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 Lugano 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 "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)

This topic will provide a brief review of the selection of treatment based on 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 classic HL. The rare subtype of nodular lymphocyte predominant Hodgkin lymphoma is presented separately. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults" and "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma" and "Hodgkin lymphoma: Epidemiology and risk factors" and "Treatment of nodular lymphocyte-predominant Hodgkin lymphoma".)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately.

●(See "COVID-19: Considerations in patients with cancer".)

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 classic Hodgkin lymphoma during and after treatment" and "Second malignancies after treatment of classic Hodgkin lymphoma" and "Approach to the adult survivor 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 on 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 classic 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 on 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 "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma" and "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'Early stage'.)

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 erythrocyte sedimentation rate (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.

Despite the 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 to II disease. There are differences in relapse rates and toxicity between treatment approaches. (See "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma".)

●ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for three (preferred) to four cycles, followed by involved-site radiation therapy to 30 Gy. This approach has the lowest relapse rate [3].

●ABVD for two cycles, followed by involved-site radiation therapy with 20 Gy may be sufficient treatment for patients with favorable disease as defined by the GHSG. This regimen has lower toxicity [2,4].

●ABVD for four to six cycles without radiation therapy is an option for patients at risk of long-term complications from radiation therapy. Assessment of response based on positron emission tomography (PET) may identify patients who are candidates for chemotherapy alone and/or may benefit from escalating chemotherapy [3,5]. Disease control with combined therapy is superior compared with chemotherapy alone, but this must be weighed against the risks of radiation therapy, 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) classic 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) classic Hodgkin lymphoma".)

Unfavorable prognosis — Patients with unfavorable prognosis stage I to II HL are treated with chemotherapy followed by involved-site radiation therapy in a combined modality program. (See "Treatment of unfavorable prognosis early (stage I-II) classic Hodgkin lymphoma in adults".)

ABVD remains the "gold standard" chemotherapy for these patients (table 3). For most patients, four cycles of ABVD plus radiation therapy appears to be adequate [6]. Combination chemotherapy alone may be an acceptable option for patients with nonbulky unfavorable early stage disease. As in patients with favorable prognosis disease, trials have explored the use of PET response to guide decision on consolidative radiation therapy or escalation of chemotherapy in early-stage, unfavorable prognosis HL [5]. (See "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment".)

Radiation clinical target volume can be safely limited to the pre-chemotherapy disease volume, but excluding initially uninvolved, displaced organs after tumor regression from chemotherapy, as determined by CT scan and PET imaging (ie, involved-site radiation) [7]. (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 "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)

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

●ABVD has been the standard regimen for several decades. Several trials have addressed escalating chemotherapy based on PET response, although randomized data are lacking [8-11]. Compared to ABVD, treatment with brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (BV + AVD) achieved superior progression-free survival, but no difference in overall survival [12]. (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) and variants of BEACOPP have shown advantages in freedom from progression, but not overall survival when compared with ABVD in several randomized trials [13-17]. 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 patients with the highest risk of relapse (table 5). BEACOPP is associated with greater toxicity, including reversible bone marrow suppression, secondary malignancies, sterility, and rare cases of fatal sepsis. Toxicities are particularly severe in older patients, making it inappropriate in this population. BEACOPP may affect the ability to provide effective salvage therapy, such as autologous hematopoietic cell transplantation (HCT), to patients who relapse. In North America, escalated BEACOPP is rarely used as initial therapy. (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. However, randomized trials have demonstrated no advantage of Stanford V over ABVD [14,18,19]. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma".)

A choice among these regimens must take into consideration the response rates, relapse rates, toxicity, and patient preference. (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. Its use depends primarily upon the initial disease bulk, initial chemotherapy administered and the patient's response to that chemotherapy [11,20,21]. Initial bulky site(s) or site(s) with incomplete response to chemotherapy may benefit from radiation therapy. 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".)

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 on 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 HCT 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 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. Patients with high-risk relapsed/refractory disease may benefit from post-transplant BV maintenance [22]. Immune checkpoint inhibitors show promise for salvage of relapsed/refractory HL [23]. 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-site radiation therapy rather than chemotherapy followed by HCT. The role of radiation therapy 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 on 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 "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'Early stage'.)

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 on 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) [24]. 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)

Facility/practitioner — Outcomes with cHL may be related to the experience and/or volume of cases treated at a facility.

A study using patient-level data from the US National Cancer Database (2003-2014) reported that among nearly 50,000 patients with cHL, those treated at higher-volume facilities had lower overall mortality than patients treated at lower-volume facilities [25]. Patients treated at higher-volume centers (≥9 patients per year) had approximately 20 percent lower mortality than those at centers treating ≤3 patients per year (which accounted for more than half of the facilities in the US). Outcomes were even better at the highest-volume centers; overall mortality was 27 percent lower at centers treating 40 patients per year than at facilities treating 10 patients per year.

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. (See "Approach to the adult survivor of classic Hodgkin lymphoma", section on 'Late complications'.)

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 "Overview of fertility and reproductive hormone preservation prior to gonadotoxic therapy or surgery".)

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".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of Hodgkin lymphoma".)

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 5^th to 6^th 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 10^th to 12^th 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 education" 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 Lugano classification (table 1). (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'Treatment stratification'.)

●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 radiation therapy. (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 selected 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 to 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.

●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 and "Approach to the adult survivor of classic Hodgkin lymphoma", section on 'Late complications'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges the late Peter M Mauch, MD for Dr. Mauch's past work as an author for this topic.