Author: George P Canellos, MD

Section Editor: Arnold S Freedman, MD

Deputy Editor: Alan G Rosmarin, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2018. | This topic last updated: Nov 29, 2016.

INTRODUCTION — The treatment of patients with Hodgkin lymphoma (HL, formerly called Hodgkin's disease) is
primarily guided by the clinical stage of disease as determined by the Cotswolds classification (table 1). This
staging system is important in determining not only prognosis and treatment, but is also important for the
comparison of results obtained with different types of treatment in different studies. (See "Staging and
prognosis of Hodgkin lymphoma".)

This topic will provide a brief review of the selection of treatment based upon disease stage. The initial
evaluation, diagnosis, and staging of patients with HL are discussed separately, as is a more detailed
description of treatment selection for patients with early or advanced stage HL. This topic reviews classical HL.
The rare subtype of nodular lymphocyte predominant Hodgkin lymphoma is presented separately. (See "Initial
evaluation and diagnosis of classic Hodgkin lymphoma in adults" and "Staging and prognosis of Hodgkin
lymphoma" and "Epidemiology, pathologic features, and diagnosis of classic Hodgkin lymphoma" and
"Treatment of nodular lymphocyte-predominant Hodgkin lymphoma".)

OVERVIEW OF SELECTION OF THERAPY — Over the past century, HL has been converted from a uniformly fatal
disease to one that is curable in approximately 75 percent of patients worldwide. While the majority of patients
will be cured of their lymphoma, treatment-related toxicities have become a competing cause of late mortality.
As such, the selection of therapy must balance the desire to maintain a high rate of cure and the need to
minimize long-term complications. Treatment has evolved such that patients with early stage disease can
achieve long term remission with less intensive therapy, while more intensive therapy is reserved for patients
with advanced stage disease. Despite agreement that therapy should be tailored to the stage of disease, there
is some disagreement regarding what should constitute intensive and less intensive therapy.

The endpoint of many clinical trials is freedom from recurrence. Although in many studies an increased relapse
risk in one treatment arm does not translate into a survival difference, survival differences are often seen in the
following situations:

● A large difference in number of recurrences seen

● Very long follow-up

● Studies with large numbers of patients (eg, Cochrane analysis)

This suggests that in many of the trials where a difference in recurrence is seen, the number of patients or the
length of follow-up is inadequate to see a survival difference. In addition, when recurrences are seen, the
potential toxicity of treatment is much greater than that seen with initial therapy.

The successful management of patients with HL requires close attention to details of the staging and
treatment protocols to achieve these results, while minimizing the potential serious toxicities of therapy. Some
of the serious effects of therapy, such as secondary malignancy and heart disease, are not evident until years
after treatment is completed. (See "Monitoring of the patient with classical Hodgkin lymphoma during and after
treatment" and "Second malignancies after treatment of classic Hodgkin lymphoma".)

In an attempt to minimize late complications, there has been a gradual change in treatment regimens, including
a considerable decrease in radiation doses and volumes; the use of multiagent chemotherapy in combination
with radiation (permitting the administration of fewer cycles of less toxic drugs); and the use of multiagent
chemotherapy alone, especially in those patients who have a high risk of late effects from the radiation
exposure (ie, young women and breast cancer risk).

Patients with HL have a significant likelihood of being cured of disease even after recurrence or relapse
following initial treatment. Therefore, consideration for the long term complications of successful primary and
secondary therapy is warranted. As examples:

Recurrence after initial chemotherapy is usually treated with conventional or high dose chemotherapy. Patients
may also achieve prolonged control of their disease after two or more recurrences by means of intensive
therapy supported by autologous hematopoietic cell transplantation regimens. When patients are not cured
(cure is less likely with each recurrence) and have exhausted standard treatment programs, they should be
managed with palliation as the goal or be considered for experimental programs. Some patients with persistent
HL, despite multiple courses of treatment, tolerate their disease relatively well for prolonged periods. (See
"Treatment of relapsed or refractory classic Hodgkin lymphoma".)

Treatment selection — Selection of initial treatment for HL is usually based upon presenting stage and
prognostic factors (table 1). The definitions used for radiation fields in the treatment of HL are shown in the
table (table 2). An important issue during any form of therapy is monitoring for extent of disease. CT scan is
usually performed, but if residual abnormalities are present, this modality cannot distinguish between necrosis
and/or fibrosis and active disease. PET/CT scanning and, if necessary, tissue biopsy are used to establish the
diagnosis. (See "Monitoring of the patient with classical Hodgkin lymphoma during and after treatment".)

