Treatment of unfavorable prognosis early (stage I-II) classic Hodgkin lymphoma in adults

INTRODUCTION — Treatment and prognosis of classic Hodgkin lymphoma (cHL, formerly called Hodgkin's disease) are based on the stage of the disease and certain prognostic features.

Treatment of unfavorable prognosis stage I to II cHL in adults will be reviewed here. Overview of treatment of cHL, and management of patients with favorable prognosis early stage cHL, and advanced stage cHL are discussed separately.

●(See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults".)

●(See "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma".)

●(See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma".)

DEFINITIONS — Initial evaluation of a patient with classic Hodgkin lymphoma (cHL) must establish the histologic subtype, stage, and various prognostic factors. This evaluation is described in detail separately. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults".)

Stage — Stage of cHL is defined by the Lugano classification (table 1) [1]. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)

In this discussion, early stage cHL is defined as stage I or II disease:

●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)

Unfavorable prognosis — We use the EORTC (European Organisation for Research and Treatment of Cancer) prognostic model, in which the presence of one or more of the following features constitutes unfavorable prognosis:

●Age >50 years

●Large ("bulky") mediastinal adenopathy

●Erythrocyte sedimentation rate (ESR) ≥50 mm/hour and no B symptoms (or ESR ≥30 mm/hour in those who have B symptoms)

●≥4 regions of involvement

Unfavorable prognosis cHL is defined differently by various research groups, and these models are described in more detail separately.

Bulky disease — We define bulky mediastinal disease as at least one-third of the maximum thoracic width or any individual tumor mass ≥10 cm in maximum diameter.

COMPONENTS OF TREATMENT — Initial treatment of unfavorable prognosis early stage cHL typically includes either combined modality therapy (ie, chemotherapy plus radiation therapy) or chemotherapy alone.

Chemotherapy regimens

ABVD chemotherapy — We recommend ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for most patients with unfavorable prognosis early stage cHL. Studies that have compared ABVD with other combination chemotherapy regimens in this setting generally have not identified important differences in overall survival (OS), but have shown reduced adverse events [2-4]. (See 'Alternative chemotherapy regimens' below.)

ABVD is administered every 14 days in 28-day cycles; two treatments are considered one cycle (table 2).

●Patients usually receive either four or six cycles of ABVD chemotherapy, as guided by the functional response by PET/CT; this may be followed by radiation therapy (RT) in those patients selected for combined modality therapy (CMT) (algorithm 1).

●Treatment with six cycles of ABVD alone may be offered to select patients who choose to not receive RT. (See 'Patients at higher risk with RT' below.)

The main grade 3/4 acute toxicities associated with ABVD chemotherapy are leukopenia (24 percent), alopecia (24 percent), and nausea/vomiting (14 percent) [3]. Long-term toxicities include cardiopulmonary toxicity and second malignancies, especially when ABVD is administered in combination with mediastinal RT. (See "Approach to the adult survivor of classic Hodgkin lymphoma".)

Alternative chemotherapy regimens — We recommend ABVD for most patients with unfavorable prognosis early stage cHL. Compared with ABVD, alternative chemotherapy regimens result in comparable clinical outcomes, but are generally associated with less favorable toxicity profiles. Alternative chemotherapy regimens for cHL include [5]:

●Stanford V regimen – Stanford V (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone) (table 3) is administered weekly for 12 weeks. Patients treated with Stanford V who achieve partial response (PR) or complete response (CR) after 12 weeks of chemotherapy proceed to RT to sites of disease greater than 5 cm; as a result, more patients will receive RT with Stanford V compared with ABVD. However, compared with six cycles of ABVD, with Stanford V the total dose of doxorubicin is only 50 percent and the bleomycin dose is only 25 percent. The total course of Stanford V treatment is shorter than treatment with ABVD plus RT.

In ECOG E2496, 264 patients with stage I to II cHL with bulky mediastinal adenopathy were randomly assigned to CMT using ABVD or Stanford V chemotherapy [4]. There was no significant difference in five-year failure-free survival (85 versus 79 percent for ABVD and Stanford V, respectively) or OS (96 versus 92 percent, respectively).

