Early stage aggressive NHL is a heterogeneous group of diseases with a high potential of cure. Systemic therapy has been the mainstream of therapy for more than 20
years. Additionally, RT had shown to increase regional control, which may lead to improvement in survival. Other possible secondary benefits of radiotherapy could be the diminishing of chemotherapy late effects.
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
]. 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 44
months, 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
] 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
]. 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
]. Radiation therapy yielded interesting survival results in this subset of patients, providing a rational selection tool for consolidative radiotherapy.
There are still many unanswered questions regarding the management of early stage aggressive NHL. The ideal chemotherapy regimen, its optimal duration, the duration of rituximab treatment, the benefits of adding RT and its dose are important issues that need further evaluation by high-quality RCT. Our systematic review suggests that RT prolongs PFS and can be considered an option for patients who cannot tolerate a high dose or prolonged schedule of chemotherapy. Further evaluation of RT after chemotherapy is still needed.