
previously
involved sites
from nadir
�
(a) FDG-avid or PET positive prior
to therapy; mass of any size
permitted if PET negative(b) Variably FDG-avid or PET
negative; regression to normal
size on CT
� 50% decrease in SPD of up to 6
largest dominant masses; no
increase in size of other nodes(a) FDG-avid or PET positive prior
to therapy; one or more PET
positive at previously involved site(b) Variably FDG-avid or PET
negative; regression on CT
(a) FDG-avid or PET positive prior to
therapy; PET positive at prior sites of
disease and no new sites on CT or PET(b) Variably FDG-avid or PET negative; no
change in size of previous lesions on CT
Appearance of a new lesion(s) > 1.5 cm in
any axis, 50% increase in SPD of more
than one node, or 50% increase in
longest diameter of a previously identified
node > 1 cm in short axisLesions PET positive if FDG-avid
lymphoma or PET positive prior to therapy
�
�
Not palpable,
nodules
disappeared
� 50% decrease in
SPD of nodules(for
single nodule in
greatest transverse
diameter); no
increase in size of
liver or spleen
> 50% increase from
nadir in the SPD of
any previous lesions
Infiltrate cleared on repeat
biopsy; if indeterminate by
morphology,
immunohistochemistry
should be negative
Irrelevant if positive prior to
therapy; cell type should be
specified
New or recurrent
involvement
Hodgkin Disease/Lymphoma
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PRINCIPLES OF SALVAGE CHEMOTHERAPY
� The selection of salvage chemotherapy regimens depends on the pattern of relapse and the agents previously used.
Some studies suggest that late relapses (selected patients) can be successfully treated with the same regimen used for initial
remission induction with favorable results if a second CR is achieved.Induction failures and early relapses will require chemotherapy regimens composed of agents not previously used before
treatment with high-dose chemotherapy with stem-cell rescue. Some of the regimens previously evaluated are: Mini-BEAM,
MINE, VIM-D, and EVA .Some studies have suggested that patients with minimal disease burden at relapse (not refractory) may not need additional
treatment prior to high-dose chemotherapy with stem-cell rescue. However, patients tend to have an improved outcome when
transplanted in a minimal disease state. Thus, cytoreduction with chemotherapy (see above) before high-dose chemotherapy
with stem-cell rescue may be beneficial. In addition, salvage chemotherapy serves as a test for drug sensitivity and to facilitate
the harvest of stem cells.Some studies suggest that nitrogen mustard, procarbazine, carmustine, and melphalan may adversely affect both quality and
quantity of stem-cell collection.
�
�
�
�
�
Examples of salvage chemotherapy prior to transplant include ICE (ifosfamide, carboplatin, etoposide), DHAP (dexamethasone,
cisplatin, high-dose cytarabine), ESHAP (etoposide, methylprednisolone, high-dose cytarabine and cisplatin).
1,2
3
4 5 6
7,8,9
10
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
1
2
3
4
5
6
7
8
9
10
Bonfante V, Santoro A, Viviani S, et al. Outcome of patients with Hodgkin's disease failing after primary MOPP-ABVD. J Clin Oncol 1997;15: 528-534.
Longo DL, Duffey PL, Young RC, et al. Conventional -dose salvage combination chemotherapy in patients relapsing with Hodgkin's disease after combinationchemotherapy: The low probability for cure. J Clin Oncol 1992;10:210-218).
Colwill R, Crump M, Couture F, et al. Mini-BEAM as salvage therapy for relapsed or refractory Hodgkin's disease before intensive therapy and autologous bone marrowtransplantation. J Clin Oncol 1995;13:396-402.
Ferme C, Bastion Y, Lepage E, et al. The MINE regimen as intensive salvage chemotherapy for relapsed or refractory Hodgkin's disease. Ann Oncol 1995;6(6):543-9.
