Can ¹⁸F-FDG PET/CT Metabolic Tumor Volume Contribute to Better Prognostication in Pediatric Hodgkin's Lymphoma?

Keywords

¹⁸F-FDG PET/CT - event-free survival - metabolic tumor volume - overall survival - pediatric Hodgkin's lymphoma - prognostication - standardized uptake value

Introduction

Pediatric Hodgkin's lymphoma (PHL), accounting for 5 to 6% of all childhood cancers, has a peak incidence at younger ages in developing countries, unlike in developed countries.[1] [2] With major advancements in PHL treatment protocols, the 5-year event-free survival (EFS) rates have improved dramatically over the last several decades, approaching 90 to 95% overall for all stages in the West.[3] [4] Developing countries have progressively bridged the gap, with recent studies in India pegging the 5-year EFS for early-stage PHL at 94%, which is comparable to Western data.[5] There was also marked improvement in the outcomes of advanced-stage PHL to 81.1% 5-year EFS.[6] Despite these excellent 5-year EFS rates, the late morbidities such as second malignancies and cardiovascular risks occur even in those with early-stage disease. Thus, newer PHL treatment protocols call attention to optimal strategies that reduce cumulative therapy, thereby mitigating potential long-term toxicity, while maintaining treatment efficacy.[7] Toward this objective, “risk-based” and “response-adaptive” strategies for PHL are based upon pretreatment prognostic factors and interim evaluation of disease response, respectively.

The “risk-based” strategy involving multiagent chemotherapy, with pretreatment prognostic risk factors defining treatment intensity, is the standard of care for all patients. Radiation therapy is “response-adapted,” being reserved for patients with residual disease based on interim positron emission tomography (PET)/computed tomography (CT).[8] [9] Although PHL stage, presence of B symptoms (fever, weight loss, night sweats), tumor bulk, erythrocyte sedimentation rate (ESR), and extranodal involvement have significant prognostic values, these are interrelated. Hence, factors with independent prognostic implications have become more difficult to pin down, as the treatment outcomes continue to improve.[10]

Since almost all lymphomas are fluorine-18 fluorodeoxyglucose (¹⁸F-FDG) avid, ¹⁸F-FDG PET/CT, which integrates morphological and metabolic function information, has now become the primary investigation for lymphoma staging, which translates to risk stratification. The interim PET assessment is also useful in prognostication, with reduction in avidity correlating with treatment response.[11] [12] Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and standardized uptake value (SUV) have been reported as diagnostic and prognostic parameters in PET/CT since the late 1990s for several adult cancers.[13] Of these, the most commonly used parameter for the quantification of tumor metabolic activity is the SUV.[14]

In lymphomas, MTV, a parameter extracted from baseline FDG PET/CT has been proposed as a prognosticator at diagnosis, with strong correlation with EFS and overall survival (OS), often outperforming clinical scores, molecular predictors, and interim PET/CT results.[12] MTV and consequently TLG are considered to better reflect metabolic tumor burden and more accurately portend prognosis than maximum standardized uptake value (SUVmax).[14] Several studies have shown that MTV predicts survival in various non-Hodgkin's lymphoma (NHL) subtypes in children[15] [16] [17] including a study from India on anaplastic large cell lymphoma (ALCL) by Mathew et al.[15] However, only a few retrospective studies have confirmed this promising role in early HL in adults.[18]

In PHL, a few studies evaluating the prognostic value of SUVmax and MTV in predicting EFS have been published, with rather conflicting results.[19] [20] The usefulness of volumetric PET/CT indices is limited by lack of consensus in determining tumor boundary and the need for advanced software.[12] [21] [22] As there is a paucity of studies from the developing world, this retrospective study was conducted to evaluate the prognostic role and feasibility of MTV assessment in PHL, and compare its performance with SUVmax.

Materials and Methods

Children aged younger than 18 years with classic Hodgkin's lymphoma (HL) diagnosed and treated in the Pediatric Hematology Oncology unit of our tertiary care hospital between the years 2017 and 2020 and who had a diagnostic and interim assessment with PET/CT scan done at the study center were included. Demographic data and basic clinical details were obtained from the electronic medical records.

