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Radiation Therapy Is an Effective Modality in the Treatment of Mantle Cell Lymphoma, Even in Heavily Pretreated Patients
Clinical Lymphoma Myeloma and Leukemia
Mantle cell lymphoma has an aggressive clinical course and continuous relapse pattern with a median survival of 3 to 7 years. Multiple courses of chemotherapy are the basis of treatment. Radiotherapy is underutilized in this disease. We undertook this study to assess the role of radiation therapy.
Materials and Methods
A total of 41 consecutive patients with mantle cell lymphoma diagnosed from December, 1999 to January, 2010 who received radiation therapy were reviewed retrospectively. The main endpoint was in-field lymphoma response at each irradiated disease site.
There were 39 evaluable patients (68 symptomatic sites). Sites treated included: nodal stations (n = 31), soft tissue (n = 13), mucosal sites (n = 11), central nervous system (n = 10), gastrointestinal tract (n = 2), and bone (n = 1). Median maximum tumor size at presentation was 3.5 cm (range, 1.3 cm-9.6 cm). The median dose of radiation was 30.6 Gy (range 18-40 Gy). Median follow-up post radiation per site was 12.3 months (range, 0.6-80.9 months). Response to treatment was complete in 47 sites (69.1%), partial in 16 sites (23.5%), and 5 sites (7.4%) had stable disease. In 9 (13.2%) sites local relapse occurred (median 7 months; range 2-21). The mean size of lymphoma at time of RT correlated with relapse, with tumors with local relapse larger than those without a local relapse (P = .005).
Our data add to accumulating evidence that mantle cell lymphoma is a radio-sensitive disease with excellent responses to relatively low radiation doses, even in patients with chemo-refractory disease.
Keywords: Chemotherapy, In-field response, Refractory disease, Relapse, Site-specific treatment.
Mantle cell lymphoma (MCL) was initially described by Lennert in 1973 as centrocytic lymphoma and subsequently by others in the United States, as reviewed by Swerdlow and Williams. 1 In 1992, a consensus statement from Banks et al. 2 summarized the morphologic, immunophenotypic, and molecular features, and the name “mantle cell lymphoma” was accepted. MCL has been similarly defined in the current World Health Organization lymphoma classification.3, 4, and 5 MCL is a mature B-cell lymphoma that comprises nearly 6% of all non-Hodgkin's lymphomas. It is characterized by an aggressive clinical course, with patients typically presenting with disseminated disease. Most patients have occasional circulating tumor cells, but approximately 10% to 20% will have leukemic disease at presentation.6, 7, and 8 Historically, the median overall survival (OS) for patients with MCL has been 3 to 4 years, although more recent series have reported a median OS of 5 to 7 years.9, 10, 11, 12, 13, and 14
The recommended treatment of MCL include systemic chemotherapy and stem cell transplantation owing to the systemic nature of the disease, with radiation therapy (RT) rarely used for management.12, 15, 16, and 17 This has led to the underusage of RT for the management of MCL.
However, some reports have described the efficacy of RT for the management of MCL. M'kacher et al. 18 showed in vitro that MCL cell lines are sensitive to RT, suggesting that the addition of RT to chemotherapy for MCL would lead to improved clinical outcomes. Two studies have demonstrated improved OS and durable local control with the use of RT as upfront therapy in patients with limited-stage MCL.19 and 20 Another report from Rosenbluth and Yahalom 16 has demonstrated significant palliative benefit using RT in patients with MCL.
In the present work, we report the results of a single institution review of the records of patients with MCL treated with involved-site RT (ISRT). Our purpose was to assess the potential role of ISRT in patients with MCL, including patients with chemorefractory MCL.
Materials and Methods
The institutional review board approved the present analysis. To determine the outcomes of patients with MCL treated with RT at the University of Texas MD Anderson Cancer Center, we reviewed the records of all patients diagnosed with MCL from December 1999 to January 2010. We limited our analysis to patients who had received RT specifically for MCL and had remained alive for the duration of RT.
