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- MATERIALS AND METHODS
- FUNDING SOURCES
Dose-intensive treatment approaches and those that incorporate myeloablative chemotherapy with autologous stem cell transplant (ASCT) are now largely considered to be the standard of care for fit patients with mantle cell lymphoma (MCL) in the frontline setting. Whereas standard dose chemotherapy (CHOP ± R: cyclophosphamide, doxorubicin, vincristine, prednisone ± rituximab or purine-based immunochemotherapy) results in a median progression-free survival (PFS) ranging from 12 to 18 months, treatments such as Hyper-CVAD ± R (cyclophosphamide-fractionated, doxorubicin, vincristine, dexamethasone ± rituximab alternating with cytarabine, methotrexate ± rituximab) and/or ASCT appear to significantly improve patient outcomes (PFS ranging 40-60 months).1-12 Recent large retrospective comparisons by our group and the National Cancer Centers Network demonstrate superior PFS with dose-intensive treatment approaches (compared with standard dose R-CHOPlike regimens).5, 13 Yet despite the advances achieved with R-HyperCVAD and/or ASCT, patients still commonly relapse over time, although some patients enjoy long disease-free intervals in excess of 10 years. Finding reliable prognostic indicators in that setting would be very helpful in the management of MCL patients.
Clinical models such as the Mantle Cell Lymphoma International Prognostic Index were developed specifically to risk stratify MCL patients for overall survival (OS).14 The cohort from whom this model was developed was based on 455 patients, of whom 33% received a rituximab-containing regimen, 18% underwent ASCT, and none was treated with HyperCVAD. Validation of the Mantle Cell Lymphoma International Prognostic Index has been reported with conflicting results. Both our group and The University of Texas MD Anderson Cancer Center lymphoma group were independently unable to validate Mantle Cell Lymphoma International Prognostic Index for OS and PFS in MCL patients treated with R-HyperCVAD.15-17 Our research has therefore focused on the identification and validation of risk factors for failure specifically in MCL patients treated with intensive approaches. One such largely untested (but promising) approach is the use of 18F fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) to identify MCL patients with inferior outcomes who are thus candidates for novel approaches and research protocols.
Although MCL is reported to be an FDG-avid non-Hodgkin lymphoma (NHL) subtype, PET-computed tomography (CT) is not currently recommended in the modified international working group response criteria to stage, survey, and assess treatment response in MCL. PET-CT is however widely used for these purposes in clinical practice.18 Although convincing data exist regarding the prognostic utility of PET-CT imaging in diffuse large B-cell lymphoma (DLBCL; post-treatment) and Hodgkin Lymphoma (interim and post-treatment), the role of PET in other lymphomas is still debated.19-27 Intriguing data have shed some light recently in follicular lymphoma as part of the PRIMA trial subset analysis.27 Results showed that 99% of patients had PET-positive disease at baseline and that negative post-treatment PET correlated highly with superior outcome. Data in MCL are still sparse; we therefore conducted a retrospective cohort study to examine the prognostic utility of PET-CT imaging in a uniform MCL patient cohort undergoing dose-intensive chemotherapy.
- Top of page
- MATERIALS AND METHODS
- FUNDING SOURCES
Over the past decade, the use and utility of FDG-PET imaging in the management of lymphoma has markedly expanded.18, 29 Upon careful review of the literature, the level of evidence to support this practice varies widely across the spectrum of NHL and Hodgkin lymphoma subtypes.18 Whereas in DLBCL (staging and post-therapy FDG-PET),20, 21, 25, 30-33 Hodgkin lymphoma (interim and post-therapy FDG-PET),19, 22, 26 and follicular lymphoma (PRIMA data, post-therapy PET)27 there is a robust literature to support the use of PET-CT to identify patients at high risk for failure, the data in other lymphoma subtypes are limited by the lack of prospective data, the heterogeneity of patient populations/treatment strategies, and most importantly, the lack of uniformity in the way FDG-PET imaging is interpreted.