¹⁸F-FDG PET/CT Image Acquisition and Analysis

For baseline and interim PET/CT image acquisition, a minimum of 6 hours of fasting prior to imaging and blood glucose levels of ≤11 mmol/L was ensured in all included cases. The dose of ¹⁸F-FDG was 3 MBq/kg body weight (minimum dose of 14 MBq) as per the European Association of Nuclear Medicine (EANM) guidelines. Image acquisition was commenced at 60 ± 5 minutes after ¹⁸F-FDG injection using Biograph 40 Truepoint PET/CT scanner (Siemens Medical Solutions, Illinois, United States). Oral (iohexol) and intravenous contrast (iopamidol) were administered, adjusted for the patient's weight, the former 1 hour before imaging and the latter with a scan delay time of 60 to 80 seconds. The CT parameters for children younger than 13 years and ≥13 years were 120 keV, 60 mA, section width of 3 mm, and pitch of 0.8 and 120 keV, 150 mA, section width of 5 mm, and pitch of 0.8, respectively.

PET/CT scans of the included patients were uploaded on the syngoMMWP VE61A software and were evaluated by a nuclear medicine expert who was blinded to clinical outcome. Following qualitative analysis for visual identification of nodal/extranodal disease and abnormal metabolic activity on PET/CT, quantitative parameters—SUVmax and MTV—were evaluated considering the spherical volumes of interest as necessary, drawn manually, so as to include all areas of lymphomatous involvement. The same method was used in the entire study cohort for calculation of the study parameters as discussed in the following sections.

Study Parameters

Visual Deauville Score

The Deauville score is a 5-point internationally recommended scale, based on visual interpretation of FDG uptake, in the initial diagnostic staging as well as assessment of treatment response of lymphomas. Diagnostic and interim ¹⁸F-FDG PET/CT assessment is based on visual Deauville score (VDS) aided by semi-quantitative measures like SUV.[23] VDS for response evaluation in HL in adults has been validated in developed countries as well as India, including this study center.[24]

Standardized Uptake Value

The most commonly used parameter for the quantification of tumor metabolic activity is the SUV. SUVmax is the maximum voxel value of SUV in the tumor. Although observer independent, it is limited by its value being from only one voxel and inherent image noise sensitivity. However, it is the most widely used metabolic parameter in the assessment of PET/CT scans.[12] [21] [22]

Metabolic Tumor Volume

MTV is a quantitative measure of the total volume of tumor FDG uptake that exceeds a certain threshold defined as SUVmax ≥2.5 or SUVmax ≥40%. MTV is the measurement of the total FDG activity contained by every voxel of the image of the lymphoma lesions, summing up all nodal and extranodal lesions, the voxel activity expressed as SUV.[12] [21] [22] From both baseline and interim FDG PET/CT scans, SUVmax of the involved area was calculated. MTV was calculated by semiautomated algorithm using an SUV of 2.5.[25] [26]

PHL Risk Stratification: Stage and Treatment Groups

All children diagnosed with PHL were risk stratified and treated as per the EuroNet-PHL-C1 interim guidelines/C2 protocol standard arm. Baseline PET/CT was performed. The children were divided into three treatment groups (TGs) based on the stage of the disease, presence of B symptoms, extranodal involvement, and presence of additional risk factors (ESR > 30 mm/h or tumor bulk ≥200 mL). Patients with Ann Arbor stage IA, IB, or IIA without risk factors or extranodal involvement were assigned to TG1, those with stages IA, IB, and IIA with extranodal involvement or additional risk factors as well as Ann Arbor IIB and IIIA were taken as TG2 with stages IIBE, IIIAE, IIIBE, IIIB, IVA, or IVB treated as TG3.[27] [28]

Treatment Protocols

All children received two courses of OEPA (Vincristine [oncovin], etoposide, prednisolone, Adriamycin) and then underwent an interim response assessment by PET/CT. If interim PET/CT showed good response, TG1 patients received one cycle COPDAC (cyclophosphamide, vincristine, prednisolone, dacarbazine), TG2 patients received two cycles of COPDAC, and TG3 patients received four cycles of COPDAC.[27] [29]

Treatment Response Assessment and Indications for Radiotherapy

Indications for radiotherapy were based on response assessment on the interim PET/CT. The patients were classified as “adequate responders” and “inadequate responders.” Children with Deauville score ≤3 were classified as adequate responders and they received only chemotherapy as mentioned earlier. Those with a Deauville score ≥4 were classified as inadequate responders and were given radiotherapy to the involved fields (in the interim PET) at the end of COPDAC cycles as per TG.[27] [29]

Outcome

The children were followed up till July 2024 for OS and EFS. OS was calculated from diagnosis till last follow-up or death, and event was defined as disease progression, recurrence, second malignancy, or death due to any cause.

