Evolution of European multicenter trial results

Substitution of cyclophosphamide for mechlorethamine in the MOPP combination results in a low risk of subsequent myelodysplasia/leukemia.[10]

Omission of procarbazine from the OPPA combination and substitution of methotrexate for procarbazine in the COPP combination (OPA/COMP) results in a substantially inferior EFS.[74]

Substitution of etoposide for procarbazine in the OPPA combination (OEPA) in boys produces comparable EFS to that of girls treated with OPPA and is associated with hormonal parameters, suggesting lower risk of gonadal toxicity.[75]

Omission of radiation for patients completely responding (defined as complete resolution or only minor residuals in all previously involved regions using clinical examination and anatomical imaging) to risk-based and sex-based OEPA or OPPA/COPP chemotherapy results in a significantly lower EFS in intermediate-risk and high-risk patients than in irradiated patients (79% vs. 91%), but no difference among nonirradiated and irradiated patients assigned to the favorable-risk group.[24]

Substitution of dacarbazine for procarbazine (OEPA-COPDAC) in boys produces comparable results to standard OPPA-COPP in girls when used in combination with IFRT for intermediate-risk and high-risk patients.[22][Level of evidence B4]

A large, multinational, randomized trial (EuroNet-PHL-C1) investigated whether radiation therapy could be omitted in children (aged <18 years) with intermediate- and advanced-stage classical Hodgkin lymphoma who achieved a morphological and adequate metabolic response to early chemotherapy with OEPA. The trial also studied whether modified consolidation with COPDAC (substituting dacarbazine for procarbazine in COPP) reduced gonadotoxicity.[76][Level of evidence B1]

A large, multinational, randomized trial (EuroNet-PHL-C1) investigated whether radiation therapy could be omitted in children (aged <18 years) with intermediate- and advanced-stage classical Hodgkin lymphoma who achieved a morphological and adequate metabolic response to early chemotherapy with OEPA. The trial also studied whether modified consolidation with COPDAC (substituting dacarbazine for procarbazine in COPP) reduced gonadotoxicity.[76][Level of evidence B1]

At a median follow-up of 66.5 months, the 5-year EFS rate was 90.1% (95% CI, 87.5%–92.7%) for patients who responded adequately to early chemotherapy with OEPA followed by COPP or COPDAC.

A large, multinational, randomized trial (EuroNet-PHL-C1) investigated whether radiation therapy could be omitted in children (aged <18 years) with intermediate- and advanced-stage classical Hodgkin lymphoma who achieved a morphological and adequate metabolic response to early chemotherapy with OEPA. The trial also studied whether modified consolidation with COPDAC (substituting dacarbazine for procarbazine in COPP) reduced gonadotoxicity.[76][Level of evidence B1]

In the analysis according to protocol treatment, the 5-year EFS rate was 89.9% (95% CI, 87.1%–92.8%) for individuals randomly assigned to COPP (n = 444) versus 86.1% (95% CI, 82.9%–89.4%) for those randomly assigned to COPDAC (n = 448). Similar results were observed in the intent-to-treat analysis.

A large, multinational, randomized trial (EuroNet-PHL-C1) investigated whether radiation therapy could be omitted in children (aged <18 years) with intermediate- and advanced-stage classical Hodgkin lymphoma who achieved a morphological and adequate metabolic response to early chemotherapy with OEPA. The trial also studied whether modified consolidation with COPDAC (substituting dacarbazine for procarbazine in COPP) reduced gonadotoxicity.[76][Level of evidence B1]

In a subgroup analysis (unplanned), the 5-year EFS rate among those with adequate early response to OEPA was 91.9% (95% CI, 88.1%–95.9%) with COPP and 82.9% (77.2%–89.0%) with COPDAC, but there was no difference in OS.

A large, multinational, randomized trial (EuroNet-PHL-C1) investigated whether radiation therapy could be omitted in children (aged <18 years) with intermediate- and advanced-stage classical Hodgkin lymphoma who achieved a morphological and adequate metabolic response to early chemotherapy with OEPA. The trial also studied whether modified consolidation with COPDAC (substituting dacarbazine for procarbazine in COPP) reduced gonadotoxicity.[76][Level of evidence B1]

A posttreatment semen analysis included 45 men at the 40-month follow-up. COPP appeared to be more gonadotoxic (19 of 23 men were azoospermic) than COPDAC (0 of 22 men were azoospermic). Biomarker analyses that included follicle-stimulating hormone (FSH) and inhibin B also suggested higher prevalence of gonadotoxicity after COPP than COPDAC. Similarly, based on biomarker analyses limited to 113 women, FSH was significantly increased in 55 women who were randomly assigned to receive COPP, compared with 58 women who were randomly assigned to receive COPDAC.

