Abstract
Background
Whole-body diffusion-weighted (DW) MRI can help detect cancer with high sensitivity. However, the assessment of therapy response often requires information about tumor metabolism, which is measured with fluorine 18 fluorodeoxyglucose (FDG) PET.
Purpose
To compare tumor therapy response with whole-body DW MRI and FDG PET/MRI in children and young adults.
Materials and Methods
In this prospective, nonrandomized multicenter study, 56 children and young adults (31 male and 25 female participants; mean age, 15 years ± 4 [standard deviation]; age range, 6–22 years) with lymphoma or sarcoma underwent 112 simultaneous whole-body DW MRI and FDG PET/MRI between June 2015 and December 2018 before and after induction chemotherapy (ClinicalTrials.gov identifier: NCT01542879). The authors measured minimum tumor apparent diffusion coefficients (ADCs) and maximum standardized uptake value (SUV) of up to six target lesions and assessed therapy response after induction chemotherapy according to the Lugano classification or PET Response Criteria in Solid Tumors. The authors evaluated agreements between whole-body DW MRI– and FDG PET/MRI–based response classifications with Krippendorff α statistics. Differences in minimum ADC and maximum SUV between responders and nonresponders and comparison of timing for discordant and concordant response assessments after induction chemotherapy were evaluated with the Wilcoxon test.
Results
Good agreement existed between treatment response assessments after induction chemotherapy with whole-body DW MRI and FDG PET/MRI (α = 0.88). Clinical response prediction according to maximum SUV (area under the receiver operating characteristic curve = 100%; 95% confidence interval [CI]: 99%, 100%) and minimum ADC (area under the receiver operating characteristic curve = 98%; 95% CI: 94%, 100%) were similar (P = .37). Sensitivity and specificity were 96% (54 of 56 participants; 95% CI: 86%, 99%) and 100% (56 of 56 participants; 95% CI: 54%, 100%), respectively, for DW MRI and 100% (56 of 56 participants; 95% CI: 93%, 100%) and 100% (56 of 56 participants; 95% CI: 54%, 100%) for FDG PET/MRI. In eight of 56 patients who underwent imaging after induction chemotherapy in the early posttreatment phase, chemotherapy-induced changes in tumor metabolism preceded changes in proton diffusion (P = .002).
Conclusion
Whole-body diffusion-weighted MRI showed significant agreement with fluorine 18 fluorodeoxyglucose PET/MRI for treatment response assessment in children and young adults.
© RSNA, 2020
Summary
Our data showed significant agreement between response assessments at whole-body diffusion-weighted MRI and fluorine 18 fluorodeoxyglucose PET/MRI after induction chemotherapy; the agreement after induction chemotherapy was higher for participants with sarcoma than for participants with lymphoma.
Key Results
■ After induction chemotherapy, treatment response at whole-body diffusion-weighted (DW) MRI and fluorine 18 fluorodeoxyglucose (FDG) PET/MRI were in good agreement (α = 0.88), with a higher agreement for participants with sarcoma (α = 0.94) than for participants with lymphoma (α = 0.74).
■ In eight of 56 participants (seven with lymphoma, one with sarcoma) FDG PET helped detect therapy response earlier than did DW MRI (P = .002).
■ After induction chemotherapy and at the end of therapy, therapy response agreed for whole-body DW MRI and FDG PET (τ = 0.85 and τ = 1.0, respectively).
Introduction
Advances in pediatric cancer therapies have led to an increasing number of survivors of pediatric cancer, and these patients now live long enough to encounter secondary cancers. However, diagnostic imaging with radiation exposure has been associated with a risk of inducing secondary cancers later in life (1–6). To address this issue, we developed a radiation-free imaging test based on whole-body diffusion-weighted (DW) MRI (7). Although our previous work showed that whole-body DW MRI can help detect tumors, it remains to be determined if it is an accurate method for monitoring response to cancer therapy.