In the case of MCL, the most recent update to the Response Criteria for Malignant Lymphoma justifiably did not find sufficient evidence to support the use of FDG-PET for staging, during therapy or after therapy, outside of the context of a clinical trial. This recommendation is in part because of paucity of data and conflicting results available in the literature.34-41
Karam et al found an association between pretreatment SUV max (<5 vs ≥5) at diagnosis and survival (event-free survival [EFS] and OS).38 Similar results were recently described the GOELAMS group, which proposed a clinical prognostic model based on pretreatment SUV max (≤6 vs >6) and International Prognostic Index in 44 heterogeneously treated (57% underwent ASCT) MCL patients.34 The model (not yet validated) is reported to risk-stratify patients (low, intermediate, and high risk) for EFS. Alternatively, Schaffel et al examined the prognostic value of FDG-PET in 75 uniformly treated patients treated with induction [R-CHOP → Rituxan, Ifosfamide, Carboplatin, Etoposide (RICE)] followed by ASCT.40 In that data set, pretreatment FDG-PET (stratified by median SUV max) was not associated with PFS or OS.
In the Memorial Sloan-Kettering data set, FDG-PET studies were performed before start of therapy (R-CHOP 14) and before ASCT (post-RICE) and demonstrated that a negative FDG-PET postinduction (post-RICE) was associated with superior PFS and OS.40 This association was most pronounced in the subset of patients with a partial response by international working group response CT criteria with positive FDG-PET imaging. By using international working group response + PET criteria, Brepoels et al did not find an association between PET-CT status (interim or post-treatment) and PFS in 37 heterogeneously treated MCL in the frontline setting.35
Our study is unique, as it is the first large series of MCL patients treated uniformly with R-HyperCVAD to examine the correlation between PET-CT and outcome in the frontline setting.
There are several limitations to our study. Most importantly, these data were collected retrospectively, relying on existing records, which can result in a data set that is less complete and less accurate. To address this, a full time data coordinator (T.Z.) attempted to obtain missing records, contact subjects lost to follow-up, and confirm all outcomes using resources such as the Social Security Death Index database. Not all subjects in our database treated with R-HyperCVAD had PET-CT imaging performed at the specified time points. To address the possibility for confounding bias, we compared demographic information (median age, sex, performance status, and Mantle Cell Lymphoma International Prognostic Index score) and survival outcomes between eligible subjects with and without PET-CT imaging and could not detect a significant difference in PFS (HR, 1.3; P = .5) or OS (HR, 1.5; P = .4), suggesting that the patient populations are similar, and missing or unavailable data are likely nondifferential. Our chart review suggested that insurance regulations and physician practice style were the most common reasons for lack of PET imaging and not clinical differences in the patient population. In addition, because the study cohort included patients who reached post-treatment PET (presumably a select group of patients who tolerated and responded R-HyperCVAD), this would make the Kaplan-Meier survival curves for the cohort better than those derived from an intent-to-treat analysis. Because our study population was treated at 2 centers, our findings may not be generalizable to other centers and patient populations. Heterogeneity of treatment approach has been a major limitation in previous work in this area. To address this issue, our inclusion criteria were limited to patients treated in a uniform manner with a standard frontline approach. Since the data came from 2 centers it allowed us to more closely monitor the completeness and integrity of the data collection. Although standard PET response criteria were used, and images were centrally reviewed to minimize misclassification, we did not test for inter-rater reliability between radiologists. In addition, because the data set comprises patients from 2 centers over a prolonged time period, small differences in the technical aspect of PET imaging may also impact these results.
Our study has several strengths. To begin with, we used established, objective criteria to define PET-CT status. Therefore the patient population, treatment approach, and response criteria are clearly defined and hence reproducible for future prospective validation studies. Although >90% of PET-CT imaging included in this analysis was performed at our centers, we obtained images performed at outside institutions/radiology centers and reviewed outside images for this analysis to minimize misclassification bias. In addition, our radiologist collaborators were blinded to the outcome of interest when determining PET-CT status to minimize selection bias. We chose a cohort study design to maximize analytical efficiency.
These results build upon previous work, which has examined the correlation between FDG-PET and outcomes in MCL. We conclude that that PET-CT performed after the completion of dose-intensive immunochemotherapy is an independent predictor of PFS, with a trend toward predicting OS in MCL patients. Performing a midtreatment (interim) PET-CT in this patient population does not have prognostic utility for PFS or OS and therefore is not clinically indicated. Although MCL is reported to be a universally FDG-avid NHL subtype, we found that 8% of patients with biopsy-proven MCL had pretreatment FDG-PET imaging that did not demonstrate FDG avidity at baseline. Therefore, pretreatment FDG-PET is recommended if this modality is used for risk stratification after the completion of systemic immunochemotherapy. This information should be incorporated into the design of future prospective clinical trials to validate these results. We are currently examining the relation of novel computer-assisted quantitative FDG-PET/CT measures of total tumor volume and total tumor metabolic burden with clinical outcome in patients with MCL.