Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma

INTRODUCTION — Once the diagnosis of Hodgkin lymphoma (HL; formerly called Hodgkin's disease) has been established, subsequent therapy and prognosis are based on the stage of the disease, as defined by the Lugano criteria (table 1). (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)

In this discussion, early stage HL is defined as those patients with 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)

Among patients with early (stage I to II) 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, erythrocyte sedimentation rate (ESR), large number of regions involved, and large mediastinal adenopathy. Cooperative research groups have used varying definitions of favorable and unfavorable prognosis disease. These are described in more detail separately. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'Early stage'.)

The two most commonly used definitions of favorable stage I-II 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 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 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].

The treatment of favorable prognosis stage I-II HL will be reviewed here. The treatment of patients with unfavorable prognosis disease, advanced stage disease, and the treatment of patients with the nodular lymphocyte predominant subtype of HL are discussed separately.

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

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

●(See "Treatment of nodular lymphocyte-predominant Hodgkin lymphoma".)

PRETREATMENT EVALUATION

Studies — The initial evaluation of a patient with HL must establish the precise histologic subtype, the extent and sites of disease, and the performance status of the patient. This evaluation is described in detail separately. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults".)

International Prognostic Score — Patients with HL can be further divided into prognostic groups using the International Prognostic Score (IPS), which incorporates seven factors (ie, serum albumin, hemoglobin, gender, age, stage, white blood cell count, and absolute lymphocyte count) to delineate six prognostic groups with very different rates of freedom from progression at five years (table 2) (calculator 1). However, the IPS is largely used for patients with advanced stage HL, not patients with stage I to II disease. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'International Prognostic Score (IPS)'.)

INITIAL THERAPY

Choice of therapy — The treatment of early stage, favorable prognosis HL requires a careful balance between providing enough therapy to eradicate the tumor and avoiding unnecessary treatment that could result in excessive long-term treatment-related side effects. For patients with early stage, favorable prognosis HL, combination chemotherapy plus involved-field radiation therapy (IFRT) results in higher-disease free survival compared with chemotherapy alone. Overall survival, however, is similar with both approaches [3,4].

Clinical trials have primarily addressed the question of treatment with combined modality therapy versus chemotherapy alone [5-10]. What follows is a general discussion of the impact of these trials on patient care.

A choice regarding the use of combined modality therapy versus chemotherapy alone must take into consideration individual factors such as patient age, gender, and the location of the tumor. As examples:

●For many patients with favorable prognosis stage I to II HL, treatment with combined modality therapy using abbreviated chemotherapy and limited radiation (involved-field or involved-site) is appropriate. As examples: older adults with cervical and axillary presentations or minimal mediastinal disease where the addition of radiation permits a reduction in the number of cycles of chemotherapy. This choice places a higher value on the avoidance of disease recurrence (and possible need for autologous hematopoietic cell transplantation) and reduction of potential chemotherapy-related complications than on the potential for long-term radiation-associated toxicities (including secondary malignancies). (See 'Combined modality therapy' below.)

●For other patients, treatment with chemotherapy alone is appropriate. As an example: young (age <30) females with disease requiring irradiation of the breast tissue. This preference places a lower value on the slightly increased risk of relapse and a high value on the avoidance of potential radiation-associated complications. (See 'Chemotherapy alone' below.)

Combined modality therapy is associated with higher disease-free survival, but overall survival is similar with both approaches. Modern radiation therapy with lower dose and smaller field size will likely be associated with less long-term toxicity than treatment with higher doses and larger field size, without compromised efficacy, but this can only be confirmed with longer follow-up.

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 (without any difference in long-term survival). Treatment should also be individualized when a particular approach might result in a higher risk of a serious late complication (eg, the use of lung irradiation 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".)

Studies are in progress to determine whether mid-treatment imaging (eg, PET) can be used to determine whether adjuvant radiation is needed in individual patients with early stage disease, or to modify the treatment approach in patients who continue to have PET-positive disease after one or more courses of chemotherapy. This is discussed in more detail separately. (See "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment", section on 'Radiologic studies'.)

