RT in Early-Stage FL

RT is the preferred treatment of stage I and stage II (non bulky) FL based on several studies that suggest overall survival (OS) is improved compared with chemotherapy alone or observation, with fewer toxicities than RT plus chemotherapy.2,6 Historical series suggest that RT is curative for many patients, with 10-year disease free-survival rates of 40% to 50%.RT in this setting is associated with few toxicities, with one study finding no difference in cardiovascular disease–related death or development of a secondary cancer.7

Yet, RT is underutilized in both academic and community-based clinics.


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In an analysis of the LymphoCare Study published in 2009, of 474 patients with stage I FL treated between 2004 and 2007, 29% and 22% of patients who received care at an academic or community clinic, respectively, were treated with RT.A more recent study published in 2015 found that this underutilization persists. In this retrospective study of the National Cancer Data Base cohort of more than 35,000 patients with stage I or stage II FL treated between 1998 and 2012, 24% of patients underwent RT in 2012, which was a 13% decrease from 1999, when the rate was 37%.6

The reasons for the underutilization of RT are unclear, but Dr Hoppe suggested it may be related to safety concerns and the philosophy of observation instead of active treatment for patients with asymptomatic stage III or stage IV disease. “The oncologists and hematologists who see these patients at the time of their diagnosis will often follow that same philosophy even for patients who have stage I or stage II disease in part because they fear that RT may cause significant side effects,” he said.

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ILROG Study Design and Results

The International Lymphoma Radiation Oncology Group (ILROG) retrospectively evaluated 512 patients with stage I-II FL treated between 2000 and 2017 across 16 international centers.1 All patients were staged by 18F-FDGPET/CT and were treated with upfront RT, primarily by involved-field RT (INRT) or ISRT, with a median dose of 30 Gy (range, 24-52 Gy).

Stage I disease was present in 80.1% of patients and 99% were without B symptoms. The median follow-up was 52 months. Nodal disease was present in all patients with stage II disease and 72.4% of patients with stage I cancer.

RT resulted in substantially higher rates of FFP and OS compared with historical values. For patients with stage I or stage II FL, the FFP rate was 74.1% or 49.1%, respectively, for an overall rate of 68.9% at 5 years. Dr Hoppe commented that, “In older experiences with RT alone without PET staging, the results were closer to 50%.” He noted that, “many of those patients were likely stage III or IV and we would not expect them to benefit that much from the RT that was given.”

The 5-year OS was 95.7%. In-field relapse occurred in only 1.6% of patients and 0.8% experienced a marginal recurrence, resulting in a disease control rate of 97.6%. There was no difference in FFP between INRT or ISRT, or nodal or extranodal presentation. Risk of progression was significantly associated with BCL2-positivity and stage II disease.

Dr Hoppe said that in this study the side effects associated with RT were “very minimal.” RT was well tolerated, with 22.8% of patients experiencing grade 1-2 adverse events. There were 3 grade 3 toxicities, which included dysphagia,dehydration, and mucositis. There were 2 cases of late toxicity of grade 1 dry  mouth and grade 2 hypothyroidism. Secondary malignancy was rare (2.1%) and nearly all occurred outside the field of radiation, except a breast ductal carcinoma in situ.

“In the older literature, the doses of radiation were much higher, probably a median of 40 Gy. Since side effects of radiation are very much related to dose, we would expect that with contemporary treatment, that patients have fewer side effects from radiation,” Dr Hoppe said.

Implications of the ILROG Study

The results of this study suggest that upfront, early-stage FL treatment with RT is safe and results in excellent outcomes. Importantly, these results are of “more than 500 patients, all of whom have been treated in a contemporary fashion with PET staging,” Dr Hoppe said, highlighting that it is typically challenging to evaluate a large number of patients because FL is so uncommon.

Dr Hoppe recommends that oncologists and hematologists with a patient diagnosed with FL who has been PET-staged with stage I or stage II disease seek the opinion of a radiation oncologist. “That doesn’t commit the patient to being treated by a radiation oncologist, but you can properly inform the patient [of] the potential risks and benefits of treatment.” He further highlighted that “this gives the patient the best opportunity to participate in making an informed decision as to what the treatment should be.”

References

  1. Brady JL, Binkley MS, Hajj C, et al. Definitive radiotherapy for localized follicular lymphoma staged by 18F-FDG PET-CT: a collaborative study by ILROG. Blood. 2019;133:237-245.
  2. National Comprehensive Cancer Network; Zelenetz AD, Gordon LI, Abramson JS, et al. B-Cell Lymphomas, Version 1.2019. NCCN Clinical Practice Guidelines in Oncology. Nccn.org. Updated February 12, 2019.
  3. Metser U, Hussey D, Murphy G. Impact of 18F-FDG PET/CT on the staging and management of follicular lymphoma. Br J Radiol. 2014;87(1042):20140360.
  4. Wöhrer S, Jaeger U, Kletter K, et al. 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) visualizes follicular lymphoma irrespective of grading. Ann Oncol. 2006;17(5):780-784.
  5. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano Classification. J Clin Oncol. 2014;32:3059-3067.
  6. Vargo JA, Gill BS, Balasubramani G, Beriwal S. What Is the optimal management of early-stage low-grade follicular lymphoma in the modern era? Cancer. 2015;121(18):3325-3334.
  7. Barzenje DA, Cvancarova Småstuen M, Liestøl K, et al. Radiotherapy compared to other strategies in the treatment of stage I/II follicular lymphoma: a study of 404 patients with a median follow-up of 15 years. PLoS ONE. 2015;10(7):e0131158.
  8. 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.