Noninvasive Phosphorus Magnetic Resonance Spectroscopic Imaging Predicts Outcome to First-line Chemotherapy in Newly Diagnosed Patients with Diffuse Large B-Cell Lymphoma

Rationale and Objectives

Based on their association with malignant proliferation, using noninvasive phosphorus MR spectroscopic imaging ( 31 P MRSI), we measured the tumor content of the phospholipid-related phosphomonoesters (PME), phosphoethanolamine and phospholcholine, and its correlation with treatment outcome in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) receiving standard first-line chemotherapy.

Experimental Design

The PME value normalized to nucleoside triphosphates (PME/NTP) was measured using 31 P MRSI in tumor masses of 20 patients with DLBCL before receiving standard first-line chemotherapy. Response at 6 months was complete in 13 patients and partial in seven. Time to treatment failure (TTF) was ≤11 months in eight patients, from 18 to 30 months in three, and ≥60 months in nine.

Results

On a t test, the pretreatment tumor PME/NTP mean value (SD, n ) of patients with a complete response at 6 months was 1.42 (0.41, 13), which was significantly different from the value of 2.46 (0.40, 7) in patients with partial response ( P < .00001). A Fisher test significantly correlated the PME/NTP values with response at 6 months (sensitivity and specificity at 0.85, P < .004) while a Cox proportional hazards regression significantly correlated the PME/NTP values with TTF (hazard ratio = 5.21, P < .02). A Kaplan–Meier test set apart a group entirely composed of patients with TTF ≤ 11 months (hazard ratio = 8.66, P < .00001).

Conclusions

The pretreatment tumor PME/NTP values correlated with response to treatment at 6 months and time to treatment failure in newly diagnosed patients with DLBCL treated with first-line chemotherapy, and therefore they could be used to predict treatment outcome in these patients.

For many cancer patients, established first-line therapies are either ineffective or initially effective but not curative. For instance, 63% of patients with diffuse large B-cell lymphoma (DLBCL) show a complete response to first-line therapy, but only 40% have prolonged survival . An a priori method to identify unresponsive patients to standard treatments would be of extreme value to offer these patients alternate treatment options, thereby maximizing therapeutic success, sparing toxicity, and lowering health care costs.

Newly diagnosed patients with DLBCL receive equivalent first-line chemotherapy regardless of the substandard treatment outcome on a large number of patients. Over the years, the most common regimen has been CHOP, a doxorubicin-based drug cocktail with added cyclophosphamide, vincristine, and prednisone . Other first-line multidrug treatments can be used to treat DLBCL but their mechanisms of action and response rates are similar to CHOP; therefore, they are considered comparable (CHOP-like therapy). Only recently, rituximab has been added to first-line regimens to treat DLBCL (ie, R-CHOP) increasing relapse-free and overall survival . However, even though rituximab has improved treatment outcome, still a significant proportion of patients experience early treatment failure, partial response, or recurrence. A method that could appropriately and timely identify high-risk newly diagnosed patients with DLBCL bound to be unresponsive to the established first-line therapies should allow early consideration of alternate treatments, like high-dose therapy, autologous stem cell transplantation , and/or promising new agents that target cellular signaling processes , with the aim to maximize therapeutic success in high-risk patients without compromising those patients who will respond to the present standard of care.

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Patients and methods

Patients

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Study Design

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Assay Method

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![Figure 1, Example of the noninvasive three-dimensional localized 31 P magnetic resonance spectroscopic imaging ( 31 P MRSI) exam from a target tumor mass of a newly diagnosed patient with diffuse large B-cell lymphoma (DLBCL). Top , T1-weighted spin-echo MR images acquired in the three orthogonal orientations from the right inguinal area of the patient are shown. In the images, a tumor mass of ∼32–35 mm in each diameter is shown ( white arrows ). Each image is overlaid with a grid representing the projection of the three-dimensional acquisition matrix of voxels where 31 P spectral signals were localized. Shaded in gray are the two-dimensional projections of a voxel that was included in the tumor mass. Bottom , The 31 P spectrum of the voxel highlighted in the images is shown with corresponding peak assignments (PE, phosphoethanolamine; PC, phosphocreatine; Pi, inorganic phosphate; PDE, the phosphodiester region; PCr, location of the phosphocreatine signal not present in the tumor spectrum but prominent in the spectra of surrounding muscle; and NTP, the α, β, and γ phosphates of nucleoside triphosphates). The sum of the phosphomonoester (PME) signals PE and PC and the triplet of the Pβ of NTP (highlighted in red in the spectrum) were integrated to obtain the tumor PME/NTP value. (Color version of figure is available online.)