A total of 41 consecutive patients with MCL diagnosed from December 1999 to January 2010 were treated with RT at our institution. Each patient's records and images were retrospectively reviewed to determine the patient characteristics, tumor characteristics, and patient outcome. The main endpoint was the in-field lymphoma response at each irradiated disease site. The response to RT was determined by visual inspection, physical examination and palpation, and/or radiographic studies, including computed tomography or positron emission tomography. The local response (LR) was categorized as a complete response (CR) or partial response (PR). A CR was defined as the complete disappearance of clinical evidence of disease, and a PR was defined as at least a 50% decrease in the tumor diameter, as specified in the International Working Group response criteria. 21 If the treated lymphoma had no response or had progressed, it was recorded as being stable disease or progressive disease, respectively.
The data for age at treatment, stage, previous systemic therapy, outcome, radiation dose, and toxicity were retrospectively tabulated for all patients. Survival was defined as the interval from the date of RT completion to the date of death or last follow-up examination (in months).
We performed Kaplan-Meier analyses to provide estimates of OS for all patients, for patients categorized by gender, and for patients categorized by age. For all analyses, our threshold for statistical significance was P = .05. Data analysis was performed using the Statistical Analysis Systems software, version 9.3 (SAS Institute, Cary, NC). Toxicities were categorized using the Common Terminology Criteria for Adverse Events, version 4.0.
Of the 41 patients, 39 were evaluable (68 symptomatic sites); 2 patients were excluded from the analysis because they had died before RT completion. The patient characteristics are summarized in Table 1 . The median patient age at RT was 71 years (range, 48-81 years). Of the 39 patients 16 (41%) were women and 23 (59%) were men. Thirty-three (84.6%) patients had stage IV disease, 1 (3%) stage III, 2 (5%) stage II, and 3 patients (7.7%) had stage I disease. The hyper-CVAD chemotherapy regimen (hyperfractionated, course A, cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone; course B, methotrexate, cytarabine) was administered to 37 patients (95%), with a median of 6 cycles (range, 1-8). Twenty-nine patients (74%) received ≥ 3 systemic regimens (median 4, range 1-11). Forty-eight sites (71%) had been treated with ≥ 3 cycles (median 3, range 0-11) of chemotherapy before RT. Seventeen patients (43.5%) were treated with ≥ 2 radiation courses (median 1; range, 1-5). The sites treated included nodal stations in 31, soft tissue sites in 13, mucosal sites in 1, central nervous system in 10, gastrointestinal tract in 2, and bone in 1. The median maximum tumor size at presentation was 3.5 cm (range, 1.3-9.6 cm); 4 patients were treated for consolidation after complete remission with chemotherapy, and 1 patient was treated to the surgical bed. The median radiation dose was 30.6 Gy (range, 18-40 Gy). The median follow-up interval after RT per site was 12.3 months (range, 0.63-80.93 months).
|Male gender||59 (23)|
Data presented as % (n), unless otherwise noted.
The clinical outcomes are summarized in Table 2 . The overall LR rate was 94.1% in the treated sites, with a CR in 47 (69.1%) and a PR in 17 (25%). Four sites (5.8%) had stable disease. Of the treated patients, 21 had some pain, discomfort, or functional deficit before treatment, and 20 of 21 (95%) had symptom relief after RT ( Figure 1 ). The median OS for all patients after treatment was 72.9 months, and the 1-year OS after treatment was 84.6% ( Figure 2A ). The median OS for men was significantly greater than the median OS for women (80.3 months vs. 33.1 months, P = .001; Figure 2B ). The median OS for those < 60 years old was significantly longer than that of those > 60 years old (113.8 months vs. 57.6 months, respectively; P = .0006; Figure 2C ).
|Complete response||69.1 (47)|
|Partial response||25 (17)|
|Stable disease||5.8 (4)|
|Progressive disease||0 (0)|
|Local relapse||13.2 (9)|
Nine sites (13.2%) exhibited local relapse in the previously irradiated area, occurring a median of 7 months (range, 2-21 months) after RT. No correlation was found with the radiation dose, fractionation, or initial response and relapse. The mean size of the lymphoma at RT correlated with the development of relapse. Tumors with local relapse were larger (mean, 7.48 cm) than tumors without relapse (mean, 4.45 cm; P = .005).
