Exploratory prospective trial of hypoxia-specific PET imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer.

PURPOSE To explore in a prospective trial the prognostic value of hypoxia imaging before and during radiochemotherapy in patients with locally advanced head and neck cancer. PATIENTS AND METHODS Twenty-five patients with stage III/IV head and neck cancer were investigated with [(18)F]-fluoromisonidazole (FMISO) PET/CT at four time points during radiochemotherapy (baseline, 8-10 Gy, 18-20 Gy,50-60 Gy). FMISO PET/CT image parameters were extracted including maximum-tumour-to-background (TBR(max)) and thresholded volume at different TBR ratios. CT volume and baseline FDG-PET/CT image parameters were also included. Parameters at all time points were investigated for their prognostic value with the local-progression-free-survival endpoint (LPFS). Significance was evaluated with multivariate Cox (including clinical parameters) and Log-rank tests. RESULTS FMISO-image parameters were found to have a strong association with the LPFS endpoint, and were strongest at the week 1 and 2 time points (p = 0.023-0.048 and 0.042-0.061 respectively on multivariate Cox). Parameters measured at baseline were only significant on univariate analysis. None of the clinical parameters, and also FDG- or CT-delineated volumes, were significantly associated with LPFS. CONCLUSION This prospective, exploratory study demonstrated that FMISO-PET/CT imaging during the initial phase of treatment carries strong prognostic value. FMISO-PET/CT imaging at 1 or 2 weeks during treatment could be promising way to select patients that would benefit from hypoxia modification or dose-escalated treatment. A validation study is on-going.

[1]  C. Ling,et al.  Prospective trial incorporating pre-/mid-treatment [18F]-misonidazole positron emission tomography for head-and-neck cancer patients undergoing concurrent chemoradiotherapy. , 2009, International journal of radiation oncology, biology, physics.

[2]  Richard Laforest,et al.  Assessing Tumor Hypoxia in Cervical Cancer by PET with 60Cu-Labeled Diacetyl-Bis(N4-Methylthiosemicarbazone) , 2008, Journal of Nuclear Medicine.

[3]  Lei Dong,et al.  Adaptive radiotherapy for head-and-neck cancer: initial clinical outcomes from a prospective trial. , 2012, International journal of radiation oncology, biology, physics.

[4]  M. Schwaiger,et al.  Hypoxia imaging with FAZA-PET and theoretical considerations with regard to dose painting for individualization of radiotherapy in patients with head and neck cancer. , 2007, International journal of radiation oncology, biology, physics.

[5]  T K Lewellen,et al.  Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients. , 1996, International journal of radiation oncology, biology, physics.

[6]  H. Feldmann,et al.  Changes in tumor oxygenation during combined treatment with split-course radiotherapy and chemotherapy in patients with head and neck cancer. , 1998, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[7]  Liane Oehme,et al.  Automatische Volumenabgrenzung in der onkologischen PET – Bewertung eines entsprechenden Software-Werkzeugs und Vergleich mit manueller Abgrenzung anhand klinischer Datensätze , 2012 .

[8]  David L. Schwartz,et al.  Tumor Hypoxia Imaging with [F-18] Fluoromisonidazole Positron Emission Tomography in Head and Neck Cancer , 2006, Clinical Cancer Research.

[9]  Ming-fang Wang,et al.  Fully automated one-pot synthesis of [18F]fluoromisonidazole. , 2005, Nuclear medicine and biology.

[10]  M. Baumann,et al.  Prognostic Value of Radiobiological Hypoxia during Fractionated Irradiation for Local Tumor Control , 2011, Strahlentherapie und Onkologie.

[11]  Radhe Mohan,et al.  Quantification of volumetric and geometric changes occurring during fractionated radiotherapy for head-and-neck cancer using an integrated CT/linear accelerator system. , 2004, International journal of radiation oncology, biology, physics.

[12]  Daniela Thorwarth,et al.  Kinetic analysis of dynamic 18F-fluoromisonidazole PET correlates with radiation treatment outcome in head-and-neck cancer , 2005, BMC Cancer.

[13]  Johannes H Kaanders,et al.  Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: results of a phase III randomized trial. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  J. Overgaard Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck--a systematic review and meta-analysis. , 2011, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[15]  Sigrid Stroobants,et al.  Dose Painting in Radiotherapy for Head and Neck Squamous Cell Carcinoma: Value of Repeated Functional Imaging with 18F-FDG PET, 18F-Fluoromisonidazole PET, Diffusion-Weighted MRI, and Dynamic Contrast-Enhanced MRI , 2009, Journal of Nuclear Medicine.

