2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

What Is the Best First-Line Treatment Strategy
for Patients with Indolent Lymphomas?
By Gilles Salles, MD, PhD, Hervé Ghesquières, MD, and Emmanuel Bachy, MD
Overview: Although advanced follicular lymphoma is considered
incurable, patient outcomes have improved over the last
decade with the use of anti-CD20 monoclonal antibodies.
Multiple treatment options are available and their use depends
on clinical presentation (i.e., Ann Arbor stage, tumor burden,
symptoms) and patient condition and age. Radiation therapy
for patients with limited stage disease remains useful, although
its use in the era of anti-CD20 antibodies should be
re-evaluated. Single-agent rituximab has been tested in multiple
studies with patients with low tumor burden. Short
treatment duration provides a response lasting 2 to 3 years,
although the benefit of maintenance therapy with rituximab
after induction therapy with rituximab remains unproven.
When watchful waiting is not an option, a combination of
THE CLINICAL outcome of patients with indolent lymphoma
has markedly improved over the last decade.
Recent epidemiologic data have estimated that the 5- and
10-year overall survival (OS) rates for patients with indolent
lymphoma older than age 60 are close to 85% and 73%,
respectively. 1 For patients with follicular lymphoma, several
comparisons from single-center and cooperative-group studies
indicate that the median OS has increased from 8 to 10
years to 12 to 15 years 2,3
This progress has been achieved, at least partly, because
of the introduction of anti-CD20 monoclonal antibodies.
However, the lack of clinical or biologic criteria either to plan
the optimal time to initiate therapy or to select between
using anti-CD20 monoclonal antibodies as single agents or
in combination with chemotherapy likely explain the heterogeneity
of first-line treatment decisions observed in the
LymphoCare study. 4 Furthermore, several anti-CD20 antibodies
have been developed, including naked antibodies,
such as rituximab and ofatumumab, and radiolabeled antibodies,
such as tositumomab and ibritumomab tiutexan,
yet the optimal chemotherapy regimen remains undefined.
With these multiple treatment options, it is worth examining
the recent and follow-up results of studies performed
to help guide clinical decisions in the management of patients
with follicular lymphoma. Because indolent lymphomas
remain incurable and most patients experience disease
recurrence, patient quality of life, the ability to deliver
subsequent treatments, and potential long-term adverse
effects also need to be taken into account when considering
first-line treatment strategies.
Although treatment algorithms used for patients with
disseminated forms of mucosa-associated lymphoid tissue
(MALT) or nonsplenic marginal zone lymphomas can be
similar to those used for patients with follicular lymphoma,
first-line management of localized MALT 5 and patients with
lymphocytic and lymphoplamasmacytic lymphomas 6 are
quite distinct and will not be addressed in this manuscript.
We will consider several questions on first-line treatment for
patients with follicular lymphoma in light of the most recent
studies.
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rituximab with chemotherapy is the standard of care: alkylating
agents with anthracycline or bendamustine appear to be
the most widely used regimens, but alkylating agents alone
may still be used in selected patients subgroups. The toxicity
of regimens containing fludarabine appears to limit their
indication as first-line treatment. In patients responding to
one of these combinations, consolidation therapy with rituximab
maintenance has been shown to prolong progressionfree
survival with acceptable toxicity. The benefit of radioimmunotherapy
in first-line treatment is still uncertain. With
patients surviving for many years, the therapeutic strategy of
first-line management should weigh the quality and duration of
response against the risk of long-term toxicities.
Is Radiation Therapy for Patients with Limited-Stage
Follicular Lymphoma Still an Option in 2012?
Radiation therapy has long been considered the treatment
of choice for patients with follicular (or indolent) lymphoma
with Ann Arbor stage I or stage II disease. This option has
been promoted as potentially curative, although the disease
might recur in areas outside the radiation fields in most
patients. 7,8 Given the potential toxicity associated with
radiation therapy in specific areas, a watchful waiting approach
has been also proposed. 9 A large epidemiologic study
supports the use of radiation therapy in patients with
follicular lymphoma, with a significant improvement in
long-term OS for patients with stages I and II follicular
lymphoma treated with radiation therapy compared with
those not receiving radiation therapy (p � 0.0001). 10 Yet,
this study has several limitations, including the lack of
details about certain prognostic factors (e.g., lactate dehydrogenase
[LDH], tumor bulk) and the observation period
(1973 to 2004) when monoclonal antibodies where not an
option for treatment. Another recent retrospective study 11
including patients with stage I disease reported no difference
in the progression-free survival (PFS) for patients
treated with radiation therapy compared with those that
were untreated (i.e., watchful waiting), but chemotherapy
with rituximab or combined modalities were found to provide
the best outcome. This suggests that radiation therapy
use should be limited to those patients that have localized
follicular lymphoma (i.e., stage I or confluent stage II)
without adverse features (e.g., grade 3, tumor bulk, elevated
LDH). 12,13 For localized follicular lymphoma, a dose of 24 Gy
appears sufficient. 14
From the Hospices Civils de Lyon & Université Lyon 1, Pierre-Bénite, France; Centre Léon
Bérard, Lyon, France.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Gilles Salles, MD, PhD, Centre Hospitalier Lyon-Sud, 69495
Pierre Bénite, France; email: gilles.salles@chu-lyon.fr.
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10