In this review, we will first briefly summarize prior attempts to improve outcomes in advanced DLBCL using systemic therapy approaches, and then we will highlight the potential role of RT in advanced DLBCL.
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Approximately half of patients will present with advanced (stage III/IV) disease. The cornerstone of treatment is a combination of chemotherapy and immunotherapy, most commonly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Efforts to improve upon R-CHOP-including more chemotherapy cycles, dose-dense chemotherapy, alternative drug combinations, high-dose chemotherapy with autologous stem cell transplant, and maintenance rituximab-have generally proved unsuccessful. There is a growing body of retrospective and prospective data, however, suggesting a benefit for consolidation radiation therapy (RT) in select patients with advanced DLBCL. Consolidation RT has been shown to improve outcomes for patients with advanced DLBCL generally, and in specific instances including initially bulky disease, bone involvement, or in the setting of a partial response to systemic therapy. In these settings consolidation RT is highly efficacious at achieving local disease control and improving overall outcomes.
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), comprising 30% to 40% of all cases.[1,2] More than 20,000 patients are diagnosed with DLBCL each year in the United States. Approximately 50% of such patients present with stage I/II disease. As with many lymphomas, radiation therapy (RT) was historically the cornerstone of treatment for localized disease, achieving high complete response (CR) rates and long-term freedom from relapse in 40% to 45% of patients.[3-6] Over time, treatment evolved to incorporate chemotherapy[4,5,7,8] and rituximab,[9,10] both of which led to lower relapse rates and improved survival. Radiation remains an integral part of the treatment of localized disease, having been shown to decrease the risk of relapse after chemotherapy,[9-12] and it is currently designated as a category 1 treatment option by the National Comprehensive Cancer Network. Now, 80% to 90% of patients with early-stage DLBCL remain disease-free after treatment with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and consolidation RT.[9,10]
The other half of patients diagosed with DLBCL in the United States present with advanced disease managed primarily with systemic therapy. Stage is an important prognostic factor in DLBCL. Patients with advanced disease have inferior clinical outcomes compared with those with localized presentations. In this review, we will first briefly summarize prior attempts to improve outcomes in advanced DLBCL using systemic therapy approaches, and then we will highlight the potential role of RT in advanced DLBCL.
The primary modality for advanced-stage DLBCL is combination chemoimmunotherapy, now most commonly R-CHOP. A variety of treatment approaches have been explored in an attempt to improve outcomes. Phase II and randomized trials have evaluated different strategies, including delivery of more cycles of chemotherapy, dose-dense chemotherapy,[16,17] alternative drug combinations,[18-25] high-dose chemotherapy followed by autologous stem cell transplant (HDT/ASCT), and optimal incorporation of immunotherapy.[27,28] Only the addition of rituximab to standard CHOP chemotherapy has led to consistent and meaningful improvements in outcomes for patients with advanced DLBCL.
Perhaps no treatment to date has had a more profound impact on the prognosis of patients with advanced DLBCL than the incorporation of rituximab into combination chemotherapy regimens. The first study to enroll patients with advanced DLBCL was the LNH-98.5 trial conducted by the Groupe d’Etude des Lymphomes de l’Adulte (GELA). LNH-98.5 randomized elderly patients with stage II–IV DLBCL to 8 cycles of CHOP or 8 cycles of R-CHOP chemotherapy. The addition of rituximab resulted in significantly higher rates of CR, progression-free survival (PFS), and overall survival (OS). At 10 years, PFS and OS were 36.5% and 43.5%, respectively, with R-CHOP compared with 20% and 27.6%, respectively, with CHOP.
In a separate study, the MabThera International Trial (MinT) Group enrolled young patients (18 to 60 years of age) with stage II–IV DLBCL or stage I with bulky disease
(> 5 cm). Patients were randomized to 6 cycles of CHOP-like chemotherapy with or without rituximab. RT was delivered to initial sites of bulky disease (at a dose of 30–40 Gy). Rituximab improved outcomes, with a longer 6-year PFS (81% vs 64%; P < .0001) and OS (86% vs 80%; P = .046).