The assessment of tumor therapy response often requires metabolic information, which can be obtained with PET after injection of fluorine 18 fluorodeoxyglucose (FDG) (8,9). FDG PET scans are typically coregistered with CT scans (5,10,11). Recent technologic advances allow coregistration of FDG PET scans with MRI scans (12). These new FDG PET/MRI scans help reduce radiation exposure up to 80% compared with traditional FDG PET/CT scans (11,12). Whole-body DW MRI can depict tumors without any ionizing radiation exposure (7). However, the underlying tumor biology is different: FDG PET helps detect tumor metabolism, whereas whole-body DW MRI helps detect restricted proton diffusion (7,13).
Previous comparisons of the value of whole-body DW MRI and FDG PET for cancer therapy monitoring have been inconclusive (Appendix E1 [online]). Although some investigators reported a positive correlation between chemotherapy-induced changes in tumor metabolism and diffusion in adult patients (8,14), other investigators reported a mismatch (15,16). A limitation of previous comparisons of whole-body DW MRI and FDG PET/CT is that the scans were not obtained at the same time. Thus, apparent differences could be due to differences in the timing of the scan.
The purpose of this study was to compare tumor therapy response determined with whole-body DW MRI and FDG PET/MRI in children and young adults, using clinical outcomes at the end of therapy as the standard of reference.
Materials and Methods
Participants
In this prospective clinical trial, we enrolled 56 children and young adults with lymphoma or sarcoma between June 2015 and December 2018. Three participating centers obtained approval from their institutional review board. In addition, Stanford University obtained institutional review board approval to collect de-identified imaging studies in a centralized image registry and relevant clinical information (participant age, sex, tumor type, and chemotherapy status). Written informed consent was obtained from all adult participants and parents of pediatric participants. In addition, children were asked to give their consent. Inclusion criteria were (a) age less than 25 years, (b) newly diagnosed lymphoma or sarcoma, and (c) not-yet-initiated chemotherapy. Exclusion criteria were (a) MRI-incompatible metal implants, (b) claustrophobia, and (c) pregnancy. Thirty-eight participants were included in clinical trial NCT01542879, which compared the value of DWI and FDG PET/MRI at baseline imaging (before chemotherapy). Findings of baseline imaging studies of eight participants were published previously (17–19). The current study focused on the value of whole-body DW MRI and FDG PET/MRI for monitoring cancer therapy. Imaging studies after chemotherapy were not previously analyzed for any of the participants reported in this study.
Imaging
All participants underwent simultaneous whole-body DW MRI and FDG PET/MRI at baseline and after induction chemotherapy (interim scan: 3–13 weeks for lymphoma and 5–14 weeks for sarcoma). Participants with blood glucose levels less than 140 mg/dL per kg of body weight were injected with FDG (3–5 MBq per kg of body weight) and scanned 60 minutes later with a 3-T PET/MRI scanner (Signa [GE Healthcare, Milwaukee, Wis] or Biograph mMR [Siemens Healthineers, Erlangen, Germany]) using appropriate surface coils. The imaging protocol consisted of axial DW images (b values = 50 and 600 or 800 sec/mm2), Dixon sequences, and breath-hold fat-saturated T1-weighted gradient-echo sequences after administration of either a gadolinium chelate (n = 39) or ferumoxytol (n = 17; investigational new drug 111 154, Feraheme; AMAG Pharmaceuticals, Waltham, Mass) (Table E1 [online]). In addition, dedicated MRI sequences covering the primary tumor were performed. PET data were reconstructed using scanner-specific algorithms (Table E1 [online]). The total scanning time for the whole-body scan ranged from 20 to 40 minutes, with an average scanning time of 21 minutes ± 2 (standard deviation) for participants with lymphoma and 30 minutes ± 6 for participants with sarcoma.
We created apparent diffusion coefficient (ADC) maps from whole-body DW MRI data using the scanner software. In addition, whole-body DW MRI images were coregistered with T1-weighted gradient-echo images using OsiriX software (version 10.0, 64 bit; Pixmeo, Geneva, Switzerland) (7). In brief, whole-body DW MRI images (b value = 600 or 800 sec/mm2) were color encoded by applying the PET color look-up table filter and fused with T1-weighted images using the OsiriX fusion function (Fig E1 [online]). Similarly, FDG PET images were color encoded using MIM software (version 6.5; MIM Software, Beachwood, Ohio) and fused with T1-weighted images.
