PET/MRI in Oropharyngeal Squamous Cell Carcinoma Evaluation
PET/MRI in Oropharyngeal Squamous Cell Carcinoma Evaluation
Head and neck cancer (HNC) continues to be a significant health care problem in Taiwan and
 oropharyngeal squamous cell carcinoma (SCC) is the common subtype. With the concern of organ
 preservation in recent years, concurrent chemoradiation is the major treatment modality for
 oropharyngeal SCC. Endoscopy with biopsy serve as the main diagnostic tools in patients with
 oropharyngeal SCC. While computed tomography (CT) and magnetic resonance imaging (MRI) are
 commonly used to evaluate the tumor extent of HNC, MRI is more preferred in the oropharyngeal
 area by virtue of its high contrast resolution. With the advance of MRI technology, whole
 body MRI is now possible, and functional techniques become more feasible in the head and neck
 region, including diffusion-weighted imaging (DWI) which comprises of monoexponential DWI,
 IVIM (intravoxel incoherent motion) model and Kurtosis (biexponential or non-Gaussian
 fitting), and perfusion-weighted imaging (PWI) become feasible. Therefore, MRI can evaluate
 distant site status of HNC in the single examination session and provide biologic information
 of tumors, such as cellularity, angiogenesis and permeability, and so forth. Positron
 emission tomography/CT (PET/CT) is another common imaging modality to evaluate HNC, because
 of its ability to provide whole-body anatomic and metabolic information.

 Integrated PET/MRI is a novel imaging technology that combines PET and MRI in one single
 scanner. It can acquire both PET and MRI information simultaneously. Initial data convey that
 PET/MRI performed favorably in diagnostic evaluation of HNC. However, the predictive value of
 PET/MRI in treatment outcome of HNC has not been reported. A prospective study of integrated
 PET/MRI in a large cohort of patients with specific tumor origin and uniform treatment
 protocol is needed to fully validate the clinical usefulness of this novel integrated system.

 In this 3-year prospective study, the investigators will take the advantages of integrated
 PET/MRI scanner with diffusion-weighted MRI (DWI) and dynamic contrast-enhanced perfusion
 weighted MRI (DCE-PWI) to evaluate our 160 patients with oropharyngeal SCC subjected to
 chemoradiation. Non-contrast chest CT will also be performed on the same day. The
 investigators aim to (1) determine whole-body staging/restaging accurately, (2) predict
 treatment response and prognosis, and (3) to determine necessity of noncontrast chest CT. The
 investigators expect that this project will offer the validation of usefulness of integrated
 PET/MRI in tumor staging/restaging of oropharyngeal SCC and resultant clinical impact. The
 role of noncontrast chest in the workup with our PET/MRI protocol can be defined. It will
 also provide evidence about how and to what extent the various simultaneously acquired MRI
 and PET functional parameters can help prediction of treatment response and prognosis, which
 are important in timely modification of treatment regimen.
Introduction and aim of study:

 Head and neck cancer (HNC) continues to be a significant health care problem in Taiwan and
 oropharyngeal squamous cell carcinoma (SCC) is the common subtype. With the concern of organ
 preservation in recent years, concurrent chemoradiation is the major treatment modality for
 oropharyngeal SCC. Hence, accurate tumor anatomic and biologic evaluations are warranted for
 pretreatment planning, posttreatment monitoring and prognosis determination. Endoscopy with
 biopsy serve as the main diagnostic tools in patients with oropharyngeal SCC. While computed
 tomography (CT) and magnetic resonance imaging (MRI) are commonly used to evaluate the tumor
 extent of HNC, MRI is more preferred in the oropharyngeal area by virtue of its high contrast
 resolution, particularly in detecting perineural invasion. Whole body MRI is now feasible and
 thus distant site status of HNC can be evaluated in the single examination session. FDG-
 positron emission tomography/CT (PET /CT) is another common imaging modality to evaluate HNC.

