Hodgkin Lymphoma Guidelines 

Updated: Jun 30, 2015
  • Author: Priyank P Patel, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Diagnosis

Updated guidelines on the management of Hodgkin lymphoma have been issued by the National Comprehensive Cancer Network (NCCN) [1] and the European Society for Medical Oncology (ESMO) [2] The NCCN and ESMO guidelines have very similar recommendations for the diagnostic evaluation. [1, 2] Histological evaluation is required for diagnosis according to the World Health Organization (WHO) classification of either nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) or one of four classic Hodgkin lymphoma (CHL) subtypes, as follows:

  • Nodular sclerosis CHL (NSCHL)
  • Mixed cellularity CHL (MCCHL)
  • Lymphocyte-depleted CHL (LDCHL)
  • Lymphocyte-rich CHL (LRCHL)

The presence of Hodgkin and Reed-Sternberg (HRS) cells is disease defining for CHL. Detection of lymphocyte-predominant (LP) cells is required for the diagnosis of NLPHL

Biopsy recommendations are as follows:

  • Excisional biopsy is preferred
  • Core needle biopsy can be considered if excisional biopsy is not possible
  • Fine needle aspiration should be avoided

Other recommendations for diagnosis are as follows:

  • History and physical examination to determine presence of B symptoms (unexplained weight loss >10%, fever, drenching night sweats)
  • Fatigue, pruritus, and alcohol intolerance should also be noted
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Staging

Both the National Comprehensive Cancer Network (NCCN) [1] and the European Society for Medical Oncology (ESMO) [2] recommend the Cotswold modified Ann Arbor classification for staging. [3] See Table 1, below.

Table 1. Cotswold Modification of Ann Arbor Staging System (Open Table in a new window)

Stage Area of Involvement
I Single lymph node group
II Multiple lymph node groups on same side of diaphragm
III Multiple lymph node groups on both sides of diaphragm

In 2014, the International Conference on Malignant Lymphomas, a multi-disciplinary team of researchers, representing major lymphoma clinical trial groups and cancer centers from North America, Europe, Japan and Australasia, published guidelines for the evaluation, staging, and response assessment. These guidelines were intended to be an update to the 2007 revised guidelines of the International Harmonization Project. [4] The revised recommendations for staging are as follows [5] :

  • PET-CT is preferred for pretreatment assessment and routine staging
  • Contrast-enhanced CT is more accurate for measurement of nodal size and is also preferred for radiation planning
  • Chest x-ray is not required
  • PET-CT is preferred for determining splenic involvement with cutoff for splenomegaly of more than 13 cm
  • Liver size is not a reliable measure of hepatic involvement; diffusely increased or focal uptake, with or without focal or disseminated nodules, supports liver involvement
  • Bone marrow aspirate/biopsy is not required for early-stage HL (stage I-IIA) if PET-CT was performed (an exception noted by NCCN is if PET-CT is negative but the patient has unexplained cytopenias [1] )
  • Bone marrow biopsy and aspirate is required for patients with advanced-stage HL (stage IIB-IV)

In addition, these guidelines offered consensus on further modifications to the Ann Arbor staging classification. See Table 2, below. [5]

Table 2. International Conference on Malignant Lymphomas Modification of Ann Arbor Staging (Open Table in a new window)

Stage Area of Involvement Extranodal (E) Status
I Single node or adjacent group of nodes Single extranodal lesions without nodal involvement
II Multiple lymph node groups on same side of diaphragm Stage I or II by nodal extent with limited contiguous extranodal involvement
II bulky* Multiple lymph node groups on same side of diaphragm with bulk >10 cm N/A
III Multiple lymph node groups on both sides of diaphragm; nodes above the diaphragm with spleen involvement N/A
IV Multiple noncontiguous extranodal sites N/A
A/B B symptoms: weight loss >10%, fever, drenching night sweats N/A
*Stage II bulky disease is defined as limited or advanced on the basis of histology and a number of prognostic factors.
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Risk Stratification

Based on the clinical scenario, staging, and degree of end-organ damage, patients with Hodgkin lymphoma are further categorized into the following three groups:

  • Early-stage favorable
  • Early-stage unfavorable
  • Advanced-stage

National Comprehensive Cancer Network (NCCN) guidelines define unfavorable factors for stage I-II as follows [1] :

