Advanced-stage classical Hodgkin lymphoma (stage III to IV)
Advanced-stage classical Hodgkin lymphoma is Hodgkin lymphoma involving nodes on both sides of the diaphragm or organs such as the liver, lungs or bone marrow. It is treated with six cycles of combination chemotherapy, and two trials changed the standard: replacing bleomycin with brentuximab vedotin (ECHELON-1) and then with nivolumab (SWOG S1826), which cured more patients with less toxicity.
Overview
Advanced classical Hodgkin lymphoma was the first disseminated cancer cured by chemotherapy, with MOPP in the 1960s and then ABVD from 1975, and for forty years the argument was between ABVD and the more intensive escalated BEACOPP of the German Hodgkin Study Group, which cures more patients up front at the cost of infertility, leukaemia and toxicity. PET-adapted therapy eased the trade-off: the RATHL trial (New England Journal of Medicine 2016) showed bleomycin can be dropped after two cycles in PET-negative patients without loss of efficacy, and HD18 showed escalated BEACOPP can be shortened to four cycles in PET-negative patients. The International Prognostic Score, the Deauville score on interim PET and baseline metabolic tumour volume stratify risk.
Two trials then rebuilt the regimen. ECHELON-1 (New England Journal of Medicine 2018) randomised 1,334 patients to ABVD or to brentuximab vedotin with AVD (A+AVD), replacing bleomycin with the CD30 antibody-drug conjugate; modified progression-free survival improved and, in the six-year update (New England Journal of Medicine 2022), overall survival was higher with A+AVD (93.9 against 89.4 percent), the first survival gain in advanced Hodgkin lymphoma in a generation. SWOG S1826 (New England Journal of Medicine 2024) then randomised 994 patients aged 12 and over to A+AVD or to nivolumab with AVD (N+AVD): one-year progression-free survival was 94 against 86 percent with fewer peripheral neuropathy and infection problems and almost no radiotherapy, making N+AVD the preferred regimen in the NCCN guideline for adults and adolescents. In Europe, GHSG HD21 (Lancet 2024) showed that BrECADD, a brentuximab-containing variant of escalated BEACOPP, was less toxic and at least as effective as escalated BEACOPP with four-year progression-free survival of 94.3 against 90.9 percent, giving a second intensive PET-guided option. Paediatric groups are testing brentuximab vedotin and PD-1 antibodies in children with advanced disease, older patients receive AVD-based or brentuximab-sequenced regimens because bleomycin and BEACOPP are too toxic, and consolidation radiotherapy is now limited to residual PET-positive bulky disease.
State of the art
- Nivolumab-AVD is the new standard, curing more patients with less toxicity than brentuximab-AVD.
- PET-guided BrECADD gives Europe a less toxic intensive alternative.
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
- ECHELON-1 delivered the first overall survival gain in advanced disease in decades.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowBleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
- Emergency services nowHypophysitis or adrenal crisis
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
- Emergency services nowSkin reaction
Blisters, peeling, or sores in the mouth or eyes with a rash. Enfortumab vedotin carries a boxed warning for Stevens-Johnson syndrome and toxic epidermal necrolysis, mostly in the first cycle.
- Check before combiningFood and drink: Doxorubicin
Cumulative dose: risk rises steeply above 400-550 mg/m² (see the anthracycline calculator).
- Check before combiningLiver: Doxorubicin
Reduce by 50% for bilirubin 20-50 µmol/L and 75% for 50-85 µmol/L.
- Good to knowCardiotoxicity (LVEF decline, cardiomyopathy)
Heart damage from cancer treatment: anthracyclines weaken the heart muscle permanently in a dose-related way, trastuzumab does so reversibly, and some kinase inhibitors raise blood pressure or disturb rhythm. Heart function (LVEF) is monitored by ultrasound during treatment.
