[A1] Based on the available evidence and the experience of this group of experts, the panel agrees that the following factors should be essentially considered during decision-making in the everyday practice for the initial assessment of patients with Stage III/IV HL before any first-line treatment:

(*) Strong expert consensus; (**) expert consensus

[A2] Based on the available evidence and the experience of this group of experts, the panel believes that these factors are critical when selecting first-line treatment in patients with advanced LH:

(*)Strong expert consensus; (**) expert consensus

[A3] Based on the available evidence and the experience of this group of experts, the panel considers that interim PET/CT-adapted ABVD or BV-AVD are first-line treatment options for patients with Stage III/IV HL, depending on the availability of drugs and diagnostic methods. This group of experts does not routinely use BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) as first-line treatment for advanced stages of HL; for this reason, BEACOPP was not considered in this analysis.

Previous trials demonstrated the effectiveness of ABVD for the treatment of Stage III/IV HL.4,5,17,18 The RATHL study proved that removing bleomycin (and continuing treatment with AVD) is safe in patients with negative PET/CT after two cycles of therapy with ABVD. The three-year PFS and OS rates in the AVD arm were 84.5 %, (95 % confidence interval [95 % CI]: 80.7–87.5) and 97.6 % (95 % CI: 95.6–98.7), respectively, and 85.7 % (95 % CI: 88.1–88.6) and 97.2 % (95 % CI: 95.1–98.4) in the ABVD arm. As a result, this approach has now been included in treatment guidelines. This same study tested the strategy of escalating to BEACOPP-14 or BEACOPPESC after a positive interim PET/CT (at the investigator's discretion), with an adequate toxicity profile and a three-year PFS of 67.5 % (95 % CI: 59.7–74.2). 4

Since the advent of ABVD, ECHELON-1 was the first trial to demonstrate improvements in OS with BV-AVD with an OS of 93.9 % (95 % CI: 91.6–95.5) for the BV-AVD arm versus 89.4 % (95 % CI: 86.6–91.7) for the ABVD arm. 9

[A4] Based on the available evidence and the experience of this group of experts, the panel recommends PET/CT-based staging for all patients with Stage III/IV HL.

PET/CT has proven to be more accurate and sensitive than conventional CT for initial staging in several trials. As shown by Hutchings et al., the greater sensitivity of PET/CT is particularly improved for spleen and bone marrow involvement. 15 These data are also consistent with other papers reporting a higher sensitivity for PET/CT in contrast to conventional CT, thereby leading to a change from 10 % to 40 % in staging, as well as changes in treatment intensity in 20 % of these patients. 19–21

Finally, when planning RT, PET/CT-guided staging can also significantly influence the extent of the involved field, compared with RT planning based on CT alone. 4

[A5] Based on the available evidence and the experience of this group of experts, the panel recommends an interim PET/CT (preferably at 12–14 days) for all patients with Stage III/IV HL who initially received 2–3 cycles of ABVD.

The RATHL, GATLA LH-05, FIL HD0801 and Gallamini et al. trials support the proven benefit of interim PET/CT-adapted ABVD treatment.4,5,22,23 Interim PET/CT scanning should be performed >10 days after the preceding dose of chemotherapy, i.e., as close as possible to the next cycle of cancer treatment.24

PET/CT scans should not be performed at 7–10 days after chemotherapy in order to avoid the peak inflammatory response during this period.23

[A6] Based on the available evidence and the experience of this group of experts, the panel suggests treatment escalation in patients with Stage III/IV HL who initially received two cycles of ABVD and have a Deauville score (DS) ≥4 in their interim PET/CT.

As previously described, the RATHL study4 escalated treatment to BEACOPP/BEACOPPESC in patients with positive interim PET/CT scans (DS 4–5) and achieved a three-year PFS rate of 71 %. A similar BEACOPP escalation strategy for patients with positive interim PET/CT scans was evaluated by the US Intergroup trial S0186 17,25 and by the Italian Group GITIL/FIL HD 06074,26 with PFS rates of 65 % and 60 %, respectively. In the approach used by the Italian Group (HD0801), patients were escalated to salvage therapy and consolidated with an autologous transplant, resulting in a two-year PFS rate of 75 %. 27 Although this strategy is used and accepted in high-complexity centers, most institutions still continue to use ABVD for six cycles due to the intensity of BEACOPPESC, or choose to escalate to less intensive regimens and with fewer complications than BEACOPP.