Early stage HL (stage I-II) — In this discussion, patients with stage I or stage II disease are considered to
have "early stage" HL (table 1):

● Stage I – Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (Ie)

● Stage II – Involvement of two or more lymph node regions on the same side of the diaphragm alone (II) or
with involvement of limited, contiguous extralymphatic organ or tissue (IIe)

Among patients with early disease, there is subsequent stratification into favorable and unfavorable prognosis
disease based upon the presence or absence of certain clinical features, such as age, B symptoms, number of
sites involved, and large mediastinal adenopathy. Cooperative research groups have used varying definitions of
favorable and unfavorable prognosis disease. (See "Staging and prognosis of Hodgkin lymphoma", section on
'Favorable or unfavorable risk early stage disease' and "Treatment of favorable prognosis early (stage I-II)
classical Hodgkin lymphoma".)

The two most commonly used definitions of favorable disease are those proposed by the European
Organization for the Research and Treatment of Cancer (EORTC) and the German Hodgkin Study Group (GHSG):

● The EORTC defines the limited stage favorable prognostic group as patients age 50 or under; without large
mediastinal adenopathy; with an ESR of less than 50 mm/h and no B symptoms (or with an ESR of less
than 30 mm/h in those who have B symptoms); and disease limited to three or fewer regions of
involvement [1].
 ● The GHSG defines the limited stage favorable prognostic group as patients with no more than two sites of
disease; no extranodal extension; no mediastinal mass measuring one-third the maximum thoracic
diameter or greater; and ESR less than 50 mm/h (less than 30 mm/h if B symptoms present) [2].

Patients who do not fall into these categories are considered to have unfavorable prognosis early stage HL.
Patients with favorable prognosis disease appear to have acceptable outcomes with less intensive therapy than
that required for those with unfavorable prognosis early stage or advanced stage disease.

Patients with early stage disease are treated with a combination of chemotherapy plus radiation therapy. The
amount of chemotherapy and dose of radiation differs for patients with favorable and unfavorable prognosis
disease. While treatment with initial radiotherapy had resulted in high cure rates among patients with early
stage disease, toxicity was substantially reduced and long-term disease control was improved when
chemotherapy was added. As such, radiotherapy is rarely, if ever, used currently as the sole treatment of HL.
Patients who relapse after initial treatment with radiotherapy alone can be successfully treated with
combination chemotherapy [3,4].

Despite the increasing availability of guidelines for the treatment of HL, there must remain room for
individualization of treatment. In particular, patient preference must be considered with different treatment
options, some of which result in a higher recurrence risk at the gain of less toxic initial treatment. Treatment
should also be individualized when a particular approach might result in a higher risk of a serious late
complication (eg, the use of large radiation fields and the risk of late breast cancer in young females and of
lung cancer in smokers). (See "Second malignancies after treatment of classic Hodgkin lymphoma".)

Favorable prognosis — As described above, cooperative research groups have used varying definitions of
favorable prognosis early stage disease. The following treatment options are generally used in patients with
favorable prognosis stage I-II disease. There are differences in relapse rates and toxicity between treatment
approaches. (See "Treatment of favorable prognosis early (stage I-II) classical Hodgkin lymphoma".)

● ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for three (preferred) to four cycles, followed by
involved field irradiation to 30 Gy with fields encompassing the initially involved lymph node site (involved-
site radiation therapy). This approach has the lowest relapse rate.

● ABVD for two cycles, followed by involved-field (or perhaps involved-site) irradiation with 20 Gy may be
sufficient treatment for patients with favorable disease as defined by the GHSG. This regimen has lower
toxicity.

● ABVD for four to six cycles without radiation therapy. This is an emerging option for patients at risk of long-
term complications from radiotherapy. Disease control with combined therapy is superior compared with
chemotherapy alone, but this must be weighed against the risks of radiotherapy including cardiac disease
and secondary malignancies, particularly in young women who are at high risk for the development of
breast cancer after chest irradiation. (See "Treatment of favorable prognosis early (stage I-II) classical
Hodgkin lymphoma", section on 'Chemotherapy alone'.)

Experts disagree regarding the best choice among these treatment approaches. (See "Treatment of favorable
prognosis early (stage I-II) classical Hodgkin lymphoma".)

