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Monitoring early response to chemoradiotherapy with 18F-FMISO dynamic PET in head and neck cancer.

ABSTRACT: PURPOSE:There is growing recognition that biologic features of the tumor microenvironment affect the response to cancer therapies and the outcome of cancer patients. In head and neck cancer (HNC) one such feature is hypoxia. We investigated the utility of 18F-fluoromisonidazole (FMISO) dynamic positron emission tomography (dPET) for monitoring the early microenvironmental response to chemoradiotherapy in HNC. EXPERIMENTAL DESIGN:Seventy-two HNC patients underwent FMISO dPET scans in a customized immobilization mask (0-30 min dynamic acquisition, followed by 10 min static acquisitions starting at ?95 min and ?160 min post-injection) at baseline and early into treatment where patients have already received one cycle of chemotherapy and anywhere from five to ten fractions of 2 Gy per fraction radiation therapy. Voxelwise pharmacokinetic modeling was conducted using an irreversible one-plasma two-tissue compartment model to calculate surrogate biomarkers of tumor hypoxia (k 3 and Tumor-to-Blood Ratio (TBR)), perfusion (K 1 ) and FMISO distribution volume (DV). Additionally, Tumor-to-Muscle Ratios (TMR) were derived by visual inspection by an experienced nuclear medicine physician, with TMR > 1.2 defining hypoxia. RESULTS:One hundred and thirty-five lesions in total were analyzed. TBR, k 3 and DV decreased on early response scans, while no significant change was observed for K 1 . The k 3 -TBR correlation decreased substantially from baseline scans (Pearson's r = 0.72 and 0.76 for mean intratumor and pooled voxelwise values, respectively) to early response scans (Pearson's r = 0.39 and 0.40, respectively). Both concordant and discordant examples of changes in intratumor k 3 and TBR were identified; the latter partially mediated by the change in DV. In 13 normoxic patients according to visual analysis (all having lesions with TMR = 1.2), subvolumes were identified where k 3 indicated the presence of hypoxia. CONCLUSION:Pharmacokinetic modeling of FMISO dynamic PET reveals a more detailed characterization of the tumor microenvironment and assessment of response to chemoradiotherapy in HNC patients than a single static image does. In a clinical trial where absence of hypoxia in primary tumor and lymph nodes would lead to de-escalation of therapy, the observed disagreement between visual analysis and pharmacokinetic modeling results would have affected patient management in <20% cases. While simple static PET imaging is easily implemented for clinical trials, the clinical applicability of pharmacokinetic modeling remains to be investigated.

SUBMITTER: Grkovski M

PROVIDER: S-EPMC6563902 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Monitoring early response to chemoradiotherapy with <sup>18</sup>F-FMISO dynamic PET in head and neck cancer.

Grkovski Milan M Lee Nancy Y NY Schöder Heiko H Carlin Sean D SD Beattie Bradley J BJ Riaz Nadeem N Leeman Jonathan E JE O'Donoghue Joseph A JA Humm John L JL

European journal of nuclear medicine and molecular imaging 20170524 10

<h4>Purpose</h4>There is growing recognition that biologic features of the tumor microenvironment affect the response to cancer therapies and the outcome of cancer patients. In head and neck cancer (HNC) one such feature is hypoxia. We investigated the utility of <sup>18</sup>F-fluoromisonidazole (FMISO) dynamic positron emission tomography (dPET) for monitoring the early microenvironmental response to chemoradiotherapy in HNC.<h4>Experimental design</h4>Seventy-two HNC patients underwent FMISO ...[more]