Phillips JK, Spearing RL, Davies JM, et al. VIM-D salvage chemotherapy in Hodgkin's disease. Cancer Chemother Pharmacol 1990;27(2):161-3
Canellos GP, Petroni GR, Barcos M, et al. Etoposide, vinblastine and doxorubicin: An active regimen for the treatment of Hodgkin's disease in relapse following MOPP.J Clin Oncol 1995;13:2005-2011.
Sweetenham JW, Taghipour G, Milligan D, et al. High-dose therapy and autologous stem cell rescue for patients with Hodgkin's disease in first relapse afterchemotherapy: results from the EBMT. Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. 1997;20(9):745-52.
Bierman PJ, Anderson JR, Freeman MB, et al. High-dose chemotherapy followed by autologous hematopoietic rescue for Hodgkin's disease patients following firstrelapse after chemotherapy. (2) .
Chopra R, McMillan AK, Linch DC, et al. The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin's disease. A single-center eight-year study of 155 patients. .
Stewart DA, Guo D, Gluck S, et al. Double high-dose therapy for Hodgkin's disease with dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP) prior tohigh-dose melphalan and autologous stem cell transplantation. Bone Marrow Transplant 2000;26(4):383-8.
Ann Oncol 1996;7 :151-6
Blood 1993;81:1137-45
HODG-E
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Table 1
Definitions of Stages in Hodgkin's Disease
Stage I
Stage II
Stage III
Stage IV
Involvement of a single lymph node region (I) or localized involvement of a single
extralymphatic organ or site (I ).
Involvement of two or more lymph node regions on the same side of the diaphragm (II)
or localized involvement of a single associated extralymphatic organ or site and its regional
lymph node(s), with or without involvement of other lymph node regions on the same side of
the diaphragm (II ).
Note: The number of lymph node regions involved may be indicated by a subscript (e.g. II ).
Involvement of lymph node regions on both sides of the diaphragm (III), which may
also be accompanied by localized involvement of an associated extralymphatic organ or site
(IIIE), by involvement of the spleen (III ), or by both (III ).
Disseminated (multifocal) involvement of one or more extralymphatic organs, with or
without associated lymph node involvement, or isolated extralymphatic organ involvement with
distant (nonregional) nodal involvement.
A No systemic symptoms present
B Unexplained fevers >38 C; drenching night sweats; or weight loss >10% of body weight
E
E
3
S E+S
Adapted from Carbone PP, Kaplan HS, Musshoff K et al. Report of the Committee on Hodgkin's Disease Staging
Classification. Cancer Res 1971;31(11):1860-1.
Staging
ST-1
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Manuscriptupdate inprogress
This manuscript is being updated to correspondwith the newly updated algorithm.
Manuscript
NCCN Categories of Consensus
Overview
Category 1
Category 2A
Category 2B
Category 3
All recommendations are category 2A unless otherwise noted.
: There is uniform NCCN consensus, based on high-level
evidence, that the recommendation is appropriate.
: There is uniform NCCN consensus, based on lower-
level evidence including clinical experience, that the
recommendation is appropriate.
: There is nonuniform NCCN consensus (but no major
disagreement), based on lower-level evidence including clinical
experience, that the recommendation is appropriate.
: There is major NCCN disagreement that the
recommendation is appropriate.
National statistics demonstrate improvement in the 5-year survival
rates of patients with Hodgkin disease (HD). Such an improvement is
unmatched in any other cancer over the past four decades. There will
be 7,350 new cases and 1,410 estimated deaths in 2005 in the United
States alone. Provided that the proper therapy is selected and appro-
priately administered, the newly diagnosed patient has an overwhelm-
ing likelihood of being cured. In fact, cure rates for Hodgkin disease
have increased to such an extent that the overriding treatment consid-
erations often relate to long-term toxicity, especially for patients with
early- or intermediate-stage disease . For advanced disease,
clinical trials still emphasize improvement in cure rates, but the poten-
tial long-term effects of treatments remain an important consideration.
