Radiotherapy boost in patients with hypoxic lesions identified by 18F-FMISO PET/CT in non-small-cell lung carcinoma: can we expect a better survival outcome without toxicity? [RTEP5 long-term follow-up]

Véra, Pierre; Mihailescu, Sorina-Dana; Lequesne, Justine; Modzelewski, Romain; Bohn, Pierre; Hapdey, Sébastien; Pépin, Louis-Ferdinand; Dubray, Bernard; Chaumet-Riffaud, Philippe; Decazes, Pierre; Thureau, S.

doi:10.1007/s00259-019-04285-9

Cited by 43 publications

(24 citation statements)

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“…Radiotherapy, alone or in combination with systemic therapies are the mainstay of treatment in patients diagnosed with stage I-IV NSCLC, and with advances in radiotherapy planning and delivery, a remarkable improvement in local tumor control has been seen 10 , 11 . It is hypothesized that imaging approaches for detecting the multiple factors that influence radioresistance would make further impact.…”

Section: Introductionmentioning

confidence: 99%

Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [¹⁸F]fluoromethyl-(1,2-²H₄)-choline

Dubash¹,

Inglese²,

Mauri³

et al. 2020

Theranostics

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Purpose : The spatio-molecular distribution of choline and its metabolites in tumors is highly heterogeneous. Due to regulation of choline metabolism by hypoxic transcriptional signaling and other survival factors, we envisage that detection of such heterogeneity in patient tumors could provide the basis for advanced localized therapy. However, non-invasive methods to assess this phenomenon in patients are limited. We investigated such heterogeneity in Non-Small Cell Lung Cancer (NSCLC) with [ 18 F]fluoromethyl-(1,2- 2 H 4 ) choline ([ 18 F]D4-FCH) and positron emission tomography/computed tomography (PET/CT). Experimental design : [ 18 F]D4-FCH (300.5±72.9MBq [147.60-363.6MBq]) was administered intravenously to 17 newly diagnosed NSCLC patients. PET/CT scans were acquired concurrently with radioactive blood sampling to permit mathematical modelling of blood-tissue transcellular rate constants. Comparisons were made with biopsy-derived choline kinase-α (CHKα) expression and diagnostic [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) scans. Results : Oxidation of [ 18 F]D4-FCH to [ 18 F]D4-fluorobetaine was suppressed (48.58±0.31% parent at 60 min) likely due to the deuterium isotope effect embodied within the design of the radiotracer. Early (5 min) and late (60 min) images showed specific uptake of tracer in all 51 lesions (tumors, lymph nodes and metastases) from 17 patients analyzed. [ 18 F]D4-FCH-derived uptake (SUV 60max ) in index primary lesions (n=17) ranged between 2.87-10.13; lower than that of [ 18 F]FDG PET [6.89-22.64]. Mathematical modelling demonstrated net irreversible uptake of [ 18 F]D4-FCH at steady-state, and parametric mapping of the entire tumor showed large intratumorally heterogeneity in radiotracer retention, which is likely to have influenced correlations with biopsy-derived CHKα expression. Conclusions : [ 18 F]D4-FCH is detectable in NSCLC with large intratumorally heterogeneity, which could be exploited in the future for targeting localized therapy.

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Section: Introductionmentioning

confidence: 99%

Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [¹⁸F]fluoromethyl-(1,2-²H₄)-choline

Dubash¹,

Inglese²,

Mauri³

et al. 2020

Theranostics

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“…Targeted molecular imaging of hypoxia offers an attractive, minimally invasive, and repeatable assessment of hypoxia and its reversibility (34). Functional PET/CT hypoxia imaging can directly display areas and degrees of tumor hypoxia (35)(36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

Intratumoral Injection of Anlotinib Hydrogel Combined With Radiotherapy Reduces Hypoxia in Lewis Lung Carcinoma Xenografts: Assessment by Micro Fluorine-18-fluoromisonidazole Positron Emission Tomography/Computed Tomography Hypoxia Imaging

Gao

Jiang

et al. 2021

Front. Oncol.

