Systemic Therapy for Advanced-Stage Hodgkin Lymphoma.

Advanced-stage classic Hodgkin lymphoma (cHL) represents one of the major success stories in modern oncology, with long-term survival now exceeding 80% for most patients. In this review, we examine the evolution of frontline therapy for advanced-stage cHL, tracing the transition from empiric combination chemotherapy to contemporary, biologically informed treatment strategies. We begin by revisiting the early development of multiagent chemotherapy regimens, including MOPP and ABVD. These regimens established, for the first time, that advanced lymphoma could be cured with systemic therapy. We then discuss efforts to improve outcomes through treatment intensification, which culminated in the development of BEACOPP-based approaches that improved disease control at the cost of substantial acute and long-term toxicity. Subsequently, the incorporation of functional imaging ushered in the era of PET-adapted therapy, enabling dynamic treatment modification based on early response and providing a framework to better balance efficacy with toxicity reduction. Finally, we review the integration of novel agents, including brentuximab vedotin and PD-1 blockade, which have reshaped the frontline treatment landscape and further improved outcomes for high-risk patients while challenging historical chemotherapy paradigms. Collectively, the treatment history of advanced-stage cHL reflects a broader evolution in oncology: from maximizing cytotoxic intensity toward increasingly personalized strategies designed to optimize cure while minimizing long-term harm. Ongoing efforts focused on biomarker-driven risk stratification and the utilization of circulating tumor DNA are poised to further refine this balance in the coming decade.