Combined modality therapy — Combined modality therapy consisting of combination chemotherapy plus involved-field or involved-site radiation therapy (ISRT) yields the highest rates of initial disease control in patients with favorable prognosis stage I to II HL. While the RT acts to control known sites of tumor, the chemotherapy is aimed at occult disease outside the radiation field. The combination of the two modalities allows for a decrease in the number of chemotherapy cycles given.

In most of the modern trials, when compared with chemotherapy alone, combined modality treatment has resulted in higher rates of freedom from recurrence but no difference in overall survival [4]. This lack of an overall survival benefit in most trials may be related to the effectiveness of salvage therapy after failure of treatment with chemotherapy alone.

Given these effective salvage therapies, trials in HL historically have required exceedingly long follow-up to see a difference in overall survival with initial therapy. As an example, a survival benefit to combined modality therapy compared with radiation alone was demonstrated only after 10-year follow-up of the large EORTC H8F trial [11].

Chemotherapy regimen — ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is the preferred combination chemotherapy regimen for the treatment of favorable prognosis stage I-II HL [11-14]. Stanford V with radiation therapy remains an acceptable alternative [15].

●ABVD is administered every 14 days in 28-day cycles (table 3); two administrations are considered one cycle. Patients treated with combined modality therapy usually receive between two and four cycles of ABVD. As such, the total time of chemotherapy ranges from 8 to 16 weeks. Involved-field or involved-site radiation therapy, which requires two to four weeks, usually begins three to four weeks after the completion of chemotherapy. The main severe (grade 3/4) acute toxicities are neutropenia, nausea/vomiting, and alopecia. Long term toxicities include cardiopulmonary toxicity, which is more frequently seen in children and in combination with mediastinal irradiation. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma", section on 'ABVD chemotherapy'.)

●Stanford V incorporates weekly chemotherapy (agents vary weekly, but include mechlorethamine, doxorubicin, vinblastine, prednisone, vincristine, bleomycin, and VP-16) administered over eight weeks, followed one to three weeks later by involved-field or involved-site irradiation to sites of initial involvement [15].

There are few randomized trials that have compared different chemotherapy regimens in combination with RT for the treatment of patients with favorable prognosis stage I to II HL. Many of the early randomized trials that examined combined modality therapy used regimens that contained an alkylating agent, usually MOPP (mechlorethamine, vincristine, procarbazine, prednisone) or an equivalent [3,16].

Our preference for ABVD rather than alkylating-agent containing chemotherapy regimens for early stage favorable prognosis disease is largely based upon the extrapolation of trials that compared ABVD with other regimens in patients with more advanced HL. ABVD has demonstrated superior efficacy (ie, freedom from progression) and less toxicity when compared with MOPP in patients with unfavorable prognosis, early stage and advanced stage HL [17,18]. Additional studies suggest that ABVD plus involved-field irradiation may be more effective and less toxic than alkylating agent regimens plus RT in stage I to II HL [17]. ABVD plus IFRT or ISRT has not been directly compared with Stanford V plus RT in the treatment of early stage favorable prognosis HL. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma", section on 'ABVD chemotherapy'.)

Omission of dacarbazine and/or bleomycin from ABVD decreases its efficacy. This was best illustrated in the German Hodgkin Study Group (GHSG) HD13 trial of 1502 patients with favorable prognosis stage I to II HL treated with two cycles of combination chemotherapy followed by 30 Gy involved-field radiation therapy [19]. Patients were randomly assigned to receive one of four regimens: standard ABVD or the same schedule and doses without bleomycin (AVD), without dacarbazine (ABV), or without both bleomycin and dacarbazine (AV). The ABV and AV arms were closed early due to high rates of progression during initial therapy (3 to 5 versus <1 percent with ABVD). Freedom from treatment failure (FFTF) at five years was 93 percent following ABVD and inferior following AVD (89 percent, hazard ratio [HR] 1.50), ABV (81 percent, HR 2.06), and AV (77 percent, HR 2.57). Overall survival at five years was not significantly different (98, 98, 94, and 98 percent, respectively). Given these results, neither bleomycin nor dacarbazine should be omitted from ABVD routinely. In contrast, bleomycin is omitted from subsequent cycles in patients who develop symptomatic or asymptomatic bleomycin-induced pulmonary toxicity during treatment. (See "Bleomycin-induced lung injury".)

