Dose-intensive response-based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate-risk hodgkin lymphoma: a report from the Children's Oncology Group Study AHOD0031

Abstract

Purpose: The Children's Oncology Group study AHOD0031, a randomized phase III study, was designed to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. To avoid treatment-associated risks that compromise long-term health and to maintain high cure rates, dose-intensive chemotherapy with limited cumulative doses was used.

Patients and methods: Patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone (ABVE-PC) followed by response evaluation. Rapid early responders (RERs) received two additional ABVE-PC cycles, followed by complete response (CR) evaluation. RERs with CR were randomly assigned to involved-field radiotherapy (IFRT) or no additional therapy; RERs with less than CR were nonrandomly assigned to IFRT. Slow early responders (SERs) were randomly assigned to receive two additional ABVE-PC cycles with or without two cycles of dexamethasone, etoposide, cisplatin, and cytarabine (DECA). All SERs were assigned to receive IFRT.

Results: Among 1,712 eligible patients, 4-year event-free survival (EFS) was 85.0%: 86.9% for RERs and 77.4% for SERs (P < .001). Four-year overall survival was 97.8%: 98.5% for RERs and 95.3% for SERs (P < .001). Four-year EFS was 87.9% versus 84.3% (P = .11) for RERs with CR who were randomly assigned to IFRT versus no IFRT, and 86.7% versus 87.3% (P = .87) for RERs with positron emission tomography (PET) -negative results at response assessment. Four-year EFS was 79.3% versus 75.2% (P = .11) for SERs who were randomly assigned to DECA versus no DECA, and 70.7% versus 54.6% (P = .05) for SERs with PET-positive results at response assessment.

Conclusion: This trial demonstrated that early response assessment supported therapeutic titration (omitting radiotherapy in RERs with CR; augmenting chemotherapy in SERs with PET-positive disease). Strategies directed toward improved response assessment and risk stratification may enhance tailoring of treatment to patient characteristics and response.

Trial registration: ClinicalTrials.gov NCT00025259.

Fig 1.

Study schema. ABVE-PC, doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone; CR, complete response; DECA, dexamethasone, etoposide, cisplatin, and cytarabine; IFRT, involved-field radiation therapy; PD, progressive disease; RER, rapid early responder; SER, slow early responder.

Fig 2.

CONSORT diagram. ABVE-PC, doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone; CR, complete response; DECA, dexamethasone, etoposide, cisplatin, and cytarabine; ER, early response; IFRT, involved-field radiation therapy; RER, rapid early responder; SER, slow early responder.

Fig 3.

Event-free survival (EFS) and overall survival (OS). (A) EFS and OS for the entire study cohort. (B) EFS and OS for two-cycle rapid early responders (RERs) and slow early responders (SERs; EFS, P < .001; OS, P < .001). (C) EFS and OS by involved-field radiation therapy (IFRT) random assignment for RERs with complete remission (EFS, P = .11; OS, P = .51). (D) EFS and OS by dexamethasone, etoposide, cisplatin, and cytarabine (DECA) random assignment for SERs (EFS, P = .11; OS, P = .16). (E) EFS by IFRT random assignment for RERs with complete remission and negative (neg) cycle-2 positron emission tomography (PET) results (P = .87) and for RERs with complete remission and positive/equivocal (pos/equ) cycle-2 PET results (P = .80). (F) EFS by DECA random assignment for SERs with neg cycle-2 PET (P = .54) and for SERs with pos/equ cycle-2 PET results (P = .05).