See all on the product pages:Brentuximab vedotinDacarbazineDoxorubicinNivolumabVinblastine·Printable cards in the navigator
Anatomy and lymph node drainage
- Bone marrow (leukaemia, MDS, MPN, myeloma)
- Lymph node germinal centre (lymphomas)
- Spleen
- Blood (leukaemic phase)
- Lytic bone lesions (myeloma)
- Skin and extranodal sites
- Nodes: cervical
- Nodes: axillary
- Nodes: mediastinal
- Nodes: para-aortic and mesenteric
- Nodes: inguinal
Leukaemias, myeloma and MDS live in the marrow and blood; lymphomas grow in lymph nodes and spleen. The node stations are the disease map, not a route of spread, and staging counts them.
- Bone marrow (leukaemia, MDS, MPN, myeloma)
- Lymph node germinal centre (lymphomas)Stage III classical Hodgkin lymphoma (nodes on both sides of the diaphragm) · Stage IV classical Hodgkin lymphoma (extranodal spread to liver, lung, bone or marrow) · Advanced classical Hodgkin lymphoma with a high International Prognostic Score (4 or more) · Advanced classical Hodgkin lymphoma in adolescents and young adults (S1826 population) · Advanced classical Hodgkin lymphoma in older adults (over 60; bleomycin-free regimens) · Interim PET-positive advanced classical Hodgkin lymphoma (escalation or consolidation)
- Spleen
- Blood (leukaemic phase)
- Lytic bone lesions (myeloma)
- Skin and extranodal sitesStage IV classical Hodgkin lymphoma (extranodal spread to liver, lung, bone or marrow)
- cervical
- axillary
- mediastinal
- para-aortic and mesenteric
- inguinal
In lymphoma the node stations are the disease itself; staging (Ann Arbor / Lugano) counts how many regions and sides of the diaphragm are involved.
Same organ: Marginal zone lymphoma, Cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome), Primary mediastinal (thymic) large B-cell lymphoma, Leukaemia (all types), Acute myeloid leukaemia, Acute lymphoblastic leukaemia, Chronic lymphocytic leukaemia, Chronic myeloid leukaemia (CML), Diffuse large B-cell lymphoma, Follicular lymphoma, Hodgkin lymphoma, Mantle cell lymphoma, Multiple myeloma, Non-Hodgkin lymphoma (all types), Myelodysplastic syndromes / neoplasms (MDS), Myeloproliferative neoplasms (PV, ET, myelofibrosis), Polycythaemia vera (PV), Essential thrombocythaemia (ET), Waldenström macroglobulinaemia, Hairy cell leukaemia, Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma), Blastic plasmacytoid dendritic cell neoplasm (BPDCN), Burkitt lymphoma, HIV-associated (AIDS-related) lymphomas, Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms, Systemic mastocytosis, Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms, Langerhans cell histiocytosis (LCH), Post-transplant lymphoproliferative disorder (PTLD), FLT3-mutated acute myeloid leukaemia, IDH1- and IDH2-mutated acute myeloid leukaemia, NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia, Secondary and therapy-related acute myeloid leukaemia, Acute promyelocytic leukaemia, Acute myeloid leukaemia in older or unfit patients, Smouldering multiple myeloma, Newly diagnosed multiple myeloma, transplant-eligible, Newly diagnosed multiple myeloma, transplant-ineligible, Relapsed or refractory multiple myeloma, Plasma cell leukaemia, Lower-risk myelodysplastic syndromes, Higher-risk myelodysplastic syndromes, Chronic lymphocytic leukaemia, first treatment, Relapsed or refractory chronic lymphocytic leukaemia, Richter transformation of chronic lymphocytic leukaemia, Chronic myeloid leukaemia, chronic phase, Chronic myeloid leukaemia, accelerated and blast phase, Primary myelofibrosis, Standard-risk B-cell acute lymphoblastic leukaemia in children, High-risk acute lymphoblastic leukaemia in children (high-risk B-ALL and T-ALL), Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL), Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like or BCR::ABL1-like ALL), Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year), Relapsed and refractory acute lymphoblastic leukaemia in children, Acute myeloid leukaemia in children, Erdheim-Chester disease, Rosai-Dorfman-Destombes disease, Single-system Langerhans cell histiocytosis (bone, skin or one other organ), Multisystem Langerhans cell histiocytosis (with or without risk-organ involvement), Indolent and smouldering systemic mastocytosis, Advanced systemic mastocytosis (aggressive SM, SM with an associated haematological neoplasm, mast cell leukaemia), Early-stage classical Hodgkin lymphoma (stage I to II), Nodular lymphocyte-predominant Hodgkin lymphoma (nodular lymphocyte-predominant B-cell lymphoma), Relapsed and refractory classical Hodgkin lymphoma
About half of classical Hodgkin lymphoma at diagnosis; most patients are cured, but a fifth to a quarter relapse after ABVD, and older patients fare worse.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
FDG-PET/CT with Lugano staging, International Prognostic Score, fertility counselling and cardiac and pulmonary baselines.
