There are several classifications currently in use for NHL that are somewhat overlapping. The Revised European American Lymphoma (REAL) classification [3] was initially proposed. However, a REAL-based classification is now widely accepted, also known as the World Health Organization (WHO) classification for hematologic malignancies. This classification is based on cell of origin, maturity, morphology, immunophenotype, genetic and clinical features [4]. Considered outdated by many, the International Working Formulation [5] (WF) had divided NHL in low, intermediate and high grade, based on morphology and natural history. It remains important because studies designed more than 10years ago were based on this classification.

In some series, more than one third of patients with NHL have an aggressive phenotype. For patients with localized disease, radiotherapy (RT) was the first curative approach and continues to be a part of combined modality therapy [6-8]. Previous studies have shown that almost 70% of patients with localized NHL can be cured by RT alone [9,10]. However, the high relapse rate outside the radiation field justifies the requirement of chemotherapy in this setting [11,12].

Since the early 1980s, the synergistic effect of both modalities has been evaluated, and their combination widely advocated in the treatment of patients with NHL [13-17]. The benefit of this strategy was first shown in a randomized trial including 316 patients, comparing RT versus chemotherapy versus combined therapy [18]. In this trial, the combination arm had better failure-free survival and OS when compared to chemotherapy alone, or RT alone arms. The use of RT after systemic therapy is frequently recommended, based on expert opinion, to improve local control of the disease, and possibly to diminish relapse and death [19].

Considering that relapses usually occur at the site of disease, and RT alone can cure up to 70% of patients, it seems rational to test RT after chemotherapy in patients with ALNHL. The achievement of local control could be, in this setting, a surrogate of survival improvement.

Since the publication of the SWOG 8736 trial [32], radiation therapy has become the standard therapy in North America. Unfortunately, the benefit of the treatment in prolonging PFS and OS has not been sustained over the years [33]. The ECOG 1484 trial [34] evaluated the addition of RT in patients with complete response with unfavorable results. In the trial, DFS (but not OS) was better in the combination arm. The GELA LNH 93–1 trial [31] compared short-course chemotherapy regimen plus RT to an intensified chemotherapy regimen. The group receiving the ACVBP regimen showed improved survival when compared to the group receiving CHOP for 8 cycles [39] for non-localized NHL or CHOP plus RT for localized disease [31]. Despite that, the more intensive regimen has not been widely accepted due to long term adverse events, like acute myelogenous leukemia, myelodysplastic syndrome and lung cancer [40]. This is especially important for patients with one IPI risk factor [36], in whom cure rates usually exceed 80% with CHOP-based chemotherapy [31,32]. Thus, some advocate ACVBP should not be considered a valid alternative to CHOP in patients without high risk of recurrence. Recently, ACVBP plus rituximab (R-ACVBP) was compared to CHOP plus rituximab in young patients with advanced diffuse large B-cell lymphoma. With a median follow up of 44months, R-ACVBP improved overall survival [41]. Long term follow up is needed to address long term adverse events.

Both the GELA LNH 93-1 [31] and SWOG 8736 [32,33] trials suggested that radiotherapy cannot replace inadequate chemotherapy regimens. The GELA LNH 93–4 trial [35] evaluated the addition of RT to 4 cycles of CHOP in the treatment of elderly patients with ALNHL. No improvements in terms of PFS or OS were observed. Five-year PFS in the chemotherapy alone arm was 61%, comparable to 64% in the chemotherapy alone arm after 8 cycles of CHOP in the SWOG trial in younger patients with a more favorable prognosis [32].

This systematic review showed that RT could enhance PFS after chemotherapy, with no impact on ORR and OS. Heterogeneity among trials limits a definite conclusion. The interventions under study and trial design characteristics, such as definition of outcomes, inclusion criteria, risk factors and statistical considerations can cause substantial differences when pooling data, and may constitute the major causes of heterogeneity found in the current meta-analysis. Our results are consistent with those addressed in an overview published in 2003 [7]. The high efficacy of chemotherapy in inducing remission of ALNHL would increase the number of subjects in clinical trials evaluating the role of consolidative RT. Thus, all included trials were individually underpowered to assess improvement of response rate, PFS and OS.

More recently, rituximab has been incorporated into the treatment of patients with NHL, with clear benefits in PFS and OS [37,38]. Now the combination of rituximab with a CHOP-based chemotherapy regimen has been considered as the standard treatment for aggressive NHL patients. There is still no prospective trial evaluating the role of RT in the era of targeted therapy, so far the role of radiation after chemotherapy plus rituximab remains speculative. Recently, a retrospective study suggested improvement in both OS and PFS with consolidative RT after rituximab-CHOP chemotherapy. This improvement occurred in both early (I and II) and advanced stage (III and IV) [42]. Despite these gains, these evidences are not sufficient to support or repel the use of consolidative RT in ALNHL. The possible interaction between rutuximab and radiation therapy makes the results of these combinations unpredictable. Thus, radiation therapy should be studied in this new context, and cannot be considered a standard of care until its benefit is proven. Some studies have recently addressed the role of radiation therapy in the management of localized disease in patients with positive Positron Emission Tomography (PET) after chemotherapy [43-45]. Radiation therapy yielded interesting survival results in this subset of patients, providing a rational selection tool for consolidative radiotherapy.