Approach

The management approach outlined in this topic focuses on adults with HL.

Chemotherapy and radiotherapy are the cornerstone of treatment for HL. The goal of treatment for all patients with HL is cure while minimising risk of toxicity and long-term complications.

HL in older patients (aged >60 years) is associated with poorer outcomes and higher treatment-related toxicity and mortality compared with younger patients.[47][48][49]​​​​​ Alternative treatment regimens may be considered for patients >60 years, or with poor performance status or substantial comorbidities. Bleomycin should be used with caution; standard regimens may be adapted to remove bleomycin or restrict its use to only two cycles.[33]

Early-stage (stage I to stage II) classical HL

The absence or presence of specific prognostic criteria determines whether the patient has favourable or unfavourable early-stage disease. German Hodgkin Study Group (GHSG) favourable prognosis criteria (see Diagnostic criteria) are most commonly used in the US:[44][50]

  • Mediastinal mass ratio (MMR) <0.33

  • Erythrocyte sedimentation rate (ESR) <50 mm/hour if no B symptoms; ESR <30 mm/hour if B symptoms are present

  • Involvement of ≤2 nodal sites

  • No extranodal disease.

The most effective treatment for early-stage disease (favourable or unfavourable) is combined-modality therapy, which comprises combination chemotherapy (typically ABVD [doxorubicin, bleomycin, vinblastine, dacarbazine]) followed by radiotherapy.[51][52][53][54][55][56][57][58][59][60][61] 

A chemotherapy-alone approach may be considered if avoiding radiotherapy is preferred (e.g., due to patient age, sex, family history of cancer or cardiac disease, comorbidities, sites of involvement).[33][62][63][64][65][66] The decision to omit radiotherapy should involve expert input by a multidisciplinary team, and discussion with the patient regarding risks and benefits. Chemotherapy alone is associated with a slightly lower rate of tumour control and higher rate of relapse compared with combined-modality therapy, but survival rates are similar.[51][52][53][58][60][64][66][67][68][69] [ Cochrane Clinical Answers logo ]

Radiotherapy for early-stage HL

Involved-site radiotherapy (ISRT) is preferred to traditional involved-field radiotherapy (IFRT) due to its lower risk of adverse effects.[70][71][72][73] ISRT focuses radiation only on involved lymph nodes and nearby sites, minimising radiation exposure to uninvolved structures.

Acute adverse effects of radiotherapy depend on the region treated and the dose employed.

Patients receiving treatment to the mediastinum can develop oesophagitis, clinically apparent as odynophagia that sometimes requires opioid analgesics to maintain oral intake. Infradiaphragmatic radioherapy can cause nausea and/or diarrhoea.

Fatigue is common in all patients receiving radiotherapy. Possible long-term adverse effects of radiotherapy include secondary malignancies, cardiovascular disease, and decreased pulmonary function.

PET-adapted treatment for early-stage HL

A PET-adapted treatment approach is recommended for all patients with early-stage disease (favourable or unfavourable) as it offers the opportunity to balance efficacy and toxicity of treatment.[5][33][54][65][66][74][75] This approach typically involves performing an interim PET/CT scan after two initial cycles of chemotherapy (e.g., ABVD) to assess metabolic response to treatment, and to inform subsequent treatment (e.g., additional chemotherapy and/or radiotherapy).

Metabolic response is determined using the Deauville criteria, which assigns a score of 1 to 5 based on fluorodeoxyglucose (FDG) uptake at involved sites.[40]​​​ Patients with a Deauville score of 1 to 3 (i.e., negative PET/CT) are considered to have a complete metabolic response. Patients with a Deauville score of 4 or 5 (i.e., positive PET/CT) are considered to have a partial metabolic response (see Diagnostic criteria). 

Treatment for favourable early-stage HL

Patients with favourable early-stage disease generally receive two initial cycles of ABVD followed by an interim PET/CT scan.[33]

Those intended for combined-modality therapy can receive the following subsequent treatments based on their Deauville score on interim PET/CT:

  • Deauville score 1 to 2: 20 Gy radiotherapy, or one additional cycle of ABVD followed by 30 Gy radiotherapy.[60][61][65][67]

  • Deauville score 3: 20 Gy radiotherapy, or two additional cycle of ABVD followed by 30 Gy radiotherapy (based on the RAPID study).[61][65]

  • Deauville score 4: two additional cycles of ABVD followed by a restaging PET/CT scan to assess metabolic response and inform subsequent treatment.[60][65][67] If restaging PET/CT is negative (Deauville score 1 to 3) then 30 Gy radiotherapy can be given. If restaging PET/CT is positive (Deauville score 4 or 5) then a biopsy is recommended to inform subsequent treatment (e.g., salvage therapy).[33] 

  • Deauville score 5: a biopsy is recommended to inform subsequent treatment (e.g., salvage therapy).[33] 