 According to the investigators' experience in patients with head and neck cancer, MRI and
 PET/CT have different advantages over each other and may complement to each other. In
 evaluating primary tumor status, the high spatial and contrast resolution of MRI can
 delineate the tumor extent from surrounding normal tissue in the complex head and neck
 anatomical region, while delineation of FDG-positive tissue by PET may help differentiation
 tumor growth from surrounding noncancerous tissue, particularly in irradiated bed. In
 evaluating regional nodal status, MRI is superior to PET/CT in detecting retropharyngeal or
 cystic necrotic metastatic adenopathy, whereas PET/CT excels MRI in detecting metastasis in
 sub-centimeter nodes. The combined use of MRI and PET can clearly demonstrate the patterns of
 nodal spread.[7]. Regards to the evaluation of the distant sites, whole body MRI is better in
 detecting metastatic lesion in high metabolic organs such as brain, liver or spleen, while
 PET/CT is superior in detecting those metastatic lesions in the curved, flat bones, and
 second primary bowel tumor such as esophagus cancer or colon cancer.

 Currently, diffusion-weighted MR imaging (DWI) and dynamic contrast-enhanced perfusion
 weighted imaging (DCE-PWI) become clinically feasible to assess the functional aspects of
 HNC. The quantified parameter of DWI sequence is apparent diffusion coefficient (ADC) that
 relates to cellularity. DCE-PWI provides the volume transfer rate constant (Ktrans), relative
 extravascular extracellular space (Ve) and relative vascular plasma volume (Vp) as well as
 the efflux rate constant (Kep). These functional MRI techniques may provide biologic
 information, such as cellularity, angiogenesis and permeability. On the other hand, PET can
 provide its metabolic quantified parameters: standardized uptake value (SUV) that reflects
 glucose metabolism, metabolic tumor volume (MTV) that reflects tumor burden, and total lesion
 glycolysis (TLG) that integrates both glucose metabolism and tumor burden. These MRI and PET
 functional parameters appear promising for predicting chemoradiation response and prognosis
 of HNC. In our previous studies of oropharyngeal or hypopharyngeal SCC patients, Ktrans of
 the primary tumor was the only imaging parameter associated with local control, while ADC and
 Ve values of the neck metastatic nodes were independent prognostic factors for neck control.
 The maximal SUV of the regional lymph nodes was significantly associated with the occurrence
 of distant metastasis. TLG were significantly associated with overall survival.

 Integrated PET/MRI is a novel imaging technology introduced into the clinical practice. The
 combination of PET and MRI in one single, hybrid scanner is promising. Initial data convey
 that PET/MRI performed favorably for HNC. It showed good diagnostic capability similar to
 PET/CT and can serve as a legitimate alternative to PET/CT in the clinical workup of patients
 with HNC. The metabolic ratios measured PET/MRI showed excellent agreement with those on
 standard PET/CT. PET/MRI incorporating the Dixon sequence for attenuation correction purposes
 yielded similar SUV values when compared to PET/CT.Nevertheless, most studies were limited in
 number of cases or no particular tumor entity was specifically analyzed, which somewhat
 weakened their power in terms of evidence-based medicine. In addition, the predictive value
 of PET/MRI in treatment outcome of HNC has not been reported. A prospective study of PET/MRI
 in a large cohort of patients with specific tumor origin and uniform treatment protocol would
 complement these pioneering efforts to fully validate the clinical usefulness of the novel
 integrated system.

 Recently, integrated PET/MRI scanner (Biograph mMR, Siemens) has been installed in our
 hospital. In this scanner, the PET detectors are fully integrated into the 3 Tesla MR system
 with one single gantry, enabling simultaneous acquisition of both PET and MR data. Before its
 wide practical use, its clinical usefulness should be explicitly defined. In this research
 project, the investigators will investigate our 150 patients with oropharyngeal SCC subjected
 to chemoradiation with FDG-PET/MRI. Non-contrast chest CT will also be performed on the same
 day. The investigators have the following aims:

 Aim 1: to determine whole-body staging/restaging MRI and PET/CT have different advantages
 over each other, and visual correlation of these separate imaging modalities can yield a
 slightly higher diagnostic capability. However, some lesions may not be matched well for each
 other because of different examination date and positioning. Therefore, the investigators
 believe that tumor involvement should be made more accurately with simultaneously acquired
 PET/MRI imaging, leading to more accurate tumor staging/restaging, and in turn, to more
 precise treatment planning and better treatment outcome. However, the data of integrated
 PET/MRI for whole whole-body staging/restaging on oropharyngeal SCC are still unavailable
 currently. In this prospective project, the investigators aim to determine the feasibility
 and clinical impact of integrated PET/MRI in tumor staging and restaging of oropharyngeal SCC