Assessments
Three radiologists (A.J.T. [in training], F.S., and H.E.D.L with 4, 5, and >20 years of experience, respectively) evaluated the original and fused whole-body DW MRI and FDG PET/MRI scans in consensus. The radiologists were blinded to tumor histopathologic findings, clinical data, treatment outcomes, and FDG PET/MRI results while assessing whole-body DW MRI scans and vice versa. They identified up to six measurable target lesions per participant and deemed tumor lesions measurable if they were larger than 10 mm (20,21).
One reviewer (A.J.T.) calculated the maximum standardized uptake value (SUV) of the target lesions on FDG PET/MRI scans using MIM software, as follows: [tissue tracer activity (in millicuries per milliliter)]/[injected dose (in millicuries)/patient body weight (in grams)].
In addition, the same reviewer calculated minimum ADC as follows: –(1/b) ln (signal intensity from the DW image [Sdwi]/ signal intensity in the b50 image [S50]). We chose to measure minimum ADC according to previous treatment response studies that measured minimum ADC (22,23) and studies that reported that minimum ADC is a more accurate measure of treatment response compared with mean ADC, especially in heterogeneous tumors such as osteosarcomas (24–26).
SUV and ADC were measured in a random order and at least 2 weeks apart. To evaluate reader reproducibility, two investigators (A.J.T. and F.S.) measured maximum SUV and minimum ADC of 10 lymphomas and 10 sarcomas and compared results with a t test (Fig E2 [online]).
For lymphomas, therapy response was assessed according to the Lugano classification for FDG PET/MRI (20). Response criteria for whole-body DW MRI were adapted to the Lugano classification and based on a previous adaptation by Mayerhoefer et al (Table E2 [online]) (13).
For sarcomas, chemotherapy response was determined according to PET Response Criteria in Solid Tumors, or PERCIST, criteria for FDG PET/MRI (21). Response criteria for whole-body DW MRI were adapted to PERCIST and based on a previous study by Barabasch et al (Table E3 [online]) (22). All clinical data 6 months after the end of therapy, including histologic findings, blood biomarkers, and images, served as information for a clinical team, which consisted of a radiologist, nuclear medicine physician, pediatric oncologist, and pathologist, to determine the standard of reference for tumor therapy response (complete response, partial response, stable disease, and progressive disease).
We calculated ionizing radiation exposure from FDG PET/MRI using the RADAR Medical Procedure Radiation Dose Calculator for FDG PET exposure (7).
Statistical Analysis
An expert statistician (J.R., with 20 years of experience) performed all analyses. Correlation of maximum SUV and minimum ADC values was tested with a Spearman rank correlation. Agreements between whole-body DW MRI– and FDG PET/MRI–based therapy response assessments after chemotherapy induction (complete response, partial response, stable disease, and progressive disease) were assessed using Krippendorff α (27). Differences in maximum SUV and minimum ADC values between responders (complete response and partial response) and nonresponders (stable disease and progressive disease) were tested with Wilcoxon tests. Prediction of clinical response using change in maximum SUV and change in minimum ADC was assessed with the area under the receiver operating characteristic curve. Agreements of whole-body DW MRI– and FDG PET/MRI–based therapy response assessments after chemotherapy induction with response assessments at the end of therapy were assessed using Kendall τ. Comparison of the timing of the interim scan between participants who had discordant response assessments and those who had concordant response assessments was tested using the Wilcoxon test. Comparison of the difference in proportion of response assessment disagreements up to 60 days versus after 60 days was tested using the Fisher exact test. Statistical analyses were performed with software (Stata, version 15; StataCorp, College Station, Tex). P < .05 indicated a statistically significant difference.
The minimal number of participants needed to obtain statistically significant results for this study is 50, as determined with power calculations according to our previous experience with clinical MRI studies in children. As an overall indicator of power, we considered the following calculation: If approximately 90% of participants are responders and 10% of participants are nonresponders, then 50 participants will provide 90% power at two-sided 5% error to detect differences in biomarkers as small as 1.5 standard variations. A sample size of 50 will provide 90% power at two-sided 5% error to detect correlations as low as 0.65. If we did not enroll 10% nonresponders with an overall sample size of 50, we would oversample until a target group of at least 10% nonresponders has been reached.
