Page 1375 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 75 Hodgkin Lymphoma 1221

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number of cycles required to sustain efficacy while reducing toxicity 84% ABVD, p = .39). Thus, although treatment with BEACOPP
to an acceptable level. FFTF at 5 years was sequentially superior with resulted in better initial tumor control, the long-term outcome of the
six cycles of escalated BEACOPP (89.9%) and eight cycles of two regimens appeared to be the same, suggesting that neither was
BEACOPP-14 (85.4%) when compared with eight cycles of escalated superior overall. It is important to note, however, that in this study
BEACOPP (84.4%), as was OS (95.3% for 6× escBEACOPP vs. initial ABVD was associated with significantly less treatment-related
94.5% for 8× BEACOPP-14 and 91.9% for 8× escBEACOPP). toxicity, including infertility and secondary malignancy, compared
Furthermore, eight cycles of escalated BEACOPP was associated with with escalated BEACOPP. Overall then, if the aim of treatment in
a higher mortality rate when compared with either six cycles of this patient population is to achieve cure with minimal toxic risk,
escalated BEACOPP or eight cycles of BEACOPP-14 (7.5% vs. 4.6% then a less aggressive frontline approach of ABVD seems reasonable,
and 5.2%, respectively), as well as an increased frequency of second- reserving more intense treatment with HDCT and ASCT for those
ary malignancies (1.8% vs. 0.7% and 1.1%, respectively). It was with refractory or relapsed disease. For those with more adverse
concluded that overall, in patients younger than 60 years, six cycles prognostic risk, however, more intense treatment with escalated
of escalated BEACOPP followed by PET-directed RT was more BEACOPP may be warranted upfront. One potential strategy, which
effective and less toxic. This regimen was subsequently adopted as is currently being explored in clinical studies, includes reducing the
standard of care for patients with newly diagnosed advanced HL in total number of cycles of escalated BEACOPP and using interim-
Europe. PET assessment to guide ongoing risk-adapted treatment. The overall
goal is to maintain optimal disease control while limiting toxicity by
restricting exposure to only those with high-risk disease in whom it
ABVD Versus Escalated BEACOPP may be better justified from a risk-benefit perspective. The role of
interim-PET in this setting is discussed in more detail later (see New
ABVD and escalated BEACOPP are internationally accepted as Directions in the Treatment of Advanced HL).
appropriate first-line treatments for patients with newly diagnosed At present, ABVD and escalated BEACOPP are both considered
advanced HL, but which of these approaches is optimal remains acceptable strategies for the initial treatment of patients with advanced
under debate. Although ABVD is more widely used in the Unites HL and are each currently recommended as standard of care.
States, escalated BEACOPP tends to be the more favored approach
in Europe.
A number of studies have directly compared these two strategies, Consolidation Approaches in Advanced
not only in an attempt to establish superiority of one over the other
in terms of OS, but also to identify specific subgroups of patients Hodgkin Lymphoma
with advanced HL who might benefit more from a more intensive,
or indeed less intensive, treatment approach. Consolidative Radiotherapy
A randomized study carried out by the EORTC in 2012 investi-
gated whether patients with high-risk advanced disease (IPS ≥3) were Consolidation is frequently adopted following initial chemotherapy
likely to achieve greater benefit with a more intensive upfront regimen to augment response and to prevent progression of disease at residual
comprising four cycles of escalated BEACOPP followed by four sites. The role of consolidative RT for patients with advanced HL
cycles of standard BEACOPP or eight cycles of ABVD. Initial results who achieve complete response or partial response (PR) following
of this study showed no significant difference in event-free survival initial chemotherapy has been widely investigated in clinical trials,
(EFS) or OS between the two treatment groups at a median follow-up but a clear survival benefit has not been demonstrated. Some have
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of 3.9 years. Relapse rates were higher with ABVD, but the fre- pointed to small sample sizes in randomized studies as a reason for
quency of early discontinuations was greater with escalated BEACOPP. this. In an attempt to draw valid conclusions from the available data,
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More recently, in 2014, Mournier and colleagues published results Loeffler et al conducted a large metaanalysis of all studies comparing
from the LYSA H34 trial, a parallel study investigating the same two chemotherapy alone versus combined modality treatment (n = 1740).
regimens but in patients with advanced HL deemed to be at lower- Combined modality treatment did not reduce rate of relapse in
risk (IPS 0−2). At a median follow-up of 5.5 years, PFS was signifi- patients with stage IV disease and was, overall, associated with sig-
cantly better in the BEACOPP arm (93% vs. 75%, p = .007), but nificantly inferior long-term survival compared with chemotherapy
OS was comparable (99% vs. 92%, p = .06). Again, fewer relapses alone.
were observed with BEACOPP. In 2003 an important prospective randomized study investigating
Although greater response rates and improved PFS have been well the use of IFRT after chemotherapy for patients with previously
demonstrated with escalated BEACOPP across a number of studies, untreated advanced HL was published by the EORTC. In this study
making it an attractive option for many, its toxicity profile is not of 739 patients, those achieving CR after initial treatment with
insignificant and should be carefully considered. Whether the MOPP-ABV (n = 421) were randomized to receive either IFRT to
treatment-related risks associated with this regimen can be justified all originally involved nodal and extranodal sites or no further treat-
in all patients remains controversial, particularly when effective ment. At a median follow-up of 79 months, IFRT was not shown to
salvage strategies with stem cell transplantation exist for patients who improve 5-year EFS or OS in those already achieving a CR after
subsequently relapse. It is this argument that has led others to favor initial chemotherapy compared with observation alone (EFS 79% vs.
the use of the less aggressive ABVD approach first for patients with 84%, respectively, p = .35; OS 85% vs. 91%, respectively, p = .07).
advanced HL. However, benefit with consolidative IFRT was observed in those only
In 2011 Viviani and colleagues reported results from a trial achieving a PR after initial chemotherapy and interestingly, the
directly comparing frontline ABVD with escalated BEACOPP in overall outcome of these patients matched that of the group who
patients with unfavorable or advanced HL (stage IIB, III, or IV, or achieved a CR (5-year EFS 79% and OS 87%). This observation
IPI score ≥3). Following this, patients with residual or progressive suggests a potential role for consolidative RT in this subgroup of
disease went on to receive high-dose chemotherapy (HDCT) and patients. Further evaluation is needed, however, and at present the
autologous stem cell transplant (ASCT). Escalated BEACOPP exact subgroups of patients who are likely to consistently benefit from
(eBEACOPP) was found to be superior to ABVD with respect to this modality have still not been fully established.
duration of first remission (PFS at 7 years 85% vs. 73%, respectively, The use of more intensive first-line chemotherapy has led to more
p = .004). Interestingly however, after completion of treatment durable responses, and as such, the need for consolidation RT has
overall, it emerged that salvage HDCT was sufficient to achieve come into question for patients with advanced HL. The increasing
comparable 7-year EFS and OS rates between the two groups, regard- use of PET to assess early response and potentially direct ongoing
less of which initial chemotherapy regimen was administered (EFS treatment may further question its role. However, importantly, PET-
78% eBEACOPP vs. 71% ABVD, p = .15; OS eBEACOPP 89% vs. directed management may also clarify those patients with localized