# Advanced-stage classical Hodgkin lymphoma (stage III to IV)

Source: https://onco.cc/cancers/advanced-stage-classical-hodgkin-lymphoma/  
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## TL;DR

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.

## Summary

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-18
- Also known as: Stage III to IV classical Hodgkin lymphoma; Advanced Hodgkin lymphoma; Disseminated Hodgkin lymphoma; High-risk Hodgkin lymphoma (IPS 4 or more)
- Tags: subtype-page; haematologic
- Group: haematologic
- Burden: 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.
- Subtypes: 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)
- Biomarkers: 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)

## Standard of care

- Staging and risk: FDG-PET/CT with Lugano staging, International Prognostic Score, fertility counselling and cardiac and pulmonary baselines. ([FDG PET](https://onco.cc/technologies/fdg-pet/), [Lugano classification / Ann Arbor staging](https://onco.cc/terms/lugano-classification/), [Oncofertility and fertility preservation](https://onco.cc/technologies/fertility-preservation/), [Cardio-oncology](https://onco.cc/technologies/cardio-oncology/))
- First line, adults and adolescents 12 and over: 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. ([Nivolumab](https://onco.cc/drugs/nivolumab/), [SWOG S1826](https://onco.cc/trials/swog-s1826/), [Brentuximab vedotin](https://onco.cc/drugs/brentuximab-vedotin/), [ECHELON-1](https://onco.cc/trials/echelon-1/), [Doxorubicin](https://onco.cc/drugs/doxorubicin/), [Vinblastine](https://onco.cc/drugs/vinblastine/), [Dacarbazine](https://onco.cc/drugs/dacarbazine/), [RATHL](https://onco.cc/trials/rathl/), [PD-1 blockade + AVD chemotherapy](https://onco.cc/pairings/pd1-plus-avd-hodgkin/), [Caution: bleomycin lung toxicity, especially with brentuximab or G-CSF](https://onco.cc/pairings/bleomycin-omission-caution/))
- First line, intensive European option: BrECADD for four to six cycles guided by interim PET (GHSG HD21), replacing escalated BEACOPP. ([GHSG HD21](https://onco.cc/trials/hd21/), [Brentuximab vedotin](https://onco.cc/drugs/brentuximab-vedotin/), [ABVD, BEACOPP and BrECADD (Hodgkin lymphoma regimens)](https://onco.cc/terms/abvd-beacopp/), [PET-adapted (response-adapted) therapy](https://onco.cc/technologies/pet-adapted-therapy/))
- Children: Response-adapted Children's Oncology Group or EuroNet regimens; brentuximab vedotin with AVD in advanced paediatric disease; radiotherapy for slow responders only. ([A Study of Brentuximab Vedotin + Adriamycin, Vinblastine, and Dacarbazine in Pediatric Participants With Advanced Stage Newly Diagnosed Hodgkin Lymphoma](https://onco.cc/trials/nct02979522/), [Brentuximab vedotin](https://onco.cc/drugs/brentuximab-vedotin/), [Children's Oncology Group (COG)](https://onco.cc/institutions/childrens-oncology-group/), [PET-adapted (response-adapted) therapy](https://onco.cc/technologies/pet-adapted-therapy/))
- Older or frail patients: AVD with brentuximab vedotin sequenced before and after, or nivolumab-AVD; avoid bleomycin and BEACOPP. ([Brentuximab vedotin](https://onco.cc/drugs/brentuximab-vedotin/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Doxorubicin](https://onco.cc/drugs/doxorubicin/), [Cardio-oncology](https://onco.cc/technologies/cardio-oncology/))
- End of treatment: PET-directed consolidation radiotherapy only for residual PET-positive bulky disease; long-term survivorship follow-up. ([FDG PET](https://onco.cc/technologies/fdg-pet/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Deauville five-point scale](https://onco.cc/terms/deauville-score/), [Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/))

## State of the art

- Nivolumab-AVD is the new standard, curing more patients with less toxicity than brentuximab-AVD.
- ECHELON-1 delivered the first overall survival gain in advanced disease in decades.
- PET-guided BrECADD gives Europe a less toxic intensive alternative.

