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CLINICAL ONCOLOGY
high-dose chemo therapy with carmustine,
etoposide, cytarabine, and melph alan
plus autologous hemato poietic stem-cell
support. After completion of treatment
including the salvage therapy, the 7-year
rate of overall survival was 89% in patients
initially treated with BEACOPP compared
to 84% in patients who had received ABVD.
As this difference in overall survival was not
significant, the authors concluded that treatment
with BEACOPP resulted in a more
effective disease control, but not in a better
long-term outcome, compared with ABVD.
They argued that while a major proportion
of patients could be cured by the initial
BEACOPP therapy, this clinical benefit
might be neutralized by a high rate of longterm
adverse events, in particular myelotoxicity,
infections and secondary neoplasias.
Viviani et al. 8 deduced that the BEACOPP
regimen presents an over treatment strategy
for a large number of patients and
recommended ABVD for patients with
advanced-stage or unfavorable Hodgkin
lymphoma. This study has triggered an
intense discussion about the need for an
intensive BEACOPP therapy in advancedstage
Hodgkin lymphoma, as few patients
who relapse can be rescued with a high-dose
salvage therapy. However, this trial 8 was not
powered to demonstrate a survival difference
between the two treatments and the 7-year
overall survival differed by 5% in favor of
the BEACOPP regimen. Moreover, median
observation time (61 months) and the
number of patients were low. As a result, an
appropriate treatment intensity in advancedstage
or unfavorable Hodgkin lymphoma is
still debated.
The improvements in our understanding of
the molecular pathogenesis of non-Hodgkin
lymphoma have led to the develop ment of
novel therapeutic agents that interfere with
signaling pathways involved in lymphomagenesis.
For instance, the addition of the
proteasome inhibitor bortezomib enhanced
the activity of chemo immunotherapy with
R-CHOP as first-line treatment for diffuse
large B-cell lymphoma (DLBCL) and mantle-
cell lymphoma. 9 Ruan et al. 9 demon strated
that, in particular, patients with a nongerminal
center B-cell-like (GCB) subtype,
which is usually associ ated with a worse
outcome, benefit from the addition of bortezomib.
This increased clinical benefit can
be explained by the fact that the non-GCB
subtype is characterized by a deletion in a
tumor-suppressor gene that activates NF-κB
and this activation is blocked by bortezomib.
Thus, a worse prognosis in this subgroup of
patients with DLBCL could be overcome by
bortezomib treatment.
Overall, 2011 saw exciting developments
in the understanding and treatment of B-cell
lymphomas. Whereas research in Hodgkin
lymphoma aims to reduce the adverse effects
of first-line treatment, in most other lymphomas
more-effective therapies are needed.
The growing understanding of the pathogenesis
of these lymphomas will facilitate
the develop ment of novel therapeutic agents.
Department of Internal Medicine I and Center
for Integrated Oncology Köln-Bonn, University of
Cologne, Joseph-Stelzmann-Straße. 9, 50924
Cologne, Germany (P. Cramer, M. Hallek).
Correspondence to: M. Hallek
michael.hallek@uni-koeln.de
Competing interests
M. Hallek declares associations with the following
companies: Celgene, Mundipharma, Roche. See the
article online for full details of the relationships.
P. Cramer declares no competing interests.
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MELANOMA IN 2011
A new paradigm tumor for drug
development
Alexander M. M. Eggermont and Caroline Robert
Melanoma has emerged as the paradigm tumor for drug development
through mutation-targeted therapies (inhibitors targeting BRAF, MEK, and
c-KIT) and immunotherapy. Exploring the combinations of both approaches
is a challenge that will require scientific rationale and the cooperation of
the pharmaceutical industry. But, with these challenges comes another
opportunity to change the paradigms in drug development.
Eggermont, A. M. M. & Robert, C. Nat. Rev. Clin. Oncol. 9, 74–76 (2012); published online 10 January 2012;
doi:10.1038/nrclinonc.2011.201
For the past 40 years no treatments developed
for melanoma have significantly
improved survival over dacarbazine, a drug
with a response rate of around 10%. In the
past decade, we have witnessed—in the fields
of mutation-driven drug development and
immuno modulation—the establishment of
treatments actively impacting survival. This
is just the beginning of a promising journey
to develop rational and biology-driven treatments
for patients with melanoma with clinically
significant impact to greatly change the
thera peutic landscape.
The treatment of melanoma has evolved
from using non-selective inhibitors to more
selective agents, with BRAF, MEK and c-KIT
inhibitors leading the field. BRAF mutations
are the most frequently occurring and most
important mutations that provide drugable
targets in melanoma. The first selective
BRAF inhibitor developed in the clinical
setting was vemurafenib. 1 In a randomized
phase III trial published in 2011, this
drug led to major tumor responses in 50%
of patients, and minor responses in >30% of
patients. 2 The most common adverse events
were arthralgia, fatigue, and cutaneous
mani festations such as rash, photo sensitivity,
pruritis, and squamous-cell carcinoma of
the keratoacanthoma-type in around 20%
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