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Statistical Analyses

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Results

Patient Population

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Table 1

Clinical and Biological Characteristics of the Cohort of Patients with Diffuse Large B-Cell Lymphoma

Treatment No. Gender Age Stage IPI ∗ RT6 m † TTF ‡ PME/NTP § CHOP ⋮ 1 F 68 II 1 CR +23.0 2.16 2 F 49 I 2 CR 18.0 0.84 3 F 48 II 0 CR +186.0 1.52 4 M 29 IV 1 PR 9.8 1.85 5 M 59 III 1 PR 8.0 2.83 6 F 68 IV 2 CR +165.7 1.32 7 M 53 II 1 CR +157.1 1.92 8 F 51 III 2 CR +161.8 1.88 9 M 77 II 3 PR +4.7 1.97 10 F 74 IV 3 CR 140.0 1.32 11 M 63 III 1 CR 76.4 1.51 12 M 53 II 1 CR 108.1 1.39 ProMACE-CytaBOM ¶ 13 F 19 III 0 CR +100.0 1.43 CHOP plus ICE # 14 F 47 IV 4 PR 5.2 2.86 CNOP ∗∗ 15 M 48 IV 2 CR 58.0 0.86 PMitCEBO †† 16 M 85 III 3 PR 7.1 2.59 CHOP-like 17 M 70 III 4 PR 10.5 2.50 (not specified) 18 F 66 IV 2 PR 6.1 2.65 19 M 65 I 3 CR +30.6 1.46 20 M 58 III 2 CR +10.8 0.89

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Descriptive Statistics

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Table 2

Student t Test Analysis of the Correlation of Response to Treatment at 6 Months with the Pretreatment Tumor PME/NTP and IPI Parameters

Complete Response ∗ Partial Response ∗ P † Mean SD_n_ Mean SD_n_ PMR 1.42 0.21 13 2.46 0.40 7 .00001 IPI ‡ 2 1 13 3 1 7 .06

SD, standard deviation; n, number of observations.

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Table 3

Fisher Probability Analysis of the Correlation of Response to Treatment at 6 Months with the Pretreatment Tumor PME/NTP and IPI Using the Maximum of the Youden Index for Comparative Purposes (left and middle truth tables, respectively) and the Pretreatment Tumor PME/NTP Using the Cutoff for Maximum Sensitivity (right truth table)

Treatment Response Treatment Response Treatment Response CR PR Total CR PR Total CR PR Total PME/NTP ≤ 1.92 12 1 13 IPI ≤ 2.0 11 3 14 PME/NTP ≤ 2.2 13 2 15 > 1.92 1 6 7 > 2.0 2 4 6 > 2.2 0 5 5 total 13 7 20 total 13 7 20 total 13 7 20 accuracy = 0.90

prevalence = 0.65

sensitivity = 0.92

specificity = 0.86

false-negative rate = 0.08

false-positive rate = 0.14

positive predictive value = 0.92

negative predictive value = 0.86

P < .001 accuracy = 0.75

prevalence = 0.65

sensitivity = 0.85

specificity = 0.57

false-negative rate = 0.15

false-positive rate = 0.43

positive predictive value = 0.79

negative predictive value = 0.86

P < .07 accuracy = 0.90

prevalence = 0.65

sensitivity = 1.00

specificity = 0.71

false-negative rate = 0.00

false-positive rate = 0.29

positive predictive value = 0.87

negative predictive value = 1.00

P < .001

CR, complete response; PR, partial response.

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Survival Tests

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Power Calculations

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Discussion

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Acknowledgments

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Noninvasive Phosphorus Magnetic Resonance Spectroscopic Imaging Predicts Outcome to First-line Chemotherapy in Newly Diagnosed Patients with Diffuse Large B-Cell Lymphoma

Rationale and Objectives

Experimental Design

Results

Conclusions

Patients and methods

Patients

Study Design

Assay Method

Statistical Analyses

Results

Patient Population

Descriptive Statistics

Survival Tests

Power Calculations

Discussion

Acknowledgments

References

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