Compared with ABVD, there was more grade 3/4 peripheral neuropathy with Stanford V (7 versus 1 percent, respectively), comparable rates of grade 3/4 neutropenia, and similar rates of second malignancies after five years (two with ABVD and six with Stanford V) [4]. The long-term risks of Stanford V are less well defined; compared with ABVD there may be less cardiac and pulmonary toxicity (due to lower doses of anthracycline and bleomycin), but there may be more second malignancies (due to more frequent use of RT).

●BEACOPP – Escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) (table 3) was used in several European trials and is associated with greater toxicity than ABVD [2,6-8].

Examples of studies that compared escalated BEACOPP to ABVD for unfavorable prognosis early stage cHL include the following:

•A systematic analysis that compared escalated BEACOPP versus ABVD as first-line therapy for unfavorable prognosis early stage cHL included four trials with nearly 2900 patients [9]. Compared to ABVD, progression-free survival (PFS) was significantly longer for BEACOPP (HR 0.53; 95% CI 0.44-0.64), but there was no difference detected for OS. BEACOPP was associated with more hematologic toxicities (eg, anemia, neutropenia, thrombocytopenia) and infections, and with more myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML); there was no difference in secondary malignancies, treatment-related mortality, or infertility.

A subsequent systematic analysis of the same four trials added a trial of BEACOPP versus ABVD in advanced stage cHL (stages III/IV) [10]. This analysis did detect a difference in OS (HR 0.74; 95% CI 0.57-0.97) as well as PFS, but the survival difference is attributable to superior outcomes in patients with advanced disease.

•As examples of trials of unfavorable prognosis early stage cHL, the German Hodgkin Study Group (GHSG) and EORTC randomly assigned patients to RT plus BEACOPP versus RT plus ABVD. In both GHSG HD11 and EORTC H9U, there was no difference in OS or freedom from progression [11,12]. However, compared with ABVD, overall grade 3/4 toxicity was greater with BEACOPP (74 versus 52 percent, respectively), most notably in regard to leukopenia (38 versus 25 percent, respectively), alopecia (58 versus 31 percent, respectively), and anemia (7 versus 1 percent, respectively) [11].

•GHSG HD14 randomly assigned patients to CMT using hybrid chemotherapy (two cycles of escalated BEACOPP followed by two cycles of ABVD) versus CMT with four cycles of ABVD [3,13]. After a median follow-up of 43 months, CMT with hybrid chemotherapy was associated with improved PFS, but greater toxicity and no difference in OS.

Number of cycles — The total number of chemotherapy cycles is guided by the functional response to treatment, as assessed by combined PET/CT.

We perform PET/CT imaging after cycle 2 ("PET 2") of ABVD and after cycle 4 in patients who are PET 2 positive. Patients are treated with a total of four cycles of ABVD if a complete response (CR) is achieved after cycle 2, if RT is incorporated in therapy; for other patients, the course of treatment is informed by results from PET/CT (algorithm 1).

GHSG HD11 reported that four cycles of ABVD was adequate chemotherapy when combined with RT (30 Gy), and resulted in five-year freedom from treatment failure (85 percent), OS (94 percent), and PFS (87 percent) in unfavorable prognosis early stage cHL [11]. The EORTC H9U trial included patients with unfavorable prognosis early stage cHL who were randomly assigned to 30 Gy involved-field RT (IFRT) plus either six cycles of ABVD or four cycles of ABVD; five-year event-free survival and OS were similar in all arms, suggesting that four cycles of ABVD is sufficient in this setting [12].

Radiation therapy (RT) — RT alone is not adequate treatment for unfavorable prognosis early stage cHL. CMT includes RT that follows chemotherapy (generally ABVD).

Radiation field size — For most patients, involved-site RT (ISRT) is preferred over larger radiation fields (eg, involved field or extended field). With ISRT, the radiation field is reduced based on disease regression after chemotherapy in order to limit radiation to uninvolved normal organs. Intensity modulated RT, breath-hold techniques, and proton therapy can be used to further limit damage to normal tissues in select cases.

Compared with older techniques, contemporary approaches reduce acute and long-term toxicities while maintaining PFS rates [14]. Various definitions of RT techniques have been applied (table 4). We agree with the guidelines for modern RT in cHL published by the International Lymphoma Radiation Oncology Group (ILROG) [15].

