Description of the condition

Follicular lymphoma (FL) is the most common indolent and the second most common non‐Hodgkin's lymphoma (NHL) sub type in the Western world. It constitutes up to 30% of all NHL (NHLCP 1997), and its incidence has risen in the last decades and is currently 3.3‐3.8 cases per 100,000 patient years, in the white US population (Morton 2006). It is defined as a group of malignancies composed of follicle center cells, usually a mixture of centrocytes (cleaved cells) and centroblasts (large noncleaved cells) (Vitolo 2008).

The Revised European‐American Classification of Lymphoid Neoplasms (REAL classification) (Harris 1994), and more recently the updated World Health Organization (WHO) classification (Swerdlow 2008) propose the term follicle center lymphoma, and divide it into grades 1, 2, 3a, 3b. The grades are distinguished by the presence of predominantly small, mixed small and large, and large cells, respectively. Pathologically, according to the "Berard Criteria", the grades are defined by the number of centroblasts per high power field (Mann 1983). In grade 3a centrocytes are still present, while grade 3b involves centroblasts only. Grade 3 FL is biologically distinct from grades 1 and 2 in its clinical behavior and response to chemotherapy and is treated as aggressive lymphoma. Due to imprecision in differentiating between grade 3a and 3b, its relative infrequency and the nature of the trials involved, it is difficult to assess its natural history. Yet, some consider FL grades 1, 2, 3a as a single histologic entity, and keep it apart from grade 3b, which is treated closely to diffuse large B‐cell lymphoma (Chau 2003; Ganti 2006; Vitolo 2008). FL encompasses most malignancies previously classified as nodular lymphoma in the Working Formulation, most tumors classified as follicular center cell lymphoma in the Lukes‐Collins classification, and all cases in Kiel classification category of centroblastic/centrocytic follicular or follicular centroblastic lymphoma (Vitolo 2008).

The molecular hallmark of FL is the acquisition of translocation t(14;18) by pre‐B cells during an abnormal immunoglobulin rearrangement in the bone marrow, and the overexpression of bcl2 protein, which protects cells from apoptosis (Bendandi 2008). However, only 70% to 95% of FL patients are t(14;18) positive (Vitolo 2008), and t(14;18)‐positive cells may also be found in healthy individuals and patients with other malignancies. Staging of FL is done according to the Ann Arbor system, according to number of involved lymph‐node regions, presence of extra‐lymphatic involvement and presence of B symptoms. Stages I/II are considered early disease, while stages III/IV are considered advanced. Advanced disease is present in more than 80% of FL patients, and bone marrow involvement in more than 60% (Vitolo 2008).

Contemporary scoring systems specific for FL are the Italian Lymphoma Intergroup Index (ILI) (Federico 2000) and the more widely accepted Follicular Lymphoma International Prognostic Index (FLIPI) (Solal‐Celigny 2004). The FLIPI designates prognostic groups as having low, intermediate, or high risk based on the presence or absence of five adverse prognostic factors: age > 60 years, Ann Arbor stage III/IV, hemoglobin level < 12 g/dL, involvement of more than four nodal sites, and elevated serum LDH level. The risk of transformation is higher in patients with advanced stage and higher FLIPI. Recently, another scoring system was offered by the same group, FLIPI2, which is intended to stratify risk in the era of immunotherapy, and takes progression free survival as the principal outcome measure. It takes into account β₂‐microglobulin higher than the upper limit of normal, longest diameter of the largest involved node longer than 6 cm, bone marrow involvement, hemoglobin level lower than 12 g/dL, and age older than 60 years (Federico 2009). FL has had over the years a median survival of eight to 10 years. Its course is largely unpredictable, and it may undergo more aggressive histologic and clinical transformation to aggressive lymphoma at a rate of 3%/y (Bendandi 2008), which is usually poorly responsive to chemotherapy. The median survival from transformation is about one year (Vitolo 2008). 