  • Bulky mediastinal disease (Mediastinal mass ratio [MMR; maximum width of mass/maximum intrathoracic diameter] greater than 0.33) or bulky disease greater than 10 cm
  • B symptoms
  • Erythrocyte sedimentation rate (ESR) >50 mm/hr
  • More than two-three nodal sites of disease

The European Society for Medical Oncology (ESMO) guidelines recommend the slightly different definitions of risk factors from the European Organization for Research and Treatment of Cancer /Lymphoma Study Association (EORTC/LSA) and the German Hodgkin Study Group (GSHG), as outlined in Table 3, below.{Ref 2}

Table 3. Unfavorable Risk Factors for Stages I and II Hodgkin Lymphoma (Open Table in a new window)

Risk Factor GSHG EORTC/LSA
Age                    – ≥50 y
Histology                    – MC or LD
ESR or B symptoms >50 mm/hr if A or >30 if B >50 mm/hr if A or > 30 if B
Mediastinal mass* MMR >0.33 MMR >0.35
Number of nodal sites >2 >3
Extranodal lesions Any                    –
* Mediastinal mass is measured on chest x-ray by the mediastinal mass ratio (MMR), which is the maximum width of the mass/maximum intrathoracic diameter.ESR = erythrocyte sedimentation rate; LD = lymphocyte depletion; MC = mixed cellularity.

Patients with advanced disease are further risk stratified using the International Prognostic Score (IPS), which includes the following risk factors (for scoring, each factor receives 1 point) [6] :

  • Albumin <4 g/dL
  • Hemoglobin <0.5 g/dL
  • Male
  • Age ≥45 y
  • Stage IV disease
  • Leukocytosis: white blood cell count (WBC) >15,000/μL
  • Lymphopenia: Lymphocyte count <8% of WBC and/or absolute lymphocyte count <600 cells/μL

Based on the IPS score, patients with advanced disease can be categorized as follows [5] :

  • Good risk (IPS 0-1)
  • Fair risk (IPS 2-3)
  • Poor risk (IPS 4-7)
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Treatment for Classic Hodgkin Lymphoma

Recommendations for primary treatment of classic Hodgkin lymphoma (CHL) vary by stage and risk stratification. Chemotherapy is followed by restaging with PET-CT.

Early-stage Favorable Disease

Combined modality is the treatment of choice in patients with early-stage CHL. The National Comprehensive Cancer Network (NCCN) guidelines give the ABVD (doxorubicin [Adriamycin]/bleomycin/vinblastine/dacarbazine) regimen a category 1 rating (ie, the recommendation is based on high-level evidence and uniform NCCN consensus that the intervention is appropriate), but also list an 8-week Stanford V regimen (doxorubicin, vinblastine, mechlorethamine [or cyclophosphamide], etoposide, vincristine, bleomycin, and prednisone) as an alternative. [1]

ABVD is administered in four cycles. However, two cycles are suggested in highly selected patients with very favorable disease characterized by the following [1] :

  • No bulky disease
  • No extralymphatic involvement
  • Fewer than three sites of disease
  • Erythrocyte sedimentation rate (ESR) <30 mm/hr, or <50 mm/hr in patients without B symptoms
  • The European Society for Medical Oncology (ESMO) guidelines recommend two to three cycles of ABVD followed by involved-field radiation therapy (IFRT). ESMO recommends against interim PET-guided treatment outside of clinical trials. [2]

Early-stage Unfavorable Disease

The NCCN supports the following treatments for stage I-II unfavorable (non-bulky) CHL [1] :

  • ABVD regimen for two cycles and additional ABVD cycles or ABVD with involved-site radiation therapy (ISRT), as warranted or
  • Stanford V regimen for three cycles (12 weeks) (the regimen includes ISRT) or
  • Escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) regimen for two cycles with ISRT

NCCN recommendations for treatment of early-stage unfavorable (bulky) disease are as follows:

  • ABVD for four cycles (category 1 recommendation) follow by ISRT or
  • Stanford V regimen for three cycles (12 weeks) or
  • Escalated BEACOPP regimen for two cycles plus ABVD for two cycles plus ISRT

The ESMO guidelines recommend four cycles of ABVD with IFRT. In younger patients (≤60 years) a more intensive treatment can be considered, consisting of two cycles of escalated BEACOPP followed by two cycles of ABVD with IFRT. [2]

