A Systematic Review Evaluating the Addition of Radiation Therapy to Chemotherapy for Localized Aggressive Non-Hodgkin’s Lymphoma: What Is the Role for Radiotherapy?.
Authors: Fried Daniel B. , Morris David E. , Shea Thomas C. , Orlowski Robert Z. , Van Deventer Hendrik W. , Mitchell Beverly S. 
Published: April 2020

Abstract
Purpose/Objective: We performed a systematic review and meta-analysis of chemotherapy alone compared to chemotherapy plus radiation in the management of adult early stage aggressive non-Hodgkin’s lymphoma (NHL). Overall survival (OS) and disease-free survival (DFS) at 5 years were evaluated.
Materials/Methods: Randomized trials published after 1990 comparing chemotherapy alone to chemotherapy plus radiation therapy in the management of adult aggressive NHL were identified through searches of MEDLINE and CANCERLIT databases. In addition, a search of ASTRO, ASCO, and ASH Proceedings from 1999 to the present was performed to identify updates of published articles and abstracts. Studies that were limited to GI sites only were excluded. Only studies employing CHOP or CHOP-like regimens and radiation therapy to a minimum dose of 30 Gy were deemed acceptable. Chemotherapy alone regimens had to consist of a minimum of 4 cycles of therapy. All trials reported OS and DFS at 5 years. A meta-analysis was performed using STATA statistical software, including tests for homogeneity and publication bias. Trials were analyzed by risk ratio (RR) method.
Results: Five randomized trials (n = 1933, range for individual studies 215 to 647) were identified that met all inclusion criteria. The 5-yr OS and DFS RRs for the addition of radiation therapy to chemotherapy are presented in Figures 1 and 2, respectively. Three studies suggested an OS and DFS benefit with the addition of radiation to chemotherapy and two suggested an improved OS and DFS among patients treated with chemotherapy alone. Only two of the studies reported patterns of relapse (Aviles et al and Horning et al). These studies showed improved local control with combined modality therapy (16 – 23% vs. 4 – 5%). Risk ratios for OS ranged from 0.90 to 1.56. DFS estimates range from 0.89 to 1.82. A meta-analysis was conducted to estimate the overall treatment effects for this group of studies for both OS and DFS. Due to the high degree of heterogeneity among these trials (p-value for heterogeneity &lt;0.001 for both OS and DFS), summarizing these results with a pooled estimate of effect would be inappropriate. Heterogeneity was decreased only marginally with the exclusion of any individual study from the pooled estimate.
Conclusions: It remains unclear whether early stage aggressive NHL patients benefit from the addition of radiation to CHOP-based chemotherapy. However, at this time we are not able to delineate those patients who will benefit from radiotherapy from those who will not. Currently CHOP-based chemotherapy plus radiation remains a standard of care in the US for early stage aggressive NHL. However, controversy remains regarding the role of radiation in light of conflicting results. Our ability to draw firm conclusions based on this review is limited due to the study heterogeneity. Differences among study populations may largely account for this heterogeneity.