The success of rituximab prompted the Eastern Cooperative Oncology Group (ECOG; trial 4494) and Cancer and Leukemia Group B (CALGB; trial 9793) to conduct a joint trial to test the efficacy of maintenance rituximab as a means to prevent relapse among patients who initially responded to induction therapy. In this two-stage randomized study, patients were randomized first to CHOP or R-CHOP, with responders subsequently randomized to maintenance rituximab or observation. Although there was an improvement in rates of failure-free survival with maintenance rituximab, this was only apparent in patients who did not receive upfront rituximab. Thus, when rituximab is incorporated into the induction regimen, maintenance rituximab does not appear to confer an advantage.
In the pre-rituximab era, more “intense” chemotherapy regimens were developed and tested in single-arm, single-institution studies. OS rates were 62% for M-BACOD (methotrexate, bleomycin, doxorubicin, cyclo-phosphamide, vincristine, dexamethasone), 69% for ProMACE-CytaBOM (prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate), and 76% for MACOP-B (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin), whereas CHOP was considered to confer OS rates in the 30% range. SWOG and ECOG conducted a randomized study of these three regimens compared with CHOP, reporting OS rates of 50% for patients treated with ProMACE-CytaBOM and MACOP-B, 52% for those treated with M-BACOD, and 54% for patients who received CHOP.
One exception was a regimen consisting of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) with additional consolidation chemotherapy.[21,22] Rituximab was subsequently added to this regimen (R-ACVBP) and compared against standard R-CHOP-21 in a recently reported French trial, GELA LNH03-2B. While this regimen improved 3-year PFS (87% vs 73%; P = .0015) and OS (92% vs 84%; P = .0071), it has not been adopted into routine clinical practice out of concern about excess toxicity and increasing interest in alternative therapies such as DA-EPOCH-R (rituximab, dose-adjusted continuous infusion doxorubicin, vincristine, and etoposide with bolus cyclophosphamide and oral prednisone). A randomized study by the CALGB (50303) is currently testing R-CHOP vs DA-EPOCH-R in untreated DLBCL.
Another strategy that has been investigated is dose-dense chemotherapy, in which the same total doses of chemotherapy are given in a shorter time period. In the pre-rituximab era, the German High-Grade Non-Hodgkin Lymphoma Study Group (Deutsche Studiengruppe Hochmaligne Non-Hodgkin Lymphome [DSHNHL]) demonstrated that administration of 6 cycles of CHOP every 2 weeks (CHOP-14, OS 50.3%) was superior to administration every 3 weeks (CHOP-21, OS 40.6%). A subsequent study by GELA compared 6 cycles of dose-dense R-CHOP-14 with 6 cycles of R-CHOP-21. There was no improvement in treatment efficacy (OS was 69% for patients treated with R-CHOP-14 and 72% for those randomized to CHOP-21). At the same time a UK study compared 6 cycles of dose-dense R-CHOP-14 vs 8 cycles of R-CHOP-21, again finding dose-dense therapy conferred no benefit.
As rituximab-containing regimens emerged as the standard of care, an interest arose in determining the optimal treatment schedule. The DSHNHL conducted the RICOVER-60 (Rituximab With CHOP Over 60 Years) trial. This study was designed to build upon the prior study which showed a benefit for treatment with dose-dense CHOP (CHOP-14). The study was conducted to ascertain both the benefit of rituximab added to CHOP-14 and the optimal number of chemotherapy cycles. In a 2 × 2 factorial design, patients were randomized to CHOP-14 vs R-CHOP-14, and then to either 6 or 8 cycles of chemotherapy. The 3-year OS rates were 67.7% for patients treated with 6-CHOP-14, 66.0% for those randomized to 8-CHOP-14, 78% for patients who received 6-R-CHOP-14, and 72.1% for those treated with 8-R-CHOP-14. The results of RICOVER-60 not only verified the superiority of rituximab-containing regimens but they also demonstrated no additional benefit for 8 cycles vs 6 cycles of R-CHOP-14. More treatment-associated deaths (8% vs 5.6%) and second malignancies (5% vs 2%) with 8 cycles vs 6 cycles likely contributed to the observed outcomes.