Advanced-stage Disease

The NCCN supports the following treatments for stage III-IV, (non-bulky) CHL [1] :

  • ABVD for six cycles or
  • In patients with an IPS <3, Stanford V regimen for three cycles (12 weeks) or
  • In patients with an IPS ≥4, escalated BEACOPP regimen for six cycles
  • For stage III-IV (bulky) CHL, the NCCN recommendations are the same as above, with the addition of ISRT to original sites of bulky disease

The ESMO guidelines recommend the following [2] :

  • ABVD for six to eight cycles, followed by localized radiotherapy of residual lymphoma larger than 1.5 cm
  • Escalated BEACOPP for six cycles, followed by localized radiotherapy of residual lymphoma larger than 2.5 cm

Refractory or Relapsed Disease

Both the NCCN and ESMO guidelines recommend high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) for refractory or relapsed disease. The selection of second-line chemotherapy is determined by comparison with the agents previously used. [1, 2] Brentuximab vedotin is recommended for patients who have a failure of autologous stem cell transplantation or failure of at least two prior multi-agent chemotherapy regimens. [1, 2]

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Treatment for NLPHL

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a distinct entity with unique clinical features and a different treatment paradigm. The National Comprehensive Cancer Network (NCCN) prefers involved-site radiation therapy (ISRT) over involved-field radiation therapy (IFRT) for treatment of early-stage favorable NLPHL. (Involved-site fields are generally smaller than classic involved fields.) For early-stage unfavorable or advanced-stage NLPHL, an ABVD regimen (doxorubicin [Adriamycin]/bleomycin/vinblastine/dacarbazine) plus ISRT is recommended. CHOP (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], and prednisone) may also be used. [1]

Rituximab may be considered in combination with ABVD or CHOP. For refractory disease, maintenance rituximab may be considered. Individualized treatment is recommended. At relapse, patients biopsy should be performed due to the high rate of conversion to aggressive B-cell lymphoma. [1]

ESMO recommends IFRT for treatment of patients with stage IA NLPHL who have no risk factors. For early-stage unfavorable or advanced stage disease, the treatment recommendation is identical to that for CHL. [2]

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Long-Term Monitoring

Both the National Comprehensive Cancer Network (NCCN) [1] and the European Society for Medical Oncology (ESMO) [2] guidelines provide recommendations for the long-term follow-up of treated patients with Hodgkin lymphoma who are in complete remission. The NCCN recommends interim physical exams and blood tests every 3 to 6 months for 1 to 2 years and then every 6 to 12 months for the next 3 years and then annually. [1] ESMO suggests follow-up every 3 months for the first 6 months, and every 6 months until year 4, then annually. [2]

Follow-up examination recommendations are similar for both guidelines, but those from the NCCN are more detailed. NCCN recommendation for follow-up in the first 5 years include the following [1] :

  • History and physical examination
  • Complete blood cell count (CBC), serum chemistry panel, and erythrocyte sedimentation rate (ESR)
  • Thyroid-stimulating hormone (TSH) levels (at least annually if the patient has had neck radiation therapy)
  • Annual influenza vaccine
  • Chest x-ray or CT scans every 6-12 months in the first 1 year, and then as clinically indicated.
  • Abdominal and pelvic CT scans every 6-12 months in the first 2 years
  • Use of PET scans for surveillance in patients with complete remission is specifically not encouraged by the NCCN, due to the possibility of false-positive results.

Recommendations for annual monitoring for late complications after 5 years include the following [1] :

  • CBC, serum chemistry panel, and erythrocyte sedimentation rate (ESR)
  • TSH levels (at least annually if the patient has had neck radiation therapy)
  • Blood pressure monitoring
  • Management of cardiovascular risk factors; stress test/echocardiogram and carotid ultrasound (if the patient has had neck radiation therapy) every 10 years
  • Vaccinations against pneumococcus, Haemophilus influenzae, and meningococcus (especially in patients who have had splenectomy), with revaccination every 5-7 years
  • Annual influenza vaccine
  • Chest x-ray or low-dose CT scans of the chest in patients with increased risk of lung cancer
  • In women who have received chest irradiation¸ annual screening with mammography, starting at age 40 years or 8-10 years after radiation therapy; breast magnetic resonance imaging (MRI) in addition to mammography is indicated for patients who received chest radiation therapy between the ages of 10 and 30 years
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