Number of cycles — ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is the preferred chemotherapy for most patients with favorable prognosis stage I to II HL. While most of the trials that have evaluated this approach used four or more cycles of ABVD, attempts have been made to decrease the number of chemotherapy cycles in an attempt to lessen toxicity without compromising efficacy [2,20-22].

The German Hodgkin Study Group (GHSG) HD10 Trial randomly assigned 1370 patients with favorable prognosis early stage HL to receive one of the following four treatments [2]:

●Four cycles of ABVD followed by 30 Gy IFRT

●Four cycles of ABVD followed by 20 Gy IFRT

●Two cycles of ABVD followed by 30 Gy IFRT

●Two cycles of ABVD followed by 20 Gy IFRT

Eligibility criteria for this trial included patients with no more than two sites of disease, no extranodal extension, no mediastinal mass greater than or equal to one-third the maximum thoracic diameter, and ESR less than 50 (less than 30 if B symptoms present). At a median follow-up of 7.5 years, there was no significant difference between four and two cycles of ABVD chemotherapy in five-year overall survival (97.1 versus 96.6 percent), freedom from treatment failure (93.0 versus 91.1 percent), and progression-free survival (93.5 versus 91.2 percent). Estimated eight-year survival rates were also similar (95 versus 94 percent). However, there were significant differences in major toxicity (WHO grade III/IV) between four and two cycles of ABVD in the overall number of events (52 versus 33 percent) including leukopenia (24 versus 15 percent), infections (5.1 versus 1.7 percent), and hair loss (28 versus 15 percent).

The results of this trial suggest that two cycles of ABVD followed by 20 Gy involved-field (or perhaps involved-site) radiation therapy, a treatment program that can be completed in three months, may be sufficient treatment for patients with favorable presentations of stage I to II HL, as defined by the GHSG. Three to four cycles of ABVD followed by 30 Gy ISRT can be used for patients with favorable risk early stage disease that would not fit the enrollment criteria for the GHSG study (eg, those with three sites of disease).

Radiation field size — Over time there has been a movement to decrease the field of radiation in order to limit acute and long-term toxicities while maintaining survival rates. Various definitions have been applied. For our discussion, the following definitions will be used (table 4):

●Extended-field radiation (EFRT) – Radiation field includes not only the clinically involved nodes, but also the adjacent, clinically uninvolved sites (eg, mantle field or inverted-Y field).

●Involved-field radiation (IFRT) – Radiation field is limited to the clinically involved regions (eg, mediastinal plus low bilateral supraclavicular field which covers the entire mediastinum) (image 1) [23].

●Involved-site radiation (ISRT) – Radiation field includes only pre- and post-chemotherapy tumor volumes plus a margin of healthy tissue to accommodate uncertainties in determining the pre-chemotherapy tumor volume [24].

●Involved-node radiation (INRT) – Radiation field includes pre- and post-chemotherapy nodal volumes plus a very limited margin of healthy tissue (0.5 to 1 cm) (image 2) [25-27]. INRT requires optimal pre-chemotherapy PET/CT imaging acquired with the patient in the treatment position that can be fused with post-chemotherapy imaging [24].

The International Lymphoma Radiation Oncology Group (ILROG) has published field guidelines for modern radiation in HL [24]. For most patients, ISRT is preferred over larger radiation fields (eg, IFRT or EFRT). INRT can be considered a form of ISRT with more stringent requirements for pre-chemotherapy imaging studies. With ISRT and INRT, the radiation field is reduced in consideration of disease regression after chemotherapy to limit radiation to uninvolved normal organs. Intensity modulated RT, breath-hold techniques, and proton therapy can be used to limit damage to normal tissues further in select cases. In most cases, ISRT and INRT treatment fields are significantly smaller than those used with IFRT [27,28].  

Multiple trials have demonstrated decreased toxicity and similar survival rates when IFRT is used in combination with chemotherapy instead of EFRT in patients with early stage HL [11,29]. Most of these trials have been in patients with unfavorable prognosis early stage disease and are described separately. Initial studies also suggest that INRT decreases the radiation field without compromising disease control [24-27,30]. However, INRT is technically challenging in that it requires pre-chemotherapy imaging studies obtained with the patient in the planned RT position and stored in a format that can be fused with post-chemotherapy imaging. ISRT uses a more conservative measure of disease by adjusting for uncertainties due to suboptimal imaging and other factors. Disease control following ISRT is expected to be at least as good as that obtained with INRT. (See "Treatment of unfavorable prognosis early (stage I-II) classic Hodgkin lymphoma in adults", section on 'Radiation field size'.)