The protocols that mandated shifting patients onto more intensive regimens following an interim PET/CT seem to have shown better outcomes compared with other protocols similar to the one published by Gallamini et al., where patients with a positive interim PET/CT completed six cycles of ABVD with a two-year PFS of 12.8 %, or the GATLA LH-05 trial, in which patients with a positive interim PET/CT continued treatment with ABVD + RT and achieved a three-year PFS rate of 58 %. 3,28

[A7] Based on the available evidence and the experience of this group of experts, the panel recommends performing a new biopsy in all patients with Stage III/IV HL who initially received six cycles of treatment and had an end-of-treatment PET/CT DS of 4–5.

An end-of-treatment PET/CT DS of 4–5 is indicative of treatment failure; patients are deemed as primary refractory, prescribed with salvage therapy and eventually consolidated with autologous hematopoietic stem cell transplantation. Histologic confirmation with a new biopsy of areas with hypermetabolic activity is recommended before making this decision. This confirmatory biopsy may be avoided in the case of poorly accessible sites remaining PET/CT positive from baseline after proper discussion with a multidisciplinary team and the patient. 11

[B1] Based on the available evidence and the experience of this group of experts, factors including comorbid lung disease and extranodal involvement strongly influence the decision to prescribe BV-AVD versus ABVD as first-line therapy.

Comorbid lung disease should be carefully considered, as bleomycin-induced lung injury, especially at the interstitial level, was reported in 7 % of patients from the ABVD arm versus 2 % of patients receiving BV-AVD.

The benefit of adding BV to front-line therapy was greater in patients with Stage IV disease and was even higher among patients with extranodal involvement in more than one site. 6

[B2] Based on the available evidence and the experience of this group of experts, factors including age, the international prognostic score (IPS), and the presence of mild peripheral neuropathy (of any cause) influence the decision to prescribe BV-AVD versus ABVD as first-line therapy.

Good practice point: As defined by the panel, this treatment is contraindicated in patients with moderate-to-severe peripheral neuropathy (B4 recommendation).

Age might be a highly relevant factor when prescribing BV-AVD. On one hand, a significant benefit in OS was observed in under 60-year-old patients (hazard ratio [HR] = 0.51; 95 % CI: 0.29–0.89) compared with over 60-year-old patients (HR: 0.83; 95 % CI: 0.47–1.47). Although this may be due to the small sample size in the subgroup of patients aged over 60, this difference in the benefit and the higher risk of associated complications (especially increased bone marrow toxicity) should be considered when selecting the most adequate therapy.

In a subgroup analysis, no statistically significant benefits were reported in the PFS of over 60-year-old patients with BV-AVD. These patients experienced greater toxicity compared with patients aged under 60. In addition, BV-AVD was associated with a higher incidence of neuropathy and febrile neutropenia, although the incidence of pulmonary toxicity was lower compared with ABVD. 29

The subgroup analysis also reported benefits in the IPS. Importantly, IPS was a stratification factor at randomization, thereby ensuring a balanced patient distribution with several risk groups within the score. In terms of outcomes, an IPS of 4–7 had a HR of 0.48 (95 % CI: 0.26–0.88), whereas groups with an IPS of 2/3 and 0/1 had little or no benefit at all (HR: 0.62; 95 % CI: 0.33–1.14 and HR: 0.97; 95 % CI: 0.34–2.77, respectively).

In the ECHELON-1 trial, exclusion criteria included sensory and/or motor peripheral neuropathy. Peripheral neuropathy occurred in 67 % of patients in the BV arm and 67 % resolved without sequelae. For this reason, current evidence on the use of BV-AVD does not include patients with a previous history of neuropathy. 9

[B3] Based on the available evidence and the experience of this group of experts, gender does not influence the decision to prescribe BV-AVD versus ABVD as first-line therapy.

No statistically significant benefit was reported in PFS (HR: 0.68; 95 % CI: 0.46–1.01) or OS [HR: 0.96; 95 % CI: 0.51–1.80) rates among women receiving BV-AVD versus ABVD, in contrast to male patients (HR: 0.67; 95 % CI: 0.49–0.91 and HR: 0.43; 95 % CI: 0.25–0.73). 7 The reason for the difference in mortality between genders remains unknown. Of note, the risk factors assessed in this analysis were not adjusted for confounders.

This group of experts believes that outcomes derived from the subgroup analyses should be interpreted with caution. Further evidence is required in order to make any recommendations on the role of gender as a determining factor when prescribing BV-AVD over ABVD.