The NCCN guidelines for HD focus exclusively on patients from
post-adolescence through the seventh decade of life who do not
have serious intercurrent disease. These guidelines do not address
HD in pediatric or elderly patients or in patients with unusual
situations, such as HIV-positive or pregnant patients. Individualized
treatment may be necessary for these patients, older patients, and
patients with concomitant disease.
The guidelines begin with the diagnosis and workup of HD. The
WHO classification divides HD into two main types: classical HD and
nodular lymphocyte-predominant HD (NLPHD). Classical HD
includes nodular sclerosis (NSHD), mixed cellularity (MCHD),
lymphocyte-depleted (LDHD), and lymphocyte-rich (LRHD).
The discussion of clinical management issues starts with classical
HD (stages I-IV, nonbulky and bulky). Next, the guidelines discuss
nodular lymphocyte-predominant disease (stages I-IV). The
discussion then considers interim and end of treatment restaging,
follow-up strategies, and management of disease relapse.
In general, these guidelines emphasize the use of combined
modality therapy (abbreviated chemotherapy and limited irradiation)
in early stage nonbulky disease; combined modality therapy for the
intermediate-prognosis patients (bulky mediastinal stage II disease);
and systemic treatment with or without local field irradiation for
patients with stage III-IV disease. Consistent with NCCN philosophy,
participation in clinical trials is always encouraged.
Radiation oncologists who participated in the development of the HD
guidelines have somewhat divergent views, which are reflected in a
broad range of radiation doses for specific clinical situations and
combined modality therapy. For radiation therapy (RT) alone, which
1
2
Radiation Therapy Doses
( )Table 1
MS-1
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is not commonly used, the range of recommended doses is 30 to 44
Gy to involved regions and 30 to 36 Gy to uninvolved sites. The
dose of 30 Gy is primarily used for excised NLPHD.
In combined modality therapy dose ranges are determined by
whether the disease is bulky or nonbulky. For patients with stages I-
IV bulky disease, a radiation dose of 20 to 36 Gy is recommended
even after they have received a full course of chemotherapy. This
recommendation reflects limited experience with the use of lower
doses in this setting. In the absence of bulky disease in patients with
stage I-IV the radiation dose could be reduced to 20 to 30 Gy. This
recommendation is based on the range of experience and practice
across NCCN institutions.
Unfavorable prognostic factors in early stage disease influence the
management guidelines. The mediastinal mass ratio identifies
patients who have a poor prognosis when treated with single-
modality therapy. A recommended measurement of mediastinal bulk
is the ratio of the maximum width of the mediastinal mass on chest
x-ray to the maximum intrathoracic diameter. A ratio exceeding one
third is unfavorable. Alternatively, mediastinal bulky disease may be
defined as greater than 35% of the thoracic diameter at the T5-T6
interspace. Another measurement of bulk is any mass greater than
10 cm, which occurs only rarely outside the mediastinum.
An erythrocyte sedimentation rate (ESR) of 50 or more is also
considered unfavorable. This is based largely on European
Organization for Research and Treatment of Cancer (EORTC) data
and the definition of unfavorable prognostic groups for their trials.
Another EORTC report analyzing prognostic factors in early stage
HD identified a poor prognostic group as having more than three
sites of disease. “B” symptoms are also considered an unfavorable
factor in patients with localized HD. The guidelines include flexibility
with respect to how the ESR or number of disease sites impacts
management.
An international collaborative effort evaluating more than 5,000
cases of advanced HD identified seven adverse prognostic factors,
each of which reduces survival rates by 7% to 8% per year. These
factors are 1) age of 45 years or older, 2) male gender, 3) stage IV
disease, 4) albumin level below 4 g/dL, 5) hemoglobin level below
10.5 g/dL, 6) white blood cell count above 15,000/mm , and 7)
lymphocytopenia (lymphocyte count below 600/mm or less than 8%
of the total white count). The number of unfavorable factors helps to
determine clinical management and predict prognosis. For instance,
if the patient has more than four unfavorable factors and advanced
disease, the use of dose-escalated BEACOPP (bleomycin,
etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine,
and prednisone) regimen may be considered as a treatment option.