 Aim 2. to predict treatment response and prognosis Functional MRI parameters and FDG-PET/CT
 parameters can be quantified and have been used for predicting response to chemoradiation in
 HNC. However, variable results had been obtained, mainly due to different tumor origins,
 sample sizes, methodologies, and treatment protocols. Another important confounding factor is
 that MRI and PET/CT were done at different time intervals. Because integrated PET/MRI can
 provide simultaneous PET and MR functional data that allow for direct comparison in the
 selected regions of interest, and thus should be more accurate and more reproducible.
 However, the predictive values of simultaneous functional PET/MRI techniques in oropharyngeal
 SCC have not been reported till now. On the other hand, DWI with intravoxel incoherent motion
 (IVIM ) technique can quantify both molecular diffusion and microcirculation in the capillary
 network that may be useful for predicting tumor chemoradiosensitivity, while DWI with
 kurtosis (biexponential or non-Gaussian fitting) modeling has been documented to yield a
 better fit of the in vivo water molecule diffusion than does that with monoexponential
 modeling[32]. In this research project, the investigators added functional MRI sequences as
 parts of PET/MRI procedures, including DCE-PWI as well as dedicated DWI that can yield
 monoexponential DWI, IVIM and Kurtosis data. We aim to obtain MRI and PET functional results
 on integrated PET/MRI system in the single imaging session in the patient cohort of
 oropharyngeal SCC uniformly treated with chemoradiation. The investigators expected that the
 predictive values of the various functional parameters of integrated PET/ MRI can be more
 clearly elucidated.

 Aim 3. to determine necessity of noncontrast chest CT. One of the concerns of replacing the
 CT portion of PET/CT with MRI is the ability of MRI to depict and differentiate lung nodules,
 while the most common location for distant metastases of HNC is lung. According to the
 investigators' previous study, the CT component of integrated PET/CT can improve not only the
 specificity but also the sensitivity of FDG-PET data. In addition, CT also help to lessen PET
 false-positive findings in calcified mediastinal nodal disease, such as anthracosis. However,
 on the other hand, the investigators' previous studies showed the detection rates of
 pulmonary metastases with 3.0-T MRI using half-Fourier acquisition single-shot turbo
 spin-echo (HASTE), volumetric interpolated breath-hold examination (VIBE) and short τ
 inversion recovery (STIR) sequences were similar to those of PET/CT. One recent study has
 shown that radial VIBE free-breathing MRI with simultaneously acquired PET data has high
 sensitivity in the detection of nodules with a diameter of at least 0.5 cm, but has limited
 sensitivity in the detection of small or non-FDG-avid nodules. Considering the limited data
 on PET/MR in detecting lung malignant lesion, the investigators aim to prospectively validate
 the performance of our integrated PET/MRI protocol sequences for lung lesions by adding
 noncontrast enhanced CT for comparison.

 Material and methods:

 In this three-year prospective project, a total of 160 patients with histologically proven
 oropharyngeal SCC subjected to chemoradiation will be enrolled. Exclusion criteria include
 previous head or neck malignant tumor, a second malignant tumor, distant metastasis,
 contraindications to MRI (renal insufficiency, cochlear implant, cardiac pacemaker placement
 or intracranial aneurysmal ferromagnetic clips), and serum glucose level >200 mg/dl. Before
 pretreatment, each enrolled patients will undergo PET/MRI and detail clinical examination,
 including human papillomavirus test. The participants will also undergo low dose chest CT on
 the same day before PET/MRI. In the posttreatment period, baseline whole body MRI will be
 obtained 3 months after chemoradiation. Thereafter, the patients will then be followed up
 also with alternative extend-field CT and whole body MRI by every 6 months. If tumor
 recurrence is confirmed or highly suspected, PET/MRI will also be performed for tumor
 re-staging.