Statistical Analysis

For continuous variables, mean value with standard deviation was calculated. The mean SUVmax and MTV in the baseline PET/CT were compared for correlation. The study parameters (SUVmax and MTV) were compared and analyzed based on the PHL stage, TGs, response groups, and outcome. A comparison of the median baseline PET/CT MTV was done among the four stages at diagnosis and three TGs using paired t-tests. Based on the interim PET/CT response, the patients were divided into “adequate” and “inadequate” responders. The Median SUVmax and MTV in the baseline PET were compared between the two groups using paired t-test. Percentage reduction of MTV from baseline to interim PET was assessed and compared with stage, TGs, and response groups using the rank-sum nonparametric test. The study patients were further classified into two outcome groups with or without an event. The median SUVmax and MTV in the baseline PET/CT were compared between the two outcome groups using paired t-test. Receiver operating characteristic (ROC) analysis was used to identify sensitivity and specificity of PET/CT for predicting EFS. Using the ROC curve, the 85th percentile MTV value cutoff was determined to identify the subjects with high MTV. A p-valve of less than 0.05 was considered statistically significant.

Ethical Approval

All procedures performed in the study subjects were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments/comparable ethical standards. This retrospective study was approved by the Institutional Review Board (IRB) of the institution (IRB Min No. 14743/6.7.22).

Results

Sixty-one children with PHL were included in the study; their baseline characteristics with subjects classified by age, gender, stages, TGs, and response assessment are shown in [Table 1]. The mean age at diagnosis was 10.10 years, with a male-to-female ratio of 1:0.6. The majority were in stage III (21/61) at diagnosis, and designated to TG3 (34/61).

Table 1 Baseline characteristics of subjects

Baseline characteristics	Number
Age (y)	Mean: 10.10 (4–17)
0–5	5
6–10	30
11–15	22
16–18	4
Gender	Male:female = 1:0.6
Male	37
Female	24
Stage
IA	11
IIA	10
IIB	5
IIIA	7
IIIB	14
IVA	7
IVB	7
Treatment levels
Level 1	16
Level 2	11
Level 3	34
SUVmax
Baseline PET	11.1 (± 3.5)
Interim PET	1.9 (± 3.4)
Metabolic tumor volume
Baseline PET	232.73 (± 206)
Interim PET	72.7 (± 192.4)
Response assessment
Adequate response	47
Inadequate response	14

MTV and SUVmax were assessed for all patients in the baseline as well as interim PET/CT scan. The mean SUVmax in the baseline PET/CT was 11.1 (± 3.5) and that in the interim PET/CT was 1.9 (± 3.4). Similarly, the mean MTV in diagnostic and interim PET/CT was 232.73 (± 206) and 72.7 (± 192.4) mL, respectively. Percentage change in MTV and SUVmax between the two PET/CT scans were compared, and both showed significant reduction in the values (p = 0.001). The positive correlation between SUVmax and MTV (r = 0.41, p = 0.002) is shown in [Fig. 1].

Fig. 1 Correlation between maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV) in the baseline PET scan.

[Table 2] shows the median SUVmax and MTV of various stages of disease and TGs. The median SUVmax and MTV were found to increase with advanced stages of the disease. The difference in the median MTV was statistically significant for stage II versus stage III (p = 0.004), but not for the median SUVmax (p = 0.13). The difference in the median MTV was statistically significant for TG2 versus TG3 (p = 0.001) but not for the median SUVmax (p = 0.06)

Table 2 Median maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV) versus stage of disease and treatment groups