Fine needle aspiration (FNA) alone is insufficient for diagnosis. Core
needle biopsy may be adequate, but the panel recommends
excisional nodal biopsy. Immunohistochemistry is recommended but
not necessary for classical HD. Immunostaining for CD15, CD30,
CD3, CD20, and CD45 is recommended for classical HD. For
nodular lymphocyte-predominant HD, the guidelines recommend
staining for CD20, CD57, CD15, CD30, CD3, and CD21.
The workup should include a thorough history and physical
examination such as “B” symptoms, EtOH intolerance, pruritus,
fatigue, patient performance status, and examination of the
lymphoid regions, spleen and liver. Standard laboratory testing
Unfavorable Factors
3
4
5
6
3
3
2
Diagnosis and Workup
MS-2
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should include a complete blood count (CBC), differential, platelets,
erythrocyte sedimentation rate (ESR), serum lactate dehydrogenase
(LDH) level, albumin, and liver and renal function tests. Chest x-ray
and chest/abdominopelvic computerized tomographic (CT) scans
are appropriate imaging studies. If the CT scan is equivocal,
positron emission tomography (PET) imaging is helpful in defining
the extent of disease. Data show that PET imaging has a high
sensitivity compared to CT in detection of both nodal disease and
organ involvement. Adequate bone marrow biopsy should be
performed on patients who have stage IB-IIB disease or higher.
Other tests should be based on specific symptoms or abnormalities
on the standard staging studies.
Additional information is useful in selected cases. Pregnancy test
should be done for women of childbearing age before treatment. For
patients with risk factors for HIV or unusual disease presentations,
an HIV test is needed. If chemotherapy or pelvic RT is contemplated
in male patients, semen cryopreservation should be done. For
premenopausal female patients, if pelvic RT is planned,
oophoropexy should be performed. In addition, a neck CT scan is
recommended in selected patients. Pulmonary functions tests
(PFTs), diffusion capacity of the lungs for carbon monoxide (DLCO),
and evaluation of ejection fraction are also useful if patients are
going to get ABVD (doxorubicin, bleomycin, vinblastine, and
dacarbazine) or BEACOPP therapy.
If splenic RT is contemplated, pneumococcal vaccine, H-flu vaccine,
and meningococcal vaccine are recommended.
The guidelines begin with consideration of classical HD. Nodular
lymphocyte predominant HD (NLPHD) has a different natural history
and response to therapy than does classical HD, especially stages I-
II. For that reason, NLPHD is addressed separately.
The guidelines stratify classical HD according to the presence of
bulky disease. For patients with nonbulky disease, the preferred
treatment is combined modality therapy. An example is
chemotherapy such as four cycles of ABVD with involved-field
irradiation (20-30Gy) (category 1). Highly selected patients who
cannot tolerate chemotherapy may be treated with RT alone, which
should include sequential treatment to the mantle and paraortic-
spleen fields (category 1) or Mantle field irradiation alone (category
2B). For highly selected patients where RT is contraindicated,
chemotherapy alone is also a treatment option (category 2B).
For patients who have bulky disease, which is almost always
mediastinal, the panel recommends routine combined modality
therapy, beginning with chemotherapy, and followed by limited
radiation. Generally, irradiation of the mediastinum, including
contiguous sites of bulky involvement and bilateral supraclavicular
areas, is sufficient. The usual dose is 30 to 36 Gy. Minimal disease
(less than 5 cm) outside that field may be left unirradiated if a full
course of chemotherapy has been administered.
