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Measuring the “Unmeasurable”

Posted Aug 31, 2010 Updated Apr 7, 2023
By Behnaz Goudarzi MD , Heather A. Jacene MD , Richard L. Wahl MD
14 min read

Rationale and Objectives

To determine if anatomically “nonmeasurable” disease in bone marrow (BM) is assessable for response to therapy by [ 18 F]-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT).

Materials and Methods

FDG PET/CT images of 27 patients with lymphoma, FDG-avid bone marrow (BM) lesions, and ≥1 FDG-avid, tumor-involved lymph node (LN) at baseline were retrospectively reviewed. FDG uptake in target LNs and BM foci was determined pre- and posttherapy using the standardized uptake value corrected for lean body mass (SUL mean ). Size of the same target LNs was measured pre- and posttherapy on CT. Percentage decreases of LN size and LN and BM SUL were calculated. Response was classified according to revised International Workshop Criteria (IWC) with and without modification for metabolic evaluation of BM and correlated to overall survival. Statistical analyses were performed using paired t -tests, Pearson correlation coefficients, and z-tests.

Results

LN size, LN SUL mean , and BM SUL mean were significantly higher pre- versus posttherapy (2337 mm 2 ± 1810 vs. 309 mm 2 ± 323; 6.94 ± 4.96 vs. 1.02 ± 1.00; and 6.81 ± 4.58 to 1.84 ± 1.58, all P < .001, respectively). After therapy, significant correlation was found between percentage declines of LN size and SUL mean of LNs ( r = 0.84, P < .001) or BM ( r = 0.56, P = .002) and SUL mean of LN and BM ( r = 0.76, P < .001). Including a metabolic assessment of BM correctly altered overall response assessment in 5/27 (19%) patients and better predicted overall survival than revised IWC.

Conclusion

Anatomically “unmeasurable” BM infiltration with lymphoma behaves similarly to LN disease after therapy and is “measurable” by FDG PET/CT. FDG PET/CT is valuable for monitoring tumor response in “measurable” disease and BM, which was previously considered “unmeasurable” by anatomical imaging.

Tumor involvement of bone marrow (BM) in patients with lymphoma defines a higher stage and portends a worse prognosis. Biopsy is the current standard for diagnosing lymphomatous infiltration of BM. Sensitivity for identifying disease in BM increases 10%–20% by multiple sampling; however, even with negative bilateral biopsies, patients may subsequently prove to have BM disease .

Bone and BM lesions are considered “nonmeasurable” in therapy response criteria, which are primarily based on anatomic imaging. The terms “measurable” and “nonmeasurable” were introduced in the Response Evaluation Criteria in Solid Tumors (RECIST) approach . Per RECIST, “measurable lesions” can be accurately measured in at least one dimension with the longest diameter being ≥10 or 20 mm depending on computed tomography (CT) technique. Bone lesions and several others (eg, ascites, pleural/pericardial effusions, leptomeningeal disease, lymphangitis cutis/pulmonis, cystic lesions) are specifically considered as “truly nonmeasurable” per RECIST. Although no direct measurements of tumor burden are taken, response of “nonmeasurable” lesions is “considered” when assigning a posttreatment response classification.

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Materials and methods

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Patient Selection

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Table 1

Patient Characteristics (Total Group, n = 27)

Characteristics Sex (M/F) 20/7 Age (mean ± SD) 45 ± 21 years Histologies HL 9 Nodular sclerosing 7 Mixed cellularity 1 Not otherwise specified 1 NHL 18 Large B cell 16 ∗ Follicular 2 Pretherapy PET indication Initial staging 18 Restaging 9 Interval therapy Chemotherapy alone † 21 Radioimmunotherapy 4 Donor lymphocyte infusion 1 Stem cell transplant 1 Timing of posttherapy PET Mid-therapy After 2 cycles of chemotherapy 4 After 3 cycles of chemotherapy 10 After completion of therapy ‡ 13 Days between (mean ± SD) Pre- and posttherapy PET 95 ± 50 Last therapy day and posttherapy PET 31 ± 27 Last therapy day and pretherapy, restaging PET 100 ± 54

HL, Hodgkin’s lymphoma; NHL, non-Hodgkin’s lymphoma; PET, positron emission tomography.

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PET/CT Imaging

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Image Interpretation

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Posttherapy Response Assessments

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Statistical Analyses

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Results

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Table 2

Lymph Node Size and Lymph Node and Bone Marrow FDG Uptake

Before Therapy After Therapy_P_ Value Lymph node ( n = 130) SPD (size, mm 2 ) 2337 ± 1810 309 ± 323 <.001 SUL mean 6.94 ± 4.96 1.02 ± 1.00 <.001 SUL max 8.74 ± 6.19 1.29 ± 1.32 <.001 Bone marrow lymphoma ( n = 91) SUL mean 6.81 ± 4.58 1.84 ± 1.58 <.001 SUL max 8.26 ± 5.2 2.16 ± 1.95 <.001 Normal bone marrow SUL mean 0.85 ± 0.33 0.93 ± 0.32 .28 SUL max 1.00 ± 0.34 1.12 ± 0.37 .37

SPD, sum of products of the diameters; SUL mean , mean standardized uptake value; SUL max , maximum standardized uptake value.

