Abstract
Introduction
Functional metabolic imaging with 18 F-fluorodeoxyglucose positron emission tomography combined with computed tomography (PET/CT) is considered the gold standard for staging and response assessment in classical Hodgkin Lymphoma (cHL). Total metabolic tumor volume (TMTV) is a new functional and quantitative parameter extracted from the baseline PET/CT that has been reported as a strong predictor of outcome in HL. This review aims to describe the available methods used to perform TMTV calculation and discuss the reported published data and future direction about TMTV application in cHL.
Methods
A computerized search of PubMed was conducted to find relevant studies published regarding baseline TMTV in HL between 2010 and 2021. The following search terms were used: “{Hodgkin[title]} and {positron[title] or PET[title] or metabolic[title]) not “non-Hodgkin”[title]”. Twenty-six eligible studies were selected. We described and summarized the results in this review article.
Results
The optimal cut-off for predicting risk using TMTV depends on the selected TMTV segmentation method, population characteristics, and treatment. A high TMTV at baseline PET/CT was associated with worse progression-free survival (PFS) and overall survival (OS) in early-stage cHL. High baseline TMTV was also a predictor of treatment failure after autologous stem cell transplant in relapsed and/or refractory cHL. In advanced-stage HL treated with eBEACOPP protocol, there was no statistically significant association between high TMTV value and reduction in PFS or OS. In the pediatric population studies, a high baseline TMTV was associated with worse outcomes.
Conclusion
There is no agreement about which is the best method for TMTV segmentation; however, regardless of the chosen method, it may predict prognosis with comparable precision. Risk stratification using PET/CT quantitative parameters in addition to baseline clinical parameters could be a future direction in PET/CT tailored strategy in cHL.
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Data availability
Data sharing does not apply to this article as no datasets were generated or analyzed during the current study.
Abbreviations
- FDG:
-
18F-fluorodeoxyglucose
- ABVD:
-
Adriamycin, bleomycin, vinblastine, and dacarbazine
- ABVE-PC:
-
Doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide
- AS:
-
Advanced stage
- AHCT:
-
Autologous hematopoietic cell transplantation
- BV:
-
Brentuximab–vedotin
- cHL:
-
Classical Hodgkin lymphoma
- CT:
-
Computed tomography
- eBEACOPP:
-
Dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone
- DS:
-
Deauville scale
- ES:
-
Early stage
- EFS:
-
Event-free survival
- F:
-
Favorable
- FFP:
-
Freedom from progression
- iPET:
-
Interim-PET
- IPS:
-
International prognosis score
- MRD:
-
Minimal residual disease
- NPV:
-
Negative predictive value
- OS:
-
Overall survival
- PET:
-
Positron emission tomography
- PFS:
-
Progression-free survival
- PPV:
-
Positive predictive value
- r/r :
-
Refractory and/or relapsed disease
- ctDNA:
-
Tumor circulating DNA
- TLG:
-
Total lesion glycolysis
- TMTV:
-
Total metabolic tumor volume
- U:
-
Unfavorable
- VOI:
-
Volume of interest
- SUV:
-
Standard uptake value
- SD:
-
Standard deviation
References
Mottok A, Steidl C (2018) Biology of classical Hodgkin lymphoma: implications for prognosis and novel therapies. Blood 131:1654–1665. https://doi.org/10.1182/blood-2017-09-772632
Illidge TM, Phillips EH, Counsell N et al (2020) Maximum tumor diameter is associated with event-free survival in PET-negative patients with stage I/IIA Hodgkin lymphoma. Blood Adv 4:203–206. https://doi.org/10.1182/bloodadvances.2019001023
