Chemotherapy with or without radiation therapy

Four cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) plus involved-field radiation therapy (IFRT) (20 Gy–30 Gy).[4-7]

Six cycles of ABVD.[2,3]

A randomized, prospective trial from the National Cancer Institute of Canada (NCIC) involving 276 patients with early unfavorable HL compared ABVD for four to six cycles with ABVD for two cycles plus extended-field radiation therapy (EFRT).[2][Level of evidence A1]

A randomized, prospective trial from the National Cancer Institute of Canada (NCIC) involving 276 patients with early unfavorable HL compared ABVD for four to six cycles with ABVD for two cycles plus extended-field radiation therapy (EFRT).[2][Level of evidence A1]

With a median follow-up of 11.3 years, the freedom from progression score favored combined-modality therapy (86% vs. 94%; P = .006), but the OS rate was better for ABVD alone (92% vs. 81%; P = .04).

A randomized, prospective trial from the National Cancer Institute of Canada (NCIC) involving 276 patients with early unfavorable HL compared ABVD for four to six cycles with ABVD for two cycles plus extended-field radiation therapy (EFRT).[2][Level of evidence A1]

The trend toward a worse survival for the combined-modality arm was attributed to excess secondary malignancies and cardiovascular deaths. In this trial, the EFRT used higher doses and significantly larger exposure to body sites than are employed in current practice.

A randomized, prospective trial from the National Cancer Institute of Canada (NCIC) involving 276 patients with early unfavorable HL compared ABVD for four to six cycles with ABVD for two cycles plus extended-field radiation therapy (EFRT).[2][Level of evidence A1]

This trial established that six cycles of ABVD can be used alone and that long-term complications from radiation therapy can negate differences for progression-free survival (PFS).

In the HD11 trial, the German Hodgkin Study Group (GHSG) randomly assigned 1,395 patients with early unfavorable HL to receive one of the following:The following results were observed:

In the HD11 trial, the German Hodgkin Study Group (GHSG) randomly assigned 1,395 patients with early unfavorable HL to receive one of the following:The following results were observed:

Four cycles of ABVD plus 30 Gy of IFRT.

In the HD11 trial, the German Hodgkin Study Group (GHSG) randomly assigned 1,395 patients with early unfavorable HL to receive one of the following:The following results were observed:

Four cycles of ABVD plus 20 Gy of IFRT.

In the HD11 trial, the German Hodgkin Study Group (GHSG) randomly assigned 1,395 patients with early unfavorable HL to receive one of the following:The following results were observed:

Four cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) plus 30 Gy of IFRT.

In the HD11 trial, the German Hodgkin Study Group (GHSG) randomly assigned 1,395 patients with early unfavorable HL to receive one of the following:The following results were observed:

Four cycles of BEACOPP plus 20 Gy of IFRT.

In the HD11 trial, the German Hodgkin Study Group (GHSG) randomly assigned 1,395 patients with early unfavorable HL to receive one of the following:The following results were observed:

With an 8.8-year median follow-up, no differences were observed in OS rates (93%–96%) for all four groups.[8][Level of evidence A1]

In the HD11 trial, the German Hodgkin Study Group (GHSG) randomly assigned 1,395 patients with early unfavorable HL to receive one of the following:The following results were observed:

In the study arms using 30 Gy of IFRT, there was no difference in freedom from treatment failure between BEACOPP and ABVD (P = .65), but a significant difference against ABVD was seen for PFS when 20 Gy of IFRT was used (10-year PFS rate, 84% vs. 76%; hazard ratio (HR), 1.5; 95% confidence interval [CI], 1.0–2.1).[5][Level of evidence B1]

In the HD11 trial, the German Hodgkin Study Group (GHSG) randomly assigned 1,395 patients with early unfavorable HL to receive one of the following:The following results were observed:

In this trial, four cycles of ABVD plus 30 Gy of IFRT established this regimen as the preferred approach (or BEACOPP with 20 Gy of IFRT).

In the HD14 trial, the GHSG randomly assigned 1,528 patients with early unfavorable HL to receive either four cycles of ABVD plus 30 Gy of IFRT or two cycles of escalated BEACOPP followed by two cycles of ABVD plus 30 Gy of IFRT.[6][Level of evidence A1]

In the HD14 trial, the GHSG randomly assigned 1,528 patients with early unfavorable HL to receive either four cycles of ABVD plus 30 Gy of IFRT or two cycles of escalated BEACOPP followed by two cycles of ABVD plus 30 Gy of IFRT.[6][Level of evidence A1]

With a median follow-up of 43 months, no difference was observed in OS.

In the HD14 trial, the GHSG randomly assigned 1,528 patients with early unfavorable HL to receive either four cycles of ABVD plus 30 Gy of IFRT or two cycles of escalated BEACOPP followed by two cycles of ABVD plus 30 Gy of IFRT.[6][Level of evidence A1]

In this trial, four cycles of ABVD plus 30 Gy of IFRT established this regimen as the preferred approach.