The chemotherapy that NCCN panelists recommend for early stage
disease is ABVD for 4 cycles or Stanford V (mechlorethamine,
7
8,9
Clinical Management
Stage I-IIA
Classical Hodgkin Disease/Lymphoma
MS-3
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doxorubicin, etoposide, vincristine, vinblastine, bleomycin, and
prednisone) regimen for 8 weeks (2 cycles).
Complete restaging takes place at completion of chemotherapy if 4
cycles of ABVD are planned and after 4 cycles if 6 cycles are
planned. Consolidative irradiation follows. If no irradiation is given,
but the patient has achieved a complete remission (CR) or CRu
(complete remission uncertain), 2 additional cycles of chemotherapy
should be administered.
If Stanford V regimen is being used, complete restaging takes place
at the completion of chemotherapy (2 cycles). Consolidative irradia-
tion is optimally instituted within 3 weeks (30 Gy to all involved fields).
Clinical stage IB HD is uncommon, but occasional patients present
with stage IIB disease. The treatment recommended for patients
with nonbulky stage I-IIB disease is combined chemotherapy plus
RT to the involved nodal regions (category 1). Some panel members
feel that chemotherapy alone is an appropriate management option
for highly selected patients where RT is contraindicated; however,
differences of opinion exist among the panelists regarding its
suitability (category 2B).
Patients who have stage IIB disease with bulky mediastinal
involvement should be treated with chemotherapy plus involved-field
RT. Whenever possible, the high cervical regions (all patients) and
axillae (women) should be excluded from the radiation fields.
ABVD is generally administered for 4-6 cycles and the Stanford V
chemotherapy is administered for 12 weeks (3 cycles). Complete
restaging takes place at the completion of chemotherapy.
Consolidative irradiation is optimally instituted within 3 weeks (36
Gy to initial sites >5 cm).
Interim restaging of stage I-II patients should be conducted
following 4 cycles of chemotherapy, or at the end of chemotherapy if
less than 4 cycles of chemotherapy or combined modality therapy is
planned. All previous positive imaging studies need to be repeated.
If a CR or CRu is confirmed, completion of therapy is recommended.
Patients with response less than CRu should undergo a PET scan.
Positive results with either CRu or response less than CRu indicate
the need for additional chemotherapy, RT, or high-dose therapy
individualized according to sites of disease. However, completion of
planned therapy is recommended if the PET scan results are
negative. If disease is progressive or there is no response to current
therapy, a biopsy (may be a core needle biopsy) is strongly
recommended to confirm the diagnosis, and a subsequent
autologous hematopoietic stem cell transplant (AHSCT) with or
without locoregional RT is recommended.
The gold standard of chemotherapy treatment for HD is ABVD. A
randomized trial by the Cancer and Leukemia Group B (CALGB)
showed that ABVD-containing regimens (ABVD alone or alternating
MOPP/ABVD) were superior to MOPP alone. Some concern exists
regarding using ABVD in combination with full-dose irradiation of the
mediastinum because of potential overlapping toxicity of doxorubicin
and bleomycin with radiation.
On the basis of experience at the NCCN institutions, the Stanford V
regimen is also considered an acceptable drug combination for
advanced disease. This is a brief (12 weeks) intensive
chemotherapy regimen that includes mechlorethamine, doxorubicin,
etoposide, vincristine, vinblastine, bleomycin, and prednisone.
Although the regimen is dose intensive, the cumulative doses of
such drugs as mechlorethamine, doxorubicin, and bleomycin are
Stage I-IIB
Choice of Chemotherapy in Advanced Disease
10
11-13
MS-4
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significantly less than those in MOPP, ABVD, alternating, or hybrid
regimens, thereby reducing the risks of infertility, secondary
neoplasms, and cardiac and pulmonary toxicity. An integral part of
the treatment program is the incorporation of irradiation (36 Gy) to
initial sites >5 cm and spleen, if involved, after completion of
chemotherapy. This has been a very successful therapy and has
been introduced in the management of advanced disease (stage III-
IV and bulky stage II) in the E2496 intergroup trial.