Nivolumab with AVD for six cycles (SWOG S1826, preferred); brentuximab vedotin with AVD (ECHELON-1) as an alternative; PET-adapted ABVD with bleomycin omission after two cycles (RATHL) where antibodies are unavailable.
BrECADD for four to six cycles guided by interim PET (GHSG HD21), replacing escalated BEACOPP.
Response-adapted Children's Oncology Group or EuroNet regimens; brentuximab vedotin with AVD in advanced paediatric disease; radiotherapy for slow responders only.
AVD with brentuximab vedotin sequenced before and after, or nivolumab-AVD; avoid bleomycin and BEACOPP.
PET-directed consolidation radiotherapy only for residual PET-positive bulky disease; long-term survivorship follow-up.
Subtypes & biomarkers
top- Stage III classical Hodgkin lymphoma (nodes on both sides of the diaphragm)
- Stage IV classical Hodgkin lymphoma (extranodal spread to liver, lung, bone or marrow)
- Advanced classical Hodgkin lymphoma with a high International Prognostic Score (4 or more)
- Advanced classical Hodgkin lymphoma in adolescents and young adults (S1826 population)
- Advanced classical Hodgkin lymphoma in older adults (over 60; bleomycin-free regimens)
- Interim PET-positive advanced classical Hodgkin lymphoma (escalation or consolidation)
- International Prognostic Score (IPS 0 to 7)
- Interim FDG-PET after cycle two (Deauville score, RATHL and HD18 escalation or de-escalation)
- Baseline metabolic tumour volume
- CD30 expression (universal; brentuximab target)
- 9p24.1 amplification and PD-L1 expression (PD-1 responsiveness)
- Circulating tumour DNA (research)
How often this target appears
- 1964MOPP chemotherapy cures advanced Hodgkin lymphoma at the NCI
- 1975ABVD introduced in Milan and later shown superior to MOPP
- 2003GHSG HD9: escalated BEACOPP improves outcomes over standard regimens
- 2016RATHL: PET-guided omission of bleomycin
- 2018ECHELON-1: brentuximab vedotin with AVD beats ABVD
- 2022ECHELON-1 six-year update shows an overall survival advantage
- 2024SWOG S1826 (nivolumab-AVD) and HD21 (BrECADD) published; nivolumab-AVD becomes the preferred regimen
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 12 changes by month →- 2026-09-18This recordAdvanced-stage classical Hodgkin lymphoma (stage III to IV)Facts on this page last checked
When this page itself was last checked or edited.
- 2024Trial resultGHSG HD21GHSG HD21 reported
4-year PFS 94.
- 2024MilestoneSWOG S1826SWOG S1826 (nivolumab-AVD) and HD21 (BrECADD) published; nivolumab-AVD becomes the preferred regimen
A milestone in how this cancer is treated.
- 2023Trial resultSWOG S1826SWOG S1826 reported
2-year PFS 92% vs 83%, HR 0.
- 2022MilestoneECHELON-1ECHELON-1 six-year update shows an overall survival advantage
A milestone in how this cancer is treated.
