What is responsible for the recent improvements in outlook for patients with follicular lymphoma?

Since the earliest reports of the use of systemic chemotherapy for low grade or follicular lymphoma, the prevailing dogma has stated that the choice of initial therapy had no impact upon the overall survival (OS) of patients. This paradigm was given credence by the lack of change in outcome of patients with follicular lymphoma from series reported from the 1960s to the 1980s [1]. In this issue of the journal, Conconi et al. from the Oncology Institute of Southern Switzerland describe an improvement in the cause-specific survival of 281 consecutively treated patients with newly diagnosed follicular lymphoma at single institution over the period 1979–2007 [2]. This difference in outcome has been attributed to alterations in therapeutic agents chosen to treat the disease over this timeframe, namely alkylating agents, anthracycline based chemotherapy combinations, and use of the anti-CD20 monoclonal antibody rituximab in combination therapy. Unlike several recent previous reports from large co-operative groups and cancer institutions, an improvement in OS was not seen in the Swiss cohort, thought to be due to the shorter follow-up of the more recent cohort treated with immuno-chemotherapy. In this particular cohort, one-third of patients had early stage disease, where involved field radiotherapy remains the accepted standard of care. However, only 13% received this treatment, a figure similar to that seen in the US Surveillance, Epidemiology and End Results (SEER) database [3]. Excellent local control and high cure rates achieved with radiotherapy in this situation mean that alterations in outcome in this cohort with newer salvage strategies are very difficult to discern. Furthermore, the picture is sullied by the generally higher rates of bone marrow disease reported in more recent series of patients, which probably reflect more thorough and detailed examination of marrow trephine specimens [4]. Nevertheless, the apparent genuine improvement, albeit moderate, in the outcome of patients with follicular lymphoma over the last 25 years has provoked significant debate as to which of several potential factors is chiefly responsible. Due to the use of radiation in many patients in even the earliest series reported, the natural history of untreated follicular lymphoma is surprisingly unclear. Despite this, follicular lymphoma is the archetypal example of an indolent neoplasm, albeit one with a remarkable variation in progression. The development of tools such as the Follicular Lymphoma International Prognostic Index (FLIPI) has aided clinicians in assessing individual prognosis. However, disease bulk at presentation remains the most important prognostic factor in progression free survival (PFS) and OS, unlike several other hematological diseases which utilize cytogenetic and molecular risk factors to stratify prognosis and treatment. Following responses to the alkylating agent chlorambucil in the 1950s, chemotherapy become the mainstay of treatment for advanced follicular lymphoma, and the disease became characterized by responses to treatment, although with inevitable relapses of shortening duration [5]. Early reported series of intensification using combination chemotherapy such as CVP (cyclophosphamide, vincristine, prednisone) or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) failed to show a benefit in PFS or OS [6]. Nevertheless, a recent long term follow-up of large series suggested that initial treatment with CHOP reduced the risk of