In the H9-U trial, the European Organisation for Research and Treatment of Cancer–Groupe d'Étude des Lymphomes de l'Adulte (EORTC/GELA) randomly assigned 808 patients with early unfavorable disease (including 40% with bulky disease) to receive one of the following:[7][Level of evidence A1]:The following results were observed:

In the H9-U trial, the European Organisation for Research and Treatment of Cancer–Groupe d'Étude des Lymphomes de l'Adulte (EORTC/GELA) randomly assigned 808 patients with early unfavorable disease (including 40% with bulky disease) to receive one of the following:[7][Level of evidence A1]:The following results were observed:

Six cycles of ABVD plus 36 Gy of IFRT.

In the H9-U trial, the European Organisation for Research and Treatment of Cancer–Groupe d'Étude des Lymphomes de l'Adulte (EORTC/GELA) randomly assigned 808 patients with early unfavorable disease (including 40% with bulky disease) to receive one of the following:[7][Level of evidence A1]:The following results were observed:

Four cycles of ABVD plus 36 Gy of IFRT.

In the H9-U trial, the European Organisation for Research and Treatment of Cancer–Groupe d'Étude des Lymphomes de l'Adulte (EORTC/GELA) randomly assigned 808 patients with early unfavorable disease (including 40% with bulky disease) to receive one of the following:[7][Level of evidence A1]:The following results were observed:

Four cycles of BEACOPP plus 36 Gy of IFRT.

In the H9-U trial, the European Organisation for Research and Treatment of Cancer–Groupe d'Étude des Lymphomes de l'Adulte (EORTC/GELA) randomly assigned 808 patients with early unfavorable disease (including 40% with bulky disease) to receive one of the following:[7][Level of evidence A1]:The following results were observed:

With a median follow-up of 64 months, no differences were observed (event-free survival rates, 89%–92%; P = .38; or OS rates, 91%–96%; P = .89).

In the H9-U trial, the European Organisation for Research and Treatment of Cancer–Groupe d'Étude des Lymphomes de l'Adulte (EORTC/GELA) randomly assigned 808 patients with early unfavorable disease (including 40% with bulky disease) to receive one of the following:[7][Level of evidence A1]:The following results were observed:

Based on toxicities, four cycles of ABVD plus IFRT was established as the preferred regimen.

A multicenter nonrandomized study in 117 patients (most of whom had bulky disease) showed that four cycles of BV-AVD (brentuximab vedotin + doxorubicin, vinblastine, and dacarbazine) with or without involved-site radiation therapy is well-tolerated and effective.[9]

A multicenter nonrandomized study in 117 patients (most of whom had bulky disease) showed that four cycles of BV-AVD (brentuximab vedotin + doxorubicin, vinblastine, and dacarbazine) with or without involved-site radiation therapy is well-tolerated and effective.[9]

With a median follow-up of 3.8 years, the overall 2-year PFS was 94% (95% CI, 89.7%–98.3%). The 2-year OS was 99.1% (97.3%– 100.0%).[9][Level of evidence C2]

A multicenter nonrandomized study in 117 patients (most of whom had bulky disease) showed that four cycles of BV-AVD (brentuximab vedotin + doxorubicin, vinblastine, and dacarbazine) with or without involved-site radiation therapy is well-tolerated and effective.[9]

This pilot study requires confirmation, but the results may be reassuring when using the regimen for patients who cannot take bleomycin or need to limit anthracycline exposure.

The NCIC study addressed this question in patients with early unfavorable HL. Although four to six cycles of ABVD alone had improved OS compared with a combined-modality approach, the use of EFRT in the combined-modality arm is excessive by current standards, and late effects will be magnified with these larger fields.[2] In addition, chemotherapy alone was 8% worse in freedom from disease progression compared with the combined-modality approach. An indirect comparison for using ABVD alone is that the 94% OS rate reported for patients with early unfavorable HL in the NCIC study [2] at 11 years is equivalent to the survival reported at 11 years in the GHSG's HD6 (NCT00002561), HD10 (NCT01399931), and HD11 (NCT0264953) trials using combined-modality therapy.[10] In addition, for the HD6 and HD10 trials, between the reports at 55 months and subsequently at 133 months, cardiovascular events doubled and solid tumor events tripled.[10]

A retrospective analysis of 215 patients treated with ABVD and more contemporary radiation therapy (20 Gy–30 Gy, limited field) was compared with a cohort of 860 individuals matched for age, sex, geographical region, and major medical diseases.[11] Excess morbidity was still seen in terms of second malignancies, cardiovascular disease, and respiratory disease (HR, 1.5–7.6), but at a lower rate than in reports using regimens and doses from earlier decades.[11]

A randomized prospective trial (EORTC HIOU) of 1,196 patients with early unfavorable HL investigated the use of PET-CT scans to modify therapy after two cycles of therapy.[13]This trial supports adding escalated BEACOPP to ABVD for patients with early unfavorable classic HL who have positive PET-CT results after two cycles.