PMID: 28540417

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Project description:Conventional MRI plays a key role in the management of patients with high-grade glioma, but multiparametric MRI and PET tracers could provide further information to better characterize tumor metabolism and heterogeneity by identifying regions having a high risk of recurrence. In this study, we focused on proliferation, hypervascularization, and hypoxia, all factors considered indicative of poor prognosis. They were assessed by measuring uptake of 18F-3'-deoxy-3'-18F-fluorothymidine (18F-FLT), relative cerebral blood volume (rCBV) maps, and uptake of 18F-fluoromisonidazole (18F-FMISO), respectively. For each modality, the volumes and high-uptake subvolumes (hot spots) were semiautomatically segmented and compared with the contrast enhancement (CE) volume on T1-weighted gadolinium-enhanced (T1w-Gd) images, commonly used in the management of patients with glioblastoma. Methods: Dynamic susceptibility contrast-enhanced MRI (31 patients), 18F-FLT PET (20 patients), or 18F-FMISO PET (20 patients), for a total of 31 patients, was performed on preoperative glioblastoma patients. Volumes and hot spots were segmented on SUV maps for 18F-FLT PET (using the fuzzy locally adaptive bayesian algorithm) and 18F-FMISO PET (using a mean contralateral image + 3.3 SDs) and on rCBV maps (using a mean contralateral image + 1.96 SDs) for dynamic susceptibility contrast-enhanced MRI and overlaid on T1w-Gd images. For each modality, the percentages of the peripheral volumes and the peripheral hot spots outside the CE volume were calculated. Results: All tumors showed highly proliferated, hypervascularized, and hypoxic regions. The images also showed pronounced heterogeneity of both tracers regarding their uptake and rCBV maps, within each individual patient. Overlaid volumes on T1w-Gd images showed that some proliferative, hypervascularized, and hypoxic regions extended beyond the CE volume but with marked differences between patients. The ranges of peripheral volume outside the CE volume were 1.6%-155.5%, 1.5%-89.5%, and 3.1%-78.0% for 18F-FLT, rCBV, and 18F-FMISO, respectively. All patients had hyperproliferative hot spots outside the CE volume, whereas hypervascularized and hypoxic hot spots were detected mainly within the enhancing region. Conclusion: Spatial analysis of multiparametric maps with segmented volumes and hot spots provides valuable information to optimize the management and treatment of patients with glioblastoma.

Project description:PurposeTo investigate the utility of [18F]FDG-PET as an imaging biomarker for pathological response early upon neoadjuvant immune checkpoint blockade (ICB) in patients with head and neck squamous cell carcinoma (HNSCC) before surgery.MethodsIn the IMCISION trial (NCT03003637), 32 patients with stage II‒IVb HNSCC were treated with neoadjuvant nivolumab with (n = 26) or without (n = 6) ipilimumab (weeks 1 and 3) before surgery (week 5). [18F]FDG-PET/CT scans were acquired at baseline and shortly before surgery in 21 patients. Images were analysed for SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG). Major and partial pathological responses (MPR and PPR, respectively) to immunotherapy were identified based on the residual viable tumour in the resected primary tumour specimen (≤ 10% and 11-50%, respectively). Pathological response in lymph node metastases was assessed separately. Response for the 2 [18F]FDG-PET-analysable patients who did not undergo surgery was determined clinically and per MR-RECIST v.1.1. A patient with a primary tumour MPR, PPR, or primary tumour MR-RECIST-based response upon immunotherapy was called a responder.ResultsMedian ΔSUVmax, ΔSUVmean, ΔMTV, and ΔTLG decreased in the 8 responders and were significantly lower compared to the 13 non-responders (P = 0.05, P = 0.002, P < 0.001, and P < 0.001). A ΔMTV or ΔTLG of at least - 12.5% detected a primary tumour response with 95% accuracy, compared to 86% for the EORTC criteria. None of the patients with a ΔTLG of - 12.5% or more at the primary tumour site developed a relapse (median FU 23.0 months since surgery). Lymph node metastases with a PPR or MPR (5 metastases in 3 patients) showed a significant decrease in SUVmax (median - 3.1, P = 0.04). However, a SUVmax increase (median + 2.1) was observed in 27 lymph nodes (in 11 patients), while only 13 lymph nodes (48%) contained metastases in the corresponding neck dissection specimen.ConclusionsPrimary tumour response assessment using [18F]FDG-PET-based ΔMTV and ΔTLG accurately identifies pathological responses early upon neoadjuvant ICB in HNSCC, outperforming the EORTC criteria, although pseudoprogression is seen in neck lymph nodes. [18F]FDG-PET could, upon validation, select HNSCC patients for response-driven treatment adaptation in future trials.Trial registrationhttps://www.Clinicaltrialsgov/ , NCT03003637, December 28, 2016.