Lopez-Alonso R, Qi S, Mashiach T et al (2021) The presence of a bulky mediastinal mass of 7 cm or greater in diameter confers an adverse prognosis to patients with advanced Hodgkin lymphoma in case of negative interim PET/CT. Leuk Lymphoma 62:1313–1324. https://doi.org/10.1080/10428194.2021.1872069
Zaucha JM, Chauvie S, Zaucha R et al (2019) The role of PET/CT in the modern treatment of Hodgkin lymphoma. Cancer Treat Rev 77:44–56. https://doi.org/10.1016/j.ctrv.2019.06.002
Kostakoglu L, Gallamini A (2013) Interim 18F-FDG PET in Hodgkin lymphoma: would PET-adapted clinical trials lead to a paradigm shift? J Nucl Med 54:1082–1093. https://doi.org/10.2967/jnumed.113.120451
Fuchs M, Goergen H, Kobe C et al (2019) Positron emission tomography-guided treatment in early-stage favorable Hodgkin lymphoma: final results of the international, randomized phase III HD16 trial by the German Hodgkin Study Group. J Clin Oncol 37:2835–2845. https://doi.org/10.1200/JCO.19.00964
Straus DJ, Jung S-H, Pitcher B et al (2018) CALGB 50604: risk-adapted treatment of nonbulky early-stage Hodgkin lymphoma based on interim PET. Blood 132:1013–1021. https://doi.org/10.1182/blood-2018-01-827246
Barrington SF, Phillips EH, Counsell N et al (2019) Positron emission tomography score has greater prognostic significance than pretreatment risk stratification in early-stage Hodgkin lymphoma in the UK RAPID study. J Clin Oncol 37:1732–1741. https://doi.org/10.1200/JCO.18.01799
Picardi M, Fonti R, Della Pepa R et al (2020) 2-deoxy-2[F-18] fluoro-d-glucose positron emission tomography Deauville scale and core-needle biopsy to determine successful management after six doxorubicin, bleomycin, vinblastine and dacarbazine cycles in advanced-stage Hodgkin lymphoma. Eur J Cancer 132:85–97. https://doi.org/10.1016/j.ejca.2020.03.008
Borchmann P, Goergen H, Kobe C et al (2017) PET-guided treatment in patients with advanced-stage Hodgkin’s lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group. The Lancet 390:2790–2802. https://doi.org/10.1016/S0140-6736(17)32134-7
Milgrom SA, Elhalawani H, Lee J et al (2019) A PET radiomics model to predict refractory mediastinal Hodgkin lymphoma. Sci Rep 9:1322. https://doi.org/10.1038/s41598-018-37197-z
Yang S, Qiu L, Huang X et al (2020) The prognostic significance of ΔSUVmax assessed by PET/CT scan after 2 cycles of chemotherapy in patients with classic Hodgkin’s lymphoma. Ann Hematol 99:293–299. https://doi.org/10.1007/s00277-019-03892-8
Cottereau A-S, Versari A, Loft A et al (2018) Prognostic value of baseline metabolic tumor volume in early-stage Hodgkin lymphoma in the standard arm of the H10 trial. Blood 131:1456–1463. https://doi.org/10.1182/blood-2017-07-795476
Engert A, Haverkamp H, Kobe C et al (2012) Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial. Lancet 379:1791–1799. https://doi.org/10.1016/S0140-6736(11)61940-5
Villa D, Sehn LH, Aquino-Parsons C et al (2018) Interim PET-directed therapy in limited-stage Hodgkin lymphoma initially treated with ABVD. Haematologica 103:e590–e593. https://doi.org/10.3324/haematol.2018.196782
Akhtar S, Al-Sugair AS, Abouzied M et al (2013) Pre-transplant FDG-PET-based survival model in relapsed and refractory Hodgkin’s lymphoma: outcome after high-dose chemotherapy and auto-SCT. Bone Marrow Transplant 48:1530–1536. https://doi.org/10.1038/bmt.2013.88
Baues C, Goergen H, Fuchs M et al (2021) Involved-field radiation therapy prevents recurrences in the early stages of Hodgkin lymphoma in PET-negative patients after ABVD chemotherapy: relapse analysis of GHSG phase 3 HD16 trial. Int J Radiat Oncol 111:900–906. https://doi.org/10.1016/j.ijrobp.2021.07.1697
Biggi A, Bergesio F, Chauvie S et al (2017) Concomitant semi-quantitative and visual analysis improves the predictive value on treatment outcome of interim 18F-fluorodeoxyglucose/positron emission tomography in advanced Hodgkin lymphoma. Q J Nucl Med Mol Imaging. https://doi.org/10.23736/S1824-4785.17.02993-4