Figure 1, (a) Lymph node involvement before and after therapy is shown on these scans (computed tomography [CT], left; positron emission tomography [PET]/CT, middle; PET, right). Before therapy, the lymph node ( arrows ) measured 28 × 16 mm and had a mean standardized uptake value (SUL mean ) of 8.11. After therapy, the lymph node ( crosshairs ) measured 16 × 8 mm and had a SUL mean of 0.72. (b) Bone marrow involvement in the sternum ( arrowheads ) is shown for the same patient (CT, left; PET/CT, middle; PET, right). Before therapy, SUL mean in the BM lesion was 6.76 and after therapy it was 0.84.

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Figure 2, Correlations between percent change of anatomic and metabolic parameters. There are strong positive correlations between (a) percent change in sum of products of the diameters (SPD) of LN and percent change in lymph node (LN) mean standardized uptake value (SUL mean ) after therapy ( r = 0.84, P < .001), and (b) percent change in LN SUL mean and bone marrow (BM) SUL mean after therapy ( r = 0.76, P < .001). (c) There is a positive correlation between the percent change in LN SPD and BM SUL mean after therapy ( r = 0.56, P = .002).

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Figure 3, Flow chart of histologic and imaging correlation/confirmation of FDG-avid bone marrow (BM) lesions. PET, positron emission tomography; CT, computed tomography; MRI, magnetic resonance imaging.

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Table 3

Responses After Therapy

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IWC, International Workshop Criteria; PET, positron emission tomography; BM, bone marrow; CR, complete response; PR, partial response.

Figure 4, Representative images of a 53-year-old male with Stage IVA diffuse large B-cell lymphoma. (a) Positron emission tomography (PET)/computed tomography (CT) scan for initial staging revealed numerous foci of intense FDG uptake throughout the pelvic bones with no corresponding CT abnormalities and a left presacral soft-tissue mass with intense FDG uptake ( arrows ). Iliac crest bone marrow (BM) biopsy was positive. (b) Posttherapy PET/CT scan after six cycles of rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) chemotherapy revealed complete resolution of the FDG uptake in the pelvic bones and presacral soft-tissue mass. Posttherapy iliac crest BM biopsy was negative. He was considered to be in complete remission by International Workshop Criteria+PET and PET+BM. He received intrathecal prophylaxis after chemotherapy and remained in a complete remission at 35 months after the pretherapy PET/CT scan.

Figure 5, Representative sagittal (left 3 columns) and transaxial images (right 2 columns) of a 54-year-old female with Stage IVB diffuse large B-cell lymphoma. (a) FDG positron emission tomography (PET)/computed tomography (CT) scan for initial staging revealed extensive FDG-avid lymphadenopathy (ie, para-aortic nodes, arrows ) and numerous foci of FDG uptake within bone marrow (BM) despite a normal appearance of the bone on CT (ie, L3 vertebral body; crosshairs and arrowhead ). Iliac crest BM biopsy was positive for non-Hodgkin's lymphoma. (b) Mid-therapy PET/CT scan after three cycles of rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) chemotherapy revealed complete resolution of all FDG-avid lymphadenopathy, but increased FDG uptake in several vertebral bodies was suspicious for residual active lymphoma ( b , crosshair and arrowheads ). Mid-therapy BM biopsy was negative. She was considered to be in complete remission by International Workshop Criteria+PET, but partial remission by PET+BM criteria. (c) Therapy was intensified to autologous stem cell transplant. Posttransplant FDG PET/CT scan was negative for active lymphoma. She progressed in lymph nodes ∼3 months posttransplant on FDG PET/CT scan and expired 12.3 months after the pretherapy scan. This supports PET+BM assessment as a robust predictor of outcome.

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Figure 6, Kaplan-Meier estimates of overall survival. Overall survival was longer for patients who achieved a complete response (CR) vs. partial response or progressive disease by positron emission tomography (PET)+bone marrow (BM), but not by International Workshop Criteria (IWC)+PET. PET+BM appeared a stronger predictor of outcome for survival based on CR vs. non-CR than was IWC+PET. R-CHOP, rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; R-ICE, rituximab-ifosfamide, carboplatin, etoposide; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; ABVD-PE, doxorubicin, bleomycin, vinblastine, dacarbazine-cisplatin, etoposide.

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Discussion

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Figure 7, Representative sagittal images of a 26-year-old female with Stage IVB Hodgkin's lymphoma before (a) and after (b) chemotherapy. Growth colony stimulating factors were administered with chemotherapy. (a) Pretherapy, intense FDG uptake is seen fusing to multiple vertebral bodies, most pronounced in T10 (crosshairs). Intense FDG uptake is also seen in lymph nodes behind the sternum. (b) Posttherapy, there is resolution of the FDG uptake in T10, which is now photopenic ( crosshairs ) compared to normal, stimulated bone marrow. The FDG uptake in the lymph nodes also resolved.

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Acknowledgments

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Academic Radiology, Volume 17, Issue 9
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