# Low-Dose Radiation for Indolent Lymphoma

## Introduction

Indolent lymphomas, such as follicular lymphoma (FL), marginal zone lymphoma, and small lymphocytic lymphoma, typically exhibit a slow clinical progression and demonstrate a high sensitivity to radiation therapy. Historically, these lymphomas were treated with moderate radiation doses ranging from 24 to 30 Gy. However, landmark clinical trials have shown that very low doses, specifically 4 Gy delivered in 2 fractions, can achieve excellent response rates while minimizing toxicity. This approach offers a valuable option for palliative care and, in some cases, can serve as a definitive treatment.

## Radiobiology of Indolent Lymphoma

Indolent lymphomas are exquisitely radiosensitive, with even doses as low as 2 Gy capable of inducing apoptosis in lymphoma cells. The underlying mechanism involves direct DNA damage and activation of apoptotic pathways at radiation doses far below those required to affect most solid tumors. Because these lymphoma cells lack significant DNA repair capacity, the fractionation of doses is less critical than in other malignancies. Furthermore, the linear dose-response relationship observed in these lymphomas allows effective treatment at very low radiation doses.

## Definitive Radiation for Early-Stage Disease

### Stage I-II Follicular Lymphoma

Radiation therapy alone can be potentially curative in patients with truly limited-stage follicular lymphoma. The 10-year progression-free survival (PFS) rates are approximately 50-60%, while overall survival (OS) at 10 years ranges from 70-80%. The standard radiation dose for definitive treatment is 24 Gy delivered in 12 fractions using involved-site radiation therapy (ISRT) fields. Relapses typically occur outside the radiation field, and for asymptomatic patients, observation or a watch-and-wait approach remains a reasonable alternative.

### FoRT Trial

The FoRT trial randomized patients with early-stage FL to receive either 24 Gy or a very low dose of 4 Gy (2 fractions of 2 Gy each). For curative intent in stage I-II disease, the 24 Gy dose was superior, achieving local control rates of approximately 90% compared to about 70% with 4 Gy. Consequently, 24 Gy remains the standard dose for definitive treatment of early-stage indolent lymphoma, while the 4 Gy regimen is reserved for palliative settings.

![Kaplan-Meier curves from the FoRT trial comparing 24 Gy vs. 4 Gy in early-stage follicular lymphoma showing local control outcomes](images/fort-trial-results.jpg)

## Low-Dose Radiation (4 Gy in 2 Fractions)

### FORT/BONbee Trial Evidence

Low-dose radiation therapy (LD-RT) consisting of 4 Gy delivered in 2 fractions achieves overall response rates of 80-90% in indolent lymphoma, with complete response rates around 50-60%. The median duration of response ranges from 12 to 24 months. Importantly, retreatment with an additional 4 Gy course is both feasible and effective, allowing repeated use of this low-dose approach.

| Setting | Dose / Fractions | Local Control | Key Evidence |
|---|---|---|---|
| Definitive (stage I–II) | 24 Gy / 12 fx (ISRT) | ~90% | FoRT trial (24 Gy superior to 4 Gy for curative intent) |
| Palliative / advanced stage | 4 Gy / 2 fx | ~80–90% response (50–60% CR) | FoRT / BONbee trials |
| Orbital MALT lymphoma | 24 Gy / 12 fx | > 95% | Standard |
| Retreatment (palliative) | 4 Gy / 2 fx (repeat) | Similar to initial LD-RT | Feasible and effective |

### Indications for LD-RT

LD-RT is primarily indicated for palliative treatment of symptomatic sites in advanced-stage disease. It is particularly useful for patients with multiple relapses who have exhausted systemic treatment options, as well as for elderly or frail patients who are unsuitable candidates for chemoimmunotherapy. Additionally, LD-RT can serve as a bridging therapy while awaiting systemic treatment. It is also advantageous for treating cosmetically sensitive or functionally critical sites, such as orbital lymphoma.

### Advantages

The LD-RT regimen is completed in just two treatment sessions, typically administered on consecutive days or with a one-day interval. It is associated with minimal acute toxicity and does not cause myelosuppression or treatment-related immunosuppression. The ability to repeat LD-RT at the same or different sites enhances its versatility. Moreover, this approach is cost-effective and convenient for patients.