Decazes P, Camus V, Bohers E et al (2020) Correlations between baseline 18F-FDG PET tumour parameters and circulating DNA in diffuse large B cell lymphoma and Hodgkin lymphoma. EJNMMI Res 10:120. https://doi.org/10.1186/s13550-020-00717-y
Georgi TW, Kurch L, Hasenclever D et al (2020) Quantitative assessment of interim PET in Hodgkin lymphoma: an evaluation of the qPET method in adult patients in the RAPID trial. PLoS One 15:e0231027. https://doi.org/10.1371/journal.pone.0231027
Hussien AEM, Furth C, Schönberger S et al (2015) FDG-PET Response prediction in pediatric Hodgkin’s lymphoma: impact of metabolically defined tumor volumes and individualized SUV measurements on the positive predictive value. Cancers 7:287–304. https://doi.org/10.3390/cancers7010287
Isik EG, Kuyumcu S, Kebudi R et al (2017) Prediction of outcome in pediatric Hodgkin lymphoma based on interpretation of 18FDG-PET/CT according to ΔSUVmax, Deauville 5-point scale and IHP criteria. Ann Nucl Med 31:660–668. https://doi.org/10.1007/s12149-017-1196-x
Kahle XU, Montes de Jesus FM, Kwee TC et al (2019) Relationship between semi-quantitative 18F-fluorodeoxyglucose positron emission tomography metrics and necrosis in classical Hodgkin lymphoma. Sci Rep 9:11073. https://doi.org/10.1038/s41598-019-47453-5
Kanoun S, Tal I, Berriolo-Riedinger A et al (2015) Influence of software tool and methodological aspects of total metabolic tumor volume calculation on baseline [18F]FDG PET to predict survival in Hodgkin lymphoma. PLoS One 10:e0140830. https://doi.org/10.1371/journal.pone.0140830
Kedmi M, Khaustov P, Ribakovsy E et al (2021) Outcomes related to FDG-PET-CT response in patients with Hodgkin lymphoma treated with Brentuximab-Vedotin at relapse or consolidation. Clin Lymphoma Myeloma Leuk. https://doi.org/10.1016/j.clml.2021.07.006
Lawal IO, Ankrah AO, Popoola GO et al (2018) 18F-FDG-PET metabolic metrics and International Prognostic Score for risk assessment in HIV-infected patients with Hodgkin lymphoma. Nucl Med Commun 39:1005–1012. https://doi.org/10.1097/MNM.0000000000000905
Lue K-H, Wu Y-F, Liu S-H et al (2019) Prognostic value of pretreatment radiomic features of 18F-FDG PET in patients with Hodgkin lymphoma. Clin Nucl Med 44:e559–e565. https://doi.org/10.1097/RLU.0000000000002732
Milgrom SA, Kim J, Chirindel A et al (2021) Prognostic value of baseline metabolic tumor volume in children and adolescents with intermediate-risk Hodgkin lymphoma treated with chemo-radiation therapy: FDG-PET parameter analysis in a subgroup from COG AHOD0031. Pediatr Blood Cancer. https://doi.org/10.1002/pbc.29212
Procházka V, Gawande RS, Cayci Z et al (2018) Positron emission tomography-based assessment of metabolic tumor volume predicts survival after autologous hematopoietic cell transplantation for Hodgkin lymphoma. Biol Blood Marrow Transplant 24:64–70. https://doi.org/10.1016/j.bbmt.2017.09.006
Ribeiro T, Marques A, Ferreira G et al (2021) Semi-quantitative analysis of interim 18F-FDG PET is superior in predicting outcome in Hodgkin lymphoma patients compared to visual analysis. Rev Esp Med Nucl E Imagen Mol Engl Ed 40:281–286. https://doi.org/10.1016/j.remnie.2020.06.016
Rogasch JMM, Hundsdoerfer P, Hofheinz F et al (2018) Pretherapeutic FDG-PET total metabolic tumor volume predicts response to induction therapy in pediatric Hodgkin’s lymphoma. BMC Cancer 18:521. https://doi.org/10.1186/s12885-018-4432-4
Song M-K, Chung J-S, Lee J-J et al (2013) Metabolic tumor volume by positron emission tomography/computed tomography as a clinical parameter to determine therapeutic modality for early stage Hodgkin’s lymphoma. Cancer Sci 104:1656–1661. https://doi.org/10.1111/cas.12282
Strigari L, Attili A, Duggento A et al (2016) Quantitative analysis of basal and interim PET/CT images for predicting tumor recurrence in patients with Hodgkin’s lymphoma. Nucl Med Commun 37:16–22. https://doi.org/10.1097/MNM.0000000000000399