Treatment for FL is considered separately for early versus advanced stage disease and for newly diagnosed versus relapsed or resistant disease. Historically, advanced FL was considered incurable, with no difference in overall survival between early treatment and 'watch and wait' approach, and with relapse as a rule (Bendandi 2008). However, in recent years, new treatment approaches, and specifically the introduction of rituximab – a monoclonal anti‐CD20 antibody, have decreased transformation rate (Montoto 2007) and improved survival (Tilly 2008). Thus, the first challenge, especially in newly diagnosed patients with FL, is distinguishing those most likely to benefit from an aggressive, curative‐intent approach.

Early stage FL is curable in 30% to 40% of patients, and is usually treated with localized radiotherapy, with even better results with combined‐modality therapy (Bendandi 2008), especially in patients with high‐tumor burden (Vitolo 2008). In newly diagnosed advanced FL, observation is still an option, especially in high‐risk patients and provided there are no high tumor burden features (Horning 1984). In this case, usual indications for treatment in advanced FL are symptomatic disease, hematopoietic impairment, bulky disease or rapid lymphoma progression. Specific criteria have been established to guide initiation of therapy, such as the Groupe d'Etute des Lymphomes Folliculire (GELF) criteria (Solal‐Celigny 1993). However, at least in principal, eradication should be the initial goal in the management of most patients. In relapsing or resistant FL, salvage therapy includes chemoimmunotherapy regimens not used in first‐line therapy, radioimmunotherapy and stem cell transplantation (SCT) (Bendandi 2008; Greb 2008; Vitolo 2008).

There are no standard guidelines for the initial treatment of advanced FL. The choice of chemotherapy largely depends on many factors such as: patient’s age and performance status, comorbidity, the pace of disease, and the aim of the treatment, i.e. palliation or attempt to cure. Chemotherapy regimens may include: alkylating agents, anthracycline‐based chemotherapies, purine analogues, and regimens resembling the cyclophosphamide, vincristine, prednisone (CVP) like regimens (Vitolo 2008). The combination of rituximab with nearly any chemotherapy regimen is superior to the same chemotherapy regimen alone (Tilly 2008) as was shown in many randomized trials, and summarized in a meta‐analysis published in The Cochrane Library (Schulz 2007). Thus, the concomitant administration of rituximab and a chemotherapy regimen has rapidly become the first‐line standard of treatment in FL. It also has a role in maintenance therapy as well as in relapsed, recurrent or resistant patients (Vidal 2009). According to the National LymphoCare Study (NLCS), most FL patients in the US (regardless of staging) were treated by chemotherapy and rituximab combination, 55% of whom with rituximab, cyclophosphamide, vincristine, adriamycin, prednisone regimen (R‐CHOP), 23% with R‐CVP and 15% with fludarabine‐based regimens (Friedberg 2009). High‐dose chemotherapy followed by autologous stem cell transplantation is still a controversial modality in first‐line treatment of FL.

Response to therapy is monitored through history, physical examination, CT or FDG‐PET, and bone marrow biopsy is some patients. Complete response (CR) has been achieved when: there is no clinical evidence of disease or disease‐related symptoms; all lymph nodes are normal sized on CT scan; spleen and liver are non‐palpable and without nodules; previously involved bone marrow is negative on repeat biopsy. Partial response is defined as decrease in nodal size by at least 50% and no progression otherwise (Cheson 1999; Cheson 2007). These patients are treated as refractory disease. Molecular response, detecting minimal residual disease, by using PCR for bcl‐2/IgH translocation and clonally rearranged IgH genes, correlates well with outcome as shown by several prospective studies. It is still unclear, however, whether eradicating the t(14;18)‐bearing clone is an important goal of therapy, and is not routinely preformed (Vitolo 2008).

Description of the intervention

We are going to assess the role of anthracyclines in the treatment of follicular lymphoma.  

Anthracyclines are antibiotic drugs that are among the most important antitumor agents. They include doxorubicin (adriamycin) and daunorubicin, and the analogs idarubicin and epirubicin. Mitoxantrone is an anthracenedione, but is practically considered in this group. These drugs intercalate with DNA, directly affecting transcription and replication. Moreover, they form a tripartite complex with topoisomerase II and DNA, and inhibit the re‐ligation of broken DNA strands leading to apoptosis. They also generate free radicals that damage DNA (Goodman 2006). 