 The three-years planning Adequate cases number and follow-up duration are essential for
 statistical analysis and outcome determination of oropharyngeal SCC treated with
 chemoradiation. The investigators plan to accomplish this study in 3 years. In the first
 year, the works of the this project in the first year will: (1) design the data bank
 categories; (2) set up the workflow and optimize the imaging protocols; (3) determine the
 diagnostic capability of MRI component, PET component, integrated PET/MRI in tumor staging;
 (4) determinate any added diagnostic value of noncontrast CT in integrated PET/MRI, and (5)
 study the early treatment response and the patterns of residual tumor.

 In the second year, the investigators will continue to the first-year works, and further
 include the following works: (1) to determinate incidence and predictors of treatment failure
 of oropharyngeal SCC, and (2) to study the patterns of treatment response and early
 recurrence.

 In the third year, the investigators will continue to do previous work and will also (1) get
 sufficient sample size to perform statistical analysis of the relationship between the
 imaging parameters and patient outcomes, (2) attain comprehensive imaging about patterns of
 tumor recurrence and posttreatment changes/complications, (3) investigate to what extent
 biologic imaging parameters may affect outcome and patient selection for chemoradiation, (4)
 analysis the accuracy, pitfalls and cost effectiveness of the PET/MRI alone and PET/MRI with
 noncontrast CT in evaluating in patients with oropharyngeal SCC.

 PET/MRI protocol PET/MRI data will be acquired on the integrated PET/MRI scanner (Biograph
 mMR, Siemens Healthcare, Erlangen, Germany) , which acquires simultaneous PET and MR data
 with a 3.0-T magnet. The examination protocol will combined a whole-body scan with a
 dedicated examination of the head and neck area (Table 1). All patients will fast for 6 h
 before the scan. At 50-70 min post injection of 370 MBq of FDG, the patient will be placed on
 the PET/MRI scanner bed. After fast-view T1-weighted MR localizer sequence for scout imaging
 and Dixon VIBE sequence for attenuation correction, a whole-body PET scan will be performed
 in 5 bed positions to cover from the head to the proximal thigh, with an acquisition time of
 4 min per bed position. Simultaneously, whole body MR image acquisition will be performed for
 the corresponding 5 bed positions with the axial HASTE sequence and coronal STIR sequence as
 well as the sagittal T1-weighted Turbo spine echo(TSE) and STIR sequence.

 Afterwards, regional PET and MRI images will be simultaneously performed. Regional PET will
 be performed with an acquisition time of 10 min, while a dedicated MRI of the head and neck
 region will be acquired in the axial and coronal projections with T1-weighted TSE sequence
 and T2-weighted TSE sequence with fat saturation. Axial DWI will be performed using a single
 shot spin-echo echo-planar technique with modified Stejskal-Tanner diffusion gradient pulsing
 scheme. A total of 10 b values will be used for the reconstruction of IVIM and kurtosis
 imaging, which are: 0, 20, 40, 80, 100, 200, 400, 800, 1200, 1500 sec/mm2.

 DCE-PWI at the head and neck region will be acquired by using a 3D T1-weighted spoiled
 gradient-echo sequence. A spatial saturation slab will be implanted inferior to the acquired
 region to minimize the inflow effect from the carotid arteries. Before the contrast agent
 administration, baseline longitudinal relaxation time (T10) values will be calculated from
 image acquired with different flip angles (4°, 8°, 15° and 25°). Then, the dynamic series
 will be acquired using the same sequence with a 15° flip angle, after intravenous
 administration of paramagnetic contrast agent at 3 ml/s. Thereafter, dedicated regional MRI
 will be obtained with T1-weighted TSE sequence with fat saturation in the axial and coronal
 projections. Finally, whole body axial VIBE with fat saturation will be performed. The total
 acquisition time is about 42 min, and the mean in-room time for PET/MR will be approximately
 60 min.

 Non-enhanced low-dose CT Spiral low-dose CT without contrast material enhancement will be
 performed before PET/MRI on the same examination day. Acquisition parameters include peak
 voltage of 120 kVp, mAs of 50, collimation of 64x0.5 mm and reconstruction interval of 3-mm.