- 2018MilestoneECHELON-1ECHELON-1: brentuximab vedotin with AVD beats ABVD
A milestone in how this cancer is treated.
What is in development for Advanced-stage classical Hodgkin lymphoma (stage III to IV), drawn from the whole corpus: 9 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Technologies being tested · 1
Trials under way · 1
Trials reported · 4
- SWOG S1826 · phase 3 · 2023 · positive
- GHSG HD21 · phase 3 · 2024 · positive
- ECHELON-1 · phase 3 · 2017 · positive
- RATHL · phase 3 · 2016 · positive
Combinations being explored · 2
Ideas not yet in a trial · 1
Open problems and what is being done
Long-term outcomes of nivolumab-AVD beyond a few years are not yet known.
Nivolumab-AVD and BrECADD have never been compared.
Older patients still have worse survival and more toxicity.
and how the field plans to fix it →What is being done about thisSide effects and quality of lifeAvailable now- Antibody-drug conjugate (ADC)Approved
- Cardio-oncologyEstablished
- Cytotoxic chemotherapyStandard of care
- Immune checkpoint inhibitorsStandard of care
- IMRT / IGRT (modern external beam)Standard of care
Ideas and roadmapsNothing recorded yet.
Also on OnCo: Side effects by symptom · Immune-related side effects · Toxicity compare · Survivorship planner.
Whether chemotherapy can be reduced further with PD-1 antibodies is the next trial question.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
Neu-Isenburg · consortium | Germany | none recorded | 1 | 94 | 1,947 | none recorded | - |
Portland, OR · consortium | United States | none recorded | 1 | 42 | 1,880 | none recorded | - |
Monrovia, CA · consortium | United States | none recorded | 1 | 20 | 186 | none recorded | - |
London · consortium | United Kingdom | none recorded | 1 | not matched | - | none recorded | - |
Cologne · consortium | Germany | none recorded | 1 | not matched | - | - | |
Bethesda, MD · government | United States | none recorded | 0 | 2,905 | 47,715 | - | |
Utrecht · cancer center | Netherlands | none recorded | 0 | 1,422 | 20,323 | - | |
Tianjin · cancer center | China | none recorded | 0 | 1,219 | 11,455 | - | |
Hangzhou · cancer center | China | none recorded | 0 | 1,219 | 17,635 | - | |
Rozzano (Milan) · hospital | Italy | none recorded | 0 | 1,031 | 10,720 | - | |
Naples · cancer center | Italy | none recorded | 0 | 961 | 15,028 | - | |
Changsha · cancer center | China | none recorded | 0 | 930 | 14,477 | - | |
Jinan · cancer center | China | none recorded | 0 | 920 | 7,804 | - | |
Dresden · cancer center | Germany | none recorded | 0 | 728 | 7,984 | - | |
Philadelphia, PA · hospital | United States | none recorded | 0 | 695 | 9,931 | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with Advanced-stage classical Hodgkin lymphoma but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about Advanced-stage classical Hodgkin lymphoma
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example International Prognostic Score, Interim FDG-PET after cycle two, Baseline metabolic tumour volume, CD30 expression, 9p24.1 amplification and PD-L1 expression), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include Stage III classical Hodgkin lymphoma, Stage IV classical Hodgkin lymphoma, Advanced classical Hodgkin lymphoma with a high International Prognostic Score.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Staging and risk
- For my situation (staging and risk), which of the standard options do you recommend and why?Why: Guideline options include: FDG-PET/CT with Lugano staging, International Prognostic Score, fertility counselling and cardiac and pulmonary baselines.
First line, adults and adolescents 12 and over
- For my situation (first line, adults and adolescents 12 and over), which of the standard options do you recommend and why?Why: Guideline options include: Nivolumab with AVD for six cycles (SWOG S1826, preferred); brentuximab vedotin with AVD (ECHELON-1) as an alternative; PET-adapted ABVD with bleomycin omission after two cycles (RATHL) where antibodies are unavailable.