A retrospective analysis of 97 patients with stage I-II HL treated with ABVD plus INRT and followed for a median of 50 months reported an estimated four-year survival rate of 94 percent (95% CI 89-99 percent) [30]. There were three relapses, two within the radiation field and one in a previously uninvolved region. There were eight deaths, none due to HL. These results are similar to what have been reported with abbreviated chemotherapy followed by involved field irradiation (GHSG HD10) [2].

For patients receiving combined modality treatment, we suggest ISRT rather than larger radiation fields. The volume irradiated should always be minimized to reduce the risk for treatment-related complications, especially cardiovascular and secondary cancers, and preliminary data suggest no compromise in outcomes [30] (see 'Monitoring for treatment complications' below).

Radiation dose — The majority of trials that have evaluated the use of chemotherapy in combination with involved-field radiation therapy (IFRT) in early stage HL have administered the radiation at a dose of 30 to 40 Gy (administered in single fractions of 1.8 to 2.0 Gy five times weekly) [11-13,31]. Short- and long-term toxicities increase as the dose of radiation increases. As such, attempts have been made to decrease the dose of RT administered to patients with early stage disease. While additional follow-up is necessary to investigate for long-term outcomes, lower RT doses appear to be associated with less short-term toxicity and similar efficacy.

This was best illustrated in the German Hodgkin Study Group (GHSG) HD10 Trial that randomly assigned 1370 patients with favorable prognosis early stage HL to receive one of the following four treatments [2]:

●Four cycles of ABVD followed by 30 Gy IFRT

●Four cycles of ABVD followed by 20 Gy IFRT

●Two cycles of ABVD followed by 30 Gy IFRT

●Two cycles of ABVD followed by 20 Gy IFRT

Eligibility criteria for this trial included patients with no more than two sites of disease, no extranodal extension, no mediastinal mass greater than or equal to one-third the maximum thoracic diameter, and ESR less than 50 (less than 30 if B symptoms present). At median follow-up of 7.5 years, there was no significant difference between 30 and 20 Gy IFRT in five-year overall survival (OS, 97.7 versus 97.5 percent), freedom from treatment failure (FFTF, 93.4 versus 92.9 percent), and progression-free survival (PFS, 93.7 versus 93.2 percent). However, there were significant differences in major toxicity (WHO grade III/IV) between 30 and 20 Gy IFRT (all events, 8.7 versus 2.9 percent), dysphagia (3 versus 2 percent), and mucositis (3.4 versus 0.7 percent).

The results of this trial suggest that two cycles of ABVD followed by 20 Gy involved-field (or perhaps involved-site) radiation therapy may be sufficient treatment for patients with favorable prognosis early stage HL, as defined by the GHSG. Three to four cycles of ABVD followed by 30 Gy involved-site radiation therapy can be used for patients with favorable risk early stage disease that would not fit the enrollment criteria for the GHSG study (eg, those with three sites of disease). Higher radiation doses and a minimum of four cycles of ABVD are used for patients with unfavorable risk early stage disease. (See "Treatment of unfavorable prognosis early (stage I-II) classic Hodgkin lymphoma in adults", section on 'Radiation dose'.)

Chemotherapy alone — The efficacy of chemotherapy alone for the treatment of early stage HL has been addressed in a number of clinical trials comparing chemotherapy alone versus combined modality therapy. Unfortunately, many of these trials have utilized suboptimal chemotherapy or larger field, higher dose irradiation than is currently recommended [32]. Nearly all of the trials evaluating chemotherapy with or without RT have been conducted in favorable prognosis patients. Although these trials have had a number of problems with design and patient accrual, as well as variations in the type of chemotherapy and field size of RT utilized, the overall survival of these approaches is comparable. 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.