Radiation fields are discussed in more detail separately. (See "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma".)

Radiation dose — Early stage unfavorable cHL is generally treated with 30 to 36 Gy ISRT following combination chemotherapy. This recommendation is consistent with the guidelines published by the International Lymphoma Radiation Oncology Group [15].

The GHSG HD11 trial showed that treatment with four cycles of ABVD followed by 20 Gy yielded inferior PFS and freedom from treatment failure compared with four cycles of ABVD followed by 30 Gy IFRT (or by BEACOPP followed by either 20 Gy or 30 Gy IFRT) [11,16].

Adverse effects — The most common acute adverse events from RT include cutaneous and/or mucosal irritation and cytopenias. Long-term effects of RT include sclerosis/fibrosis, cytopenias, cardiopulmonary toxicity, and second malignancies. (See "Radiation therapy techniques in cancer treatment", section on 'Radiation side effects'.)

Contemporary RT techniques (eg, ISRT) utilize lower doses and smaller field sizes than those used in the past and are associated with less toxicity without compromised efficacy. Most data regarding long-term effects of RT reflect doses and fields that were used in the past. The increase of second cancers in patients with cHL that may be attributable to treatment has been estimated at 0.4 to 0.7 percent per year [17-23].

The risks of second malignancies and other potential complications of RT are discussed in detail separately. (See "Second malignancies after treatment of classic Hodgkin lymphoma" and "Approach to the adult survivor of classic Hodgkin lymphoma", section on 'Late complications'.)

Patients at higher risk with RT — The short-term and/or long-term risks of RT may be judged to be excessive for certain patients. As an example, in a young woman with non-bulky bilateral axillary and mediastinal disease with early complete response to chemotherapy, it is generally preferable to treat with chemotherapy alone and accept a slightly higher risk of recurrence in exchange for a reduced long-term risk of breast cancer. (See 'Patients at higher risk with RT' below.)

Such decisions are often nuanced. As another example, the increased risk of developing lung cancer from RT associated with CMT in a cigarette smoker should be balanced against the danger of exacerbating cardiac and/or pulmonary disease due to higher cumulative doses of anthracycline and bleomycin with chemotherapy alone.

Combined modality therapy (CMT) — Chemotherapy followed by RT is referred to as combined modality therapy (CMT).

CMT is recommended for most patients with large ("bulky") mediastinal cHL [5], and for some other patients with unfavorable prognosis early stage cHL (eg, partial response to ABVD) (algorithm 1). CMT is especially beneficial for achieving disease control of bulky adenopathy that may not be adequately controlled by chemotherapy alone.

Patients usually receive either four or six cycles of ABVD chemotherapy, as guided by the functional assessment of response by PET/CT after cycles 2 and 4 of ABVD (algorithm 1). (See 'Functional assessment of response by PET/CT' below.)

RT usually begins three to four weeks after the completion of chemotherapy and requires three to four additional weeks of treatment. The radiation component of CMT helps to achieve disease control at known sites of tumor, while the chemotherapy treats all systemic disease, including occult sites of disease. (See 'Radiation therapy (RT)' above.)

Compared with chemotherapy alone, CMT appears to have superior efficacy for early stage cHL based on a meta-analysis, prospective randomized trials, and population-based data:

●A systematic review of three randomized trials that included nearly 1500 patients who achieved a negative PET scan after two cycles of ABVD reported that PFS was shorter in patients who received chemotherapy alone (PET-adapted therapy) compared with those who received standard CMT (HR 2.4; 95% CI 1.6-3.5) [24]. Only limited short-term adverse events were assessed, and none of the trials reported long-term adverse events.

●As an example, in one of those trials, European Organisation for Research and Treatment of Cancer/Lymphoma Study Association/Fondazione Italiana Linfoni (EORTC/LYSA/FIL) H10, patients in the unfavorable prognosis early stage group who achieved a CR by PET/CT after two cycles of ABVD were randomly assigned to receive four additional cycles (six cycles total) of ABVD alone versus CMT with four cycles (total) of ABVD followed by involved-node RT (36 Gy) [25]. The trial was terminated at the time of a planned interim analysis when it was reported that patients with unfavorable prognosis early stage disease had inferior PFS with ABVD alone compared with CMT. Longer term follow up revealed that the difference in PFS at five years between the two arms narrowed (90 versus 92 percent for ABVD alone and CMT, respectively), but noninferiority of the ABVD alone arm still could not be demonstrated based on the prespecified noninferiority margin [26].