Some NCCN institutions use dose-escalated BEACOPP regimen as
an alternative in selected cases for high-risk patients with an
International Prognostic Score (IPS 4). This regimen was
developed to improve treatment results by both dose and time
intensification. Results suggest that BEACOPP is a promising
treatment option for advanced HD.
Patients who present with stage III-IV disease may have any
histologic subtype. The primary treatment is chemotherapy alone
(eg, ABVD), as outlined above, or chemotherapy with RT (ie,
Stanford V). The guidelines do not include an option for high-dose
therapy "up front" for these patients. Two recent European trials
failed to show an advantage for high-dose therapy for patients
presenting with various combinations of unfavorable prognostic
factors. Systemic symptoms, age 40 years old, bulky mediastinal
involvement, elevated ESR, high serum LDH level, multiple
extranodal sites, and low hematocrit were defined as unfavorable
factors in this study.
The general concept is to restage patients whose studies are
positive at the outset. This restaging should be completed at certain
defined intervals, in keeping with the management philosophy of still
giving additional chemotherapy beyond the point of restaging, even
if the patient has a complete response.
Using ABVD or BEACOPP as an example, four cycles of
chemotherapy would be administered, followed by restaging. If a
complete response or CRu has occurred, two more cycles of ABVD
would be administered followed by, in selected cases, RT (20-36 Gy)
to bulky sites. If BEACOPP is being used, four additional cycles are
recommended. A final restaging, to confirm the stability of any minor
abnormalities, would follow the completion of chemotherapy.
Treatment would then be discontinued after a total of six cycles of
ABVD or 8 cycles of BEACOPP. For patients achieving response
less than CRu or if CRu is associated with a positive PET scan, 2
additional cycles of ABVD (maximum total of 6 cycles) or 4
additional cycles of BEACOPP (total of 8 cycles), if BEACOPP is
being used, may be considered.
If complete response or CRu is then achieved, an additional two
cycles of ABVD chemotherapy (maximum total of 8 cycles) is
completed. RT (20-36 Gy) to bulky sites may then be administered.
If BEACOPP was administered, RT (30-40 Gy) is then delivered to
initial sites of disease >5 cm. Both the Southwest Oncology Group
(SWOG) study of MOPP-BAP (bleomycin, doxorubicin, and
procarbazine) with or without radiation and the EORTC-GPMC trial
of MOPP/ABV with or without radiation routinely irradiated patients
who had achieved less than complete responses. A significant
proportion of those patients then achieved complete responses.
For patients with response less than CRu or those who has CRu
with a positive PET scan after interim restaging and no change after
secondary restaging, additional therapy, that is individualized
according to the sites of disease, is recommended. Therapy may
include secondary chemotherapy, RT, or high-dose therapy. Biopsy
≥
≥
6,14
14
15
16
Stage III-IV
MS-5
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should be performed if a patient is to be treated with high-dose
therapy.
If the Stanford V regimen is being used, restaging should be done
after the completion of chemotherapy. Radiation therapy (36Gy) to
initial sites (>5 cm) and macroscopic splenic disease should then be
administered.
Another issue relates to the use of consolidative low-dose irradiation to
all sites of disease following the completion of chemotherapy for
patients with stage III-IV HD. The SWOG randomized trial showed no
improvement in overall survival rates for those patients who received
irradiation, but the disease-free interval was prolonged, especially for
patients with bulky NSHD. The EORTC 20884 trial similarly showed
no improvement in survival or freedom from relapse for patients treated
with 25 Gy involved-field irradiation following completion of 8 cycles of
MOPP-ABV. One remaining issue, the role of consolidative irradiation
for stage III-IV disease with a “bulky” component, is being addressed in
a randomized trial of the German Hodgkin's Study Group (GHSG).