 Data analysis and outcome determination Readers are aware that patients have oropharyngeal
 SCC, and they will be blinded to the results of other studies and to PET/MR data. The PET,
 MRI and lung CT images will be first interpreted independently. All images will be then
 reviewed together and compared. A checklist of various distributions of tumor extension,
 nodal spread and distant metastasis will be recorded. The clinical and imaging findings will
 be discussed jointly by the Head-and-Neck research team. Endoscopic biopsy, ultrasonographic
 guided fine needle aspiration or CT-guided biopsy will be performed in any lesions suspicion
 for malignancy if possible. If biopsy of the lesion of interest is not feasible, or yields a
 negative result, close clinical and imaging follow-up will be pursued. All patients will be
 followed up for at least 12 months.

 The clinical and functional imaging data will be collected and analyzed for predicting
 treatment response and prognosis. For the diffusion MRI, regions of interest will be manually
 placed on the lesions on ADC map to encompass as much of the solid tumor area as possible.
 The signal intensities measured on the images acquired at different b-values S(b) will be
 numerically fitted against the model, S(b)=S0 e-b*ADC, where S0 and Sb are signal intensities
 at different b values, For IVIM imaging, the relationship between signal intensities and b
 values can be expressed by the equation: Sb/S0 = (1-f )．exp(-bD) + f．exp[-b( D + D＊)] where f
 is a microvascular volume fraction representing the fraction of the diffusion linked to
 microcirculation, D represents pure diffusion coefficient, and D* is perfusion-related
 incoherent microcirculation. For the DKI, the relationship between signal intensities and b
 values can be expressed by the equation: ln[S(b)] = ln[S(0)] - b x Dapp + 1/6b2 x Dapp2 x
 Kapp where S is the signal intensity (arbitrary units), b is the b-value (s/mm2), Dapp is the
 apparent diffusion coefficient (10-3 mm2/s), and Kapp is the apparent kurtosis coefficient
 denoting the deviation from a Gaussian distribution. The investigators will also perform
 monoexponential fitting by using Kapp=0 in the equation, yielding ADCmono. For the DCE-PWI
 MRI, the change in contrast agent concentration over time, Ct(t), will be determined in each
 voxel in the tumor, and the compartmental tracer kinetic model will be applied to each voxel
 by using an arterial input function, Cp(t), measured in each individual: Ct (t)=VpCp(t) +
 Ktrans ∫0t Cp (t' ) exp(Ktrans(t-t') /Ve )dt' where t' is the time (in minutes) as an
 integration variable, and Cp(t') is the concentration of contrast agent in the blood plasma
 as a function of time. For PET imaging parameters, SUV and MTV of the target lesions will be
 measured from attenuation-corrected 18F-FDG PET images by drawing the boundaries drawn large
 enough to include the lesions. An SUV threshold of 2.5 will be used to delineate the MTV. The
 TLG is calculated as the product of the mean SUV and the MTV.

 Statistical Analysis

 Using histological findings or follow-up data at 12 months as a standard of reference,
 various imaging results will be classified as true-positive, true-negative, false-positive,
 or false-negative. The diagnostic accuracies of MRI component, PET component, integrated
 PET/MRI, chest CT alone, and PET/MRI plus chest CT will be calculated and compared with the
 McNemar test. Their respective diagnostic performance will be determined with the areas under
 the receiver-operating-characteristic curve. For treatment response evaluation and prognosis
 prediction, logistic regression analyses will be used to identify the relationship between
 clinical and imaging functional variables. The control and survival rates will be plotted
 using the Kaplan-Meier method. Differences in positive and negative results will be
 determined by log-rank test. All prognostic variables identified by univariate analysis will
 be put into the multivariate model using the Cox proportional hazards model. The Spearman's
 rank correlation coefficient will be used to investigate the correlations among the
 variables. P values < 0.05 is considered statistically significant.
Inclusion Criteria:

 -  histologically proven oropharyngeal SCC subjected to chemoradiation

 Exclusion Criteria:

 -  Exclusion criteria include previous head or neck malignant tumor, a second malignant
 tumor, distant metastasis, contraindications to MRI (renal insufficiency, cochlear
 implant, cardiac pacemaker placement or intracranial aneurysmal ferromagnetic clips),
 and serum glucose level >200 mg/dl.