●Observational datasets from the SEER (Surveillance, Epidemiology, and End Results) program and the National Cancer Data Base also suggested improved survival in patients with early stage cHL treated with CMT compared with chemotherapy alone [27,28].

CMT is associated with increased toxicities, including second malignancies (eg, solid tumors, non-Hodgkin lymphoma, acute leukemia) (table 5). The risk of second malignancies has decreased with contemporary chemotherapy regimens (ie, ABVD rather than MOPP) and RT techniques (ie, smaller fields and lower doses). Long-term follow-up of the HD11 trial reported a 10-year cumulative incidence of second cancers of 5 to 7 percent when contemporary radiation techniques were coupled with either ABVD or BEACOPP; this corresponded to a 1.4- to 2.4-fold increase in second cancers compared with the age- and sex-matched general population [16].

The risks of second malignancies and other potential complications of RT are discussed in detail separately. (See "Second malignancies after treatment of classic Hodgkin lymphoma" and "Approach to the adult survivor of classic Hodgkin lymphoma", section on 'Late complications'.)

FUNCTIONAL ASSESSMENT OF RESPONSE BY PET/CT — Positron emission tomography/computed tomography (PET/CT) is used to functionally assess the response to initial chemotherapy (eg, ABVD), guide the duration of chemotherapy (ie, the number of chemotherapy cycles), and determine if any residual disease might be encompassed within a radiation field.

We recommend interval PET/CT scans after cycle 2 ("PET 2") of ABVD and after cycle 4, if PET 2 positive. PET/CT should be performed just before, or as close as possible, to the next scheduled chemotherapy treatment. We perform PET/CT at least three weeks after completion of all chemotherapy, and at least three months after completion of radiation therapy, if performed. We assess the response as follows (table 6):

●Complete response (CR) Deauville 1-3

●Partial response (PR) Deauville 4-5; the clinician's assessment of whether a PR reflects chemotherapy responsiveness or resistance may influence subsequent treatment decisions (algorithm 1)  

●Progressive disease (PD) on PET/CT, or by clinical evaluation

TREATMENT — Treatment of unfavorable prognosis early stage cHL typically requires a choice between chemotherapy alone versus combined modality therapy (CMT; chemotherapy followed by radiation therapy [RT]).

Management strategy is informed by the nature of the unfavorable prognostic factors (ie, bulky mediastinal disease versus other unfavorable prognostic factors). (See 'Combined modality therapy (CMT)' above.)

The number of cycles of chemotherapy is determined by the functional response to treatment, as judged by PET/CT. (See 'Functional assessment of response by PET/CT' above.)

Bulky mediastinal disease — For most patients with bulky mediastinal disease we recommend CMT because of the favorable balance of improved clinical outcomes (ie, improved local control and improved overall survival) weighed against the increase in short-term and long-term toxicity.

The number of cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy in CMT for bulky disease is guided by the functional response to chemotherapy on PET/CT, as follows (algorithm 1):

●If a complete response (CR) is present after cycle 2 ABVD, the patient proceeds with RT after cycle 4. PET/CT is performed three months after completion of RT.

If still in CR, the patient is observed. (See "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment".)

If a partial response or progressive disease is observed following RT, the patient is treated with salvage systemic therapy. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)

●If a partial response (PR) is present after cycles 2 or 4 and the disease is judged to be responding to ABVD chemotherapy, two additional cycles of ABVD are given (total of six cycles), followed by RT, and repeat PET/CT three months later. Some experts treat with salvage systemic therapy if CR is not achieved after cycle 6.

If CR is present, the patient is observed. (See "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment".)

If PR or progressive disease (PD) is present, the patient is treated with salvage systemic therapy.