[B4] Based on the available evidence and the experience of this group of experts, the panel considers that moderate-to-severe peripheral neuropathy, pregnancy, and severe drug allergies are absolute contraindications to first-line therapy with BV-AVD in patients with HL.

Good practice point: Neuropathy is considered the most important toxicity in the BV arm, with a significant impact on treatment adherence and greater challenges in patient management.

Patients with sensory or motor peripheral neuropathy, pregnancy, and severe cardiovascular disease were not enrolled in the ECHELON-1 trial, and so its use may not be safe in these patients.

[B5] Based on the available evidence and the experience of this group of experts, the panel considers that patients unwilling to accept the risk of neuropathy have a relative contraindication for BV-AVD as first-line therapy.

The global incidence of neuropathy may restrict the use of BV-AVD in patients with increased risk of peripheral neuropathy or in patients where this risk is intended to be minimized by preference or working/trade reasons. If treatment is still initiated in this group of patients, close follow-up is recommended for early detection of potential adverse effects.

Although there are no recommendations on their management, the original protocol does include general guidelines on dose modifications and treatment discontinuation for moderate-to-severe events. 30

[B6] Based on the opinion of this group of experts, BV-AVD may be considered as a new option for the treatment of higher-risk patients.

ECHELON-1 showed improved OS rates in the following subgroups of patients at a higher risk of relapse prior to treatment:7

• •

  Stage IV (HR: 0.48; 95 % CI: 0.29–0.80),

• •

  IPS of 4–7 (HR: 0.48; 95 % CI: 0.26–0.88),

• •

  Extranodal involvement in more than one site (HR: 0.30; 95 % CI: 0.14–0.67).

The results of a published subanalysis support the superiority of BV-AVD over ABVD in patients with Stage IV disease and a high IPS. 31

We emphasize that subgroup analyses should be interpreted with caution. Given that survival benefits were reported in the entire cohort, we suggest using BV-AVD as a treatment option for all patients with Stage III/IV HL.

[B7] Based on the experience of this group of experts, a number of factors related to the healthcare system (such as high costs, unavailability, reimbursement challenges, irregular supply, and problems with granulocyte-colony stimulating factor [G-CSF] availability) may constitute a limitation to the indication of BV-AVD.

Even though ECHELON-1 demonstrated the superiority of BV-AVD versus ABVD in terms of PFS and OS, we believe that some factors associated with the healthcare system might curb its prescription. The classical ABVD schedule is inexpensive, safe, and highly effective, with high OS rates, provided that treatment is initiated early and with adequate periodicity. Cost is a central aspect when prescribing and discussing the use of BV-AVD with payers; this may delay the authorization and interfere with early treatment initiation.

Unavailability may also be a limitation, as BV may not always be readily available after payer approval. This wait may result in delayed initiation of chemotherapy. Reimbursement challenges and irregular supply are closely related to the foregoing limitations; both factors may contribute to treatment delays or interruptions.

Lastly, shortage of G-CSFs, either because they are not authorized, available or supplied, threatens patients’ safety and chemotherapy continuity. In the event of any of these scenarios, treatment with ABVD should be considered.

[B8] Based on the available evidence and the experience of this group of experts, under 60-year-old patients with Stage IV disease, extranodal involvement in at least two sites and an IPS of 4–7 may obtain a greater benefit from treatment with BV-AVD.

Good practice point: Based on the available evidence and the experience of this group of experts, the difference in OS between treatments described in the ECHELON-1 trial is both statistically and clinically significant.

The subgroup analysis from ECHELON-1 revealed that the most important advantages of BV-AVD versus ABVD are observed in patients aged under 60, with Stage IV disease, extranodal involvement in at least two sites, and an IPS of 4–7. However, differences between these two treatments were less significant among over 60-year-old female patients with a low IPS. 32

[B9] Based on the opinion of this group of experts, considering the results of ECHELON-1 at three years and the availability in our practice, the use of interim PET/CT in patients receiving BV-AVD may be categorized as a good practice.

Good practice point: Patients who achieve a complete (DS ≤3) or partial (DS 4) metabolic response may continue therapy for up to six cycles; in case of disease progression (DS 5), patients would be switched to another strategy.

In the ECHELON-1 trial, the treatment protocol was not based on the interim PET/CT response. 6,7 In light of the extensive published literature, including the experience of this group of experts, we believe that interim PET/CT assessments should be performed whenever possible to support the decision to continue or adjust treatment. 28–32