## Open problems

- 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.
- Whether chemotherapy can be reduced further with PD-1 antibodies is the next trial question.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Hodgkin_lymphoma
- SWOG S1826 (NEJM 2024): https://doi.org/10.1056/NEJMoa2405888
- ECHELON-1 (NEJM 2018): https://doi.org/10.1056/NEJMoa1708984
- HD21 (Lancet 2024): https://doi.org/10.1016/S0140-6736(24)01315-1
- Wikipedia: https://en.wikipedia.org/wiki/Hodgkin_lymphoma

## Connected records

- cancers: [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Early-stage classical Hodgkin lymphoma (stage I to II)](https://onco.cc/cancers/early-stage-classical-hodgkin-lymphoma/), [Hodgkin lymphoma](https://onco.cc/cancers/hodgkin-lymphoma/), [Nodular lymphocyte-predominant Hodgkin lymphoma (nodular lymphocyte-predominant B-cell lymphoma)](https://onco.cc/cancers/nodular-lymphocyte-predominant-hodgkin-lymphoma/), [Relapsed and refractory classical Hodgkin lymphoma](https://onco.cc/cancers/relapsed-refractory-hodgkin-lymphoma/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Cardio-oncology](https://onco.cc/technologies/cardio-oncology/), [ctDNA monitoring in lymphoma (PhasED-seq, clonoSEQ)](https://onco.cc/technologies/ctdna-lymphoma-monitoring/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [FDG PET](https://onco.cc/technologies/fdg-pet/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Oncofertility and fertility preservation](https://onco.cc/technologies/fertility-preservation/), [PET-adapted (response-adapted) therapy](https://onco.cc/technologies/pet-adapted-therapy/)
- targets: [CD30](https://onco.cc/targets/cd30/), [PD-1](https://onco.cc/targets/pd1/), [PD-L1](https://onco.cc/targets/pdl1/)
- drugs: [Brentuximab vedotin](https://onco.cc/drugs/brentuximab-vedotin/), [Dacarbazine](https://onco.cc/drugs/dacarbazine/), [Doxorubicin](https://onco.cc/drugs/doxorubicin/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Vinblastine](https://onco.cc/drugs/vinblastine/)
- terms: [ABVD, BEACOPP and BrECADD (Hodgkin lymphoma regimens)](https://onco.cc/terms/abvd-beacopp/), [Deauville five-point scale](https://onco.cc/terms/deauville-score/), [Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [Lugano classification / Ann Arbor staging](https://onco.cc/terms/lugano-classification/), [Reed-Sternberg cell](https://onco.cc/terms/reed-sternberg-cell/)
- trials: [A Study of Brentuximab Vedotin + Adriamycin, Vinblastine, and Dacarbazine in Pediatric Participants With Advanced Stage Newly Diagnosed Hodgkin Lymphoma](https://onco.cc/trials/nct02979522/), [ECHELON-1](https://onco.cc/trials/echelon-1/), [GHSG HD21](https://onco.cc/trials/hd21/), [RATHL](https://onco.cc/trials/rathl/), [SWOG S1826](https://onco.cc/trials/swog-s1826/)
- key papers: [ECHELON-1: brentuximab vedotin replacing bleomycin in first-line chemotherapy for advanced Hodgkin lymphoma](https://onco.cc/key-papers/paper-echelon-1-brentuximab-avd-nejm-2018/), [GHSG HD21: PET-guided BrECADD versus escalated BEACOPP in advanced-stage classical Hodgkin lymphoma](https://onco.cc/key-papers/paper-ghsg-hd21-brecadd-vs-ebeacopp-advanced-hodgkin-lancet-2024/), [RATHL: adapted treatment guided by interim PET-CT in advanced Hodgkin lymphoma](https://onco.cc/key-papers/paper-rathl-interim-pet-adapted-abvd-advanced-hodgkin-nejm-2016/), [SWOG S1826: nivolumab plus AVD chemotherapy versus brentuximab-AVD for advanced Hodgkin lymphoma in adolescents and adults](https://onco.cc/key-papers/paper-swog-s1826-nivolumab-avd-nejm-2024/)
- institutions: [Children's Oncology Group (COG)](https://onco.cc/institutions/childrens-oncology-group/), [German Breast Group (GBG)](https://onco.cc/institutions/gbg/)
- pairings: [Caution: bleomycin lung toxicity, especially with brentuximab or G-CSF](https://onco.cc/pairings/bleomycin-omission-caution/), [PD-1 blockade + AVD chemotherapy](https://onco.cc/pairings/pd1-plus-avd-hodgkin/)
- ideas: [Chemotherapy-free Hodgkin lymphoma: brentuximab + PD-1 in early stage](https://onco.cc/ideas/idea-chemo-free-hodgkin/)

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