Results
Participant Demographics
The participant flowchart is shown in Figure 1. Sixty-two patients were invited to participate in our study. Six patients were excluded because they did not agree to undergo PET/MRI after induction chemotherapy (n = 5) or had an incomplete scan (n = 1), leaving 56 participants for the final analysis. We examined 19 participants at the University Hospital of Essen (Essen, Germany), five at the University Hospital of Tuebingen (Tuebingen, Germany), and 32 at Stanford University (Stanford, Calif). Participant demographics are summarized in Table 1. We enrolled 31 male and 25 female patients with a mean age (±standard deviation) of 15 years ± 4 (range, 6–22 years). Sixty-six percent (37 of 56 participants) had biopsy-proven lymphomas, and 34% (19 of 56 participants) had biopsy-proven sarcomas. Lymphoma subtypes were classic Hodgkin lymphoma (n = 26), non-Hodgkin lymphoma (n = 7), and posttransplant lymphoproliferative disorder (n = 4). Sarcomas consisted of bone sarcomas (n = 11) and soft-tissue sarcomas (n = 8). Table 1 provides information about the corresponding treatment protocols.
Figure 1:
Flowchart shows study cohort with inclusion criteria. DW = diffusion weighted, 18F-FDG = fluorine 18 fluorodeoxyglucose, WB = whole body.
Table 1:
Participant Demographics
Comparison of FDG PET/MRI and Whole-Body DW MRI for Tumor Therapy Responses
For assessment of reader reproducibility, measurement of maximum SUV and minimum ADC values in 10 participants with lymphoma and 10 participants with sarcoma by two different readers (A.J.T. and F.S.) showed no significant differences for all tumors (P = .41 and P = .87, respectively) (Fig E2 [online]).
At baseline, all tumors showed strong metabolic activity on FDG PET/MRI scans and restricted diffusion on whole-body DW MRI scans. After induction chemotherapy, 42 of the 56 participants showed decreased tumor metabolic activity on FDG PET/MRI scans and decreased signal intensity on whole-body DW MRI scans, consistent with concordant partial or complete therapy response (Fig 2). Six of the 56 participants showed unchanged or increased metabolic activity on FDG PET/MRI scans and unchanged or increased signal intensity on whole-body DW MRI scans, consistent with a lack of response.
Figure 2:
Concordant information with fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/MRI and whole-body (WB) diffusion-weighted (DW) MRI for monitoring treatment of diffuse large B-cell lymphoma. A, Coronal color-encoded fused FDG PET/MRI scan and, B, color-encoded fused whole-body DW MRI scan obtained before chemotherapy in a 13-year-old boy with diffuse large B-cell lymphoma show FDG- and DWI-positive mediastinal lymph nodes (arrows). C, Coronal color-encoded fused FDG PET/MRI scan and, D, color-encoded fused whole-body DW MRI image obtained after induction therapy show complete treatment response.
Whole-body DW MRI and FDG PET/MRI showed no difference in the assessment of tumor response after induction chemotherapy (α = 0.88) (Table 2). The agreement between whole-body DW MRI and FDG PET/MRI was higher for participants with sarcoma (α = 0.94) than for those with lymphoma (α = 0.74). This was because six of the 37 participants with lymphoma showed a complete response at FDG PET/MRI but only a partial response at whole-body DW MRI, and one participant with lymphoma showed a partial response at FDG PET/MRI but only stable disease at whole-body DW MRI (Fig 3; Tables 3, E4 [online]).