Weisman AJ, Kim J, Lee I et al (2020) Automated quantification of baseline imaging PET metrics on FDG PET/CT images of pediatric Hodgkin lymphoma patients. EJNMMI Phys 7:76. https://doi.org/10.1186/s40658-020-00346-3
Galvez-Carvajal L, Quero C, Casanova M et al (2021) Ability of final PET/CT to predict response to first-line treatment in real patients with classical Hodgkin lymphoma. Int J Hematol. https://doi.org/10.1007/s12185-021-03223-6
Lopci E, Burnelli R, Elia C et al (2021) Additional value of volumetric and texture analysis on FDG PET assessment in paediatric Hodgkin lymphoma: an Italian multicentric study protocol. BMJ Open 11:e041252. https://doi.org/10.1136/bmjopen-2020-041252
Kusumoto S (2020) Treatment strategy for newly diagnosed classical Hodgkin lymphoma: current achievements using interim PET-guided therapy. Rinsho Ketsueki 61(9):1244–1251. https://doi.org/10.11406/rinketsu.61.1244 (PMID: 33162522)
Bakst RL, Campbell BA, Pinnix CC (2020) PET guided therapy for early stage Hodgkin lymphoma: are we positive about a negative interim scan? Int J Radiat Oncol Biol Phys 107:12–17. https://doi.org/10.1016/j.ijrobp.2020.02.635
Voltin C-A, Mettler J, Boellaard R et al (2019) Quantitative assessment of 18F-FDG PET in patients with Hodgkin lymphoma: is it significantly affected by contrast-enhanced computed tomography attenuation correction? Nucl Med Commun 40:249–257. https://doi.org/10.1097/MNM.0000000000000956
Zijlstra JM, Boellaard R (2018) Baseline PET as prognostic marker for Hodgkin? Blood 131:3–4. https://doi.org/10.1182/blood-2017-11-812958
Procházka V, Klugar M, Bachanova V et al (2016) Comparing the accuracy of quantitative versus qualitative analyses of interim PET to prognosticate Hodgkin lymphoma: a systematic review protocol of diagnostic test accuracy. BMJ Open 6:e011729. https://doi.org/10.1136/bmjopen-2016-011729
Keraliya AR, Tirumani SH, Shinagare AB, Ramaiya NH (2015) Beyond PET/CT in Hodgkin lymphoma: a comprehensive review of the role of imaging at initial presentation, during follow-up and for assessment of treatment-related complications. Insights Imaging 6:381–392. https://doi.org/10.1007/s13244-015-0407-z
Kobe C, Kuhnert G, Kahraman D et al (2014) Assessment of tumor size reduction improves outcome prediction of positron emission tomography/computed tomography after chemotherapy in advanced-stage Hodgkin lymphoma. J Clin Oncol 32:1776–1781. https://doi.org/10.1200/JCO.2013.53.2507
Ilyas H, Mikhaeel NG, Dunn JT et al (2018) Defining the optimal method for measuring baseline metabolic tumour volume in diffuse large B cell lymphoma. Eur J Nucl Med Mol Imaging 45:1142–1154. https://doi.org/10.1007/s00259-018-3953-z
Im H-J, Bradshaw T, Solaiyappan M, Cho SY (2018) Current methods to define metabolic tumor volume in positron emission tomography: which one is better? Nucl Med Mol Imaging 52:5–15. https://doi.org/10.1007/s13139-017-0493-6
Meignan M, Sasanelli M, Casasnovas RO et al (2014) Metabolic tumour volumes measured at staging in lymphoma: methodological evaluation on phantom experiments and patients. Eur J Nucl Med Mol Imaging 41:1113–1122. https://doi.org/10.1007/s00259-014-2705-y
Schöder H, Moskowitz C (2016) Metabolic tumor volume in lymphoma: hype or hope? J Clin Oncol 34:3591–3594. https://doi.org/10.1200/JCO.2016.69.3747
Kostakoglu L, Chauvie S (2018) Metabolic tumor volume metrics in lymphoma. Semin Nucl Med 48:50–66. https://doi.org/10.1053/j.semnuclmed.2017.09.005
Akhtari M, Milgrom SA, Pinnix CC et al (2018) Reclassifying patients with early-stage Hodgkin lymphoma based on functional radiographic markers at presentation. Blood 131:84–94. https://doi.org/10.1182/blood-2017-04-773838