In the NCIC/ECOG HD.6 randomized trial, 405 patients with previously untreated stage IA or IIA non-bulky HL were randomly assigned treatment with four to six cycles of ABVD alone, or to treatment that included 35 Gy RT [9]. The RT arm consisted of sub-total nodal RT (treatment above and below the diaphragm, including the spleen) without chemotherapy for patients with a favorable prognosis (n = 123) and was two cycles of ABVD followed by sub-total nodal RT for patients with an unfavorable prognosis (n = 276). Patients in the chemotherapy only arm who achieved a complete remission on CT scan after two cycles received a total of four cycles and all others received six cycles. At a median follow-up of 11.3 years, chemotherapy alone was associated with a lower rate of freedom from disease progression (FFDP, 87 versus 92 percent) but a higher rate of overall survival (OS, 94 versus 87 percent) at 12 years in the entire population. This improvement in survival was attributed to an increased rate of non-relapse mortality among patients treated with sub-total nodal RT. However, this result is confounded by the fact that a number of the deaths in the radiation-containing arms were not treatment-related. On a subset analysis of patients with a favorable prognosis, there was no significant difference in FFDP (89 versus 87 percent for ABVD versus RT, respectively) or OS (98 percent in both groups). The radiotherapy used in this study, sub-total nodal RT, is likely associated with higher rates of late toxicity compared with modern techniques using lower doses and smaller fields.

The following two randomized trials evaluated whether radiation therapy could be avoided in patients with non-bulky early stage HL and a negative mid-treatment PET scan:

●The EORTC H10 trial using PET to determine the need for radiation after chemotherapy demonstrated higher recurrence rates in patients who were PET negative after two cycles of ABVD and went on to receive another two cycles without radiation compared with the addition of RT [10]. The trial closed the chemotherapy alone arm due to stopping rules.

●In the UK RAPID trial, 420 patients with early stage non-bulky HL determined by pre-treatment CT scan who achieved a negative PET scan after three cycles of ABVD chemotherapy were randomly assigned to receive 30 Gy involved-field RT or no further therapy [20]. Approximately 65 to 70 percent had favorable features by EORTC and GHSG criteria. After a median follow-up of 36 months, those assigned to RT had a lower rate of disease progression (3.8 versus 9.5 percent; three-year PFS 94.6 versus 90.8 percent) and a higher rate of death without disease progression (2.4 versus 0.9 percent). Further follow-up is needed to evaluate for long-term toxicities and for more mature survival data.  

For patients with favorable prognosis stage I to II HL, a choice between combined modality therapy and chemotherapy alone must take into account patient preferences and risk of complications. We suggest treatment with chemotherapy alone for young (age <30) females with disease requiring irradiation that includes the breasts. This preference places a lower value on an increased risk of relapse and a higher value on the avoidance of radiation-associated complications. Modern RT with lower dose and smaller field size is likely associated with less long-term toxicity than higher dose larger field size treatment, without compromised efficacy, but this must be confirmed with longer follow-up of patients treated using these techniques. (See 'Choice of therapy' above.)

SPECIAL SCENARIOS — The general treatment principles for favorable prognosis stage I to II HL apply to most disease presentations and patient populations. However, certain patient populations, such as pregnant women and older adults, require special consideration.

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

Adolescents — It appears that adult treatment protocols may be safe and provide comparable efficacy to pediatric protocols in the treatment of adolescents with HL. Careful consideration of the late effects of therapy is required in the selection of optimal therapy in this patient population. (See "Overview of Hodgkin lymphoma in children and adolescents".)

Older adults — The management of lymphoma in older adults (ie, over age 60 years) can be complicated by an increased number of comorbidities. A comprehensive geriatric assessment can assess comorbidity and functional status, thus permitting the formulation of an appropriate, individualized treatment plan. Special considerations for the use of chemotherapy in the elderly population are discussed separately. (See "Comprehensive geriatric assessment for patients with cancer" and "Systemic chemotherapy for cancer in older adults".)

We believe that older adults should be initially treated with the same dosing and schedule as younger adults with adjustments made to future cycles according to tolerance. This is principally because the amount of chemotherapy administered in the initial treatment of HL may affect overall survival. In a potentially curable disease such as HL, it is especially important to treat all patients aggressively, even older individuals.

