Upfront escalated BEACOPP or ABVD?

In a letter to the editor¹ of the Journal of Clinical Oncology, Eliza Hawkes of the Olivia Newton-John Cancer Wellness & Research Centre, et al. further discuss findings initially published by Press et al.² reporting findings of the Southwest Oncology Group (SWOG) S0816 study.

In Hawkes et al.’s letter, they noted that:

• The main finding of the S0816 study was that >80% patients with advanced Hodgkin Lymphoma (HL) can be sufficiently treated with first-line ABVD, (hence avoiding the toxicity, cost and resource required for escalated BEACOPP therapy).
• This is supported by findings of the UK based phase III RATHL study³.
• So far, no first-line escalated BEACOPP studies have produced a significantly improved OS compared to ABVD alone in patients with advanced HL.

This letter to the editor also noted that the accompanying editorial by Borchmann and Engert⁴ highlights that:

• In the German HD18 PET-adapted therapy study, which used upfront BEACOPP, no difference in prognosis was found between interim PET2-positive patients and the PET2-negative patients⁵.
• Borchmann and Engert hypothesized this is due to the improved efficacy of upfront BEACOPP.

Hawkes et al. criticized this observation by explaining that cross comparisons of trials with different study populations and definitions of poor prognosis can be unsound:

• The HD18 study defined PET2-positivity as Deauville score 3–5.
• The HD18 study had a PET2-positivity rate of 40%.
• Whereas, the SWOG S0816 and RATHL studies used a Deauville score of 4–5.
• PET2-positivity of 18% and 16%, respectively.

This indicates that the HD18 study may have included patients:

• With a better prognosis compared to the RATHL and SWOG studies.
• With earlier stage disease (HD18 and RATHL studies included stage II patients) compared to the S0816 study (stage III–IV).

The RATHL and SWOG studies support existing data for the prognostic utility of PET2. Moreover, dose intensification from ABVD to BEACOPP in PET-positive patients with poor prognoses produced impressive PFS compared with historic controls, providing the rationale for individualized treatment. However, Hawkes et al. warn that these results need to mature and further randomized studies complemented with clinical trials exploring stratification using molecular profiles are required to validate the superiority of response-adapted dose intensification therapy.

Hawkes et al. also note that the evidence supporting escalated BEACOPP overlooks the significant toxicity and additional resources required. Improvements in managing patients with HL is likely to come from using novel, targeted agents for first-line therapy, such as brentuximab vedotin. But, for now, in Hawkes et al.’s opinion, there is no convincing evidence to contest the appropriateness of ABVD for the majority of advanced HL patients.