HDT/ASCT is an effective treatment for patients with relapsed disease. Although initial results of pilot studies employing this technique as a first-line treatment strategy were promising,[35-37] subsequent randomized trials showed no significant survival benefit.[38-40] A recent meta-analysis found that, compared with conventional chemotherapy, HDT/ASCT offers no benefit in terms of OS or event-free survival (EFS), regardless of the patient’s International Prognostic Index (IPI) risk group.
A recently reported randomized trial, SWOG 97-04, investigated consolidation ASCT following induction using CHOP or R-CHOP. Unlike the meta-analysis described above, this study employed rituximab in 253 patients. While there was an improvement in PFS, this did not translate into an OS benefit. This was due, at least in part, to treatment-related deaths. An unplanned subset analysis did show a benefit of consolidation ASCT in terms of both PFS and OS in the high-risk IPI group. However, a larger study of ASCT in high-risk patients treated with rituximab-based regimens will be needed before this becomes a standard part of first-line therapy.
Many modifications of systemic therapy have been explored in an attempt to improve outcomes in patients with advanced DLBCL. With the exception of immunotherapy with rituximab, the other attempts have been proven to be largely ineffective. Rituximab-based strategies seem to have hit a ceiling, with efforts at dose intensification and maintenance therapy failing to lower rates of treatment failure or improve survival. While phase I/II data for novel treatment strategies are emerging, such as the incorporation of lenalidomide or ibrutinib into R-CHOP,[42-44] another approach worth reconsidering is consolidation RT.
Radiation may be the most active single agent in the treatment of DLBCL.[3-6] Consolidation RT has demonstrated improved outcomes for patients with early-stage DLBCL.[11,12,45-47] In both early and advanced DLBCL treated with chemotherapy alone, the most common sites of treatment failure are those in which disease was initially involved, particularly in patients with bulky lesions.[49,50] Consolidation RT after systemic chemotherapy has been shown to decrease the risk of relapse at treated sites and is often feasible if the disease is not too widely disseminated. There are at least five institutional experiences that support improved outcomes with consolidation RT for advanced-stage DLBCL.[10,49-52] Furthermore, post-hoc analysis from the RICOVER-60 trial and early results from the UNFOLDER randomized trial (Unfavorable Low-Risk Patients Treated With Densification of R-Chemo Regimens; ClinicalTrials.gov identifier NCT00278408) further support the role of consolidation RT.
Investigators at The University of Texas MD Anderson Cancer Center reviewed outcomes in patients with DLBCL treated with R-CHOP chemotherapy (Table). The report included 469 patients with all stages of disease, but approximately 60% were stage III/IV and 37% had bulky disease (> 5 cm). Of 279 patients with stage III/IV disease, 39 (14%) were treated with consolidation RT. Reasons for RT utilizations were not given. Among complete responders to R-CHOP, in-field control was 100% with the addition of RT (local control data without RT were not provided), translating into improved OS (89% with RT added vs 66% with R-CHOP alone; P = .0008) and PFS (76% vs 55%; P = .003) for patients receiving consolidation RT. Matched-pair analysis, including patients with advanced disease, also showed that RT improved OS and PFS.
We have reported our experience at Duke utilizing consolidation RT in patients with advanced-stage DLBCL (see Table). Our retrospective series included 79 patients, all with stage III/IV DLBCL, who achieved a CR to chemotherapy by functional imaging (FDG-PET [18-fluorine fluorodeoxyglucose positron emission tomography] or gallium scan). The majority (65%) were treated with R-CHOP. A total of 38 patients were treated with low-dose consolidation RT (at a median dose of 25 Gy), and 24 of these patients received RT to all sites of disease prior to chemotherapy. Consolidation RT was associated with improved in-field control (92% with R-CHOP plus RT vs 69% with R-CHOP; P = .028), PFS (85% vs 65%, respectively; P = .014), and a trend toward improved OS (85% vs 78%, respectively; P = .15). Multivariate analysis confirmed the benefit of RT for in-field control (hazard ratio [HR] = 8.01; P = .014) and PFS (HR = 4.3; P = .014). It should be noted that these benefits were seen despite use of lower-than-traditional doses of RT and the presence of larger tumors (median 7 cm vs 4 cm; P = .012) in patients who received consolidation RT.
