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Keywords:

  • mantle cell lymphoma;
  • positron emission tomography;
  • computed tomography;
  • non-Hodgkin lymphoma

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

BACKGROUND:

Although convincing data exist regarding the prognostic utility of positron emission tomographic (PET)-computed tomographic (CT) imaging in Hodgkin lymphoma and diffuse large B-cell lymphoma, its prognostic utility both during treatment and immediately after treatment have not been systematically evaluated in a large mantle cell lymphoma (MCL) patient cohort to support its use in clinical practice.

METHODS:

The authors conducted a retrospective cohort study to examine the prognostic utility of PET-CT imaging in a uniform MCL patient cohort undergoing dose-intensive chemotherapy (R-HyCVAD) in the frontline setting. The primary study endpoints were progression-free survival (PFS) and overall survival (OS). PET-CT images were centrally reviewed for the purposes of this study using standardized response criteria.

RESULTS:

Fifty-three patients with advanced stage MCL with PET-CT data were identified. With median follow-up of 32 months, 3-year PFS and OS estimates were 76% (95% confidence interval [CI], 64%-84%) and 84% (95% CI, 72%-90%), respectively. Interim PET-CT status was not associated with PFS (hazard ratio [HR], 0.9; 95% CI, 0.3-2.7; P = .8) or OS (HR, 0.6; 95% CI, 0.1-2.9; P = .5). Post-treatment PET-CT status was statistically significantly associated with PFS (HR, 5.2; 95% CI, 2.0-13.6; P = .001) and trended toward significant for OS (HR, 2.8; 95% CI, 0.8-9.6; P = .07).

CONCLUSIONS:

These data do not support the prognostic utility of PET-CT in pretreatment and interim treatment settings. A positive PET-CT after the completion of therapy identifies a patient subset with an inferior PFS and a trend toward inferior OS. Cancer 2012;3565–3570. © 2011 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

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.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Study Design

We conducted a 2-center (John Theurer Cancer Center and University of Pennsylvania) retrospective cohort study to test the association between PET-CT status and patient outcomes in a uniformly treated MCL patient population undergoing dose-intensive chemotherapy (rituximab-HyperCVAD / rituximab-araC/methotrexate) administered in the frontline setting. The protocol was approved by the institutional review boards of Hackensack University Medical Center and the University of Pennsylvania.

Exposure of Interest

The exposures of interest were the subject's pretreatment, interim treatment, and post-treatment PET-CT scans. Pretreatment PET-CTs were performed within 4 weeks before the initiation of immunochemotherapy. Interim scans were performed after 2 to 3 cycles of R-HyperCVAD (after cycle 1B or 2A). Post-treatment scans were performed within 8 weeks of the completion of R-HyperCVAD. To meet inclusion criteria, patients were required to have baseline PET-CT imaging and PET-CT performed at either the interim or post-treatment time point. For this study, all scans were reviewed by 1 of 3 radiologists with expertise in nuclear medicine. Scan results were dichotomized based on standardized response criteria proposed by the Imaging Subcommittee of International Harmonization Project in Lymphoma.18 In addition, at each time point the concomitant maximum standard update value (SUV max) was recorded at a suspected site of disease. To minimize bias, radiologists were blinded to clinical outcomes at the time of PET-CT review.

Study Outcomes

The primary endpoints for this study were PFS and OS. PFS was defined as the time (in months) from the initiation of systemic immunochemotherapy to the time of documented disease progression or death. Disease progression was defined based on the international working group response criteria.28 OS was defined as the time (in months) from the initiation of systemic immunochemotherapy to death. To assess for the primary endpoints, the medical records were independently screened by 2 investigators, and agreement between reviewers was required to assign an event. If the reviewers disagreed regarding case status, the decision was arbitrated by a third investigator (A.G.). In addition to consulting the medical record, the Social Security Death Index database was used to confirm death status and the date of death for all subjects. Patients with documented disease progression or death or who were lost to follow-up were censored from further analysis.

Statistical Analysis

We first described the survival experience for the study cohort using the Kaplan-Meier method. We then described the survival experience for subjects stratified on their PET-CT status at defined time points (interim treatment and post-treatment). Once the proportional hazards assumption was addressed, the likelihood ratio (LR) test was used to compare outcomes for subjects based on their PET-CT. By using Cox regression, we performed a univariate analysis to identify potential predictors of survival in this patient cohort. The variables included were pretreatment Mantle Cell Lymphoma International Prognostic Index score, β2 microglobulin, lactate dehydrogenase (LDH), and PET-CT status. Variables significant in univariate analysis were planned to be selected for inclusion in a multivariate analysis to identify independent predictors of survival. All tests were 2-sided at the 5% level. Statistical analyses were performed using Stata version 9.2 (StataCorp, College Station, Tex).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Patient Population