In the presence of truly progressive or no response disease, which
is very uncommon, a core needle biopsy may be warranted (if only
to confirm the diagnosis is truly HD), followed by high-dose salvage
regimens with or without locoregional RT, and autologous
hematopoietic stem cell transplant (AHSCT). Although the prognosis
in such cases is poor, and the efficacy of high-dose therapy in this
setting is not as good as in the setting of "minimal residual disease,"
this remains the best treatment option for these patients.
Nodular lymphocyte-predominant HD comprises about 4-5% of all
HD. Treatment choices for NLPHD are based on clinical stage and
presentation. For clinical stage IA, involved-field or regional RT
alone is recommended. Patients with stage IIA disease may also be
treated with involved-field or regional RT. However, some NCCN
panelists believe that chemotherapy plus involved-field radiation is
also appropriate in these cases (category 2B). For stage IA and IIA,
observation may be considered if the patient cannot tolerate RT.
Observation (category 2B) or chemotherapy with or without RT is an
appropriate option for asymptomatic patients with clinical stage III-
IVA NLPHD disease. Local RT alone is also an appropriate
treatment option for palliation purposes in this group of patients.
Rituximab is an option in selected symptomatic patients who are not
candidates for chemotherapy in patients with clinical stage III-IV
NLPHD (category 2B).
The end-of-treatment restaging occurs after an earlier restaging
process and should be performed 3 months after completion of
treatment. The treatment options are similar to those at the time of
initial restaging. Additional follow-up after completion of treatment is
recommended for patients with complete response or CRu.
Patients with response less than CRu require a PET scan. For
patients with either Cru or response less than CRu and a positive
PET scan, biopsy is recommended if lymph node is easily
accessible. In case of positive biopsy results, additional therapy
(salvage CT, RT, or high-dose therapy) that is individualized
according to the sites of disease and initial therapy, is
recommended. If lymph node is not easily accessible for biopsy,
observation is recommended until disease progression. If the PET
scan is negative, the patient may be observed.
17
2
Nodular Lymphocyte-Predominant Hodgkin Disease
End of Treatment Restaging
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A patient with progressive disease that is confirmed by a positive
biopsy will likely go on to AHSCT with or without locoregional RT.
The guidelines for follow-up are based largely on NCCN panelists'
own clinical practices and are not supported by high-level
evidence. Interim physical examinations and blood work (including
CBC, platelets, ESR, and chemistry profile) are performed less
frequently as the length of time in between follow-ups increases,
but the examinations and laboratory tests are continued annually
after 5 years.
Interim evaluations should include consideration of pneumococcal
revaccination every 5-7 years especially if the patient has been
treated with splenic RT or had a splenectomy in the past. High-risk
patients (eg, treated with bleomycin, chest RT) should also be
considered for annual influenza vaccinations. Meningococcal and
H-flu revaccination can be considered in selected cases.
Patients who have had neck or upper mediastinal irradiation
should undergo thyroid function studies at least annually to rule
out hypothyroidism.
The panel overwhelmingly agrees that given the long-term risks of
the therapies for HD, patients should be followed by oncologists
who are aware of these risks and complications especially during
the first 5-year interval then annually due to the risk of late
complications including secondary cancers and cardiovascular
disease.
Repeat imaging studies of initially involved sites are important, as
are surveillance studies of both the chest and abdomen. Chest x-
ray or CT (category 2B for CT) should be performed every 3-6
months during the first 2-3 years, then annually depending on
clinical circumstances. Chest imaging is optional after 5 years if
the patient was treated with a non-alkylating agent, did not have
RT and no other risk factors (eg, smoking) are present.
Abdominal/pelvic CT (category 2B) is monitored every 3-12
months for the first 2-3 years, then annually up to 5 years. The
frequency and types of tests may vary depending on clinical
circumstances: age and stage at diagnosis, social habits,
treatment modality, etc.
The panel recommends that women who have been irradiated
above the diaphragm undergo routine annual mammography
beginning no later than 8 years after completion of therapy, or at
age 40, whichever occurs earlier. Counseling regarding self-breast
examination should also be provided.