Median SUVmax and MTV vs. stage of disease
Stage	Median SUVmax (interquartile range [IQR])	p-value between	Median MTV (IQR), mL	p-value between
I	8.04 (6.06–10.7)	I and IV: 0.009	36.8 (7.9–46.1)	I and IV: 0.0001
II	9.95 (7.4–16.7)	I and II: 0.2	39.9 (14.8–105.3)	I and II: 0.8
III	10.3 (9.12–15.01)	II and III: 0.13	140 (83.6–309.2)	II and III: 0.004
IV	14 (11.4–16.3)	III and IV: 0.5	362.4 (180–478.8)	III and IV: 0.1
Median SUVmax and MTV vs. treatment groups
Treatment groups (TG)	Median SUVmax (IQR)	p -value between	Median MTV (IQR), mL	p -value between
1	8.2 (6.5–12.7)	1 and 3: 0.005	36.8 (8.8–51.1)	1 and 3: 0.001
2	9.6 (8.54–11.57)	1 and 2: 0.9	39.9 (14.8–105.3)	1 and 2: 0.6
3	13.7 (9.5–16.3)	2 and 3: 0.06	304 (123.7–452.7)	2 and 3: 0.001

PET/CT Parameters and Treatment Response

Further analysis was done to compare the SUVmax and MTV on the diagnostic PET/CT scan between “adequate” and “inadequate” responders as well as those who had or did not have an event. Among the 61 patients, 47 patients were classified as “adequate responders” according to the interim PET/CT and 14 as “inadequate responders” ([Table 1]). Twelve out of these 14 inadequate responders attained complete remission (CR) with chemotherapy and radiotherapy. The remaining two had disease progression and were treated with salvage chemotherapy followed by radiotherapy; one attained remission; however, the second child succumbed to the disease.

For each patient, MTV and SUVmax were calculated in the baseline and interim PET/CT. [Table 3] presents median MTV and SUVmax in “adequate” and “inadequate” responders. Both the median MTV and the SUVmax from diagnostic PET/CT were higher in the “inadequate” responders compared to “adequate” responders, but were not significantly different. The median change in MTV between the response groups were analyzed. The group of children with “inadequate” response showed significantly wider variation in reduction of MTV (p = 0.001) compared to those with “adequate” response. The MTV range among “inadequate responders” varied from good response of greater than 90% volume reduction to a paradoxical increase in volume.

Table 3 Comparison of median metabolic tumor volume (MTV) and median maximum standardized uptake value (SUVmax) in diagnostic PET/CT with Deauville score–based treatment response groups

Comparison of median MTV and median SUVmax in diagnostic PET/CT with Deauville score–based treatment response groups
Outcome	Median MTV (interquartile range [IQR]), mL	Median SUVmax (IQR)
Responders	98.35 (37.93–298.2)	10.73 (8.47–14.61)
Inadequate responders	145 (84.43–463.5)	12.25 (8.54–18.66)
p-value	0.31	0.37
Comparison between occurrence of event with median MTV and median SUVmax in the diagnostic PET/CT
Outcome	Median MTV (IQR), mL	Median SUVmax (IQR)
Event	214.3 (32.45–420.7)	11.1 (7.6–13.49)
No event	101.6 (37.9–298.2)	10.3 (8.5–15.3)
p-value	0.63	0.68

As further subgroup analysis, the median MTV reduction was compared between initial stage and treatment levels against response groups. However, there was no significant association between stage at presentation, TGs, and median percentage reduction in MTV.

Further analysis was done, based on the Milgrom et al study on the prognostic value of baseline MTV in pediatric and adolescent HL anticipating relapse/refractory disease in about 15% of patients. They opined that a subgroup analysis using the 85th percentile PET/CT MTV value may aid in identifying those who are likely to have refractory disease/disease relapse.[19] In our cohort, the 85th percentile was determined using the ROC curve area under the curve (AUC), and the cutoff was found to be 449. Based on the cutoff value, the study subjects were divided into two groups, high MTV (n = 9) and low MTV (n = 52) at presentation. The nine patients who had baseline MTV more than the 85th centile included five (55.6%) with stage IV disease, three (33.3%) with stage III disease, and one patient (11.1%) with stage IIBE disease; hence, all belonged to TG3. Three of nine (33%) children had “inadequate response” during interim assessment. Of the nine children with high baseline MTV, one had disease progression and another had disease relapse (both were stage 4 at presentation); however, both attained CR postsalvage therapy.