The toxic manifestations of these agents include: myelotoxicity; stomatitis; alopecia; GI disturbances; and dermatological manifestations such as "adriamycin flare" at the site of injection, facial flushing, conjunctivitis and lacrimation. Cardiac toxicity is a unique and the most important adverse event. Two types of cardiomyopathy may occur. An acute form, develops within 24 hours of treatment, and is characterized by abnormal ECG findings and even transient reduction in ejection fraction, elevation of troponin, and pericardial effusion. A subacute/chronic, cumulative dose‐related toxicity (usually above 550 mg/m²) is manifested as congestive heart failure. Its incidence ranges widely, but is approximately 7.5% at a cumulative dose above 550 mg/m². Elderly, females, children and patients with a history of cardiac disease are at increased risk, as are patients treated with chest irradiation, and with the administration of high‐ dose cyclophosphamide or another anthracycline, and concomitant trastuzumab or paclitaxel (Outomuro 2007). 

In FL, anthracycline‐based regimens are the most frequently employed first‐line treatment in the USA, and are considerably utilized even in early stage disease (Friedberg 2009), yet there is no proof of their superiority over regimens without anthracyclines. Even trials comparing single‐agent versus combination chemotherapy including anthracyclines have not consistently shown a benefit in response, relapse rate or survival to combination therapy (Lister 1978). In some, a benefit was significant only in higher grade FL (Peterson 2003) or in elderly patients (Coiffier 1999). Furthermore, it is undetermined whether the benefit may be attributed to anthracyclines, other drugs or the combination in itself.

In a retrospective study, 633 FL patients treated with anthracycline‐containing regimens (ACR) were compared to 128 comparable patients treated with combination chemotherapy not containing anthracyclines. The former group had better complete remission, overall five‐year survival and failure‐free survival (Rigacci 2003). This stands in contrast to previous survival data of patients with low‐grade lymphoma entered to Southwest Oncology Group (SWOG) lymphoma trials, where doxorubicin‐containing treatment did not prolong the median overall survival, in comparison to less aggressive programs (Dana 1993). Most other data come from indirect comparisons, comparing treatment arms from different trials (Brandt 2001; Bendandi 2008; Tilly 2008; Vitolo 2008; Siddhartha 2009). An analysis of five consecutive studies at M.D. Anderson Cancer Center, involving advanced FL patients has shown improvement in overall and failure‐free survival over a 25‐year period (Liu 2006). The fact that all protocols involved anthracyclines underscores the methodological difficulty in comparing outcome rates in one trial with previous trials or historical cohorts, with versus without anthracyclines as is often done. Previous studies suggested that ACR are advantageous specifically among patients with grade 3 FL (Wendum 1997; Chau 2003; Ganti 2006), and show a plateau in failure‐free survival (FFS) following ACR (Bartlett 1994). As a result, the recommended treatment for patients with Grade 3 FL (both 3a and 3b) is now R‐CHOP, even in early stage disease (Buske 2008).

Why it is important to do this review

Follicular lymphoma is the most common indolent NHL, yet there is no standard guideline for its management. It has been considered an incurable progressive disease, but in recent years, implementation of combination therapy and treatment with rituximab have prolonged survival and decreased transformation rate. Anthracycline‐containing regimens are of the most prevalent first‐line therapies, especially in advanced disease, but also in limited or relapsed cases. There is no proof, however, that they are superior to other, non‐anthracycline containing regimens, or even single agent therapy. Observational studies show conflicting results and other data is based on indirect comparisons that are not reliable. However, the optimal design for assessment of interventions are randomized controlled trials. Anthracycline use is often limited to younger patients with more advanced or high grade disease, due to concern of their adverse effects, especially cardiotoxicity, although it may be diminished in face of preventive strategies (Van Dalen 2009).

In this systematic review we will assess the evidence on the role of anthracyclines in the treatment of follicular lymphoma. This question is still important in rituximab era, since the preferred combination chemotherapy used with it has not been elucidated.