Overall, RT was well tolerated, with 92.3% of patients experiencing grade 2 or lower toxicities. Three patients (7.7%) developed grade 3 mucositis. Three patients (7.7%) had grade 2 toxicities; 2 experienced grade 2 mucositis and 1, grade 2 nausea. Eight sites were associated with grade 1 mucositis, 11 with grade 1 radiation dermatitis, 4 with grade 1 fatigue, 2 with grade 1 diarrhea, 2 with grade 1 alopecia, 1 with grade 1 cough, 1 with grade 1 dizziness, 2 with grade 1 xerostomia, 1 with grade 1 odynophagia, and 1 with grade 1 nausea.
MCL is an aggressive type of non-Hodgkin's lymphoma that frequently presents with disseminated disease. 22 The mainstay of treatment has been upfront chemotherapy, with some investigators advocating stem cell transplantation to increase the likelihood of cure.13, 23, and 24 The present reports adds to the existing body of data to demonstrate the efficacy of RT in the management of MCL. To our knowledge, ours is the second largest series of patients with MCL who underwent RT to be reported. In the present study, nearly every patient had undergone chemotherapy before RT, and 74% of the patients had received ≥ 3 cycles of chemotherapy. Their tumors were not responding to the chemotherapy, and more than one half of the patients in our study required treatment for symptomatic management. Low radiation doses provided palliation in 95% of patients, and 92.6% of the treated sites demonstrated a LR to RT. Therefore, the present study has demonstrated a significant benefit for RT even in patients with advanced-stage MCL and chemorefractory disease.
Most of the patients tolerated RT very well. Fewer than 10% of all patients developed grade 3 toxicities, and 7.7% had grade 2 toxicities, with 84.6% of patients experiencing either grade 1 toxicities or no toxicities at all. It is possible that the rate of toxicities was greater in this group of patients because of the previous chemotherapy regimens.
The clinical outcomes reported in the present study are similar to the previously published results of palliative RT used for the management of lymphoma. Rosenbluth and Yahalom 16 reviewed the outcomes of 21 patients with MCL who had received RT. The overall response rate was 100%, the CR was 64%, the 1-year OS after RT was 55%, and the rate of palliation was 94%. The 1-year OS of 85% in the present study was higher than their 1-year OS of 55%, and we reported a lower rate of local progression (13.2% vs. 34%), although the rates of CR (67.1% vs. 64%) and palliation (95% vs. 94%) were nearly identical. The greater progression rates can be attributed to the lower range of palliative radiation doses (down to 10.5 Gy; mean, 30 Gy) in the study by Rosenbluth and Yahalom. 16 Haas et al. 25 reported the outcomes of 109 patients with a variety of lymphomas who underwent low-dose RT for palliation. The overall response rate was 92%, and the CR rate was 67%, with a median time to progression of 42 months. The median time to progression reported was longer than the median time to progression in the present study, likely owing to the aggressive nature of MCL compared with the cohort with indolent lymphomas included in the study by Haas et al. 25
RT can improve the OS of patients with early-stage MCL. In a report of 26 patients with early-stage MCL treated with and without RT, the use of RT was associated with superior OS and progression-free survival. 19 The 6-year OS with RT was 71% compared with 25% in patients not receiving RT. The International Lymphoma Radiation Oncology Group (ILROG) recently reported the outcomes of 82 patients with stage I-II MCL. 26 The 5-year OS of patients treated with combined chemotherapy and RT was 68%, and the 5-year OS of patients treated with upfront definitive RT alone was 92%, demonstrating that the use of RT leads to favorable disease control and long-term survival. The present study included patients with predominantly advanced MCL, with 87.6% having stage III or IV disease, supporting a role for RT for patients with advanced-stage MCL.
The median OS after treatment with RT in the present study was 72.9 months, with a higher median OS for men than for women. The median OS was also better for patients ≤ 60 years old than for patients > 60 years old. The improved outcomes in men were not reproduced in a Surveillance, Epidemiology, and End Results-based analysis examining the outcomes of patients with MCL, in which male gender was associated with greater mortality. 27 Our finding that patient age is a prognostic factor is in agreement with both the International Prognostic Index for intermediate and aggressive non-Hodgkin's lymphoma and the Mantle Cell International Prognostic Index.28 and 29
Of the patients who had received RT in the present study, 21 (55.3%) had been treated with the intention of relieving pain, discomfort, or functional deficit. Of these 21 patients, 20 (95%) experienced relief of their symptoms after RT. The efficacy of RT in a population that has been treated with poly-chemotherapy regimens supports the findings of M'kacher et al., 18 who demonstrated in vitro that the molecular pathways of the cellular response of MCL cell lines after RT are distinct from the response of MCL cell lines to chemotherapy, suggesting the possibility of a synergistic effect when RT is used with chemotherapy.
