What is the initial treatment approach for Hodgkin's lymphoma?

Initial Treatment Approach for Hodgkin's Lymphoma

The initial treatment for Hodgkin's lymphoma is risk-stratified combined modality therapy: 2 cycles of ABVD followed by 30 Gy involved-field radiotherapy for early favorable disease, 4 cycles of ABVD plus 30 Gy for early unfavorable disease, and 6-8 cycles of ABVD (or BEACOPP escalated in patients <60 years) for advanced disease. 1

Risk Stratification Framework

Treatment selection depends on proper risk group allocation using the Cotswolds staging system with additional risk factors 1:

• Early favorable: Stage I-II without risk factors (no large mediastinal mass >1/3 horizontal chest diameter, no extranodal disease, ESR <50 with B symptoms or <30 without, fewer than 3 involved lymph node areas) 1
• Early unfavorable: Stage I-II with any of the above risk factors 1
• Advanced: Stage III-IV, or Stage IIb with large mediastinal mass or extranodal involvement 1

Treatment by Risk Group

Early Favorable Disease

Standard treatment is 2 cycles of ABVD followed by 30 Gy involved-field radiotherapy, achieving cure rates exceeding 90% at 5 years 1, 2. This approach is based on the German Hodgkin Study Group HD7 and HD10 trials and EORTC H7F/H8F trials, which demonstrated that 2 cycles of ABVD is non-inferior to 4 cycles when combined with radiotherapy 1.

Alternative chemotherapy-only approach: 4-6 cycles of ABVD alone can be considered, though prospective randomized trial data supporting this approach remains limited 1. This option may be appropriate for patients wishing to avoid radiation-related long-term toxicities 3.

Special consideration for lymphocyte-predominant HL: Stage I disease can be treated with involved-field radiotherapy (30 Gy) alone, with rituximab reserved for relapsed disease 1.

Early Unfavorable Disease

Standard treatment is 4 cycles of ABVD followed by 30 Gy involved-field radiotherapy, achieving tumor control and overall survival rates of 85-90% at 5 years 1. Extended-field radiotherapy or 6 cycles of chemotherapy alone show similar efficacy but increased toxicity 1.

Advanced-Stage Disease

For patients <60 years, 8 cycles of BEACOPP escalated is considered standard by the German Hodgkin Study Group, achieving superior outcomes with 96% overall response, 88% disease-free survival, and 92% overall survival at 5 years 1. However, this comes with significantly higher toxicity 1.

For patients ≥60 years or those unable to tolerate BEACOPP, 6-8 cycles of ABVD is the standard approach, with long-term cure rates of 50-60% 1, 2. ABVD remains widely used internationally due to its more favorable toxicity profile 1.

Radiotherapy in advanced disease: Additional radiotherapy is not generally recommended for residual masses <2.5 cm after chemotherapy 1. Outside clinical trials, larger PET-positive residual tumors should receive consolidative radiotherapy 1.

Modern Frontline Approaches

Brentuximab vedotin plus AVD (doxorubicin, vinblastine, dacarbazine) is FDA-approved for previously untreated Stage III-IV classical Hodgkin lymphoma, administered at 1.2 mg/kg every 2 weeks for up to 12 doses 4. This regimen requires G-CSF prophylaxis beginning with Cycle 1 due to high rates of neutropenia and febrile neutropenia 4.

For pediatric patients ≥2 years with high-risk disease, brentuximab vedotin 1.8 mg/kg combined with AVEPC (doxorubicin, vincristine, etoposide, prednisone, cyclophosphamide) every 3 weeks for up to 5 doses is FDA-approved 4.

Critical Treatment Considerations

Mandatory pre-treatment prophylaxis:

• G-CSF prophylaxis is required when using brentuximab vedotin-based regimens starting with Cycle 1 4
• Among patients not receiving G-CSF prophylaxis with brentuximab vedotin plus AVD, 96% experienced neutropenia and 21% had febrile neutropenia 4

Baseline assessments required:

• Bidimensional echocardiogram for left ventricular ejection fraction (anthracycline cardiotoxicity risk) 1, 2
• Dental evaluation and thyroid function testing (FT3, FT4, TSH) for patients receiving neck irradiation 1
• Fertility counseling for all patients of reproductive age 1, 2
• Hepatitis B, C, and HIV serology 1

Common pitfall: Failure to provide G-CSF prophylaxis with brentuximab vedotin-containing regimens results in unacceptably high rates of severe neutropenia and febrile neutropenia 4. Seven of 9 on-study deaths in the ECHELON-1 trial were associated with neutropenia in patients who had not received G-CSF 4.

Organ Dysfunction Modifications

For patients with hepatic impairment:

• Mild impairment (Child-Pugh A): Reduce brentuximab vedotin to 0.9 mg/kg (maximum 90 mg) 4
• Moderate/severe impairment (Child-Pugh B/C): Avoid brentuximab vedotin 4

For patients with renal impairment:

• Severe impairment (CrCL <30 mL/min): Avoid brentuximab vedotin 4

For patients with multiple comorbidities (chronic liver disease, acute kidney injury, cardiomyopathy):

• Consider modified ABVD without bleomycin followed by involved-site radiotherapy 5
• Bleomycin should be completely omitted due to pulmonary toxicity risk in compromised patients 5
• BEACOPP is absolutely contraindicated in organ dysfunction 5
• Single-agent brentuximab vedotin may be considered for severe organ dysfunction precluding standard chemotherapy 5

Response-Adapted Therapy

PET evaluation after 2 cycles of chemotherapy enables treatment optimization 2. Negative PET results may allow de-escalation, while positive PET results should prompt escalation to BEACOPP 2. However, this approach requires prospective validation and should ideally be performed within clinical trials 1.