A total of 148 patients were identified in our MCL Outcomes Database with newly diagnosed MCL treated at either the John Theurer Cancer Center or University of Pennsylvania Medical Center between 2000 and 2010. Of these, 93 patients were treated with R-HyperCVAD in the frontline setting, and 53 R-HyperCVAD–treated patients had PET-CT data available for review. Overall treatment response rate was 92% (81% complete response + 11% partial response). Baseline characteristics of the 53 patients included in this analysis are presented in Table 1. With a median follow-up of 32 months, 3-year PFS and OS estimates were 76% (95% confidence interval [CI], 64%-84%) and 84% (95% CI, 72%-90%), respectively. For the entire study cohort, median OS and PFS have not yet been reached.

Table 1. Baseline Characteristics
CharacteristicValue
  1. Abbreviations: ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; MIPI, Mantle Cell Lymphoma International Prognostic Index; ULN, upper limit of normal; WBC, white blood cell count.

  2. Median values (range) are displayed.

Age, y58 (35-74)
WBC7.8 (2.7-101.2)
ECOG performance status1 (0-2)
LDH/ULN0.83 (0.4-8.6)
Ki67 [%]28 [10%-90%]
β2 microglobulin/ULN2.1 (1.8-2.8)
Simple MIPI score4.0 {31% intermediate risk, 19% high risk}

PET-CT Central Review

A total of 152 PET-CT scans for 53 patients treated with R-HyperCVAD (42 John Theurer Cancer Center + 11 University of Pennsylvania) were reviewed for this analysis (5 patients did not have interim PET-CT data collected or available for review, and 2 patients did not have post-treatment PET data collected or available for review). Pretreatment PET-CTs were FDG avid in 92% of MCL patients, with a median SUV max of 8.1 (range, 2.5-36.7) at a suspected site of disease. Interim and post-treatment PET-CT scans were positive in 35% and 16% of patients, respectively. Median SUV max for interim and post-treatment PET-CTs were 3.2 (range, 2.0-25.6) and 3.1 (range, 1.6-32.7), respectively. Patients with a negative baseline PET-CT were included in subsequent analyses, because information regarding the false-negative rate of PET-CT in MCL is unknown.

Survival Analysis

Kaplan-Meier and Cox regression survival analyses were used to test the association between PET-CT and survival. Figure 1 depicts the Kaplan-Meier survival curves for the cohort based on post-treatment PET-CT status. Post-treatment PET-CT was able to identify MCL patients with a statistically significantly inferior PFS (P = .0002, LR test) and a trend toward an inferior OS (P = .08, LR test). The median PFS and OS survival based on post-treatment PET-CT status (positive vs negative) were PFS: 11.1 months vs not reached and OS: 56.9 months vs not reached, respectively.

thumbnail image

Figure 1. Overall survival (Top) and progression-free survival (Bottom) are shown. CT, computed tomography; PET, positron emission tomography.

Download figure to PowerPoint

On the basis of these results, univariate analyses were performed using Cox regression to examine the utility of variables reported in the literature to be prognostic for survival in MCL. Cutpoints for this analysis were prespecified before performing this analysis. In addition to PET-CT status, we also included Mantle Cell Lymphoma International Prognostic Index score (range, 0-11; low 0-3 vs intermediate 4-5 vs high risk 5-11), β2 microglobulin (≤1.5 × upper limit of normal [ULN] vs >1.5 × ULN), LDH (≤1.0 × ULN vs > 1.0 × ULN), and pretreatment SUV max (≤6 vs >6).

We found that interim PET-CT status was not associated with PFS (HR, 0.9; 95% CI, 0.3-2.7; P = .8) or OS (HR, 0.6; 95% CI, 0.1-2.9; P = .5). Post-treatment PET-CT status was statistically significantly associated with PFS (HR, 5.2; 95% CI, 2.1-13.6; P = .001; Harrell C = 0.70) and trended toward significant for OS (HR, 2.8; 95% CI, 0.8-9.6; P = .07). Mantle Cell Lymphoma International Prognostic Index score, LDH/ULN, β2 microglobulin/ULN, and pretreatment SUV max were not statistically significantly associated with either PFS or OS in this patient population. Because only post-treatment PET-CT was significant for PFS in univariate analysis, multivariate analysis was not performed. In addition, achievement of complete response (vs ≥partial response) by international working group response criteria was not statistically significantly associated with PFS in this cohort (HR, 0.73; P = .5; 95% CI, 0.25-2.2).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

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.

Conclusions

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.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES
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