A report from Emory University’s Winship Cancer Institute details patterns of failure among patients with advanced-stage DLBCL receiving R-CHOP chemotherapy, with or without consolidation RT (see Table). Among a total of 211 patients presenting with stage III/IV disease, 110 (67.5%) achieved a CR by PET/CT after treatment with a median of 6 cycles of R-CHOP–like chemotherapy. Of 110 complete responders, 14 were treated with consolidation RT. Patients treated with RT had more bulky disease (≥ 5 cm), but otherwise their characteristics did not differ significantly from those of patients not receiving RT. Consolidation RT not only improved local control (91.7% vs 48.8% without RT) but also improved distant control (92.9% vs 71.9%, respectively), PFS (85.1% vs 44.2%), and OS (92.3% vs 68.5%; P < .0001 for all comparisons). On multivariate analysis, consolidation RT was associated with improved local control and PFS, and a trend toward improved OS (P = .08). Of 45 treatment failures in patients who did not receive RT, 42 included a component of local failure.
Two additional institutional studies evaluating the role of RT in advanced DLBCL predate the widespread adoption of functional imaging and rituximab[49,50] but nonetheless provide valuable proof of principle supporting the role of RT in advanced-stage DLBCL. The first, from the Scientific Institute Hospital San Raffaele, Milan, Italy, reviewed outcomes for patients with stage III/IV, bulky (≥ 10 cm), semi-bulky (6–9 cm), or extranodal disease who achieved a CR to induction chemotherapy. Of 94 patients identified, 40 (20 with bulky disease and 20 with semi-bulky disease) were treated with consolidation RT (median dose, 38 Gy). Multivariate analysis controlling for IPI score confirmed the benefit of RT for EFS and OS. Similarly, a study from MD Anderson Cancer Center reported on outcomes for 59 patients enrolled on two prospective protocols, of whom 28 were treated with consolidation RT. Radiation improved 5-year local control (89% for those treated with chemotherapy plus RT vs 52% for those treated with chemotherapy alone; P = .0001) and freedom from progression (85% vs 51%, respectively; P = .0003). The benefit was primarily due to the improvements for patients with tumors ≥ 4 cm, with 5-year local control rates of 89% with chemotherapy plus RT vs 33% with chemotherapy alone (P = .0009).
In sum, these retrospective experiences confirm that the most common sites of recurrence after chemotherapy alone are at initially involved sites. In most reports, it is neither clear what the selection criteria were for administering RT nor what fields were irradiated. In the Duke University series, the majority of patients received RT to all known sites of disease prior to chemotherapy. In each series, consolidation RT significantly improved local control, PFS, and often OS. The studies from MD Anderson, Emory, and Duke all show a benefit, even when a CR is achieved by PET. Further, the Duke experience suggests the benefits of consolidation RT can be realized with fairly low doses (18 to 24 Gy) of radiation.
One clinical scenario that warrants special consideration of consolidation RT is the presence of bulky disease, such as a large mediastinal or abdominal mass, with or without widespread systemic involvement. RICOVER-60 was a four-arm study comparing four different chemotherapy regimens. Consolidation RT (36 Gy) was delivered to sites of initially bulky disease (≥ 7.5 cm) and/or extralymphatic involvement. As an amendment to the original trial, an additional cohort of patients was accrued and treated with the most effective regimen from the randomized trial (R-CHOP-14 × 6 cycles) but without consolidation RT; this study design was referred to as the RICOVER-noRTh trial. A total of 164 patients were enrolled and compared with outcomes in 111 patients who received R-CHOP-14 × 6 with consolidation RT during the original randomized trial. A multivariate analysis, controlling for IPI and age (> 70 years), found that among patients with bulky disease, the addition of consolidation RT improved PFS (HR = 4.4; P = .001) and OS (HR = 4.3; P = .002). Three-year PFS rates were 75% and 61% (P < .001) for those treated with and without RT, respectively. Corresponding rates of OS were 90% and 65% (P = .001).