Table 2:
Agreement between Whole-Body DW MRI and FDG PET/MRI Therapy Response Assessment after Induction Chemotherapy
Figure 3:
Discordant information with fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/MRI and whole-body (WB) diffusion-weighted (DW) MRI for monitoring treatment of Hodgkin lymphoma. A, Schematic overview of different signal kinetics of FDG PET/MRI and whole-body DW MRI before, during, and after chemotherapy. Before therapy, tumor cells show increased FDG metabolism (orange cells) and restricted diffusion (blue hydrogen protons). After induction chemotherapy, tumor cells demonstrate decreased FDG metabolism (blue cells) but still restricted diffusion. At the end of treatment, tumor cells show decreased FDG metabolism and unrestricted diffusion (blue hydrogen protons with arrows). B, Axial color-encoded fused FDG PET/MRI scan in a 22-year-old man with Hodgkin lymphoma before the start of therapy shows an FDG-avid lymph node in right inguinal region (arrow). C, Corresponding color-encoded fused whole-body DW MRI scan of same lymph node demonstrates increased DW signal (arrow). D, Axial color-encoded fused FDG PET/MRI scan after induction chemotherapy shows FDG signal resolution of the lymph node (arrow). E, Axial color-encoded fused whole-body DW MRI scan of same lymph node demonstrates decreased but still positive DW signal (arrow). F, Axial color-encoded fused FDG PET/MRI scan at the end of therapy shows complete FDG signal resolution (arrow). G, Axial color-encoded fused whole-body DW MRI scan at the end of therapy shows complete DW signal resolution (arrow). Of note, patient had increased FDG signal at the anus (* in F) on FDG PET/MRI scan at the end of therapy, suggesting bowel inflammation. This resolved completely at further follow-up without any treatment.
Table 3:
Comparison of Whole-Body DW MRI and FDG PET/MRI Therapy Response Assessments after Induction Chemotherapy
The mean maximum SUV of responders (complete response and partial response) was 11 g/mL ± 6 at baseline and 3 g/mL ± 2 after induction chemotherapy. By contrast, the mean maximum SUV of nonresponders (stable disease and progressive disease) was 11 g/mL ± 6 at baseline and 14 g/mL ± 6 after induction chemotherapy. Tumor maximum SUVs were not significantly different between responders and nonresponders at baseline (P = .81) but were significantly different on the interim scan (P < .001).
Similarly, the mean minimum ADC of responders was 0.61 mm2/sec ± 0.23 at baseline and 1.11 mm2/sec ± 0.46 after induction chemotherapy. The mean minimum ADC of nonresponders was 0.63 mm2/sec ± 0.20 at baseline and 0.53 mm2/sec ± 0.30 after induction chemotherapy. Tumor minimum ADC values of responders and nonresponders were not different at baseline (P = .67) but were different on the interim scan (P = .003).
Minimum ADC and maximum SUV showed a moderate inverse correlation (Spearman rho = –0.52, P < .001, 460 tumor foci). No difference existed in the accuracy of clinical response assessments according to changes in tumor maximum SUV (area under the receiver operating characteristic curve = 100%; 95% confidence interval [CI]: 99%, 100%) and changes in tumor minimum ADC (area under the receiver operating characteristic curve = 98%; 95% CI: 94%, 100%) (P = .37) (Fig 4).
Figure 4:
![Receiver operating characteristic curves of the true-positive rate (sensitivity) plotted as a function of the false-positive rate (1 – specificity) for different cut-off points of tumor maximum standardized uptake value (SUV) and tumor minimum apparent diffusion coefficient (ADC). Prediction of clinical response using change in maximum SUV (100%; 95% confidence interval [CI]: 99%, 100%) and using change in minimum ADC (98%; 95% CI: 94%, 100%) was not significantly different (P = .37). AUC = area under the receiver operating characteristic curve.](https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=7325702_radiol.2020192508.fig4.jpg)
Receiver operating characteristic curves of the true-positive rate (sensitivity) plotted as a function of the false-positive rate (1 – specificity) for different cut-off points of tumor maximum standardized uptake value (SUV) and tumor minimum apparent diffusion coefficient (ADC). Prediction of clinical response using change in maximum SUV (100%; 95% confidence interval [CI]: 99%, 100%) and using change in minimum ADC (98%; 95% CI: 94%, 100%) was not significantly different (P = .37). AUC = area under the receiver operating characteristic curve.