Unfavorable prognosis — Patients with unfavorable prognosis stage I to II HL are treated with

chemotherapy followed by involved field radiotherapy in a combined modality program. (See "Treatment of
unfavorable prognosis early (stage I-II) classic Hodgkin lymphoma in adults".)

ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) remains the "gold standard" chemotherapy for
these patients (table 3). For most patients, we administer ABVD plus radiation therapy. Combination
chemotherapy alone may be considered an alternative for patients with non-bulky unfavorable early stage
disease. (See "Monitoring of the patient with classical Hodgkin lymphoma during and after treatment".)

Four to six monthly cycles of ABVD are usually required for patients with bulky disease [5-7]. Patients
considered to have unfavorable disease without large mediastinal adenopathy may be treated adequately with
as few as three or four (preferred) months of ABVD followed by radiation [8], but four months of ABVD is the
general minimum for patients with bulky disease.

Radiation fields can be safely limited to involved regions as determined by CT scan and PET imaging (ie,
involved-site radiation)   It is important to take advantage of tumor regression secondary to chemotherapy and
to design treatment fields that conform to the width of the residual disease and not to the initial tumor volume.
Restricting fields reduces the risk of pulmonary complications related to the radiation, while treatment of the
original tumor volume is associated with enhanced risk. (See "Treatment of unfavorable prognosis early (stage
I-II) classic Hodgkin lymphoma in adults", section on 'Radiation field size'.)

Advanced stage HL (stage III-IV) — In this discussion, advanced stage HL refers to clinical stage (CS) III and
IV disease, although many experts and clinical trials include patients with stage II plus bulky nodal disease (CS
IIA or IIB). CS III describes involvement of lymph nodes or lymphoid structures on both sides of the diaphragm.
CS IV refers to diffuse or disseminated involvement of one or more extranodal organs or tissues, with or
without lymph node disease. (See "Staging and prognosis of Hodgkin lymphoma".)

Combination chemotherapy is the main treatment for patients with advanced stage HL. Radiation therapy may
be used for select patients as consolidation. The three treatment regimens widely used for advanced stage HL
include (table 4):

● ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) has been the standard regimen for several
decades. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma", section on 'ABVD
chemotherapy'.)

● Escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and

prednisone) programs incorporate radiation therapy for most patients and have shown advantages in
freedom from progression but not overall survival when compared with ABVD in three randomized trials.
These advantages are most marked among patients with higher risk international prognostic score (IPS)
and this more intense regimen is a reasonable alternative to ABVD for these patients with the highest risk
of relapse (table 5). BEACOPP is associated with higher rates of toxicity including reversible bone marrow
suppression, secondary malignancies, sterility, and rare cases of fatal sepsis. Toxicities are particularly
severe in the elderly, making it inappropriate in this population. BEACOPP may affect the ability to provide
effective salvage therapy, such as autologous hematopoietic cell transplantation, to patients who relapse.
(See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma", section on 'BEACOPP
chemotherapy'.)

● Stanford V (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone)

incorporates radiation therapy for all patients and may be preferred in some settings because of its short
administration schedule (12 versus 24 to 32 weeks) and decreased pulmonary toxicity. It may have
advantages for certain patients, particularly those for whom radiation will be part of their planned therapy.
Randomized trials have demonstrated no advantage over ABVD. (See "Initial treatment of advanced (stage
III-IV) classic Hodgkin lymphoma", section on 'Stanford V'.)

A choice among these regimens must take into consideration the response rates, relapse rates, toxicity, and
patient preference. Both escalated BEACOPP and Stanford V have been compared to ABVD with or without
radiation therapy in randomized trials and neither showed a survival advantage but they were both associated
with more toxicity. Stanford V requires the incorporation of radiotherapy. In North America, escalated BEACOPP
is rarely used as initial therapy. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma",
section on 'General approach'.)

The role of consolidation radiotherapy after chemotherapy induction for advanced stage HL is controversial.
Consolidation radiation therapy appears to improve freedom from progression but not overall survival. Its use
depends primarily upon the initial chemotherapy administered and the patient's response to that chemotherapy.
Radiation therapy is an essential component of the Stanford V protocol. (See "Initial treatment of advanced
(stage III-IV) classic Hodgkin lymphoma", section on 'General' and "Initial treatment of advanced (stage III-IV)
classic Hodgkin lymphoma", section on 'With Stanford V'.)