An additional study supporting the use of consolidation RT comes from the ongoing UNFOLDER trial. This study randomizes patients with bulky or extranodal DLBCL to R-CHOP-14 or R-CHOP-21. In a 2 × 2 factorial design, a second randomization to consolidation RT or observation was planned for patients achieving a CR to induction therapy. The arms omitting RT were closed early when interim analysis found excessive failures were observed when RT was omitted.
Another potential indication for consolidation RT includes patients with extranodal disease, specifically those with skeletal involvement. The DSHNHL retrospectively assessed data from nine prospective trials (including MInT and RICOVER-60) to determine the prognostic significance of, and optimal treatment for, skeletal involvement in patients with aggressive B-cell lymphomas. Multivariate analysis among patients treated with rituximab-based induction therapy showed skeletal involvement portended worse EFS. However, EFS was improved with consolidation RT to sites of skeletal involvement, regardless of disease stage.
Numerous retrospective studies have established that a positive post-chemotherapy PET scan is predictive of in-field relapse and worse long-term outcomes compared with a negative PET result.[55-60] Typically in this patient population, progression occurs in more than 50% of patients. Consolidation RT has been explored as an attempt to sterilize residual local disease and achieve long-term disease control. We have assessed our Duke experience of consolidation RT in patients with post-induction PET scans. Outcomes of 99 patients treated with RT were assessed based on post-induction PET scan. Twenty-one patients with a positive PET scan were treated (median dose, 36 Gy), resulting in 4-year local control of 71% and a favorable 5-year PFS of 65%. Of the remaining 78 patients with a negative PET, consolidation RT (median dose, 30 Gy) led to 5-year local control of 92% and PFS of 83%. A separate series from Harvard reported outcomes for 61 patients treated with R-CHOP chemotherapy and consolidation RT (median dose, 36 Gy). Of these, 20 patients had a positive interim or post-induction PET scan, yet only one in-field recurrence occurred after RT. Three-year PFS rates for patients with negative and positive PET scans were very favorable in both groups, at 97% and 90%, respectively.
A series from the British Columbia Cancer Agency provides yet further support for the use of RT in the setting of PET-positive disease following induction chemotherapy. Per institutional policy, all patients with residual masses > 2 cm on CT underwent a PET scan, followed by consolidation RT to all PET-positive sites. Those with a negative PET were observed regardless of initial or residual bulk. Of 60 patients with a positive PET who received RT, only 6 relapsed in field, translating into a 4-year OS equivalent to that of the 167 patients who had a negative PET (85% vs 83%, respectively). Among 22 patients who had a positive PET but did not receive RT for various reasons, 4-year OS was 30%. In summary, while a positive interim or post-induction PET scan indicates a worse prognosis, consolidation RT can achieve local control and long-term outcomes similar to those observed in patients with negative PET scan results.
Radiation doses utilized for patients with a variety of lymphoma histologies have been reduced over the last decade. A recent randomized study from the United Kingdom demonstrated no difference between RT at 30 Gy vs 45 Gy in patients with DLBCL. For stage I/II disease, a dose of 30 Gy is currently considered standard therapy in the setting of a negative PET scan post chemotherapy. When delivering consolidation RT for treatment of advanced DLBCL, it is reasonable to consider lower doses than those used in localized disease. These patients will not be cured if systemic therapies are not effectively killing widespread subclinical disease. Low-dose consolidation RT may be all that is needed for controlling clinically evident disease in the setting of a CR following chemotherapy. Such patients are also typically treated with more cycles of chemotherapy and thus presumably have a lower burden of residual disease. Furthermore, treatment volumes may be larger in this patient population and reducing acute and long-term toxicity is important.
Our current approach is to use doses of 18–24 Gy in the setting of a CR to chemotherapy. Low doses such as these appear to be equally effective compared with larger doses and are most likely associated with lower risks of acute and late toxicity. With such doses, local control in our experience has been 94%, consistent with series in which doses of 30–40 Gy have been utilized.[10,51,65] Our treatment volumes include all sites of original involvement when clinically feasible.
