Radiotherapeutic palliation of lymphoma

Introduction

Radiotherapeutic palliation of lymphoma is unique among cancers for several reasons. First, unlike most cancers, even patients with disseminated “stage IV” disease can be routinely cured or put into a lasting remission with systemic therapies alone. Even in the relapsed or refractory setting, salvage systemic regimens and stem cell transplantation offer curative options for patients with lymphomas. In the recent era of immunotherapies and biologically directed treatments, long-term remissions are possible even in patients with disease progression following salvage systemic therapies or transplant. Therefore, multidisciplinary discussion with medical oncologists is imperative to review the perceived treatment intent. Even if our goal is to palliate symptomatic lesions with radiotherapy (RT), there still may be a curative treatment option for the patient. Therapies across lymphomas are rapidly evolving, so it is best to check even when we think the answer is obvious based on our previous experience. Second, lymphomas are usually exquisitely sensitive to RT, even in the face of multiple prior lines of therapy. This can be harnessed in the palliative setting where low doses of RT can achieve the desired goals. The low doses used for palliation in lymphoma ties into how to approach concerns for organs at risk. Bone marrow reserve and lymphocytes are probably the most important “tissues” to consider in these patients. Relatively low RT doses can permanently suppress the bone marrow and eradicate lymphocytes that could have been harnessed for immune-based strategies, such as checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapies, and bispecific T-cell engagers. Even if a cure is not an option, many of these patients can experience long progression-free intervals following treatment from one novel therapy to the next, particularly for indolent lymphomas. Understanding which organs will limit future systemic therapies is critical when designing RT fields and considering dose and fractionation. In general, we advocate for using the lowest dose and smallest volumes necessary to accomplish palliation, as the majority of patients will rely on systemic agents for both quality and quantity of life. That being said, RT is one of the single most effective treatment modalities for lymphomas and is probably underused in the tempting arsenal at the fingertips of medical oncologists. Ultimately, a strong multidisciplinary relationship between medical oncologists, hematologists, and radiation oncologists forms the backbone of optimal care for patients with lymphomas.

Indolent non-Hodgkin lymphoma

Indolent non-Hodgkin lymphoma (NHL) encompasses a clinically and biologically heterogenous group of lymphoid neoplasms sharing the lymphocyte as a common progenitor, all of which are extraordinarily sensitive to radiation (RT). Patients with NHL typically present in advanced age, with more than half of cases in patients older than 65. The numerous low-grade NHL subtypes are divided according to cell lineage and clinicopathologic disease entities as classified by various histologic and molecular techniques. The World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues provides the international standard for oncologists and pathologists for NHL subtype classification ( Box 18.1 ). Low-grade NHL histologies include follicular lymphomas (FLs), mantle cell lymphomas, and marginal zone lymphomas (MZLs). Prognosis depends on the low-grade NHL subtype, patient age, extent of disease, and available therapeutic options. In the palliative setting, patients most commonly present with either newly diagnosed advanced stage disease with either bulky or symptomatic lesions or with early-stage disease refractory to systemic therapies.

Stages III and IV indolent NHL are considered incurable with current approaches. Asymptomatic patients not exhibiting signs of rapid disease progression can be observed or treated with single-agent systemic therapies, such as rituximab. A Stanford series of 83 low-grade NHL patients with advanced disease were observed for a median of 3 years prior to initiating cancer-directed therapy, with a 10-year overall survival (OS) of 73% and similar rates of transformation to high-grade lymphomas as compared to patients treated immediately at diagnosis. Symptomatic patients are often treated with chemotherapy, but palliative RT can play a role in select situations. Systemic therapy selection is dictated by NHL subtype, extent and pattern of disease presentation, patient age, performance status, and prior immunochemotherapeutic exposures, with an ever-expanding array of options as targeted therapies flourish.

Palliative RT doses were historically as high as 40 to 45 Gray (Gy). A randomized study conducted by the British National Lymphoma Investigation (BNLI) group showed 24 Gy to be equivalent to 40 to 45 Gy for local control (LC), progression-free survival (PFS), and OS, establishing 24 Gy as the standard of care RT dose for indolent NHL in the UK. In the late 1990s, a purely serendipitous discovery of small doses of RT eradicating low-grade NHLs occurred when a patient who refused to continue treatment after two fractions of 2 Gy had a complete response (CR) without further treatment. The 2 Gy × 2 fraction regimen was extended to 48 additional patients and reported with an 81% response rate and 57% patients experiencing a CR. Subsequently, the FORT trial enrolled 614 sites from 548 patients with low-grade NHL (86% FL and 14% MZL) to 4 Gy versus 24 Gy in 2 Gy fractions. FLs and MZLs in the 4 Gy arm showed a CR rate of 48% and 55%, respectively. Overall response rates of all low-grade NHLs was 81% and 91% in the 4 Gy and 24 Gy arms, respectively, indicating that 2 Gy × 2 fractions is an effective dose for palliation. Progression was observed in 22% of the target sites treated with 4 Gy at a median follow-up of 26 months; however, retreatment of these sites was possible because of the low doses of radiation used. Data from the FORT trial can be applied to advanced-stage NHL patients—demonstrating the effectiveness of short courses of palliative RT conferring excellent response rates while minimizing toxicities. In some cases, such as with bulky retroperitoneal adenopathy or paraspinal involvement, where surveying for clinical progression is difficult and disease progression may come at the cost of organ failure, RT doses of 24 to 30 Gy consistent with the BNLI study can be considered to provide more durable LC.