The NCCN HD panel members agrees, based upon available data
on increased long-term risk of cardiac disease, to recommend
resting and stress echocardiography annually after 10 years from
treatment.
In addition to the follow-up measures outlined above, the panel
believes counseling about the issues of the survivorship period,
including long-term treatment effects, risks of second primary
tumors, cardiac disease, skin cancer, and reproduction must be an
integral part of follow-up for HD patients. Health habits and
psychosocial issues should also be discussed with a patient.
Patients with classical HD that relapses should undergo biopsy
and restaging. Restaging procedure should include bone marrow
biopsy. Cytogenetics may be considered if bone marrow
Follow-up after Completion of Treatment and Monitoring for LateEffects
Relapse
18
18
18,19
18
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MS-8
transplantation is planned. Only in rare instances is relapse
documented on clinical grounds alone. The management of relapse
will depend on whether the primary treatment was radiation alone or
included a systemic component, such as chemotherapy or combined
modality therapy.
Patients with NLPHD may be managed according to the same
algorithm. However, some patients with NLPHD have a chronic
indolent course that may not require aggressive retreatment. These
asymptomatic patients may be observed.
Patients with classical HD whose initial treatment consisted of
radiation alone have very effective salvage potential when a
standard course of chemotherapy with or without RT is administered
(category 2B for RT), especially if the failure is outside of the initial
radiation field. Patients who achieve less than a complete
response may be candidates for high-dose therapy.
For patients treated initially with chemotherapy or combined
modality therapy, the algorithm is a bit more complicated and
therapy is more likely to be individualized. Appropriate treatment has
not been identified for patients with initial stage IA to IIA disease,
who received chemotherapy alone, and experienced failure at the
initial sites. The panel recommends an individualized approach in
this situation. For all other settings the panel recommends AHSCT
(category 1) with or without locoregional RT. Combined modality
therapy, or chemotherapy may be used for selected patients with
long disease-free interval and other favorable features.
Chemotherapy regimens should be individualized in this case.
Examples of salvage chemotherapy regimens prior to transplant
include ICE (ifosfamide, carboplatin, and etoposide), DHAP
(dexamethasone, cisplatin, high-dose cytarabine), ESHAP
(etoposide, methylprednisolone, high-dose cytarabine).
The management of HD continues to evolve. Major changes have
been incorporated into the NCCN guidelines since their inception.
Current management programs are based on comprehensive
clinical staging followed by combined modality therapy for those
patients with favorable and intermediate prognosis or chemotherapy
alone for patients with advanced disease. Relapse is uncommon,
but secondary management with peripheral stem cell transplant may
be very effective. The excellent prognosis for these patients man-
dates careful long-term follow-up to detect late treatment effects.
At the beginning of each panel meeting to develop NCCN guide-
lines, panel members disclosed financial support they have received
in the form of research support, advisory committee membership, or
speakers' bureau participation. Members of the panel indicated that
they have received support from the following: Albuquerque Area
Indian Health Board, Amgen, Biogen IDEC, Bristol-Myers Squibb,
Cancer Services of New Mexico, Genentech, Genitope Corporation,
GlaxoSmithKline, Lymphoma Research Foundation, Millennium,
NCI, National Initiative for Lymphoma Education, NIH, Novartis,
Oncomed, Ortho Biotech, Roche, and Tibotec.
Some panel members do not accept any support from industry. The
panel did not regard any potential conflicts of interest as sufficient
reason to disallow participation in panel deliberations by any
member.
Salvage Therapy
Summary
Disclosures for the NCCN Hodgkin Disease/LymphomaGuidelines Panel
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Guidelines Index
Hodgkin Disease TOC
Staging, MS, ReferencesNCCN® Practice Guidelines
in Oncology – v.1.2007
Manuscriptupdate inprogress
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