Project description:IntroductionThe presence of hypoxia in head-and-neck squamous cell carcinoma is a negative prognostic factor. PET imaging with [18F] HX4 can be used to visualize hypoxia, but it is currently unknown how this correlates with prognosis. We investigated the prognostic value of [18F] HX4 PET imaging in patients treated with definitive radio(chemo)therapy (RTx).Materials and methodsWe analyzed 34 patients included in two prospective clinical trials (NCT01347281, NCT01504815). Static [18F] HX4 PET-CT images were collected, both pre-treatment (median 4 days before start RTx, range 1-16), as well as during RTx (median 13 days after start RTx, range 3-17 days). Static uptake at both time points (n = 33 pretreatment, n = 28 during RTx) and measured changes in hypoxic fraction (HF) and hypoxic volume (HV) (n = 27 with 2 time points) were analyzed. Univariate cox analyses were done for local progression free survival (PFS) and overall survival (OS) at both timepoints. Change in uptake was analyzed by comparing outcome with Kaplan-Meier curves and log-rank test between patients with increased and decreased/stable hypoxia, similarly between patients with and without residual hypoxia (rHV = ratio week 2/baseline HV with cutoff 0.2). Voxelwise Spearman correlation coefficients were calculated between normalized [18F] HX4 PET uptake at baseline and week 2.ResultsAnalyses of static images showed no prognostic value for [18F] HX4 uptake. Analysis of dynamic changes showed that both OS and local PFS were significantly shorter (log-rank P < 0.05) in patients with an increase in HV during RTx and OS was significantly shorter in patients with rHV, with no correlation to HPV-status. The voxel-based correlation to evaluate spatial distribution yielded a median Spearman correlation coefficient of 0.45 (range 0.11-0.65).ConclusionThe change of [18F] HX4 uptake measured on [18F] HX4 PET early during treatment can be considered for implementation in predictive models. With these models patients with a worse prognosis can be selected for treatment intensification.

Project description:BackgroundWhile [18F]fluoromisonidazole (FMISO), a representative PET tracer to detect hypoxia, is reported to be able to prospect the prognosis after treatment for various types of cancers, the relation is unclear for pancreatic cancer. The aim of this study is to assess the feasibility of [18F]FMISO PET/CT as a preoperative prognostic factor in patients with pancreatic cancer.MethodsPatients with pancreatic cancer who had been initially planned for surgery received [18F]FMISO PET/CT. Peak standardized uptake value (SUV) of the pancreatic tumor was divided by SUVpeak of the aorta, and tumor blood ratio using SUVpeak (TBRpeak) was calculated. After preoperative examination, surgeons finally decided the operability of the patients. TBRpeak was compared with hypoxia-inducible factor (HIF)-1? immunohistochemistry when the tissues were available. Furthermore, correlation of TBRpeak with the recurrence-free survival and the overall survival were evaluated by Kaplan-Meyer methods.ResultsWe analyzed 25 patients with pancreatic adenocarcinoma (11 women and 14 men, median age, 73?years; range, 58-81?years), and observed for 39-1101?days (median, 369?days). Nine cases (36.0%) were identified as visually positive of pancreatic cancer on [18F]FMISO PET/CT images. TBRpeak of the negative cases was significantly lower than that of the positive cases (median 1.08, interquartile range (IQR) 1.02-1.15 vs median 1.50, IQR 1.25-1.73, p?<?0.001), and the cutoff TBRpeak was calculated as 1.24. Five patients were finally considered inoperable. There was no significant difference in TBRpeak of inoperable and operable patients (median 1.48, IQR 1.06-1.98 vs median 1.12, IQR 1.05-1.21, p?=?0.10). There was no significant difference between TBRpeak and HIF-1? expression (p?=?0.22). The patients were dichotomized by the TBRpeak cutoff, and the higher group showed significantly shorter recurrence-free survival than the other (median 218 vs 441?days, p?=?0.002). As for overall survival of 20 cases of operated patients, the higher TBRpeak group showed significantly shorter overall survival than the other (median survival, 415 vs >?1000?days, p?=?0.04).Conclusions[18F]FMISO PET/CT has the possibility to be a preoperative prognostic factor in patients with pancreatic cancer.

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Dataset Information

Monitoring early response to chemoradiotherapy with 18F-FMISO dynamic PET in head and neck cancer.

Publications

Monitoring early response to chemoradiotherapy with <sup>18</sup>F-FMISO dynamic PET in head and neck cancer.

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