## Marginal Zone Lymphoma

### Orbital/Ocular Adnexal MALT Lymphoma

For orbital MALT lymphoma, 24 Gy remains the standard definitive radiation dose, achieving excellent local control rates exceeding 95%. Low-dose radiation (4 Gy) can achieve response rates of approximately 80% and is considered for bilateral disease or retreatment scenarios. It is important to minimize radiation dose to the lens, and modern radiation techniques facilitate lens-sparing approaches to reduce the risk of cataracts.

### Gastric MALT Lymphoma

The first-line treatment for Helicobacter pylori (HP)-positive gastric MALT lymphoma is HP eradication therapy. Radiation therapy at doses of 24-30 Gy is reserved for HP-negative cases or those refractory to antibiotic treatment. Radiation fields involve the stomach with generous margins to encompass the involved site.

### Other Extranodal Sites

For cutaneous, pulmonary, and salivary gland MALT lymphomas, 24 Gy is used as definitive therapy. Low-dose radiation is effective as a palliative option across all MALT lymphoma subtypes.

## Treatment Planning

### Volume Delineation

Treatment planning follows the involved-site radiation therapy (ISRT) principles outlined by the International Lymphoma Radiation Oncology Group (ILROG). Pre-treatment imaging is essential for accurate target definition. The clinical target volume (CTV) includes visible disease with small, anatomically confined margins. Planning target volume (PTV) expansions typically range from 5 to 10 mm depending on the anatomical site.

### Techniques

For orbital lymphoma, opposed lateral fields are commonly employed. Abdominal and pelvic disease are treated using anterior-posterior/posterior-anterior (AP/PA) fields or intensity-modulated radiation therapy (IMRT). Cutaneous involvement is managed with electrons or superficial photons. Simple field arrangements are generally adequate for delivering low-dose radiation therapy.

![Treatment plan for low-dose radiation (4 Gy) to an inguinal lymph node site in relapsed follicular lymphoma](images/indolent-ld-rt-plan.jpg)

## Ultra-Low-Dose Radiation (2 Gy Single Fraction)

Emerging evidence suggests that even a single fraction of 2 Gy may be effective in treating indolent lymphoma. Small series report response rates of 60-70%, making this approach particularly attractive for multiply-relapsed, elderly patients. However, further prospective data are needed before this ultra-low-dose regimen can be widely adopted.

![Comparison table of radiation dose schedules for indolent lymphoma: definitive (24 Gy) vs. low-dose (4 Gy) vs. ultra-low-dose (2 Gy)](images/indolent-lymphoma-dose-comparison.jpg)

## Key Clinical Pearls

Early-stage (I-II) indolent lymphoma is potentially curable with 24 Gy ISRT, which remains the standard definitive radiation dose. The 4 Gy regimen delivered in 2 fractions is a highly effective palliative option, achieving response rates of 80-90% with minimal toxicity. Low-dose radiation therapy is especially suitable for elderly or frail patients, symptomatic sites in advanced disease, or as bridging therapy while awaiting systemic treatment. Its ability to be repeated at the same or different sites enhances its utility in lymphoma management. For orbital MALT lymphoma, definitive treatment with 24 Gy achieves excellent long-term control, and lens-sparing techniques help minimize ocular toxicity.

## References

1. Lowry L, Smith P, Qian W, et al. Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial. *Radiother Oncol*. 2011;100(1):86-92.  
2. Hoskin PJ, Kirkwood AA, Popova B, et al. 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised controlled non-inferiority trial. *Lancet Oncol*. 2014;15(4):457-463.  
3. Illidge T, Specht L, Yahalom J, et al. Modern radiation therapy for nodal non-Hodgkin lymphoma -- target definition and dose guidelines from the ILROG. *Int J Radiat Oncol Biol Phys*. 2014;89(1):49-58.  
4. Friedberg JW, Taylor MD, Cerhan JR, et al. Follicular lymphoma in the United States: first report of the National LymphoCare Study. *J Clin Oncol*. 2009;27(8):1202-1208.