There is increasing data that older patients are particularly vulnerable to the toxicity of bleomycin, which can be severe. Some have advocated omitting bleomycin in older patients to minimize pulmonary toxicity [33]; however, this might compromise cure rates without lessening toxicity. Studies in early stage disease have demonstrated slightly higher rates of treatment failure when bleomycin is omitted from ABVD [19]. Also, in a subset analysis of older adults in the randomized German Hodgkin Study Group (GHSG) HD10 and HD13 trials, two cycles of ABVD was no more toxic than two cycles AVD in this population [34]. In contrast, excessive pulmonary toxicity was seen in older adults receiving four cycles of ABVD.

While we don’t routinely omit bleomycin in this setting, a decision to do so can be made on an individual basis considering the risk of toxicity and potential for cure. We occasionally omit bleomycin based on advanced age (eg, ≥80 years), frailty, low probability of cure, or high-risk comorbidities (eg, underlying pulmonary disease, active smokers). Details regarding the risk factors for bleomycin-induced lung injury and its diagnosis and management are presented separately. (See "Bleomycin-induced lung injury".)

Prospective studies are evaluating novel approaches that omit bleomycin (eg, substituting brentuximab vedotin for bleomycin). Use of such regimens should be restricted to the clinical trial setting. Importantly, adding brentuximab vedotin without omitting bleomycin results in unacceptably high rates of potentially fatal pulmonary toxicity [35].

HIV-infected patients — Treatment of patients with HIV who develop HL is complicated by their immunocompromised state, and also requires specific treatment for their HIV. As such, treatment of these patients is discussed in more detail separately. (See "HIV-related lymphomas: Treatment of systemic lymphoma".)

Nodular lymphocyte predominant Hodgkin lymphoma — 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 HL, patients should be evaluated to determine the disease response to treatment and should be followed longitudinally for relapse.

Response evaluation — One month following the completion of planned therapy (or sooner if the outcome is unfavorable), the response to treatment should be documented by history, physical examination, and laboratory studies (complete blood count, erythrocyte sedimentation rate [ESR], and biochemical profile). The post-treatment imaging study of choice is the positron emission tomography/computed tomography (PET/CT) scan, which provides information on the size and activity of residual masses and allows for the distinction between active disease and fibrosis. PET/CT should be obtained six to eight weeks after completion of chemotherapy and three months after the completion of radiation therapy (RT) [36]. PET/CT imaging obtained earlier than this may demonstrate increased uptake due to an inflammatory reaction to treatment. If the mid- or post-treatment PET scan is normal then subsequent follow-up scans should be done with contrast enhanced CT scans of appropriate body regions, rather than PET scans.

Using information gathered from the history, physical, and PET/CT scan, disease response is determined by the International Working Group (IWG) response criteria [37]. A complete remission has been achieved if all of the following criteria are met:

●There is no evidence of disease or disease-related symptoms on history and physical examination.

●All post-treatment residual masses are negative on PET scan.

●The spleen and liver are non-palpable and without nodules.

For patients with advanced stage disease, the IWG response criteria also consider bone marrow involvement. If a pre-treatment bone marrow biopsy was positive, a repeat bone marrow biopsy must be negative. If morphologically indeterminate, immunohistochemistry should be negative.

A discussion of the accuracy of PET/CT in the follow-up of patients with lymphoma is presented separately. (See "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment", section on 'After treatment'.)

Patients with stage I-II disease whose PET/CT does not normalize with chemotherapy, but shows a significant response, may undergo RT as planned without further treatment, with another evaluation by PET/CT following completion of irradiation. Patients with disease that fails to respond to chemotherapy or whose disease grows on chemotherapy are treated as having refractory disease. Treatment of refractory disease is presented in detail separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)

Surveillance for relapse — Following the completion of therapy, restaging, and documentation of complete remission, patients are seen at periodic intervals to monitor for treatment complications and assess for possible relapse. The frequency and extent of these visits depends upon the comfort of both the patient and physician. Our approach is presented in more detail separately. (See "Approach to the adult survivor of classic Hodgkin lymphoma", section on 'Post-treatment management'.)

Most relapses of early stage HL occur within the first two to three years [38,39]. In one series of 1044 patients in remission after therapy for early stage HL, 32.6 percent relapsed; only 3.5 percent of these relapses occurred after five years [38].

