Radiation Therapy in the Management of Diffuse Large B-Cell Lymphoma: Still Relevant?
By Chris R. Kelsey, MD1, Anne W. Beaven, MD2, Louis F. Diehl, MD3, Leonard R. Prosnitz, MD4 |
December 17, 2010
1Assistant Professor, Department of Radiation Oncology
2Assistant Professor, Department of Medicine, Division of Medical Oncology
3Professor, Department of Medicine, Division of Medical Oncology
4Professor, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina
Randomized Trials Evaluating Consolidation RT in Advanced DLBCL
Patients presenting with stage III or IV DLBCL are at higher risk for treatment failure than patients presenting with more localized disease. Various strategies have been employed to improve outcomes in patients with later stage disease, including more intense chemotherapy and high-dose chemotherapy followed by autologous stem cell transplantation. However, the biggest advance to date has been the addition of rituximab(Drug information on rituximab) to CHOP chemotherapy. An approach that has not been widely studied is the addition of consolidation RT.
Two randomized trials, both performed by the same group in Mexico, evaluated the addition of RT in patients with stage IV DLBCL who presented with bulky disease (defined as larger than 10 cm). The chemotherapy schedule differed somewhat between the two studies, but rituximab was not included in either. Patients were randomly assigned to observation or RT (~40 Gy) to sites of bulky disease. In both studies, the addition of RT improved both progression-free and overall survival in patients who achieved a complete response after CHOP-like chemotherapy (Table 3).[29,30] PET imaging was not part of either study.
A retrospective study from Italy evaluated 94 patients with advanced DLBCL presenting with bulky (larger than 10 cm) or semibulky (larger than 6 cm) disease. Patients were treated with anthracycline-based chemotherapy regimens. The addition of RT decreased the risk of relapse and significantly improved overall survival (73% vs 57%, P = .05) for bulky disease. There was a non-significant trend for improved overall survival in semibulky disease (59% vs 41%, P = .09). A study from M.D. Anderson also demonstrated improvement in freedom from progression (85% vs 51%, P= .003) in patients with advanced disease who received consolidation RT (~40 Gy) to sites of bulky disease ( larger than 4 cm) after CHOP-like chemotherapy.
We have also reviewed our experience at Duke University, specifically evaluating patients who achieved a complete response as assessed by PET or gallium scanning. Among 56 patients who achieved a complete response to anthracycline-based chemotherapy (R-CHOP in 63%), RT was associated with a trend towards improved in-field control (91% vs 71%, P = .07), progression-free survival (83% vs 68%, P = .06), and overall survival (82% vs 64%, P = .1). Although none of the differences reached statistical significance, the number of patients was small.
The role of consolidation RT in advanced DLBCL is not established. In select patients, particularly those who present with large-volume disease and who respond favorably to chemotherapy, consolidation RT should be considered. We recommend a slightly lower dose (~18-20 Gy) compared with that used for localized presentations for several reasons. Patients will have generally received more cycles of chemotherapy, thereby necessitating less RT. Treatment volumes are often larger, with more normal tissue in the field, and this also requires a lower total dose of RT. Finally, keep in mind that an appropriate response to systemic therapy is absolutely necessary for RT to provide benefit in advanced DLBCL; this is not the case with localized disease, in which RT can potentially make up for an incomplete response to chemotherapy.
The randomized trials mentioned previously all used CT imaging to assess response to chemotherapy. Functional imaging, PET in particular, has largely supplanted CT as the preferred modality for evaluating treatment response in DLBCL, because of its ability to better distinguish viable tumor from necrosis or fibrosis within residual masses in the post-treatment setting. Numerous studies have shown that an incomplete response as assessed by PET is associated with an increased risk of treatment failure, particularly in the setting of chemotherapy alone[21-23] but also with combined modality regimens, with virtually all failures occurring within residual FDG-avid sites.
How best to proceed in patients who do not achieve a complete response as assessed by PET imaging is not clear. The risk of relapse is generally felt to be high enough that observation is not sufficient. The primary options include salvage chemotherapy followed by autologous stem cell transplant or RT. We studied 99 patients with DLBCL (79% stage I-II, 21% stage III-IV) who underwent post-chemotherapy functional imaging (80% PET, 20% gallium). A post-chemotherapy scan was positive in 21 patients. All patients completed consolidation RT without stem cell transplant. In the PET-negative patients, 5-year in-field control (95%), event-free survival (83%), and overall survival (89%) were excellent and significantly better than those in the patients with residual PET-positive disease after chemotherapy. However, with the addition of RT, outcomes in the PET-positive group were good, with 5-year in-field control of 71%, event-free survival of 65%, and overall survival of 73%. Thus, while a positive PET/gallium scan after chemotherapy was associated with an increased risk of local failure and death, RT still resulted in long-term event-free survival in 65% of patients. Further studies are needed to clarify this issue. In the meantime, for patients who achieve a good, but not complete response as assessed by PET, RT is a reasonable strategy. In general, a higher dose of RT is recommended (~40 Gy).
Select Series Evaluating Consolidation RT After Autotransplantation for DLBCL
With current treatment regimens, the majority of patients with DLBCL are cured with initial therapy. Patients with relapsed—and especially primary refractory—disease can pose a therapeutic challenge. The current standard of care is autologous stem cell transplant in patients who respond to salvage chemotherapy. The role of RT in this setting of stem cell transplant is unclear, primarily because there are no randomized studies to provide guidance. The rationale for RT lies in the observation that the majority of treatment failures after transplant (60% to 80%) occur at originally involved sites,[36-38] especially sites of bulky disease.[39,40] Furthermore, the previously cited randomized studies evaluating consolidation RT in the upfront setting demonstrate improved disease control with RT, which provides a rationale for incorporating RT in the treatment of a patient population at particularly high risk for disease recurrence.
Although the literature is not consistent, most retrospective studies have shown that the addition of consolidation RT before or after stem cell transplant improves local control and often progression-free and overall survival (Table 4). The optimal RT volume, dose, and timing of RT (pre- or post-transplantation) must be customized based on the clinical scenario, including history of prior RT, status of disease before transplant, comorbid conditions, and whether or not total body irradiation is planned. For the typical patient who has not received prior RT, 20 to 30 Gy would be appropriate, depending on sites of involvement, volumes to be irradiated, and the patient’s overall condition. Pre-transplant consolidation RT would generally be preferable to avoid radiation of infused stem cells if larger volumes are necessary.
For patients with advanced DLBCL, even when the disease has become refractory to standard chemotherapeutics, RT is effective for palliation. A typical prescription would be 20 to 30 Gy, which often provides relatively rapid symptomatic relief with minimal side effects, depending upon the site treated. Alternatively, very low-dose RT (2 Gy × 2), which is frequently used for follicular lymphoma, has also been successful for high-grade lymphomas, including DLBCL. Response rates of 50% to 80% have been reported with 2 Gy × 2, with a median time to progression of approximately 1 year.[41, 42] While these results are somewhat inferior to those seen with follicular lymphoma, for select patients with DLBCL, this regimen may be considered.
RT continues to have an important role in the management of DLBCL. The majority of the randomized trials have shown that consolidation RT decreases the risk of recurrence and improves progression-free survival in patients with localized DLBCL. Although there are fewer prospective trials evaluating the role of RT in advanced DLBCL, both randomized and retrospective studies suggest improved disease control in patients presenting with large-volume disease. Consolidation RT should also be considered in select patients with relapsed or refractory disease who proceed with autologous stem cell transplantation. The effectiveness of RT in the palliative setting is sometimes overlooked; however, RT can provide excellent palliation for patients whose disease becomes refractory to other modalities.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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