Another EuroNet-PHL-C1 trial investigated whether radiation therapy can be omitted in patients with adequate morphological and metabolic responses to OEPA.[77]

Another EuroNet-PHL-C1 trial investigated whether radiation therapy can be omitted in patients with adequate morphological and metabolic responses to OEPA.[77]

Among 738 patients with early-stage disease (median follow-up period, 63.3 months), 714 patients were assigned to and received therapy in treatment group 1.

Another EuroNet-PHL-C1 trial investigated whether radiation therapy can be omitted in patients with adequate morphological and metabolic responses to OEPA.[77]

Among the 713 patients in the intention-to-treat group, 440 had adequate responses to two cycles of OEPA and did not receive radiation therapy. The 5-year EFS rate was 86.5% (95% CI, 83.3%–89.8%).

Another EuroNet-PHL-C1 trial investigated whether radiation therapy can be omitted in patients with adequate morphological and metabolic responses to OEPA.[77]

The 5-year EFS rate was 88.6% (95% CI, 84.8%–92.5%) for the 273 patients with adequate responses to chemotherapy who also received radiation therapy.

Another EuroNet-PHL-C1 trial investigated whether radiation therapy can be omitted in patients with adequate morphological and metabolic responses to OEPA.[77]

The study findings suggested that radiation therapy can be omitted in patients with early-stage classical Hodgkin lymphoma who have had adequate responses to OEPA chemotherapy.

An open-label, single-arm, multicenter trial (NCT01920932) evaluated two cycles of AEPA (brentuximab vedotin substituted for vincristine in the OEPA regimen) and four cycles of CAPDAC (brentuximab vedotin substituted for vincristine in the COPDAC regimen) in 77 patients aged 18 years or younger with stage IIB, IIIB, or IV classical Hodgkin lymphoma. Residual node radiation therapy (25.5 Gy) was given at the end of all chemotherapy and only to nodal sites that did not achieve a CR at the early-response assessment after two cycles of therapy.[63][Level of evidence B4]

An open-label, single-arm, multicenter trial (NCT01920932) evaluated two cycles of AEPA (brentuximab vedotin substituted for vincristine in the OEPA regimen) and four cycles of CAPDAC (brentuximab vedotin substituted for vincristine in the COPDAC regimen) in 77 patients aged 18 years or younger with stage IIB, IIIB, or IV classical Hodgkin lymphoma. Residual node radiation therapy (25.5 Gy) was given at the end of all chemotherapy and only to nodal sites that did not achieve a CR at the early-response assessment after two cycles of therapy.[63][Level of evidence B4]

The 3-year EFS rate (median follow-up, 3.4 years) was 97.4%, and the OS rate was 98.7%.

An open-label, single-arm, multicenter trial (NCT01920932) evaluated two cycles of AEPA (brentuximab vedotin substituted for vincristine in the OEPA regimen) and four cycles of CAPDAC (brentuximab vedotin substituted for vincristine in the COPDAC regimen) in 77 patients aged 18 years or younger with stage IIB, IIIB, or IV classical Hodgkin lymphoma. Residual node radiation therapy (25.5 Gy) was given at the end of all chemotherapy and only to nodal sites that did not achieve a CR at the early-response assessment after two cycles of therapy.[63][Level of evidence B4]

The AEPA and CAPDAC regimens were well tolerated and allowed for omission of radiation therapy in 35% of the treated patients.

An open-label, single-arm, multicenter trial (NCT01920932) evaluated two cycles of AEPA (brentuximab vedotin substituted for vincristine in the OEPA regimen) and four cycles of CAPDAC (brentuximab vedotin substituted for vincristine in the COPDAC regimen) in 77 patients aged 18 years or younger with stage IIB, IIIB, or IV classical Hodgkin lymphoma. Residual node radiation therapy (25.5 Gy) was given at the end of all chemotherapy and only to nodal sites that did not achieve a CR at the early-response assessment after two cycles of therapy.[63][Level of evidence B4]

Only 4% of patients experienced grade 3 neuropathy.

An open-label, single-arm, multicenter trial (NCT01920932) evaluated two cycles of AEPA (brentuximab vedotin substituted for vincristine in the OEPA regimen) and four cycles of CAPDAC (brentuximab vedotin substituted for vincristine in the COPDAC regimen) in 77 patients aged 18 years or younger with stage IIB, IIIB, or IV classical Hodgkin lymphoma. Residual node radiation therapy (25.5 Gy) was given at the end of all chemotherapy and only to nodal sites that did not achieve a CR at the early-response assessment after two cycles of therapy.[63][Level of evidence B4]

Compared with historical controls, residual node radiation volumes in patients requiring radiation were very small, sparing healthy surrounding tissue.