Low dose radiation in indolent lymphoma: from dose optimization to biological insight

Indolent non-Hodgkin lymphomas are characterized by long survival, frequent relapse, and treatment decisions that must balance durable disease control with long-term toxicity. Radiation therapy plays an important role in this context. In contrast to most solid tumors, indolent non-Hodgkin lymphoma (NHL) is highly sensitive to radiation, allowing high rates of local control with radiation doses that would be considered inadequate for many other malignancies. Despite this radiosensitivity, radiotherapy continues to be underutilized, reflecting persistent concerns regarding toxicity, the durability of treatment response, and the availability of effective systemic options (1,2).

Over the past two decades, two main strategies have shaped the use of radiation therapy in indolent lymphoma treatment. Advances in radiation treatment planning, imaging, and delivery have reduced treatment volumes and, in turn, reduced radiation exposure of normal tissues. At the same time, there has been sustained interest in dose reduction, given that a substantial proportion of patients achieve a complete response (CR) and durable disease control with low dose radiotherapy (3,4). Together, these developments have changed how clinicians think about when radiation therapy should be used and how much dose is necessary.

The observation that very low dose radiotherapy (VLDRT; also known as ultra-low dose radiotherapy), most commonly 4 Gray (Gy) delivered in two fractions, can induce meaningful tumor regression represented a major shift in clinical practice (5,6). Across multiple retrospective series and prospective studies, very low dose regimens were associated with rapid responses and minimal toxicity (7,8). These findings were particularly influential in the palliative setting, where symptom relief and treatment convenience are central considerations (9). However, longer-term follow-up has raised concerns about whether disease control is durable, particularly when VLDRT is used with curative intent, and an adaptive radiotherapy strategy allowing for additional dose with incomplete response may be favored (8). The randomized FoRT trial demonstrated that while 4 Gy in two fractions is clearly effective, it is inferior to 24 Gy with respect to CR rates and long-term local control (6). Thus, prospective trials have demonstrated that radiation dose remains relevant to achieve durable disease control.

These findings have created a clear clinical dilemma for treating physicians. The efficacy of VLDRT challenged long-held assumptions about the radiation dose required to control indolent lymphoma, but randomized data showed that higher doses still provided more durable local control. Together, these observations suggested that while low dose regimens may be appropriate for selected patients, they are not sufficient for all. Naturally, this has led to interest in intermediate dose approaches that might preserve the favorable toxicity and convenience of VLDRT while improving durability. The phase 2 study by Wang and colleagues evaluating 12 Gy delivered in four fractions was designed to address this question (10).

In this multicenter, single-arm trial, patients with newly diagnosed or relapsed stage I through IV indolent NHL received involved-site radiotherapy to a total dose of 12 Gy delivered in four fractions. The study population included follicular lymphoma, marginal zone lymphoma, and other low-grade B-cell histologies, consistent with the heterogeneity encountered in routine clinical practice. With a median follow-up of 19 months, the trial met its primary endpoint, achieving a 6-month CR rate of 95% across 73 treated sites. Overall response rate was 100%, and in-field failures were uncommon. Treatment was well-tolerated, with predominantly low-grade toxicities that resolved over time. There were no treatment-related deaths.

Several features of this study are particularly relevant to clinical practice. The regimen itself is pragmatic, as 12 Gy in four fractions can be delivered over a single week, minimizing treatment burden for patients who might otherwise be managed with observation or systemic therapy. The study population is generalizable since it included patients with multiple NHL types, advanced-stage disease, bulky lesions, extranodal involvement, and prior systemic therapy, although most participants had marginal zone lymphoma and early-stage disease. The consistently high response rates observed across this spectrum reinforce the broad radiosensitivity of indolent NHL.

The toxicity and quality of life data are similarly reassuring. Historically, clinicians have raised concerns about hypofractionation in lymphoma radiotherapy, particularly at doses of 3 Gy per fraction for larger treatment volumes or anatomically sensitive sites. During the coronavirus disease 2019 (COVID-19) pandemic, the International Lymphoma Radiation Oncology Group released guidelines on hypofractionation in lymphoma radiotherapy with the goal of decreasing patient treatment time safely (11). In this study, non-hematologic toxicities were generally mild and transient. Lymphopenia occurred, which is consistent with prior observations at radiation doses in the 8 to 12 Gy range, but peripheral lymphocyte counts recovered within 6 months, suggesting limited long-term impact on immune function (12). Moreover, patient-reported quality of life declined briefly during treatment but recovered quickly, and there was improvement in several domains relative to baseline. Since most patients on this trial did not have positron emission tomography (PET) scans at follow-up, these results are particularly reassuring for real-world clinical scenarios where patients cannot have a follow-up PET to assess radiotherapy response.

Considered together, these findings provide strong evidence that 12 Gy delivered in four fractions is an effective, convenient, and well-tolerated local treatment option for indolent NHL. The data suggest that meaningful dose reduction relative to the current 24 Gy standard can be achieved without compromising short-term disease control or increasing the toxicity burden for patients. For clinicians weighing the efficacy of treatment against convenience and toxicity, this regimen represents a valuable addition to the current treatment landscape.

At the same time, the study invites broader reflection. The authors appropriately contextualize their findings within the established dose range of 4 to 24 Gy and present 12 Gy as a potential intermediate definitive dose, although more work is needed to assess its efficacy in potentially curable patients. Ongoing trials exploring other doses within this interval highlight continued interest in refining and personalizing radiation dose selection. Yet, the accumulating success of multiple low dose approaches raises a fundamental question: how much additional insight is likely to emerge from continued exploration of dose within a range where multiple radiation doses already appear effective?