Many patients who relapse after chemotherapy alone or combined modality therapy may be considered candidates for high dose chemotherapy and autologous hematopoietic cell rescue, which results in long term control of disease in at least 50 percent of patients. However, a subset of patients who present initially with favorable disease may be candidates for salvage treatment with combined modality therapy and may be able to avoid a transplant. (See "Hematopoietic cell transplantation in classic Hodgkin lymphoma" and "Treatment of relapsed or refractory classic Hodgkin lymphoma".)

Monitoring for treatment complications — Much of the long-term follow-up data (15 years or longer) for early stage HL are derived from laparotomy-staged patients who were treated with large field, high-dose RT alone. Large, single institutional studies have found at 10 to 15 years an actuarial freedom from relapse rate exceeding 80 percent and a mortality rate below 10 percent following mantle and paraaortic irradiation for pathologically staged IA to IIA disease [40-42].

These results have been achieved through careful delineation of the extent of HL, precise delivery of RT (since inadequate portals are associated with in-field or marginal recurrence rates as high as 33 percent versus 7 percent in those with adequate portals) [43], and treatment of patients who relapse with multiagent chemotherapy [44,45].

The treatment of early stage HL has become so successful that at 15 to 20 years post-treatment, the overall mortality rate from causes other than HL may exceed that seen from HL [46-49]. In one series of 794 patients, for example, 124 died at a mean follow-up of 11 years: 56 from HL, 36 from second malignancies, 15 from cardiac disease, and eight from other causes [46,49]. Deaths from HL primarily occurred in the first 5 to 10 years, with almost no Hodgkin-related deaths after 15 years; in comparison, deaths from second malignancy primarily occurred after 10 years and continued to increase with time (figure 1). The estimated excess risk of mortality was approximately 1 percent per year over the first 20 years.

Second malignancy — The estimated risk of a second cancer following large field irradiation with or without chemotherapy is approximately 15 percent at 15 years after treatment of HL. The most common second malignancies are acute nonlymphoblastic leukemia (which primarily occurs in the first 10 years and develops much more often after chemotherapy, especially MOPP, than radiation), non-Hodgkin lymphoma, and solid tumors (which account for approximately 75 percent of second malignancies and occur after both chemotherapy and radiation). This is discussed in more detail separately. (See "Second malignancies after treatment of classic Hodgkin lymphoma".)

Cardiac disease — A variety of complications related to cardiac irradiation (arrhythmias, myocardial infarction and coronary artery disease, pericarditis, myocarditis, pericardial effusion and tamponade, and cardiac death) have been carefully documented after high dose RT that includes the entire mediastinum [46,48-53].

In many of the initial studies, cardiac complications related to treatment techniques that resulted in a high radiation dose to the anterior mediastinum and heart. Current practice, which restricts the dose to the whole heart, blocks the subcarinal region part way into treatment, and limits exposure to cardiac toxins such as doxorubicin, has lowered this risk [52,53]. A retrospective study of 2232 survivors of HL treated at Stanford between 1960 and 1991 and followed for an average of 9.5 years found that 3.9 percent died from cardiac disease (myocardial infarction, heart failure, radiation pericarditis or pancarditis, cardiomyopathy, or valvular heart disease); the relative risk of death from heart disease was 3.1 [53]. This risk was increased only in those patients who received more than 30 Gy to the mediastinum. Blocking to limit cardiac exposure did not alter the risk of myocardial infarction, but did reduce the relative risk for other cardiac diseases from 5.3 to 1.4. The lack of protection against infarction may reflect exposure of the proximal portion of the coronary arteries to the full dose of radiation regardless of the amount of blocking used. Current techniques of involved site irradiation with lower doses are likely to reduce these risks further. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

In another study from Stanford University to determine long-term cardiac effects, 294 asymptomatic patients treated with mediastinal irradiation for HL underwent electrocardiography and echocardiography screening at a median time of 15 years following initial treatment [54]. In this study, the prevalence of valvular abnormality increased significantly with increasing follow-up time. For patients who were more than 20 years post-RT, >60 percent had at least one pathologic valvular abnormality (eg, aortic stenosis or regurgitation, mitral regurgitation or stenosis). Less than 10 percent of these patients had an audible murmur on examination.