●If the disease is judged to be responding inadequately to chemotherapy (PR or PD) clinically or by PET/CT after cycles 2 or 4, the patient is treated with RT (if the disease can be encompassed in a radiation port) or with salvage systemic therapy. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)

For some patients, the risk of adverse effects from CMT may be considered excessive due to anticipated effects of radiation and/or the combined effects of radiation and chemotherapy. In such circumstances, treatment with chemotherapy alone (eg, six cycles of ABVD without RT) is an acceptable alternative to CMT. (See 'Patients at higher risk with RT' above.)

Non-bulky disease — Patients with non-bulky disease (ie, unfavorable prognostic factors other than bulky mediastinal disease) may be treated with either CMT or chemotherapy alone. While CMT provides more favorable progression-free survival, overall survival has not been shown to be improved, and CMT may be associated with higher risk of long-term adverse events (which are not fully defined using contemporary radiation techniques). For individual treatment decisions, important considerations include the initial disease distribution (to assess risks of radiation) and risk factors that may affect the incidence of treatment-related late adverse events (eg, family history, smoking history, preexistent cardiac risk factors).

Further management, including the number of cycles of ABVD, is guided by the functional response to chemotherapy on PET/CT, as follows (algorithm 1):

●If a complete response (CR) is present after cycle 2 of ABVD and at the end of therapy (ie, after two to four additional cycles of ABVD), the patient is observed; some experts add involved-site RT in this setting. (See "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment".)

●If a partial response (PR) is present after cycle 2 and again after cycle 4, and the disease is judged to be responding to ABVD chemotherapy, two additional cycles of ABVD are given (total of six cycles). We generally treat with RT to residual disease. Repeat PET/CT is performed three months later:

•If CR is present, the patient is observed.

•If PR or PD is present, the patient is treated with salvage systemic therapy. An acceptable alternative is treatment with escalated BEACOPP.

●If the disease is judged to be responding inadequately to chemotherapy (PR or PD) by PET/CT or clinically, the patient is treated with RT (if the disease can be encompassed in a radiation port) and/or salvage systemic therapy. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)

Special clinical scenarios — General treatment principles for unfavorable early stage cHL apply to most disease presentations and patient populations. However, certain patient populations may require special consideration.

Patients at higher risk with RT — For some patients, the short-term or long-term risks of RT may be judged to be undesirable. (See 'Patients at higher risk with RT' above.)

In such a situation, treatment with six cycles of ABVD may be offered rather than CMT. The decision to treat with chemotherapy alone will be informed by the chemotherapy responsiveness of the tumor (ie, CR versus PR after cycle 4).  

Pregnant women — Management of cHL during pregnancy is presented separately. (See "Management of classic Hodgkin lymphoma during pregnancy".)

Children and adolescents — Treatment of cHL in children and adolescents is discussed separately. (See "Overview of Hodgkin lymphoma in children and adolescents".)

Older adults — Bleomycin lung toxicity is more common in older adults (eg, 24 percent of patients >60 years of age treated with ABVD in the E2496 trial) [29]. Bleomycin is generally omitted in the older adult population.

A comprehensive geriatric assessment may be useful in assessing comorbidity and functional status in the older patient, thereby permitting the formulation of an appropriate, individualized treatment plan. Patients over the age of 60 years are not appropriate candidates for escalated BEACOPP. Special considerations for the use of chemotherapy in the older population are discussed separately. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma", section on 'Older adults' and "Comprehensive geriatric assessment for patients with cancer" and "Systemic chemotherapy for cancer in older adults".)

Renal impairment — Renal insufficiency is known to alter bleomycin elimination, thereby increasing the likelihood of treatment-related toxicity. We generally reduce or omit bleomycin in the setting of a creatinine clearance below 25 to 35 mL/min. (See "Nephrotoxicity of chemotherapy and other cytotoxic agents".)

HIV-infected patients — Treatment of patients with HIV who develop cHL is complicated by their immunocompromised state and also requires specific treatment for their underlying HIV. Treatment of cHL in HIV-infected patients is discussed in more detail separately. (See "HIV-related lymphomas: Treatment of systemic lymphoma" and "HIV infection and malignancy: Management considerations", section on 'Hodgkin lymphoma'.)

Infradiaphragmatic disease — Approximately 5 to 10 percent of patients with early stage cHL present with disease below the diaphragm. The independent prognostic impact of infradiaphragmatic disease is controversial [30-33]. However, many patients with infradiaphragmatic disease have other unfavorable features (eg, older age, poor performance status, high number of lymph nodes involved, B symptoms).