A randomized prospective trial (EORTC HIOU) of 1,196 patients with early unfavorable HL investigated the use of PET-CT scans to modify therapy after two cycles of therapy.[13]This trial supports adding escalated BEACOPP to ABVD for patients with early unfavorable classic HL who have positive PET-CT results after two cycles.

Among the 815 patients with negative PET-CT findings (Deauville score of 1 or 2) after two cycles of ABVD, the patients randomly assigned to receive six cycles of ABVD had inferior PFS rates compared with patients who received four cycles of ABVD plus involved nodal radiation therapy (94.7% vs. 99.2%; P = .026), but no difference in OS.[Level of evidence B1]

A randomized prospective trial (EORTC HIOU) of 1,196 patients with early unfavorable HL investigated the use of PET-CT scans to modify therapy after two cycles of therapy.[13]This trial supports adding escalated BEACOPP to ABVD for patients with early unfavorable classic HL who have positive PET-CT results after two cycles.

The use of ABVD for six cycles is acceptable in the absence of radiation therapy for patients with early unfavorable classic HL who have negative PET-CT results after two cycles of ABVD, if one can accept a 5% rate of increased relapse, with no decrement in OS after salvage therapy.

A randomized prospective trial (EORTC HIOU) of 1,196 patients with early unfavorable HL investigated the use of PET-CT scans to modify therapy after two cycles of therapy.[13]This trial supports adding escalated BEACOPP to ABVD for patients with early unfavorable classic HL who have positive PET-CT results after two cycles.

In a follow-up report from this trial, 381 patients with positive PET-CT results (Deauville score of 3, 4, or 5) after two cycles of ABVD were randomly assigned to receive four cycles of ABVD plus 30 Gy of involved nodal radiation therapy versus two cycles of ABVD followed by two cycles of escalated BEACOPP plus 30 Gy of involved nodal radiation therapy.[14][Level of evidence A1]

A randomized prospective trial (EORTC HIOU) of 1,196 patients with early unfavorable HL investigated the use of PET-CT scans to modify therapy after two cycles of therapy.[13]This trial supports adding escalated BEACOPP to ABVD for patients with early unfavorable classic HL who have positive PET-CT results after two cycles. › In a follow-up report from this trial, 381 patients with positive PET-CT results (Deauville score of 3, 4, or 5) after two cycles of ABVD were randomly assigned to receive four cycles of ABVD plus 30 Gy of involved nodal radiation therapy versus two cycles of ABVD followed by two cycles of escalated BEACOPP plus 30 Gy of involved nodal radiation therapy.[14][Level of evidence A1]

The 5-year PFS rate was 91% in the BEACOPP arm compared with 77% in the ABVD arm (P = .002).

A randomized prospective trial (EORTC HIOU) of 1,196 patients with early unfavorable HL investigated the use of PET-CT scans to modify therapy after two cycles of therapy.[13]This trial supports adding escalated BEACOPP to ABVD for patients with early unfavorable classic HL who have positive PET-CT results after two cycles. › In a follow-up report from this trial, 381 patients with positive PET-CT results (Deauville score of 3, 4, or 5) after two cycles of ABVD were randomly assigned to receive four cycles of ABVD plus 30 Gy of involved nodal radiation therapy versus two cycles of ABVD followed by two cycles of escalated BEACOPP plus 30 Gy of involved nodal radiation therapy.[14][Level of evidence A1]

The 5-year OS rate was 96% in the BEACOPP arm compared with 89% in the ABVD arm (P = .02).

A randomized prospective trial (GHSG HD17 [NCT01356680]) of 1,100 patients with early-stage unfavorable HL evaluated whether radiation therapy can be omitted in patients with a complete metabolic response (CMR) on PET-CT scan after two cycles of escalated BEACOPP and two cycles of regular-dose BEACOPP (2 + 2 regimen). Patients were randomly assigned to receive combined-modality therapy (n = 548) or PET4-guided therapy (n = 552). Combined-modality therapy included both the 2 + 2 regimen and involved-field radiation therapy. PET4-guided therapy included the 2 + 2 regimen for all patients and involved-node radiation therapy for the patients with a positive PET4 scan (n = 160). A total of 333 patients in the PET4-guided therapy group were PET4-negative and received chemotherapy alone.[15]