These results demonstrate the usefulness of screening echocardiogram in identifying patients with valvular disease who might benefit from endocarditis prophylaxis. The number needed to screen with echocardiography to identify a candidate for endocarditis prophylaxis decreased dramatically with time following irradiation: 13 for patients at 2 to 10 years, 4 for patients at 11 to 20 years, and 1.6 for those beyond 20 years following initial HL therapy.

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).

Death from favorable prognosis early stage HL is unusual and mortality from causes other than HL occurs many years later. Efficacy must be judged by freedom from first recurrence rates, acute and chronic morbidity, and by new criteria such as quality of life and perhaps cost-effectiveness [55], as well as treatment-related mortality at 10 to 20 years, which may exceed HL mortality in patients with favorable early stage disease (figure 1) [46-48].

Accordingly, current clinical trials are evaluating the use of alternative chemotherapy combinations, shortened courses of chemotherapy, chemotherapy with smaller radiation fields and/or lower radiation doses [56-58], and chemotherapy without radiation therapy, as well as the use of early "interim" response to chemotherapy with PET/CT imaging to define patients who can be effectively treated with chemotherapy alone.

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. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 2), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

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

●Favorable prognosis early-stage classic Hodgkin lymphoma (cHL)

•Early-stage cHL – Stage I or II disease, according to Lugano criteria (table 1). (See 'Pretreatment evaluation' above.)

•Favorable prognosis – Criteria vary among cooperative groups. In the United States, favorable prognosis generally refers to early-stage cHL with limited numbers of nodal sites/areas of involvement, nonbulky (≤10 cm) disease, no B symptoms, and erythrocyte sedimentation rate (ESR) <50. (See 'International Prognostic Score' above.)

●Response-guided therapy – We suggest response-guided therapy using two initial cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) followed by positron emission tomography (PET)/computed tomography (CT), rather than a predetermined course of chemotherapy or combined modality therapy (CMT; ie, chemotherapy followed by radiation therapy) (Grade 2B). (See 'Response evaluation' above.)

Response-guided therapy enables excellent outcomes with less toxic treatment for most patients, while offering escalated treatment with improved survival rates for patients with inadequate responses.

●Subsequent treatment – Guided by PET response, using the five-point (Deauville) scale (table 5). (See 'Choice of therapy' above.)

Staging criteria and treatment protocols vary among research groups; selection of treatment should apply staging and response criteria used in that protocol.

•Deauville score (DS) 1 to 3 – Either chemotherapy alone or CMT is acceptable; selecting CMT should weigh the relative importance assigned to fewer recurrences versus radiation therapy (RT)-associated late toxicities, including second malignancies:

-Chemotherapy alone – According to the chosen treatment protocol/staging criteria; examples include two additional cycles of ABVD (DS 1 to 2) or four cycles of AVD, (DS 3) as discussed above.

-Combined modality therapy – According to the chosen treatment protocol/staging criteria; examples include 20 gray (Gy) involved-site RT (ISRT) alone or one additional cycle of ABVD followed by 30 Gy ISRT, based on extent of disease and patient characteristics, as discussed above.

•DS 4 – Findings vary and may affect treatment:

-Focally positive – Two additional cycles of ABVD, then restage with PET. If negative, add ISRT; if positive, treat as primary refractory cHL. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)

-Other DS 4 – As per PET 5 (below).

•DS 5 – Re-biopsy active disease to confirm the diagnosis, if accessible:

-Positive biopsy – Treat as primary refractory cHL. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)

-Negative biopsy – Two additional cycles of ABVD, then restage with PET.

For patients <60 years with DS 5, rather than repeating the biopsy, some experts favor escBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), with repeat PET after four cycles. If PET remains positive, treat as primary refractory cHL.

●Chemotherapy – We suggest initial treatment with ABVD, rather BEACOPP or other regimens (Grade 2B).

●Radiation therapy – ISRT is favored over larger fields to lessen short-term and long-term toxicity. (See 'Combined modality therapy' above.)

●Special scenarios – Treatment should be individualized for special scenarios (eg, pregnant, older, less-fit). (See 'Special scenarios' above.)

●Follow-up – PET/CT is performed after completion of planned therapy. Monitoring for relapse and complications of therapy is described above. (See 'Patient follow-up' above.)

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