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Anthracyclines in the treatment of follicular lymphoma (FL) in adults

Itchaki G, Gafter-Gvili A, Lahav M, Vidal L, Raanani P, Shpilberg O, Paul M
Published Online: 
7 July 2013

FL is the most common indolent non-Hodgkin's lymphoma (NHL). It is a slowly progressive disease, with a risk of transformation to a more aggressive lymphoma. Advanced disease (stage III and IV) has been considered incurable. However, in recent years, the use of combination therapy and treatment with the monoclonal anti-CD20 antibody rituximab, have prolonged survival and decreased transformation rate, and is now considered standard of care in FL patients. One of the most common chemotherapies used in the treatment of FL is the combination of rituximab with cyclophosphamide, vincristine, adriamycin, prednisone (R-CHOP), which contains an anthracycline (adriamycin). Other anthracycline-containing regimens (ACR) have also been used to treat FL patients. However, there is no proof that ACRs are better than non-anthracycline-containing regimens (non-ACRs), and there are no standard guidelines for the initial treatment of advanced FL. Importantly, anthracyclines have serious side effects, notably a decrease in blood counts and potential damage to the heart, depending on the dose.

The aim of this systematic review and meta-analysis was to examine if there is a benefit in the use of anthracyclines for patients with FL. We looked at overall survival (OS); measures of disease control; response rates; and side effects.

We found eight randomized controlled trials, of which five compared similar chemotherapy regimens in both trial arms, except for the anthracycline. Even among these five trials, three included more intense chemotherapy in the control arm. Most trials were conducted in the 1980s and 1990s. Only one of them included rituximab as part of the chemotherapy regimen. Almost all patients were treatment-naive with advanced disease. Follow-up ranged between three and five years in most trials. The main results from this set of trials are.

1. There is no evidence that OS is prolonged with the use of anthracyclines, although it may have been hampered by the more intense regimens given in the control arms of three of five trials.

2. Anthracyclines improved disease control. Concordantly, less patients progressed or relapsed within three years of treatment with ACR.

3. There is no statistically significant difference in complete or overall response rates.

4. Qualitatively, more side effects were reported with ACR, myelotoxicity and cardiotoxicity included.

This evidence is limited, mainly due to disparities in regimens between control and study arms, but also since most included trials were conducted over one to two decades ago, and only one employed rituximab. Importantly, results from this study were in agreement with pooled-outcomes from trials of the pre-rituximab era.

It is essential to find the optimal chemotherapeutic regimen in conjunction with rituximab and other novel agents, and understand the role of anthracyclines in this combination, especially with current methods that are able to reduce their toxicity. With longer follow-up periods we may better understand whether improved disease control will eventually translate to an increase in survival.