Primary refractory disease — Primary refractory (resistant) disease refers to patients who do not attain a
complete remission after initial therapy. The incidence of primary refractory disease varies depending upon the
stage of disease at diagnosis and the treatment regimen used. Durable responses and remissions may be
achieved in approximately one-half of these patients with second line chemotherapy that incorporates drugs
not used in initial treatment followed by high dose chemotherapy and autologous hematopoietic cell rescue.
Patients with a second relapse or progressive, resistant disease are candidates for high dose chemotherapy
and autologous hematopoietic cell transplantation as well. (See "Treatment of relapsed or refractory classic
Hodgkin lymphoma" and "Hematopoietic cell transplantation in classic Hodgkin lymphoma".)

Relapsed disease — Patients with HL relapsing after prior treatment with chemotherapy are generally treated
with either conventional chemotherapy combined with radiation therapy or high dose chemotherapy and
autologous hematopoietic cell transplantation (HCT) given with or without radiation therapy. The choice of
therapy is usually based upon prognostic features:

● Patients with a localized, asymptomatic relapse occurring more than 12 months after initial treatment are
usually treated with conventional salvage chemotherapy, often combined with radiation therapy with or
without high dose chemotherapy and autologous HCT. The value of HCT is uncertain in this group and may
be unnecessarily toxic. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)

● High dose chemotherapy and autologous HCT should be considered as the treatment of choice for the
following subsets of patients:

• Early relapse (less than 12 months after treatment) or induction failure.

• Second relapse after conventional treatment for first relapse.

• Generalized systemic relapse even beyond 12 months.

In general, patients with relapsed disease are treated with a chemotherapy regimen that is different from the
one used for initial treatment. Details on these regimens are presented separately. (See "Treatment of relapsed
or refractory classic Hodgkin lymphoma".)

Radiation therapy is indicated for patients with localized residual disease after salvage chemotherapy. In
addition, patients with a localized late relapse (>12 months) may achieve long-term remission with
chemotherapy followed by involved-field radiation therapy (IF-RT) rather than chemotherapy followed by HCT.
The role of IF-RT in the treatment of patients who achieve a complete response to chemotherapy and plan to
proceed with HCT is less clear. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma", section
on 'Radiation therapy (RT)'.)

PROGNOSIS
Early stage disease — Patients with early stage (stage I to II) HL have a high likelihood of achieving long-term
complete remission. As described above, treatment selection of these patients is largely determined based
upon other prognostic factors that allow the discrimination of patients with "favorable prognosis" early stage
HL and those with "unfavorable prognosis" early stage HL. These factors are presented in more detail
separately. (See "Staging and prognosis of Hodgkin lymphoma", section on 'Favorable or unfavorable risk early
stage disease'.)

International prognostic score — Among patients with advanced stage (stage III/IV) HL, prognosis is largely
determined by the International Prognostic Score (IPS). The IPS was created by the International Prognostic
Factor Project on Advanced Hodgkin's Disease based upon the total number of seven potential unfavorable
features at diagnosis: serum albumin less than 4 g/dL (40 g/L), hemoglobin less than 10.5 g/dL (105 g/L), male
gender, age over 45 years, stage IV disease, white blood cell count ≥15,000/microL, and lymphocyte count less
than 600/microL and/or less than 8 percent of the white blood cell count (table 5) (calculator 1) [9]. This
analysis showed a spread in freedom from progression at five years, as follows:

● No factors – 84 percent (7 percent of patients)

● One factor – 77 percent (22 percent of patients)

● Two factors – 67 percent (29 percent of patients)

● Three factors – 60 percent (23 percent of patients)

● Four factors – 51 percent (12 percent of patients)

● Five or more factors – 42 percent (7 percent of patients)

MINIMIZING LONG-TERM COMPLICATIONS OF THERAPY — HL survivors are at risk of developing therapy-

related complications that may present years after treatment (eg, second malignancies, cardiac disease,
radiation-induced hypothyroidism). These complications have surfaced as significant causes of increased
mortality among survivors. Screening for some of these entities is advised in the hope that early detection may
lead to better management.

Care should be given to tailor initial therapy to minimize over-treatment. In addition, measures can be taken at
the time of diagnosis to minimize the potential of some long-term complications of therapy.

Fertility preservation — An overall discussion of fertility issues should be undertaken in patients of childbearing
age prior to the initiation of treatment. (See "Fertility preservation in patients undergoing gonadotoxic treatment
or gonadal resection".)