A randomized prospective trial (GHSG HD17 [NCT01356680]) of 1,100 patients with early-stage unfavorable HL evaluated whether radiation therapy can be omitted in patients with a complete metabolic response (CMR) on PET-CT scan after two cycles of escalated BEACOPP and two cycles of regular-dose BEACOPP (2 + 2 regimen). Patients were randomly assigned to receive combined-modality therapy (n = 548) or PET4-guided therapy (n = 552). Combined-modality therapy included both the 2 + 2 regimen and involved-field radiation therapy. PET4-guided therapy included the 2 + 2 regimen for all patients and involved-node radiation therapy for the patients with a positive PET4 scan (n = 160). A total of 333 patients in the PET4-guided therapy group were PET4-negative and received chemotherapy alone.[15]

With a median follow-up of 46.2 months, the 5-year PFS rate was 97.3% (95% CI, 94.5%–98.7%) for patients who received combined-modality therapy and 95.1% (95% CI, 92.0%–97.0%) for patients who received PET4-guided therapy (HR, 0.523; 95% CI, 0.23–1.21). The between-group difference was 2.2% (95% CI, -0.9% to 5.3%) and excluded the noninferiority margin of 8%.[15][Level of evidence B1]

A randomized prospective trial (GHSG HD17 [NCT01356680]) of 1,100 patients with early-stage unfavorable HL evaluated whether radiation therapy can be omitted in patients with a complete metabolic response (CMR) on PET-CT scan after two cycles of escalated BEACOPP and two cycles of regular-dose BEACOPP (2 + 2 regimen). Patients were randomly assigned to receive combined-modality therapy (n = 548) or PET4-guided therapy (n = 552). Combined-modality therapy included both the 2 + 2 regimen and involved-field radiation therapy. PET4-guided therapy included the 2 + 2 regimen for all patients and involved-node radiation therapy for the patients with a positive PET4 scan (n = 160). A total of 333 patients in the PET4-guided therapy group were PET4-negative and received chemotherapy alone.[15]

In the subgroup of PET4-negative patients who received chemotherapy alone, the difference in 5-year PFS was 1.7% (95% CI, -1.8% to 5.3%).

A randomized prospective trial (GHSG HD17 [NCT01356680]) of 1,100 patients with early-stage unfavorable HL evaluated whether radiation therapy can be omitted in patients with a complete metabolic response (CMR) on PET-CT scan after two cycles of escalated BEACOPP and two cycles of regular-dose BEACOPP (2 + 2 regimen). Patients were randomly assigned to receive combined-modality therapy (n = 548) or PET4-guided therapy (n = 552). Combined-modality therapy included both the 2 + 2 regimen and involved-field radiation therapy. PET4-guided therapy included the 2 + 2 regimen for all patients and involved-node radiation therapy for the patients with a positive PET4 scan (n = 160). A total of 333 patients in the PET4-guided therapy group were PET4-negative and received chemotherapy alone.[15]

Omitting radiation therapy for patients in CMR after four cycles of BEACOPP-based chemotherapy did not significantly impair PFS.

A prospective phase II trial included 94 patients with early-stage (I/II) bulky disease (defined as mass >10 cm or >⅓ maximum intrathoracic diameter on chest x-ray). Patients received ABVD for two cycles, followed by interim PET (PET2) scan. PET-negative patients (78% of the total) were defined as Deauville 1, 2, or 3 and received two more cycles of ABVD. PET2-positive patients (Deauville 4 or 5, 22% of the total) received four cycles of escalated BEACOPP, followed by 30.6 Gy of IFRT.[16]

A prospective phase II trial included 94 patients with early-stage (I/II) bulky disease (defined as mass >10 cm or >⅓ maximum intrathoracic diameter on chest x-ray). Patients received ABVD for two cycles, followed by interim PET (PET2) scan. PET-negative patients (78% of the total) were defined as Deauville 1, 2, or 3 and received two more cycles of ABVD. PET2-positive patients (Deauville 4 or 5, 22% of the total) received four cycles of escalated BEACOPP, followed by 30.6 Gy of IFRT.[16]

With a median follow-up of 60 months, the 3-year PFS rate was 93.1% in PET2-negative patients and 89.7% in PET2-positive patients. The 3-year OS rate was 98.6% in PET2-negative patients and 94.4% in PET2-positive patients.[16][Level of evidence C3]

Most of the trials support using four cycles of ABVD plus 30 Gy of IFRT or involved nodal radiation therapy.[17]

ABVD alone for six cycles is a reasonable alternative despite a 5% to 6% decrement in PFS because the long-term toxicities of adding radiation therapy will affect OS, which is the most important patient outcome.[17]

For patients with a positive PET-CT (usually Deauville 4 or 5) after two cycles of ABVD, adding brentuximab vedotin while eliminating bleomycin can be considered. BEACOPP or clinical trials investigating the addition of brentuximab vedotin or checkpoint inhibitors in this setting would be indicated.

Radiation therapy may be omitted in patients with a negative PET-CT (Deauville 1) after two to four cycles of chemotherapy.