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Hypoxia is a common feature of solid tumors that increases tumor invasiveness and resistance to radiotherapy (RT) and chemotherapy. Local application of anlotinib (AL) might increase the regulation of new blood vessel growth and improve tumor hypoxia in RT. Therefore, it is essential to fully understand the drug delivery system of AL. Herein, we applied hypoxia imaging using micro fluorine-18-fluoromisonidazole positron emission tomography/computed tomography (micro 18F-FMISO PET/CT) to assess responses to intratumoral injections of an AL hydrogel (AL-HA-Tyr) combined with RT in mice bearing Lewis lung carcinoma (LLC). We formed AL-HA-Tyr by encapsulating AL with hyaluronic acid-tyramine (HA-Tyr) conjugates via the oxidative coupling of tyramine moieties catalyzed by H2O2 and horseradish peroxidase. AL-HA-Tyr restrained the proliferation of human umbilical endothelial cells (HUVECs) in colony formation assays in vitro (p < 0.001). We established a subcutaneous LLC xenograft model using C57BL/6J mice that were randomly assigned to six groups that were treated with AL, HA-Tyr, AL-HA-Tyr, RT, and RT+AL-HA-Tyr, or untreated (controls). Tumor volume and weight were dynamically measured. Post treatment changes in hypoxia were assessed in some mice using micro 18F-FMISO PET/CT, and survival was assessed in others. We histopathologically examined toxicity in visceral tissues and Ki-67, VEGF-A, γ-H2AX, and HIF-1α expression using immunohistochemistry. Direct intratumoral injections of AL-HA-Tyr exerted anti-tumor effects and improved hypoxia like orally administered AL (p > 0.05), but reduced visceral toxicity and prolonged survival. The uptake of 18F-FMISO did not significantly differ among the AL, AL-HA-Tyr, and RT+AL-HA-Tyr treated groups. Compared with the other agents, RT+AL-HA-Tyr decreased HIF-1α, Ki67, and VEGF-A expression, and increased γ-H2AX levels in tumor cells. Overall, compared with AL and AL-HA-Tyr, RT+AL-HA-Tyr improved tumor hypoxia, enhanced anti-tumor effects, and prolonged the survival of mice bearing LLC.

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“…In their study of 54 patients, they modified the radiation dose from the standard dose (66 Gy) used for the FMISO-negative patients to a high dose (up to 86 Gy) for FMISO-positive patients. They observed the dose escalation’s failure to improve the prognosis, but they later reported additional data in which the radiotherapy boost seemed to improve the FMISO-positive patients’ overall survival by 11.2 months [64].…”

Section: The Clinical Usefulness Of Fmisomentioning

confidence: 99%

The Roles of Hypoxia Imaging Using 18F-Fluoromisonidazole Positron Emission Tomography in Glioma Treatment

Hirata

Yamaguchi

Shiga

et al. 2019

JCM

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Glioma is the most common malignant brain tumor. Hypoxia is closely related to the malignancy of gliomas, and positron emission tomography (PET) can noninvasively visualize the degree and the expansion of hypoxia. Currently, 18F-fluoromisonidazole (FMISO) is the most common radiotracer for hypoxia imaging. The clinical usefulness of FMISO PET has been established; it can distinguish glioblastomas from lower-grade gliomas and can predict the microenvironment of a tumor, including necrosis, vascularization, and permeability. FMISO PET provides prognostic information, including survival and treatment response information. Because hypoxia decreases a tumor’s sensitivity to radiation therapy, dose escalation to an FMISO-positive volume is an attractive strategy. Although this idea is not new, an insufficient amount of evidence has been obtained regarding this concept. New tracers for hypoxia imaging such as 18F-DiFA are being tested. In the future, hypoxia imaging will play an important role in glioma management.

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Radiotherapy boost in patients with hypoxic lesions identified by 18F-FMISO PET/CT in non-small-cell lung carcinoma: can we expect a better survival outcome without toxicity? [RTEP5 long-term follow-up]

Cited by 43 publications

References 20 publications

Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [¹⁸F]fluoromethyl-(1,2-²H₄)-choline

Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [¹⁸F]fluoromethyl-(1,2-²H₄)-choline

Intratumoral Injection of Anlotinib Hydrogel Combined With Radiotherapy Reduces Hypoxia in Lewis Lung Carcinoma Xenografts: Assessment by Micro Fluorine-18-fluoromisonidazole Positron Emission Tomography/Computed Tomography Hypoxia Imaging

The Roles of Hypoxia Imaging Using 18F-Fluoromisonidazole Positron Emission Tomography in Glioma Treatment

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Radiotherapy boost in patients with hypoxic lesions identified by 18F-FMISO PET/CT in non-small-cell lung carcinoma: can we expect a better survival outcome without toxicity? [RTEP5 long-term follow-up]

Cited by 43 publications

References 20 publications

Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [18F]fluoromethyl-(1,2-2H4)-choline

Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [18F]fluoromethyl-(1,2-2H4)-choline

Intratumoral Injection of Anlotinib Hydrogel Combined With Radiotherapy Reduces Hypoxia in Lewis Lung Carcinoma Xenografts: Assessment by Micro Fluorine-18-fluoromisonidazole Positron Emission Tomography/Computed Tomography Hypoxia Imaging

The Roles of Hypoxia Imaging Using 18F-Fluoromisonidazole Positron Emission Tomography in Glioma Treatment

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Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [¹⁸F]fluoromethyl-(1,2-²H₄)-choline

Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [¹⁸F]fluoromethyl-(1,2-²H₄)-choline