Smoking cessation — The combination of chest irradiation and smoking can dramatically increase a patient's
risk for lung cancer. We recommend smoking cessation for all patients. (See "Overview of smoking cessation
management in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles
are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and
are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Hodgkin lymphoma in adults (The Basics)")

● Beyond the Basics topics (see "Patient education: Hodgkin lymphoma in adults (Beyond the Basics)")

SUMMARY

● The treatment of patients with Hodgkin lymphoma (HL, formerly called Hodgkin's disease) is primarily
guided by the clinical stage of disease as determined by the Cotswolds classification (table 1). (See
"Staging and prognosis of Hodgkin lymphoma".)

● While the majority of patients will be cured of their lymphoma, treatment-related toxicities have become a
competing cause of late mortality. As such, the selection of therapy must balance the desire to maintain a
high rate of cure and the need to minimize long-term complications. (See 'Overview of selection of therapy'
above.)

● Patients with early stage disease (stage I to II) are usually treated with a combination of chemotherapy
plus radiation therapy. The amount of chemotherapy and dose of radiation differs for patients with
favorable and unfavorable prognosis disease. Chemotherapy alone is an acceptable alternative for patients
with favorable disease characteristics at higher risk for complications from radiotherapy. (See 'Early stage
HL (stage I-II)' above.)

● Combination chemotherapy is the main treatment for patients with advanced stage (stage III to IV) HL.
Radiation therapy may be used for select patients as consolidation. (See 'Advanced stage HL (stage III-IV)'
above.)

● Patients with primary refractory (resistant) disease may attain durable responses and remissions with
second line chemotherapy that incorporates drugs not used in initial treatment followed by high dose
chemotherapy and autologous hematopoietic cell rescue. Patients with a second relapse or progressive,
resistant disease are candidates for high dose chemotherapy and autologous hematopoietic cell
transplantation as well. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma" and
"Hematopoietic cell transplantation in classic Hodgkin lymphoma".)

● Patients with early stage (stage I-II) HL have a high likelihood of achieving long-term complete remission. A
variety of prognostic factors allow for the discrimination of patients with "favorable prognosis" early stage
HL and those with "unfavorable prognosis" early stage HL. These factors are presented in more detail
separately. (See "Staging and prognosis of Hodgkin lymphoma", section on 'Favorable or unfavorable risk
early stage disease'.)

● Among patients with advanced stage (stage III/IV) HL, prognosis is largely determined by the International
Prognostic Score (IPS) (table 5) (calculator 1).

● HL survivors are at risk of developing therapy-related complications that may present years after treatment
(eg, second malignancies, cardiac disease, radiation-induced hypothyroidism). Measures to minimize the
incidence of these complications and to screen for them after therapy is complete are part of the
management of this disease. (See 'Minimizing long-term complications of therapy' above.)

ACKNOWLEDGMENT — We are saddened by the death of Peter M Mauch, MD, who passed away in September
2017. UpToDate wishes to acknowledge Dr. Mauch's past work as an author for this topic.
 Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Cosset JM, Henry-Amar M, Meerwaldt JH, et al. The EORTC trials for limited stage Hodgkin's disease. The
EORTC Lymphoma Cooperative Group. Eur J Cancer 1992; 28A:1847.
2. Engert A, Plütschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin's
lymphoma. N Engl J Med 2010; 363:640.
3. Bonfante V, Santoro A, Viviani S, et al. ABVD in the treatment of Hodgkin's disease. Semin Oncol 1992;
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radiotherapy alone or combined radiotherapy and chemotherapy. Ann Oncol 1994; 5 Suppl 2:101.
6. Colonna P, Jais JP, Desablens B, et al. Mediastinal tumor size and response to chemotherapy are the only
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results of the Paris-Ouest-France 81/12 trial, including 262 patients. J Clin Oncol 1996; 14:1928.
7. Andrieu JM, Bayle-Weisgerber C, Boiron M, et al. The chemotherapy--radiotherapy sequence in the
management of Hodgkin's disease. Results of a clinical trial. Eur J Cancer 1979; 15:153.
8. Colonna P, Andrieu JM, Ghouadni R, et al. Hodgkin's disease, clinical stages IA to IIIB: combined modality
therapy (3 MOPP followed by curative and prophylactic radiotherapy including the spleen). Six-year
results. Eur J Haematol 1987; 39:356.
9. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin's disease. International Prognostic
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