What is the recommended treatment approach for a patient with Hodgkin lymphoma nodular sclerosis?

Treatment of Hodgkin Lymphoma Nodular Sclerosis

The optimal treatment for Hodgkin lymphoma nodular sclerosis depends critically on disease stage and risk stratification, with combined modality therapy (chemotherapy plus radiotherapy) being the cornerstone for early-stage disease and chemotherapy alone for advanced disease. 1

Risk Stratification Framework

Before initiating treatment, patients must be classified into one of three risk groups based on Ann Arbor staging with Cotswolds modification 1:

• Early favorable: Stage I-II without risk factors
• Early unfavorable: Stage I-II with risk factors (large mediastinal mass >1/3 chest diameter, extranodal disease, ESR >50 with B symptoms or >30 without, ≥3 involved lymph node areas)
• Advanced stage: Stage III-IV, or stage IIB with large mediastinal mass or extranodal involvement

Treatment by Risk Group

Early Favorable Disease (Stage I-II, No Risk Factors)

Administer 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) followed by 30 Gy involved-field radiotherapy. 1

• This regimen achieves overall survival exceeding 90% at 5 years 1, 2
• The GHSG HD7 and HD10 trials, along with EORTC H7F and H8F trials, established that 2 cycles of ABVD is non-inferior to 4 cycles when combined with 30 Gy radiotherapy 1
• Chemotherapy-only approaches (4-6 cycles of ABVD) remain investigational with limited prospective randomized data 1

Early Unfavorable Disease (Stage I-II with Risk Factors)

Administer 4 cycles of ABVD followed by 30 Gy involved-field radiotherapy. 1

• This achieves tumor control and overall survival of 85-90% at 5 years 1, 2
• Extended-field radiotherapy or 6 cycles of chemotherapy alone show similar efficacy but increased toxicity 1
• For patients under 60 years eligible for intensive treatment, 2 cycles of BEACOPP escalated followed by 2 cycles of ABVD and 30 Gy IF-RT may provide superior freedom from treatment failure, though long-term toxicity data (particularly infertility) are lacking 1, 3

Advanced Stage Disease (Stage III-IV)

For patients ≤60 years: Choose between 6-8 cycles of ABVD or 8 cycles of BEACOPP escalated, with radiotherapy reserved for residual masses >1.5 cm. 1, 4

ABVD Regimen:

• Administer 6 cycles if complete remission after 4 cycles, or 8 cycles if partial remission after 4 cycles 1, 4
• Achieves long-term cure rates of 50-60% 1, 4
• Lower acute toxicity profile compared to BEACOPP 1, 4

BEACOPP Escalated Regimen:

• Administer 8 cycles for patients <60 years 1
• Provides superior outcomes: 96% overall response, 88% disease-free survival, and 92% overall survival at 5 years 1, 4
• Represents a 10% absolute survival advantage at 5 years compared to ABVD 4
• Critical caveat: Requires G-CSF support and carries significantly higher acute hematological toxicity 1, 4

For Patients >60 Years:

Administer 6-8 cycles of ABVD only—do not use BEACOPP due to excessive toxicity in this age group. 1

Radiotherapy in Advanced Disease:

• Consolidative radiotherapy (30 Gy) should be given to residual lymphoma >1.5 cm after chemotherapy 1, 4
• Radiotherapy may be omitted in patients with residual disease but negative FDG-PET after chemotherapy completion 1, 4
• Radiotherapy to residual masses <2.5 cm is not generally recommended outside clinical trials 1

Role of PET-Adapted Therapy

Interim PET scanning after 2-4 cycles allows treatment optimization, though this approach cannot yet be considered standard practice 1, 4, 3:

• Negative interim PET may enable treatment de-escalation 2, 3
• Positive interim PET may warrant escalation to BEACOPP 2, 3
• Multiple ongoing trials are evaluating PET-guided strategies, but results are not yet conclusive 1

Relapsed or Refractory Disease

For most patients with relapsed disease after combined modality therapy, administer salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT). 1

Salvage Regimens:

• DHAP (dexamethasone, high-dose ara-C, cisplatin) 1
• ESHAP 1
• ICE (ifosfamide, carboplatin, etoposide) 1
• IGEV (ifosfamide, gemcitabine, vinorelbine, dexamethasone) 1
• MiniBEAM 1

Special Scenarios:

• Low-risk patients relapsing after 2 cycles of chemotherapy plus radiotherapy may be salvaged with intensive conventional chemotherapy like BEACOPP escalated 1
• Patients with localized late relapse may be treated with salvage radiotherapy alone 1

Post-ASCT Relapse:

• Consider gemcitabine-based palliative chemotherapy 1
• Reduced-intensity conditioning allogeneic stem cell transplantation for young, chemosensitive patients in good condition (investigational) 1
• Brentuximab vedotin for CD30-positive disease 3, 5, 6
• Anti-PD-1 antibodies 5, 6

Critical Toxicity Monitoring

Cardiotoxicity (Doxorubicin):

• Perform baseline left ventricular ejection fraction (LVEF) evaluation before treatment 2, 4
• Women who receive mediastinal radiotherapy require breast cancer screening with clinical examination and mammography starting at age >40 years 1

Pulmonary Toxicity (Bleomycin):

• Obtain baseline pulmonary function testing 4
• Monitor for pulmonary symptoms during treatment 2

Fertility Preservation:

• Counsel all young patients about fertility preservation options before initiating therapy 2, 3
• BEACOPP escalated carries particular risk for infertility 1, 2

Common Pitfalls to Avoid

• Do not use BEACOPP in patients >60 years—the toxicity outweighs benefits 1
• Do not routinely irradiate residual masses <1.5 cm after chemotherapy in advanced disease 1, 4
• Do not use MOPP-based regimens—they carry higher risk of secondary hematologic malignancies compared to ABVD 7
• Do not omit bone marrow biopsy and comprehensive CT staging—accurate risk stratification is essential for treatment selection 1, 3