We approach the treatment of patients with unfavorable infradiaphragmatic disease in the same way that we approach patients with unfavorable supradiaphragmatic disease.

Nodular lymphocyte-predominant HL — The treatment of patients with the nodular lymphocyte-predominant subtype of HL is discussed separately. (See "Treatment of nodular lymphocyte-predominant Hodgkin lymphoma".)

PATIENT FOLLOW-UP — After completion of the initially planned treatment of cHL, patients should be evaluated clinically and by PET/CT, three months after completion of combined modality therapy or at least four to six weeks after chemotherapy alone, to determine the disease response to treatment and should be followed longitudinally for relapse. The follow-up of patients with early (stage I to II) cHL is presented separately. (See "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma", section on 'Patient follow-up' and "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment".)

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

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 info" and the keyword(s) of interest.)

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

SUMMARY AND RECOMMENDATIONS

●Unfavorable prognosis early stage classic Hodgkin lymphoma (cHL) is defined by certain unfavorable prognostic features (eg, older age, presence of bulky mediastinal disease, elevated erythrocyte sedimentation rate, four or more sites of involvement) and either stage I or stage II disease. (See 'Definitions' above.)

●Management of unfavorable prognosis early stage cHL is informed by:

•The nature of the unfavorable prognostic features (ie, bulky mediastinal disease versus other unfavorable features) guides the choice of chemotherapy alone versus combined modality therapy (CMT; ie, chemotherapy followed by radiation therapy [RT]). (See 'Combined modality therapy (CMT)' above.)

•Functional response to initial chemotherapy, as judged by positron emission tomography/computed tomography (PET/CT) response (table 6), guides the number of cycles of chemotherapy (algorithm 1). (See 'Functional assessment of response by PET/CT' above.)

●For most patients, we recommend ABVD (table 2) rather than alternative chemotherapy regimens because of equivalent efficacy but its more favorable toxicity profile (Grade 1B). (See 'ABVD chemotherapy' above.)

Acceptable alternatives to ABVD include Stanford V or BEACOPP. (See 'Alternative chemotherapy regimens' above.)

●The number of cycles of ABVD is determined by the results of PET/CT after two cycles of chemotherapy, as follows (see 'Number of cycles' above):

•Complete response (CR) – Two to four additional cycles of ABVD (total of four to six cycles)

•Partial response (PR) – Four additional cycles of ABVD (total of six cycles) followed by RT.

•Progressive disease (PD) – Based on PET/CT results or clinical evaluation, managed as refractory disease. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)

●The decision to treat with RT after completion of chemotherapy is guided by the presence of bulky mediastinal disease at the time of diagnosis, or persistence of localized disease (algorithm 1).

●For most patients with early stage bulky cHL, we recommend CMT, rather than chemotherapy alone (Grade 1B). In this setting, CMT is associated with improved progression-free survival and overall survival. (See 'Combined modality therapy (CMT)' above and 'Bulky mediastinal disease' above.)  

For patients with bulky disease, we treat with 30 to 36 Gray (Gy) involved-site RT (ISRT). (See 'Combined modality therapy (CMT)' above.)

In select patients with bulky mediastinal disease for whom the addition of RT would pose an unacceptably high risk (eg, a woman under age 30 years who would require substantial breast irradiation), six cycles of ABVD alone may be an acceptable alternative. (See 'Patients at higher risk with RT' above.)

●Patients with non-bulky unfavorable prognosis early stage cHL are treated with either ABVD chemotherapy alone or CMT, with an individualized decision based on review of benefits and risks of both approaches. (See 'Non-bulky disease' above.)

●Repeat PET/CT is performed three months of completion of all planned therapy, with subsequent management as follows:

•CR – Observation (see "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment")

•PR or PD – Management of refractory cHL (see "Treatment of relapsed or refractory classic Hodgkin lymphoma")

●Certain patient populations with unfavorable prognosis early stage cHL (eg, pregnant women, older adults) require special consideration. (See 'Special clinical scenarios' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Peter M Mauch, MD, who contributed to earlier versions of this topic review.