Modern radiation oncology has advanced considerably by refining dose, fractionation, and treatment volumes for NHL. These efforts have been essential in reducing toxicity, improving convenience, and expanding applicability across disease stages. Increasingly, however, the available evidence suggests that further improvements achieved solely by adjusting radiation dose are likely to be modest. High response rates have now been observed across a wide dose range, from 4 Gy through intermediate regimens and up to conventional definitive doses of 24 to 30 Gy. Within this range, incremental dose adjustments may influence durability at the margins, but they are unlikely to account for the marked variability in outcomes observed among patients.

This observation should not be interpreted as a critique of dose de-escalation; rather, it reflects its success. As NHL is now shown to respond across a broad dose spectrum, these studies have revealed that dose is no longer the primary constraint for many patients. Instead, differences in underlying tumor biology increasingly appears to explain why some patients have durable responses to radiation therapy while others do not.

Despite shared histologic cells of origin, indolent lymphomas encompass biologically diverse diseases. Patients differ in patterns of spread, risk of local versus systemic relapse, and durability of response to localized treatment. Some achieve prolonged disease control after a single course of VLDRT, while others recur locally or progress despite apparently adequate therapy. Such differences are unlikely to be fully explained by modest dose variation and instead point toward underlying biological features that govern radiosensitivity and resistance (13-15).

Radiosensitivity should therefore be viewed as a biological property that varies across patients, rather than as an intrinsic property of lymphomas. Genomic alterations, epigenetic states, tumor microenvironmental factors, and immune context are all likely contributors. Variability in DNA damage response, cell cycle regulation, apoptotic signaling, and chromatin organization could plausibly modulate sensitivity even at low radiation doses (16). Additionally, VLDRT may exert distinct effects on the tumor microenvironment compared with conventional definitive dosing (17). Interactions between tumor cells and the immune system may further shape both immediate response and longer-term disease control following localized therapy (18,19). At present, no clinically validated biomarkers of radiation sensitivity are used to guide treatment decisions in indolent lymphoma. The biological determinants of radiation response remain incompletely defined, and proposed genomic, epigenetic, and immune correlates are largely investigational. As such, future studies of low dose and hypofractionated radiotherapy represent an opportunity to incorporate correlative biological endpoints aimed at identifying predictors of radiation response and resistance.

For hematology oncologists, this perspective is familiar. The field has long recognized that therapeutic sensitivity varies across patients and disease subtypes, and that understanding the biological basis of response enables more precise treatment. Targeted agents, epigenetic therapies, and immunomodulatory approaches have transformed lymphoma care not by escalating systemic therapy dose alone, but by identifying and exploiting biological vulnerabilities. Radiation therapy in NHL may now be positioned for a similar evolution.

One practical implication of this shift is improved patient selection for dose de-escalation. Rather than asking whether 12 Gy is superior to 8 Gy or inferior to 16 Gy, a more fruitful pursuit may be identifying which patients can safely receive lower dose radiation with a high likelihood of durable benefit. Biomarkers of radiosensitivity could allow clinicians to tailor treatment intensity with greater confidence, sparing selected patients unnecessary exposure while identifying those who may benefit from more intensive local therapy (20).

Beyond patient selection, exploring the biology of radiosensitivity in lymphomas opens the possibility of biological modification. If radiosensitivity and resistance are biologically mediated, they may also be modifiable. This concept is commonplace in hematologic oncology, where combination strategies are routinely used to enhance efficacy. Importantly, radiosensitization in chemoradiation does not require higher radiation doses; rather, it involves altering tumor biology so that a given dose (often lower) produces greater effect. Epigenetic modifiers, inhibitors of DNA damage response pathways, immune modulating agents, and targeted therapies represent potential avenues for enhancing radiation response while preserving the favorable toxicity profile of low dose regimens (21,22).

The present study indirectly supports this direction. The ability to achieve excellent local control with modest radiation doses, coupled with transient immune effects and rapid lymphocyte recovery, suggests that low dose hypofractionated radiation may be particularly well suited to combination strategies. In this setting, radiation therapy can function not only as a local cytotoxic treatment but also as a biologically integrated component of multimodal care.

Importantly, a shift toward biologically informed investigation does not counsel abandoning clinical trials of radiation therapy. Rather, it argues for designing future studies with integrated biological endpoints. Correlative analyses using tissue samples, circulating biomarkers, and immune profiling could help identify predictors of response and resistance. This will allow the field to move beyond empiric dose testing toward a mechanistic understanding of radiation response in indolent lymphoma.

A trial of 12 Gy in four fractions should therefore be viewed as both validation of low dose radiation in NHL and an inflection point for the field. It validates low dose hypofractionated radiation as an effective, well-tolerated strategy, and it reinforces confidence that meaningful disease control can be achieved with reduced treatment intensity. At the same time, it highlights that further progress is unlikely to come solely from continued refinement of radiation dose. The most pressing unanswered questions are biological in nature, and addressing them will require collaboration across radiation oncology, hematology oncology, and translational science.

In summary, this phase 2 study provides strong evidence that 12 Gy delivered in four fractions is an effective treatment for indolent NHL, but its significance extends beyond the specific regimen evaluated. By demonstrating the breadth of the therapeutic window for radiation therapy, it underscores the opportunity to redirect future effort toward understanding the biological determinants of radiosensitivity. Doing so has the potential to refine patient selection, enable rational combination strategies, and ultimately improve outcomes while preserving the attributes that make low dose radiation attractive in this disease.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Blood. The article has undergone external peer review.

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-55/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-55/coif). The author has no conflicts of interest to declare.

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