Timing of Interim Scanning Affects the Agreement of FDG PET/MRI and Whole-Body DW MRI
Eight of the 56 participants were assigned different therapy response categories according to FDG PET/MRI and whole-body DW MRI scans (ie, the complete response, partial response, stable disease, and progressive disease assignment was not consistent with the two imaging modalities). This included six participants with lymphoma who showed a complete response at FDG PET/MRI and partial response at whole-body DW MRI (Fig 3), as well as one participant with lymphoma and one participant with osteosarcoma who showed a partial response at FDG PET/MRI and stable disease at whole-body DW MRI. In all cases, FDG PET/MRI demonstrated earlier tumor response compared with whole-body DW MRI. We did not encounter any tumor that showed a complete response at whole-body DW MRI and a partial response at FDG PET/MRI.
We found that participants with different FDG PET/MRI and DW MRI response assessments (n = 8) underwent interim imaging earlier (mean, 42 days ± 15) than participants with concordant FDG PET/MRI and DW MRI response assessments (n = 48) (mean, 64 days ± 18) (P = .002) (Fig E3 [online]).
Thirty-one of the 37 participants with lymphoma (83%) received their interim FDG PET/MRI and whole-body DW MRI response assessment after one to two cycles of chemotherapy (4–8 weeks after start of chemotherapy), and 15 of the 19 participants with sarcoma (79%) received their interim scan response assessment at 8–12 weeks after the start of chemotherapy. Considering a threshold of 60 days, we found seven disagreements in the 26 response assessments performed before day 60 (six lymphomas and one bone sarcoma, days 17–54) and only one disagreement in the 30 assessments performed after day 60 (one lymphoma, day 61). This difference in proportions was significant (P = .02).
Interim Whole-Body DW MRI and FDG PET/MRI Scans Enable Prediction of Clinical Response at the End of Therapy
Assessment of tumor therapy response with whole-body DW MRI showed good agreement with tumor therapy response at the end of therapy (τ = 0.85) (Table 4). Sensitivity and specificity of whole-body DW MRI in the prediction of clinical response at the end of therapy were 96% (95% CI: 86%, 99%) and 100% (95% CI: 54%, 100%), respectively. FDG PET/MRI–based tumor therapy response assessments after induction chemotherapy also demonstrated agreement with tumor therapy response at the end of therapy (τ = 1.0) (Table 4). Sensitivity and specificity of FDG PET/MRI in the prediction of clinical response at the end of therapy were 100% (95% CI: 93%, 100%) and 100% (95% CI: 54%, 100%), respectively.
Table 4:
Comparison of FDG PET/MRI and Whole-Body DW MRI Therapy Response Assessments after Induction Chemotherapy with Tumor Response at the End of Therapy
Mean ionizing radiation exposure from FDG PET/MRI was 3.2 mSv ± 1.0.
Discussion
Our data showed significant agreement between treatment response assessments with whole-body diffusion-weighted (DW) MRI and fluorine 18 fluorodeoxyglucose (FDG) PET/MRI after induction chemotherapy. The agreement after induction chemotherapy was higher for participants with sarcoma than for those with lymphoma. To our knowledge, the diagnostic accuracy of whole-body DW MRI for cancer therapy monitoring depends on the imaging time point after the start of therapy. Seven of the 37 participants with lymphoma had discordant response assessments after induction chemotherapy. Participants with discordant tumor therapy response assessments at whole-body DW MRI and FDG PET/MRI underwent interim scanning earlier (at 4–8 weeks) than those with concordant response assessments (8–12 weeks). After induction chemotherapy and at the end of therapy, tumor therapy response agreed for whole-body DW MRI and FDG PET/MRI.
Previous studies validated biomarkers of tumor therapy response for DW MRI and FDG PET. Chemotherapy decreases tumor cell density and increases proton diffusion, which is quantified by ADCs at DW MRI (13,28–31). FDG PET enables measurement of changes in tumor metabolism, which is quantified by SUVs (13,14,32). Previous studies showed equal sensitivities and specificities of DW MRI and FDG PET for tumor detection (7). However, results have been inconclusive with regard to treatment monitoring. Some investigators reported strong agreement of ADC and SUV (13,14), while others reported a “mismatch” (33). Previous studies in patients with Ewing sarcoma and osteosarcoma showed higher ADCs in patients with good therapeutic response (>90% necrosis at histologic examination) than in patients with poor response (24,34). In soft-tissue sarcomas, studies suggest that both DW MRI (35) and FDG PET/CT (36) can help detect tumor therapy response. Although our preliminary data suggest, in accordance with the literature, an excellent agreement between SUV and ADC of sarcomas 8–12 weeks after the start of therapy (37), to our knowledge, no head-to-head comparisons exist in the early posttreatment phase. This is important because early identification of nonresponders could help prevent side effects from ineffective therapies and could enable stratification of patients to alternative treatments in a timely manner.
