Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma

All patients first received 2 cycles of ABVD; after a negative interim PET-CT (score 1 to 3 on the 5-point scale, 9 to 13 days after day 15 of the second cycle), 4 further cycles of ABVD every 28 days: doxorubicin 25 mg/m², bleomycin 10,000 IU/m², vinblastine 6 mg/m² and dacarbazine 375 mg/m², all IV on days 1 and 15 (6 cycles in total).

Full dose and on schedule, without delay or dose reduction for haematological toxicity; dose capping was not allowed (except in severe obesity: ideal body weight, but not less than 85% of the dose calculated on actual weight); G-CSF was not routinely recommended. Bilirubin 1.7 to 2.5 times the upper limit of normal: 50% dose of doxorubicin and vinblastine; 2.5 to 4.0 times: 25% dose. Grade 3 or higher ileus: delay until recovery and continue vinblastine at 75% dose. Any patient with dyspnoea had a chest X-ray and pulmonary function tests before the next bleomycin dose; bleomycin was stopped only with clinical or radiographic evidence of pulmonary infiltrates or fibrosis or a fall in diffusing capacity to below 50% of predicted. Consolidation radiotherapy was not recommended.

After 2 cycles of ABVD (at the same doses) and a negative interim PET-CT, 4 cycles of AVD every 28 days: doxorubicin 25 mg/m², vinblastine 6 mg/m² and dacarbazine 375 mg/m², all IV on days 1 and 15 (bleomycin omitted). The same rules for full dosing, hepatic adjustment and vinblastine adjustment for ileus. Radiotherapy was not recommended in patients with a negative interim PET.

Escalation to BEACOPP according to each centre's prespecified choice (of 182 patients with a positive interim PET, 94 received BEACOPP-14 and 78 escalated BEACOPP); first cycle within 6 weeks of the last ABVD dose.

BEACOPP-14 (every 14 days): doxorubicin 25 mg/m² IV on day 1; cyclophosphamide 650 mg/m² IV on day 1; etoposide 100 mg/m² IV on days 1 to 3; procarbazine 100 mg/m² orally on days 1 to 7; prednisolone 80 mg/m² orally on days 1 to 7; bleomycin 10,000 units/m² IV on day 8; vincristine 1.4 mg/m² IV on day 8 (maximum 2 mg); G-CSF 263 or 300 micrograms (or equivalent) subcutaneously on days 9 to 13, or a single dose of pegfilgrastim.

Escalated BEACOPP (every 21 days): doxorubicin 35 mg/m² IV on day 1; cyclophosphamide 1250 mg/m² IV on day 1; etoposide 200 mg/m² IV on days 1 to 3; procarbazine 100 mg/m² orally on days 1 to 7; prednisolone 40 mg/m² orally on days 1 to 14; bleomycin 10,000 units/m² IV on day 8; vincristine 1.4 mg/m² IV on day 8 (maximum 2 mg); G-CSF 263 or 300 micrograms (or equivalent) subcutaneously from day 9 until count recovery, or a single dose of pegfilgrastim.

A third PET-CT after 4 cycles of BEACOPP-14 or 3 cycles of escalated BEACOPP; if negative, 2 further cycles of BEACOPP-14 or 1 further cycle of escalated BEACOPP; if positive, salvage therapy per local protocol. The next cycle started provided white cells were above 2.5×10⁹/L and platelets above 80×10⁹/L, and the day 8 drugs were given at full dose regardless of counts. In escalated BEACOPP, after any predefined toxicity (grade 4 leucopenia for more than 4 days, grade 4 thrombocytopenia, infection, mucositis or an adverse event requiring a 2-week delay), the cyclophosphamide and etoposide doses were reduced by one level on a 5-level scale (cyclophosphamide 1250, 1100, 950, 800, 650 and etoposide 200, 175, 150, 125, 100 mg/m²); with toxicity in 2 consecutive cycles, standard dosing for all subsequent cycles. Radiotherapy to sites with FDG uptake at the end of chemotherapy was allowed.