Patients with favourable early-stage disease who are intended for a chemotherapy-alone approach can receive the following subsequent treatments based on their Deauville score on interim PET/CT:

  • Deauville score 1 or 2: two additional cycles of ABVD.[60][64][66][67]

  • Deauville score 3: two additional cycles of ABVD or four additional cycles of AVD.[60][64][66][67][68] 

  • Deauville score 4: two additional cycles of ABVD followed by a restaging PET/CT scan to assess metabolic response and inform subsequent treatment.[60][64][66][67] If restaging PET/CT is negative (Deauville score 1 to 3) then 30 Gy radiotherapy should be considered. If restaging PET/CT is positive (Deauville score 4 or 5) then a biopsy is recommended to inform subsequent treatment (e.g., salvage therapy).[33] 

  • Deauville score 5: a biopsy is recommended to inform subsequent treatment (e.g., salvage therapy).[33]

Treatment for unfavourable early-stage HL

Patients with unfavourable early-stage disease generally receive two initial cycles of ABVD followed by an interim PET/CT scan to assess metabolic response and inform subsequent treatment.

Those with non-bulky or bulky disease who are intended for combined-modality therapy can receive the following subsequent treatments based on their Deauville score on interim PET/CT:

  • Deauville score 1 to 3: two additional cycles of ABVD followed by 30 Gy radiotherapy.[54][60][67]

  • Deauville score 4 or 5: two additional cycles of ABVD or escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone), followed by a restaging PET/CT scan.[54][60][67]​​ If restaging PET/CT is negative (Deauville score 1 to 3) then 30 Gy radiotherapy can be given. If restaging PET/CT is positive (Deauville score 4 or 5) then a biopsy is recommended to inform subsequent treatment (e.g., salvage therapy).[33]

Those with non-bulky unfavourable early-stage disease who are intended for chemotherapy alone can receive the following subsequent treatments based on their Deauville score on interim PET/CT:

  • Deauville score 1 to 2: two additional cycles of ABVD.[60][64][66][67]​​​

  • Deauville score 3: two additional cycles of ABVD or four additional cycles of AVD.[68]

  • Deauville score 4: two additional cycles of ABVD followed by a restaging PET/CT scan to assess metabolic response and inform subsequent treatment.[60][64]​​​[66][67]​ If restaging PET/CT is negative (Deauville score 1 to 3) then two additional cycles of AVD followed by 30 Gy radiotherapy should be considered. If restaging PET/CT is positive (Deauville score 4 or 5) then a biopsy is recommended to inform subsequent treatment (e.g., salvage therapy).[33] 

  • Deauville score 5: a biopsy is recommended to inform subsequent treatment (e.g., salvage therapy).[33]

Those with bulky unfavourable early-stage disease who are intended for chemotherapy alone can receive the following subsequent treatments based on their Deauville score on interim PET/CT:

  • Deauville score 1 to 3: four additional cycles of AVD.[68]

  • Deauville score 4 or 5: two additional cycles of escalated BEACOPP followed by a restaging PET/CT scan.[54][60][68]​​[76][77]​ If restaging PET/CT is negative (Deauville score 1 to 3) then two additional cycles of escalated BEACOPP can be given. If restaging PET/CT is positive (Deauville score 4 or 5) then a biopsy is recommended to inform subsequent treatment (e.g., salvage therapy).[33]

Advanced (stage III to stage IV) classical HL

Initial treatment options for advanced-stage disease include:[78][79][80][81][82][83][84][85][86][87]

  • ABVD

  • Brentuximab vedotin (an anti-CD30 monoclonal antibody conjugated to monomethyl auristatin E) plus AVD

  • Escalated BEACOPP.

ABVD and brentuximab vedotin plus AVD are the preferred initial treatments for patients with advanced-stage disease.[33][68]

Brentuximab vedotin plus AVD offers a survival advantage compared with ABVD in patients with advanced-stage disease.[33][86][87][88] However, caution is required when used in older patients (age >60 years) and in those with baseline neuropathy. For older patients, sequential brentuximab vedotin plus AVD may be a preferred option.[84] This involves administering 2 cycles of brentuximab vedotin followed by 6 cycles of AVD followed by 4 cycles of brentuximab vedotin.[84]

Escalated BEACOPP is an intensive chemotherapy regimen that improves disease control compared with ABVD, but is associated with increased risk of toxicity and secondary acute leukaemias.[79][80][89][90][91] Furthermore, given the effectiveness of second-line therapy for patients who relapse after ABVD, use of first-line escalated BEACOPP does not offer a survival advantage compared with ABVD.[90][91][92][93] Use of escalated BEACOPP as initial treatment may be considered for younger patients (age <60 years) with a poor prognosis.[33]