The 52 patients with low MTV belonged to the following stages: stage I = 11, stage II = 14, stage III = 18, and stage IV = 9. Sixteen of 52 children were in TG1, 11 of 52 were in TG2, and 25 of 52 were part of TG3. In all, 43 of 52 children had adequate response in the interim PET. Nine of 52 children, however, had inadequate response in the interim PET. One had progressive disease requiring salvage chemotherapy; however, the remaining eight attained CR at the end of chemotherapy with radiotherapy.

PET/CT Parameters and Follow-Up Outcome

At a median follow-up period of 54 months (5–97 months), the OS was 96.7% (59/61) and the EFS was 85.2% (52/61). Among the study subjects who had an event (n = 9), eight of nine children had stage IV disease at initial diagnosis (TG3). All but one child who had a relapse had adequate response in the iPET. Two of nine children had primary progressive disease: one attained remission with salvage chemotherapy and radiotherapy, whereas the other child did not respond to therapy and expired. Seven of nine children had disease relapse: one had an early relapse (3 months after completion of initial treatment) and six had late relapse (after 1 year of initial treatment). Six of seven children who relapsed are in complete remission now, following salvage treatment for first relapse, and one succumbed to the illness.

Children who had an event were studied according to their initial SUVmax, initial MTV, percentage reduction in MTV, and response to treatment. As depicted in [Table 3], the median MTV and SUVmax values in the children with an event were found to be higher, but the difference when compared to those who remained event free was not statistically significant. In addition, the median reduction of MTV between the above two groups also showed no significant difference.

The ROC curve was constructed to assess sensitivity and specificity of diagnostic PET/CT MTV as a prognostic parameter in assessing EFS; the AUC was 0.52 (95% confidence interval [CI]: 0.243–0.815); hence, further analysis was not feasible.

Discussion

In our PHL cohort of 61 subjects, the ¹⁸F-FDG PET/CT parameters (MTV and SUVmax) were measured in baseline and interim PET/CT. The median values of both parameters in the baseline PET/CT scan were found to increase as the stage advanced and there was a significant positive correlation. The percentage reduction in MTV and SUVmax between baseline and interim PET/CT was statistically significant. MTV in baseline PET/CT distinguished stages II and III and TG2 and TG3 significantly better than SUVmax, similar to the German study on 50 subjects with PHL by Rogasch et al who were treated according to the EuroNet-PHL-C1 or EuroNet-PHL-C2 treatment protocol.[25] In their study, the mean MTV values were 386.2 mL (137.9–537.8 mL) in stage III and 350.6 mL (207.4–555.9 mL) in stage IV, in comparison to our study values of 140 (83.6–309.2) and 362.4 (180–478.8) mL for the corresponding stages, alluding to a more significant positive correlation with advancing stage.[25] Our study had almost equal distribution of patients across all stages, unlike the Rogasch et al study, which had only one subject in stage I; thus, we were able to demonstrate more convincingly that there was a positive correlation of MTV with advancing stage.[25]

The MTV and SUVmax values in the baseline PET/CT were evaluated as treatment response prognosticators in this study. Although these were noted to be higher among “inadequate” responders as compared to “adequate” responders, the difference was not statistically significant. Nevertheless, the median change in MTV values between the response groups showed wider variation in reduction for the group with “inadequate” response compared to the group with “adequate” response, which was statistically significant. Our study results contrast the Rogasch et al observation, where log-linear analysis showed a significant correlation between a high MTV and response to induction therapy (p < 0.001).[25] Similarly, the Reed et al study on 69 subjects in South Africa showed that only MTV on baseline PET/CT, not SUVmax or TLG, was predictive of treatment response.[20] The subjects across stages in our study were more uniformly represented compared to the studies by Rogasch et al and Reed et al, in which stage 1 had only one subject each.