Lymphomas represent a heterogeneous group of neoplasms with variable tumor cell size, extracellular matrix composition, and baseline ADCs (38). Initial evidence suggests that specific tumor subtypes have a higher frequency of concordant interim staging results than others. In a preliminary study of eight pediatric patients with diffuse large B-cell lymphoma (DLBCL), Siegel et al (28) reported 98% concordance of SUV- and ADC-based response assessments on interim scans. Similarly, Lin et al (39) reported 93% agreement of interim FDG PET and DW MRI scans in 15 adults (13 with DLBCL and two with follicular lymphoma). In our limited cohort, two participants with DLBCL showed concordant results. It is possible that therapy response of DLBCL is particularly amenable to DW measurements.
Hagtvedt et al (40) noted discordant SUV and ADC data of lymphoma after induction chemotherapy. These results were not compared with end-of-therapy scans. Latifoltojar et al (33) noted that a discordance existed between therapy response assessments of lymphomas at whole-body MRI and FDG PET/CT. However, because these studies were obtained with different scanners at different time points after chemotherapy (interval of 9–29 days and 0–7 days, respectively, between the two scans), apparent differences could have been due to different timing of the two scans. We investigated simultaneous whole-body DW MRI and FDG PET/MRI scans of pediatric tumors to eliminate scanning time as a confounding variable. This has only recently become possible with novel integrated PET/MRI technologies.
We found 97% (29 of 30 participants) agreement between whole-body DW MRI scans and FDG PET scans obtained more than 60 days after chemotherapy, when chemotherapy-induced cell death had occurred. This is in accordance with a previous study in adults that reported no significant difference in whole-body DW MRI and FDG PET therapy response assessments of lymphomas at 12 weeks of chemotherapy (13). The study did not capture early time points after chemotherapy. We found that the agreement between whole-body DW MRI and FDG PET/MRI readouts increased with increasing time interval after initiation of chemotherapy.
Compared with adult patients with lymphoma, who have a 5-year survival rate of 72% for non-Hodgkin lymphoma and a rate of 87% for Hodgkin lymphoma (41), pediatric lymphoma patients have a better prognosis, with a 5-year survival rate of 87% for non-Hodgkin lymphoma and a rate of 98% for Hodgkin lymphoma (42). This leads to an increased number of survivors of pediatric cancer, and therefore, disease- and treatment-related sequelae play a much bigger role in children. In addition, residual life expectancy for survivors of pediatric cancer is much higher than in adults. Therefore, further studies, with the goal to reduce radiation exposure, must evaluate if patients with pediatric lymphoma could undergo an integrated FDG PET and whole-body DW MRI examination during the early posttreatment phase for response assessment and then further be followed-up with whole-body DW MRI.
Although our study confirms agreement of whole-body DW MRI and FDG PET/MRI scans at this relatively late time point (8–12 weeks), we noted that chemotherapy-induced changes in tumor metabolism preceded changes in proton diffusion in some participants. Similarly, Su et al (43) found in an animal model that chemotherapy first inhibited tumor glucose metabolism and then induced cell death and increased proton diffusion. Cullinane et al (44) reported that tumor cell lines treated with imatinib first showed changes in glucose metabolism followed by changes in cell viability and cell counts. Previous imaging studies in patients did not recognize this sequence of events (14,37), possibly because DW MRI and FDG PET/CT scans were obtained sequentially, rather than simultaneously.