- Am I a candidate for Nivolumab, Brentuximab vedotin, Doxorubicin or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of SWOG S1826 and ECHELON-1 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
First line, intensive European option
- For my situation (first line, intensive european option), which of the standard options do you recommend and why?Why: Guideline options include: BrECADD for four to six cycles guided by interim PET (GHSG HD21), replacing escalated BEACOPP.
- Am I a candidate for Brentuximab vedotin, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of GHSG HD21 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Children
- For my situation (children), which of the standard options do you recommend and why?Why: Guideline options include: Response-adapted Children's Oncology Group or EuroNet regimens; brentuximab vedotin with AVD in advanced paediatric disease; radiotherapy for slow responders only.
- Am I a candidate for Brentuximab vedotin, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of A Study of Brentuximab Vedotin + Adriamycin, Vinblastine, and Dacarbazine in Pediatric Participants With Advanced Stage Newly Diagnosed Hodgkin Lymphoma apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Older or frail patients
- For my situation (older or frail patients), which of the standard options do you recommend and why?Why: Guideline options include: AVD with brentuximab vedotin sequenced before and after, or nivolumab-AVD; avoid bleomycin and BEACOPP.
- Am I a candidate for Brentuximab vedotin, Nivolumab, Doxorubicin, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
End of treatment
- For my situation (end of treatment), which of the standard options do you recommend and why?Why: Guideline options include: PET-directed consolidation radiotherapy only for residual PET-positive bulky disease; long-term survivorship follow-up.
Any stage
- Are there clinical trials I could join, for example of SWOG S1826, GHSG HD21, A Study of Brentuximab Vedotin + Adriamycin, Vinblastine, and Dacarbazine in Pediatric Participants With Advanced Stage Newly Diagnosed Hodgkin Lymphoma, PD-1 blockade + AVD chemotherapy?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Long-term outcomes of nivolumab-AVD beyond a few years are not yet known”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Nivolumab-AVD and BrECADD have never been compared”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with Advanced-stage classical Hodgkin lymphoma, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
9targets
3drugs
6companies
5institutions
2terms
5trials
5pairings
2ideas
1key papers
4For fit younger patients treated in the intensive German tradition, BrECADD replaces escalated BEACOPP; how it compares with nivolumab-AVD from S1826 is the open question.
S1826 moved checkpoint blockade into first-line Hodgkin lymphoma and made N-AVD a preferred regimen for advanced disease in patients from adolescence to older age, while removing radiotherapy for most. It also showed the value of a single trial spanning paediatric and adult groups. Longer follow-up is needed for overall survival and late immune effects in young patients.
ECHELON-1 made a targeted antibody-drug conjugate part of first-line Hodgkin therapy and eventually showed that this saves lives, not just relapses. It set the reference arm against which nivolumab-AVD (SWOG S1826) and BrECADD (HD21) were later compared. Neuropathy is the main price and needs proactive dose modification.
An interim PET scan after two cycles guides treatment of advanced Hodgkin lymphoma: drop bleomycin if negative, intensify if positive.
Latest papers
topQuery for this cancer: (TITLE:"Advanced-stage classical Hodgkin lymphoma" OR ABSTRACT:"Advanced-stage classical Hodgkin lymphoma" OR TITLE:"stage III to IV" OR ABSTRACT:"stage III to IV" OR TITLE:"Stage III to IV classical Hodgkin lymphoma" OR ABSTRACT:"Stage III to IV classical Hodgkin lymphoma" OR TITLE:"Advanced Hodgkin lymphoma" OR ABSTRACT:"Advanced Hodgkin lymphoma" OR TITLE:"Disseminated Hodgkin lymphoma" OR ABSTRACT:"Disseminated Hodgkin lymphoma" OR TITLE:"High-risk Hodgkin lymphoma IPS 4 or more" OR ABSTRACT:"High-risk Hodgkin lymphoma IPS 4 or more") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Advanced-stage classical Hodgkin lymphoma (stage III to IV), not a curated reading list.
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