Localized FL: how long in response to be cured?

In this issue of Blood, Brady and colleagues¹  report the outcome after treatment with definitive radiotherapy (RT) in 512 patients with localized follicular lymphoma (FL) staged with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) with positron emission tomography-computed tomography (PET-CT) to prove the hypothesis that a more accurate staging results in a better outcome, supporting the curative potential of RT.

The outcome of patients diagnosed with FL has significantly improved in recent years^2-4  in a way that was unthinkable in the last century. Although new therapeutic options (mainly monoclonal antibodies) are commonly perceived to be the main cause, there have also been significant advances in the staging and assessment of the response with the advent of FDG-PET,⁵  which have also contributed to a better management and outcome of patients with lymphoma. This improvement, however, is mostly seen in patients with advanced disease,³  and rather little in patients with early-stage FL. Localized FL is often neglected from clinical research, for 2 main reasons. First, the number of patients diagnosed with early-stage FL is limited, which makes prospective trials time consuming and expensive. Second, as it is considered “curable,” there is less incentive for research in this population. In this sense, Brady and colleagues should be congratulated for their efforts to further improve the outcome of patients with localized FL. The authors of this study hypothesized that a better staging of patients with FL with ¹⁸F-FDG PET-CT would lead to a better outcome following local RT. They performed a retrospective multicenter study to analyze the outcome of 512 patients with localized FL staged by FDG-PET and reported a 5-year freedom from progression (FFP) of 69%. The median follow-up in this study was 52 months. Brady et al concluded that the results are significantly better than historical controls, supporting their hypothesis that a better staging has led to a better selection of patients and, subsequently, to increased curability.

Localized FL has traditionally been considered “curable” with local RT. One of the first studies to mention “curability” was the series from Stanford published in 1996.⁶  With a median follow-up of almost 8 years, the 10-year relapse-free survival was 44%, and it was 37% at 20 years. The authors concluded that relapse after at 10 years is infrequent (but clearly not nonexistent). Indeed, other studies with a relatively long follow-up have shown that relapses after 5 years are not uncommon, and with longer observation, there is not a clear plateau in the FFP curve. Other studies have reported similar figures with around half the patients free of disease at 10 years.⁷  Thus, although one can argue that RT can be curative, this does not mean that the majority of patients with localized FL will be cured with RT. Last week, I reviewed one of my patients with FL in clinic. He had been diagnosed with localized disease in 2010 and treated with local RT with a curative intention. The patient was on annual follow-up, and when I told him that, 8 years after the initial treatment, he had recurrent disease, he was devastated as he was expecting to be cured. The fact that he has again localized lymphoma that can be treated with local RT did not make the news less devastating. The language that we use when we talk to patients matters. When we say “this lymphoma is curable,” what they hear is “all patients with this lymphoma will be cured” and “you will be cured.” Paradoxically, often the disappointment after a relapse increases proportionally to the length of time in remission. There is a fine line between helping patients to enjoy a fulfilled life not continuously worrying about the possibility of a relapse on one hand and making them aware of the (small) possibility of a late recurrence on the other hand, and the (often too optimistic) way we interpret published results might not help with the latter.

Notwithstanding the above, it is plausible that, as the authors state, a more accurate staging has resulted in better outcomes for patients treated with local RT (although the follow-up in the present study is too short to draw definitive conclusions based on comparison with older series). It is also a reality that local RT is potentially curative for a proportion of patients with localized FL and that it is, undoubtedly, a simple, well-tolerated and safe treatment. Despite this, and against guidelines recommendations, RT is offered only to a small proportion of patients with localized FL.⁸  Of note, this is not a new phenomenon: Pugh and colleagues demonstrated that the proportion of patients with localized FL treated with RT as the initial therapy in the United States remained unchanged over a period of 30 years.⁹  The reasons behind the reluctance to refer patients for RT are difficult to understand. Ideally, this reluctance should be fought with randomized trials comparing RT with other(s) treatment option(s), but, as discussed before, this is not realistic. Thus, performing studies such as the one that Brady and colleagues performed (with all the caveats of a retrospective study) might be the way to convince the broader community about the efficacy of RT.