Our study had some limitations. Owing to the retrospective nature of the study, the possibility of underreporting toxicities applies. However, each patient was followed up closely by the radiation oncology and medical oncology practitioners who specialize in treating lymphoma; thus, we expect the underreporting was minimal. Also, significant heterogeneity was present in the site treated, previous chemotherapy regimens used, and radiation dose. Owing to the relative rarity of the MCL diagnosis and a lack of standard of care treatment, it was necessary to group all patients together. Regardless of the heterogeneity of patients in the present cohort, we believe our results are instructive, because the response of MCL to RT was demonstrated in every site treated, despite the previous use of chemotherapy. Finally, our cohort was a small, single-institution cohort, which might limit the generalizability of the findings. The number of patients in the present study was relatively low, primarily owing to the underusage of RT for patients with MCL. Despite the relatively low number of patients, our study represents one of the largest series of patients with MCL receiving RT, and is a strength of the study.
The median radiation dose in the present study was 30.6 Gy (range, 18-40 Gy). Other published reports have listed a similar range of radiation doses, with a median radiation dose of 30 to 35 Gy, with similar outcomes.16, 19, 20, 24, and 25 At out institution, typically, a dose of 30.6 Gy in 1.8-Gy daily fractions was used for management of MCL, with a larger dose used if the tumor was larger and could be safely tolerated by the surrounding normal tissues. RT is indicated for early-stage MCL, because it can control the disease locally and potentially improve long-term survival. 19 For advanced-stage MCL, RT can be used for palliation with a high degree of efficacy and is considerably less toxic than additional chemotherapy.
Given the rarity of MCL treated with RT, additional multi-institution collaborative studies are warranted to determine the optimal role for RT in MCL in terms of front-line therapy for cure in early-stage disease, consolidative therapy for bulky or advanced disease, and for palliation in advanced MCL, because of both its efficacy and the relatively favorable side effect profile of RT compared with systemic chemotherapy.
MCL is an aggressive type of non-Hodgkin's lymphoma with a poorer prognosis than most other lymphoma types. Owing to the aggressive nature of the disease, the treatment for MCL has been systemic therapy and not RT. Numerous reports, however, have shown the effectiveness of RT for early-stage MCL for cure and for advanced-stage MCL for durable palliation. The present study is among the single largest series reported of patients with MCL who had received RT and contributes to accumulating evidence that MCL is a very radiosensitive disease with an excellent response to a relatively low radiation dose in patients with chemorefractory disease, allowing for effective palliation with mild toxicity. Additional studies are warranted to determine the optimal role of RT for MCL as front-line therapy for cure in early-stage disease, consolidation in bulky, advanced disease, and for palliation in patients with advanced-stage MCL.
Clinical Practice Points
- MCL is an aggressive non-Hodgkin's lymphoma that frequently presents with disseminated disease. The median survival can be ≤ 5 to 7 years, and treatment includes systemic chemotherapy and stem cell transplantation.
- RT is currently underused for the management of MCL.
- The present study has demonstrated the therapeutic benefits of RT, even in patients with chemorefractory disease. Nearly all of our patients had already been treated with chemotherapy when referred for RT; most of these patients had tumors that had failed to respond to chemotherapy. The patients were very symptomatic and needed relief of pain or other symptoms. Low-dose radiation helped them, with excellent LRs.
- Patients with advanced-stage, chemorefractory MCL will not live long; however, our data suggest a dual benefit from RT: it can control disease locally, thus relieving symptoms, and it could also help lengthen OS.
- MCL is a radiation-sensitive disease; as such, RT can be used for palliation, even in patients with chemorefractory disease, as definitive therapy for localized disease, and for consolidation after initial chemotherapy.
- We believe our study can lead to the increased use of RT for the management of MCL.
The authors have stated that they have no conflicts of interest.
No funding was used for support of the present study.
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1 Department of Radiation Oncology, University of Texas Medical Branch, Galveston, TX
2 Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
3 Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX
4 Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX
∗ Address for correspondence: Bouthaina Dabaja, MD, Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030
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