Limitations of this study include small numbers of different tumor subtypes, which is a typical limitation in pediatric oncology. Pediatric cancer is rare, and the rapid evolution of novel imaging technologies makes it difficult to generate large data sets. The variable timing of the interim scan was dictated by clinically defined imaging time points of specific treatment protocols. Because of the small number of different histopathologic tumor subtypes, we could not evaluate the effect of different drugs or combination therapies on tumor proton diffusion or metabolism.
In conclusion, we demonstrated that whole-body diffusion-weighted MRI can help assess therapy response of pediatric tumors, especially 8–12 weeks after start of treatment in patients with lymphoma and sarcoma.
APPENDIX
SUPPLEMENTAL FIGURES
Acknowledgments
Acknowledgments
We thank Dawn Holley, CNMT, RT(N)(CT)(MR), and Harsh Gandhi, MS, CNMT, PET, RT(MR), at the Richard M. Lucas Center, Stanford Medicine, for their expert help with the FDG PET/MRI scans. We thank Christopher Stave, MLS, for his valuable help and assistance with the systematic literature search. We would also like to acknowledge Amy N. Thomas, BA, who helped design Figure 3 for this manuscript. We thank Julie Gosse, PhD, a medical writer, for editing the English language of this manuscript.
Disclosures of Conflicts of Interest: A.J.T. Activities related to the present article: received a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Activities not related to the present article: disclosed no relevant relationships. Other relationships: disclosed no relevant relationships. F.S. disclosed no relevant relationships. A.M.M. Activities related to the present article: received a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Activities not related to the present article: disclosed no relevant relationships. Other relationships: disclosed no relevant relationships. J.G.D. disclosed no relevant relationships. J.K. disclosed no relevant relationships. O.M. disclosed no relevant relationships. M.P.L. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: is a consultant for Incyte, ADC Therapeutics, Epizyme, Lily, and Steba biotech; institution has grants/grants pending with Janssen Research and Development and Seattle Genetics; has received reimbursement for travel/accommodations/meeting expenses from the American Society of Clinical Oncology. Other relationships: disclosed no relevant relationships. S.S. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: institution has grants/grants pending with Alex’s Lemonade Stand, Bayer Healthcare Pharmaceuticals, Bristol Myers Squibb, Cookies for Kids’ Cancer, F. Hoffmann-LaRoche, Incyte, Loxo Oncology, Novartis, Pfizer, Sanofi US Services, St. Baldrick’s Foundation, and University of California, Santa Cruz. Other relationships: disclosed no relevant relationships. A.P. disclosed no relevant relationships. J.R. disclosed no relevant relationships. K.H. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: receives payment for board membership from Sofie Biosciences; is a consultant for Ipsen and Siemens Healthineers; institution has grants/grants pending with BTG; receives payment for lectures, including service on speakers bureaus, from Adacap, Amgen, Bayer, BTG, Curium Pharma, Endocyte, GE Healthcare, Ipsen, Siemens Healthineers, and Sirtex; holds stock/stock options in Sofie Biosciences. Other relationships: disclosed no relevant relationships. S.G. disclosed no relevant relationships. J.F.S. Activities related to the present article: institution received a grant from the German Childhood Cancer Foundation. Activities not related to the present article: receives payment for board membership from the Philips Healthcare speakers bureau. Other relationships: disclosed no relevant relationships. M.M. disclosed no relevant relationships. L.U. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: institution has grants/grants pending with Siemens Healthineers; institution has received payment for lectures, including service on speakers bureaus, from Siemens Healthineers and Bayer Healthcare; institution has received payment from Bayer Healthcare for development of educational presentations; and institution has received reimbursement for travel/accommodations/meeting expenses from Siemens Healthineers and Bayer Healthcare. Other relationships: disclosed no relevant relationships. H.E.D.L. Activities related to the present article: received a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Activities not related to the present article: disclosed no relevant relationships. Other relationships: disclosed no relevant relationships.
Supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD081123A). J.G.D. supported by a training grant from the National Heart, Lung, and Blood Institute (T35HL007473-36).
Abbreviations:
- ADC
- apparent diffusion coefficient
- CI
- confidence interval
- DW
- diffusion weighted
- FDG
- fluorine 18 fluorodeoxyglucose
- SUV
- standardized uptake value
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