At a median follow-up of 54 months, the OS and EFS in this study were 96.7 and 85.2%, respectively. Baseline PET/CT parameters (MTV and SUVmax median values), although higher in the group with an event, were not significantly different from the group without an event, even on univariate analysis. This is similar to that observed by Reed et al, where none of the metabolic parameters (SUVmax, MTV, or TLG) in the baseline PET/CT were independent predictors of neither EFS nor OS in PHL.[20] The above two contrasts the findings of Milgrom et al, who assessed the prognostic value of baseline MTV in intermediate-risk PHL patients treated with chemoradiation therapy as per the children's oncology group (COG) AHOD0031 trial. This group was able to demonstrate that total-body MTV based on four thresholds (MTV20% SUVmax, MTV1.5Lv, MTV1.5Lv + 2SD, and MTV2BP) and TLG based on two thresholds (TLG60% SUVmax and TLG2BP) were significantly associated with EFS on univariate Cox regression analysis. MTV2BP could distinguish high from low tumor burden and showed the highest sensitivity (91%) and specificity (60%) in identifying the 5-year EFS. This significance was retained on multivariate analysis (p = 0.012) after controlling for other prognostically influential covariates, such as disease bulk and response to chemotherapy.[19] A study from China by Zhou et al on 47 PHL subjects, with a median follow-up of 36 months, showed that unlike SUVmax, MTV and TLG in the baseline PET/CT of patients with disease progression were significantly higher than those without disease progression (p = 0.036 for MTV and p = 0.015 for TLG). However, on multivariate analysis, only TLG was found to be an independent prognostic factor for PFS (p = 0.021).[30] Lopci and Mascarin analyzed the usefulness of MTV and TLG in the prediction of outcomes in 150 children with high-risk PHL (stage III/IV disease) who were treated on the EuroNet-PHL-C2 protocol.[31] They were able to show that a high baseline tumor burden (defined as TLG >1,841) correlated with EFS. There was a statistically significant difference for all baseline parameters and treatment evaluation at early response assessment PET/CT (interim PET) between adequate and inadequate responders (p < 0.05), with logistic regression confirming significant association for MTV (p = 0.008) and TLG (p = 0.009).[31]

The difference between varying study groups may be related to sample size and subject characteristics. MTV in children, unlike in adults, could be significantly influenced by the proportion of the tumor burden in relation to the body weight. This has not been factored in by most pediatric studies, despite being an obvious confounder.[20] Studies have also shown that liver SUVmean and liver SUVmax may show variation with age, which may result in variation in MTV calculation in different age groups as well.[32] The other confounders that have been studied are blood glucose levels during the PET/CT scan, differential uptake time, contrast decay, and lack of standardization/consensus in tumor boundary assessment.[12] [16] [17] The differences in ethnicity, coexisting comorbidities in the recruited subjects, differences in definitions of treatment responders, and median follow-up times postinterim PET/CT[12] [19] [20] [25] [33] could also contribute to interstudy variations. However, as most studies, like ours, were single-center retrospective studies on small sample cohorts, we expect them to have lower intra and intercenter variability in technique as well as interpretation of PET/CT as compared to large multicenter trials.[31]

In our study, diagnostic ¹⁸F-FDG PET/CT MTV and SUVmax increased with advanced stages of the disease. Diagnostic PET/CT MTV was a better correlate than SUVmax in delineating stage and TGs. However, we found that diagnostic PET/CT MTV or SUVmax alone was not sensitive or specific enough in prognosticating treatment response or EFS (relapse or death).

We note as a limitation that in our study diagnostic and interim PET/CT TLG was not performed. Interim PET/CT MTV and SUVmax were also not analyzed against outcomes. However, given that treatment is modified (“response adapted”) based on the interim PET/CT results, the true predictive/prognostic value derived from the interim PET/CT MTV and SUVmax values in HL is difficult to predict.[34]

Conclusion and Future Directions

In our PHL cohort of 61 subjects, we used diagnostic PET/CT MTV and SUVmax values to assess their discriminating ability among staging and TG allocation, as well as their ability in predicting treatment response, EFS, and OS. Baseline PET/CT MTV was a better correlate than SUVmax in delineating stage and TGs as the difference in the value of baseline MTV showed a significant difference between each group. However, MTV in isolation, in our setting, was not sensitive or specific enough in prognosticating treatment response, EFS, or OS. Future studies should involve larger sample sizes with validated clinico-biochemical parameters such as Childhood Hodgkin International Prognostic Score[35] in addition to PET/CT parameters to more accurately prognosticate outcomes in PHL.

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