PET-adapted treatment for advanced-stage HL

A PET-adapted treatment approach can be used in patients with advanced-stage disease to guide treatment decisions regarding escalation or de-escalation of chemotherapy.[68][94][95][96]

Patients with advanced-stage disease who are intended for standard induction with ABVD chemotherapy typically receive two initial cycles of ABVD, followed by an interim PET/CT scan to assess metabolic response and inform subsequent treatment.[68] Patients can receive the following subsequent treatments based on their Deauville score on interim PET/CT:

  • Deauville score 1 to 3: four additional cycles of AVD.[33][68] 

  • Deauville score 4 or 5 (patients aged ≤60 years): three additional cycles of escalated BEACOPP, followed by a restaging PET/CT scan.[68] If restaging PET/CT is negative (Deauville score 1 to 3) then one additional cycle of escalated BEACOPP can be given.[68] If restaging PET/CT is positive (Deauville score 4 or 5), then a biopsy is recommended to inform subsequent treatment (e.g., salvage therapy).[33] 

  • Deauville score 4 or 5 (patients aged >60 years): individualised treatment is recommended.[5][33] Older patients typically have more medical comorbidities and a poorer prognosis than younger patients; therefore, treatment should be individualised to minimise toxicity while maintaining efficacy. Bleomycin should not be used for more than 2 cycles in older patients.[5][33]

Selected patients (e.g., those with an International Prognostic Score [IPS] ≥4 and age <60 years) may be suitable for upfront intensive induction chemotherapy comprising two initial cycles of escalated BEACOPP, followed by an interim PET/CT scan to assess metabolic response and inform subsequent treatment.[94][95][96] Patients can receive the following subsequent treatments based on their Deauville score on interim PET/CT:

  • Deauville score 1 to 3: two additional cycles of escalated BEACOPP or four additional cycles of ABVD.[33][94][95][96] Bleomycin may be omitted from ABVD to reduce toxicity.

  • Deauville score 4 or 5: a biopsy is recommended to inform subsequent treatment (e.g., salvage therapy or treatment escalation).[33] Patients with a positive biopsy may require salvage therapy. Patients with a negative biopsy can receive two additional cycles of escalated BEACOPP followed by a restaging PET/CT scan.[94][95][96] If restaging PET/CT is negative (Deauville score 1 to 3) then two additional cycles of escalated BEACOPP can be given.[33][94][95][96] If restaging PET/CT is positive (Deauville score 4 or 5) then another biopsy is recommended.[33] 

Consolidation radiotherapy for advanced-stage HL

Consolidation radiotherapy (i.e., after initial chemotherapy) can be avoided in patients with advanced-stage disease if end-of-treatment PET/CT is negative.[76][82][97][98][99][100]​​[101][102]​​

Consolidation radiotherapy (30 to 36 Gy) may be considered for patients with residual PET-positive disease following completion of initial treatment with chemotherapy.

Refractory or relapsed classical HL

Refractory or relapsed HL should be confirmed with biopsy.

Treatment for refractory or relapsed HL must be individualised, taking into consideration factors such as previous first-line treatment, patient age, medical comorbidities, duration of first remission, and stage at relapse. The goal of treatment, at least initially, is cure.

Salvage therapy, followed by high-dose chemotherapy (for conditioning) and autologous stem cell transplantation (ASCT), is the standard approach for most patients who relapse following first-line treatment.[33][103][104][105][106][107][108]​ Radiotherapy may be used alongside high-dose chemotherapy (as part of conditioning) in eligible patients. Allogeneic stem cell transplantation (AlloSCT) may be considered in patients who relapse after ASCT, but this is controversial.[109][110]​ In selected patients, radiotherapy alone or chemotherapy alone is appropriate following salvage therapy.[111][112]

The role of salvage therapy is to reduce tumour burden and mobilise stem cells before conditioning and ASCT.[5] Combination chemotherapy regimens can be used for salvage therapy. The optimal salvage regimen is unclear due to the lack of head-to-head randomised trials; however, the following are commonly used:[106][107][113][114][115][116][117]

  • BeGEV (bendamustine, gemcitabine, vinorelbine)

  • DHAP (dexamethasone, cytarabine, cisplatin)

  • GVD (gemcitabine, vinorelbine, pegylated liposomal doxorubicin)

  • ICE (ifosfamide, carboplatin, etoposide)

  • IGEV (ifosfamide, gemcitabine, vinorelbine)

Several immunotherapeutic agents are available for patients with relapsed or refractory classical HL. The following immunotherapy-based combination regimens may also be considered for use as salvage therapy before ASCT (in those who have not previously undergone ASCT) in the refractory or relapsed setting:[118][119][120][121][122]