Higher doses are warranted in the setting of a positive post-chemotherapy PET scan. With chemotherapy alone, lack of a CR as determined by PET is associated with a substantial risk of relapse.[55,56,58,66,67] Even with combined modality therapy, a post-chemotherapy PET is associated with inferior outcomes. In a study from Duke, 4-year rates of local control were 97% vs 81% (P < .01) for negative and positive post-chemotherapy PET scans, respectively. The corresponding median RT doses were 30 Gy and 36 Gy, respectively. In the setting of a partial response with positive post-chemotherapy PET scan, doses of 36–40 Gy are generally warranted.
In all scenarios, we recommend adherence to involved-site RT as defined in the recently published guidelines from the International Lymphoma Radiation Oncology Group. In general, this involves delineating the pre-
chemotherapy tumor volumes, excluding organs that were clearly uninvolved but which were displaced by the tumor. A planning volume is generated by adding an appropriate margin, accounting for patient setup variation and organ motion.
In conclusion, current treatment approaches rely heavily on systemic chemotherapy and immunotherapy. However, local recurrence remains a significant cause of treatment failure. RT represents an effective local therapy for DLBCL, and its incorporation into the treatment of advanced DLBCL needs to be considered. A growing body of retrospective and prospective data demonstrates the ability of RT to prevent local recurrences in patients with DLBCL, thereby improving both PFS and OS. To illustrate this point, a variety of clinical scenarios involving patients with advanced-stage DLBCL are presented below.
A case example of this clinical scenario is depicted in Figure 1. This 77-year-old woman presented with mediastinal and bilateral hilar adenopathy, a right lower lobe nodule, and a single involved retroperitoneal lymph node (stage IVA). She received 6 cycles of R-CHOP, achieving a CR by PET. In addition, she was treated with low-dose (18 Gy) RT to all sites of disease, including the lung nodule. She is now disease-free 6 years after completing consolidation RT.
With an understanding that RT improves outcomes in stage I/II disease, incorporating RT in the treatment of patients with limited advanced disease is rational. The diaphragm is an arbitrary divider of stage I/II and stage III/IV presentations, and patients with limited disease on both sites of the diaphragm also likely benefit from consolidation RT. Due to the limited extent of disease in the case described here, treating all initial sites of disease was feasible and safe.
A case example is depicted in Figure 2. This 61-year-old man presented with a large abdominal mass with extensive mesenteric nodal disease adjacent to the mass.
There were other involved sites, including the left iliac bone, the right inguinal region, T4 vertebral body, a small superior mediastinal lymph node, and the left supraclavicular fossa (stage IVA). He was treated with 6 cycles of R-CHOP and achieved a CR by PET. He went on receive low-dose (18 Gy) consolidation RT to the initially involved bulky abdominal disease and immediately adjacent mesenteric adenopathy. He is disease-free 3 years after completing RT.
While it was not feasible in this case to treat all sites of disease, the bulky disease was considered the most likely site of treatment failure. Radiation in this setting was delivered at a low dose to minimize toxicity.
A case example is depicted in Figure 3. This 53-year-old man presented with a large mediastinal mass with pericardial lymphadenopathy. He also had involvement of the left iliac crest with B-symptoms at presentation (Stage IVB). The patient was treated with 6 cycles of R-CHOP and achieved a CR by PET imaging. He was treated with consolidation RT (20 Gy) to the mediastinum with a modified mantle field, as well as to the involved iliac crest, and is disease-free 7 years after RT. Treatment to all sites of disease, including the osseous site, was considered to be safe and feasible.
A case example is depicted in Figure 4. This 51-year-old man presented with a large right chest wall mass with diffuse skeletal disease, pulmonary nodules, and cervical adenopathy. He was treated with 6 cycles of R-CHOP. Post-chemotherapy PET showed a CR at all sites except the chest wall mass (Deauville 4). He received consolidation RT (40 Gy) to the chest wall mass only. Post-RT PET showed interval improvement, and the patient is disease-free 1 year after RT. Because a CR was not achieved in the chest wall, this region was treated with a higher dose of radiation in an effort to establish local control and prevent treatment failure.
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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