Barrington SF, Meignan M (2019) Time to prepare for risk adaptation in lymphoma by standardizing measurement of metabolic tumor burden. J Nucl Med 60:1096–1102. https://doi.org/10.2967/jnumed.119.227249
Moskowitz AJ, Schöder H, Gavane S et al (2017) Prognostic significance of baseline metabolic tumor volume in relapsed and refractory Hodgkin lymphoma. Blood 130:2196–2203. https://doi.org/10.1182/blood-2017-06-788877
Mikhaeel NG, Smith D, Dunn JT et al (2016) Combination of baseline metabolic tumour volume and early response on PET/CT improves progression-free survival prediction in DLBCL. Eur J Nucl Med Mol Imaging 43:1209–1219. https://doi.org/10.1007/s00259-016-3315-7
Ilyas H, Mikhaeel NG, Dunn JT et al (2018) Defining the optimal method for measuring baseline metabolic tumour volume in diffuse large B cell lymphoma. Eur J Nucl Med Mol Imaging. https://doi.org/10.1007/s00259-018-3953-z
André MPE, Girinsky T, Federico M et al (2017) Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol 35:1786–1794. https://doi.org/10.1200/JCO.2016.68.6394
Fermé C, Eghbali H, Meerwaldt JH et al (2007) Chemotherapy plus involved-field radiation in early-stage Hodgkin’s disease. N Engl J Med 357:1916–1927. https://doi.org/10.1056/NEJMoa064601
Martín-Saladich Q, Reynés-Llompart G, Sabaté-Llobera A et al (2020) Comparison of different automatic methods for the delineation of the total metabolic tumor volume in I–II stage Hodgkin lymphoma. Sci Rep 10:12590. https://doi.org/10.1038/s41598-020-69577-9
Mettler J, Müller H, Voltin C-A et al (2019) Metabolic tumor volume for response prediction in advanced-stage Hodgkin lymphoma. J Nucl Med 60:207–211. https://doi.org/10.2967/jnumed.118.210047
Gallamini A, Rambaldi A, Patti C et al (2021) Baseline metabolic tumor volume and IPS predict ABVD failure in advanced-stage Hodgkin lymphoma with a negative interim pet scan after 2 chemotherapy cycles. A retrospective analysis from the GITIL/FIL HD0607 trial. Hematol Oncol. https://doi.org/10.1002/hon.19_2879
Sureda A, Arranz R, Iriondo A et al (2001) Autologous stem-cell transplantation for Hodgkin’s disease: results and prognostic factors in 494 patients from the Grupo Español de Linfomas/Transplante Autólogo de Médula Ósea Spanish Cooperative Group. J Clin Oncol 19:1395–1404. https://doi.org/10.1200/JCO.2001.19.5.1395
Devillier R, Coso D, Castagna L et al (2012) Positron emission tomography response at the time of autologous stem cell transplantation predicts outcome of patients with relapsed and/or refractory Hodgkin’s lymphoma responding to prior salvage therapy. Haematologica 97:1073–1079. https://doi.org/10.3324/haematol.2011.056051
Guo B, Tan X, Ke Q, Cen H (2019) Prognostic value of baseline metabolic tumor volume and total lesion glycolysis in patients with lymphoma: a meta-analysis. PLoS One 14:e0210224. https://doi.org/10.1371/journal.pone.0210224
Ceriani L, Milan L, Martelli M et al (2018) Metabolic heterogeneity on baseline 18FDG-PET/CT scan is a predictor of outcome in primary mediastinal B-cell lymphoma. Blood 132:179–186. https://doi.org/10.1182/blood-2018-01-826958
Chung HH, Kang SY, Ha S et al (2016) Prognostic value of preoperative intratumoral FDG uptake heterogeneity in early stage uterine cervical cancer. J Gynecol Oncol 27:e15. https://doi.org/10.3802/jgo.2016.27.e15
Davnall F, Yip CSP, Ljungqvist G et al (2012) Assessment of tumor heterogeneity: an emerging imaging tool for clinical practice? Insights Imaging 3:573–589. https://doi.org/10.1007/s13244-012-0196-6
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Feres, C.C.P., Nunes, R.F., Teixeira, L.L.C. et al. Baseline total metabolic tumor volume (TMTV) application in Hodgkin lymphoma: a review article. Clin Transl Imaging 10, 273–284 (2022). https://doi.org/10.1007/s40336-022-00481-0
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DOI: https://doi.org/10.1007/s40336-022-00481-0