  • Brentuximab vedotin plus bendamustine

  • Brentuximab vedotin plus nivolumab

  • Brentuximab vedotin plus ICE

  • Nivolumab plus ICE

  • Pembrolizumab plus GVD

PET-adapted treatment for refractory or relapsed HL

A PET-adapted treatment approach is used for refractory or relapsed HL in order to optimise outcomes following stem cell transplantation. A negative pre-transplantation PET/CT (Deauville score 1 to 3) is associated with optimal outcomes following transplantation and should, therefore, be the goal of salvage therapy prior to ASCT.[123][124]​ Patients with a positive PET/CT (Deauville score 4 or 5) following salvage therapy may be considered for a different salvage regimen to achieve a negative PET/CT.[125][126][127]

Maintenance therapy following ASCT

Brentuximab vedotin is recommended as consolidation/maintenance treatment following ASCT in patients at high risk for relapse (e.g., those refractory to initial treatment; those who relapse within 12 months following initial treatment with ABVD or escalated BEACOPP; or those with extranodal disease).[128][129][130]

Maintenance brentuximab vedotin is recommended for 16 cycles (as per the AETHERA trial) or until unacceptable toxicity or relapse (whichever occurs first).[129] It is not recommended in patients with prior evidence of disease refractory to brentuximab vedotin.[129] However, it may be considered for patients previously treated with brentuximab vedotin if durable remission (at least 12 months) was achieved before relapse.

Early (stage I to stage II) nodular lymphocyte-predominant HL (NLPHL)

NLPHL is a rare subtype of HL. Most patients with NLPHL present with early-stage disease involving peripheral nodal regions (e.g., groin, axilla, neck). The goal of treatment is cure while minimising risk of late effects. Overall prognosis for patients with early-stage NLPHL is excellent.

Asymptomatic early (stage IA and IIA) non-bulky NLPHL

Radiotherapy alone at a dose 30 to 36 Gy is recommended for most patients with stage IA and IIA non-bulky disease.[33][70][131] ISRT is the preferred approach (although most available data are for IFRT).[70] 

Retrospective studies have reported excellent remission and survival outcomes with radiotherapy alone for early-stage NLPHL.[132][133][134][135] Randomised trials of treatments for NLPHL are lacking due to the rarity of this disease subtype.

Observation may be appropriate for patients with asymptomatic early-stage non-bulky disease, particularly if there is concern regarding toxicity related to radiotherapy.[136] Observation is also an option for selected patients with stage IA non-bulky disease who have a completely excised solitary lymph node.[33]

Asymptomatic early (stage IA and IIA) bulky NLPHL and symptomatic early (stage IB and IIB) NLPHL

Systemic treatment with rituximab plus combination chemotherapy (e.g., R-ABVD [rituximab, doxorubicin, bleomycin, vinblastine, dacarbazine], R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone], or R-CVbP [rituximab, cyclophosphamide, vinblastine, prednisolone]) followed by radiotherapy (30 to 36 Gy) is recommended for patients with stage IA or IIA bulky disease, and those with stage IB or IIB disease.[33][131][137]

The CD20 antigen is present on most NLPHL cells; therefore, anti-CD20 treatment with rituximab is a key component of systemic treatment for NLPHL.

Observation may be appropriate for patients with asymptomatic early-stage bulky disease, particularly if there is concern regarding toxicity related to systemic treatment and radiotherapy.[136]

Advanced (stage III to stage IV) NLPHL

Observation may be appropriate for patients with asymptomatic advanced-stage disease.[33][131] Systemic treatment with rituximab plus combination chemotherapy (e.g., R-ABVD, R-CHOP, or R-CVbP) with or without radiotherapy is recommended for patients with symptomatic advanced-stage disease or rapid progression.[33][138][139]

Refractory or relapsed NLPHL

Refractory or relapsed NLPHL should be confirmed by biopsy to rule out transformation to aggressive non-Hodgkin's lymphoma.

Treatment for refractory or relapsed NLPHL must be individualised, taking into consideration factors such as previous first-line treatment (e.g., R-ABVD with radiotherapy), patient age, medical comorbidities, duration of first remission, and stage at relapse.[131]

Salvage therapy with a rituximab-based chemotherapy regimen or rituximab alone is the preferred approach for most patients with refractory or relapsed NLPHL. Observation may be considered for asymptomatic patients as an initial approach.[33] ASCT may be considered for patients with aggressive disease.

The optimal regimen for salvage chemotherapy is unclear, but the following rituximab-based regimens can be considered if not previously used:[33]

  • R-ABVD

  • R-CHOP

  • R-CVbP

  • R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin)

  • R-ICE (rituximab, ifosfamide, carboplatin, etoposide)

  • R-IGEV (rituximab, ifosfamide, gemcitabine, vinorelbine)

  • Rituximab plus bendamustine.

Rituximab alone can be considered for patients who relapse with limited-stage disease and low tumour volume.[33][140]

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