[16]  R. Fisher,et al.  Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of Trans-Tasman Radiation Oncology Group Study 98.02. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  M. Krause,et al.  Pre-treatment number of clonogenic cells and their radiosensitivity are major determinants of local tumour control after fractionated irradiation. , 2007, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[18]  S. Welz,et al.  Hyperfractionated, accelerated chemoradiation with concurrent mitomycin-C and cisplatin in locally advanced head and neck cancer, a phase I/II study. , 2006, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[19]  J. Kaanders,et al.  ARCON: experience in 215 patients with advanced head-and-neck cancer. , 2001, International journal of radiation oncology, biology, physics.

[20]  J. Petersen,et al.  Imaging hypoxia to improve radiotherapy outcome , 2012, Nature Reviews Clinical Oncology.

[21]  Matthias Reimold,et al.  Prognostic impact of hypoxia imaging with 18F-misonidazole PET in non-small cell lung cancer and head and neck cancer before radiotherapy. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[22]  J. Steinbach,et al.  Two or four hour [¹⁸F]FMISO-PET in HNSCC. When is the contrast best? , 2010, Nuklearmedizin. Nuclear medicine.

[23]  L. Bastholt,et al.  A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85. , 1998, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[24]  Daniela Thorwarth,et al.  Modelling and simulation of [18F]fluoromisonidazole dynamics based on histology-derived microvessel maps , 2011, Physics in medicine and biology.

[25]  Kevin Harrington,et al.  An exploratory study into the role of dynamic contrast-enhanced magnetic resonance imaging or perfusion computed tomography for detection of intratumoral hypoxia in head-and-neck cancer. , 2009, International journal of radiation oncology, biology, physics.

[26]  Michael C. Joiner,et al.  Basic Clinical Radiobiology , 2009 .

[27]  Roland Bares,et al.  Hypoxia-imaging with 18F-Misonidazole and PET: Changes of kinetics during radiotherapy of head-and-neck cancer , 2007 .

[28]  M. Baumann,et al.  Radiobiological hypoxia, histological parameters of tumour microenvironment and local tumour control after fractionated irradiation. , 2010, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[29]  M. Baumann,et al.  Zwei oder vier Stunden [18F]FMISO-PET in Kopf-Hals-Karzinomen: , 2011 .

[30]  B. Beuthien-Baumann,et al.  Radiobiological hypoxia, oxygen tension, interstitial fluid pressure and relative viable tumour area in two human squamous cell carcinomas in nude mice during fractionated radiotherapy. , 2001 .

[31]  J. Lee,et al.  Segmentation of positron emission tomography images: some recommendations for target delineation in radiation oncology. , 2010, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[32]  S. Roberts,et al.  Changes in oxygenation during radiotherapy in carcinoma of the cervix. , 1999, International Journal of Radiation Oncology, Biology, Physics.

[33]  Marianne Patt,et al.  [18F]Fluoroazomycinarabinofuranoside (18FAZA) and [18F]Fluoromisonidazole (18FMISO): a comparative study of their selective uptake in hypoxic cells and PET imaging in experimental rat tumors. , 2003, Nuclear medicine and biology.

[34]  J. Overgaard,et al.  Plasma osteopontin, hypoxia, and response to the hypoxia sensitiser nimorazole in radiotherapy of head and neck cancer: results from the DAHANCA 5 randomised double-blind placebo-controlled trial. , 2005, The Lancet. Oncology.

[35]  Tomio Inoue,et al.  Assessment of tumor hypoxia by 62Cu-ATSM PET/CT as a predictor of response in head and neck cancer: a pilot study , 2011, Annals of nuclear medicine.

[36]  B. S. Sørensen,et al.  Gene expression classifier predicts for hypoxic modification of radiotherapy with nimorazole in squamous cell carcinomas of the head and neck. , 2012, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[37]  P. Wust,et al.  Hyperfractionated accelerated chemoradiation with concurrent fluorouracil-mitomycin is more effective than dose-escalated hyperfractionated accelerated radiation therapy alone in locally advanced head and neck cancer: final results of the radiotherapy cooperative clinical trials group of the German , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  F Hofheinz,et al.  Automatic volume delineation in oncological PET , 2011, Nuklearmedizin.

[39]  M. Senda,et al.  18F-fluoromisonidazole positron emission tomography before treatment is a predictor of radiotherapy outcome and survival prognosis in patients with head and neck squamous cell carcinoma , 2011, Annals of nuclear medicine.

[40]  Georgy Shakirin,et al.  Preliminary assessment of dynamic contrast-enhanced CT implementation in pretreatment FDG-PET/CT for outcome prediction in head and neck tumors , 2010, Acta radiologica.