Patients with lymphoma have historically been excluded from palliative radiation oncology trials given that these tumors are more radioresponsive than other solid tumors. Though radiation dose/fractionation schemes used to palliate lymphoma are often extrapolated from those used for solid tumors, we highlight here unique considerations for palliation of patients with indolent, non-Hodgkin B-cell lymphomas.
FORT (Follicular Radiotherapy Trial), a phase 3 randomized trial, compared whether low-dose radiation therapy (RT) of 4 Gy in 2 fractions was non-inferior in local control to the standard 24 Gy in 12 fractions for patients with either follicular (FL) or marginal zone lymphoma (MZL). Target sites, rather than patients, were randomized 1:1, stratified by histology, treatment intent, and treatment center. The non-inferiority margin for local progression at 2 years was pre-specified as ≤10%, corresponding to a hazard ratio (HR) of 1.37. Patients were treated with involved-field RT, rather than the more recently adopted involved-site RT (Illidge, 2014), and most patients received 3D RT.
From 2006 to 2011, 614 target sites from 548 patients were randomized across 43 centers in the UK. Initial results were reported by Hoskin et al. in 2014 at a median follow-up of 26 months, demonstrating that 4 Gy was inferior to 24 Gy with 70 local progressions in the 4 Gy arm and 21 local progressions in the 24 Gy arm (HR of 3.42; 95% CI 2.09-5.55, p<0.0001) (Hoskin, 2014). More recently, the authors reported long-term results at a median follow-up of 74 months (Hoskin, 2021). The findings remain unchanged, with a 5-year local progression-free rate of 70% after 4 Gy and 90% after 24 Gy (HR 3.46, 95% CI 2.25-5.33, p<0.0001), confirming the inferiority of 4 Gy. There was no difference in 5-year OS: 78% (4 Gy) and 75% (24 Gy).
Despite FORT being a negative trial, it nonetheless provides important, prospective data on the efficacy of 4 Gy with an eye for palliation. This modest dose has impressive results: the rate of complete or partial response was 81%; about two-thirds of patients had durable (5-year) local control; and even in those who progressed, the site was controlled for a median of 12 months. As expected, acute grade 3-4 toxicity was 1% with 4 Gy.
Given that most patients are diagnosed with FL in their 60’s, that the clinical trajectory is indolent, and that advanced stage FL and MZL are not curable, treatment selection is based on minimizing both acute and late toxicity as goals are focused on quality of life. Furthermore, 4 Gy does not burn bridges, allowing future retreatment with an additional 4 Gy in the minority of patients that have a local recurrence (Saleh, 2020). Meanwhile, two-thirds of patients will have been spared from receiving a higher dose. This is particularly attractive for sensitive locations, such as the orbit where a dose of 24 Gy often causes chronic symptoms (dry eye, keratitis, etc.) that may negatively impact quality of life (Goda, 2011).
Taken together, for patients with incurable stage III-IV disease 4 Gy offers a quick and effective approach to provide local control to a site that is symptomatic or likely to become symptomatic. While often delivered over 2 fractions, 4 Gy in a single fraction has also been reported (Haas, 2003) and can be useful for patients with logistical issues or other barriers to treatment. All in all, we agree with Hoskin et al. that “in the palliative setting, 4 Gy of radiotherapy might provide a pragmatic treatment for local symptom control.”
— Kareem R. Fakhoury, MD and Yolanda D. Tseng, MD, MPhil
