François-Xavier Hanin

The role of neck dissection in the setting of chemoradiation therapy for head and neck squamous cell carcinoma with advanced neck disease

Concurrent chemotherapy and radiotherapy (CRT) has become standard treatment for many patients with advanced head and neck squamous cell carcinoma (HNSCC). This has led to controversy concerning the role of neck dissection (ND) in this setting. The current debate is focused on N2-N3 disease and the ability of a clinical complete response to predict the absence of viable cells in the ND specimen. Proponents of a systematic planned ND argue that it improves regional control and possibly disease-specific survival. They assert that a clinical response does not predict the pathologic response, and that in the event of recurrence in the neck, a surgical salvage procedure is unlikely to succeed. Conversely, there are many arguments in favor of performing ND only for patients who have evidence of residual neck disease because of the very low probability of isolated neck recurrence following a complete response. Proponents argue that for complete responders, planned ND is associated with no survival benefit. As planned surgery will only benefit patients with residual disease in the neck alone, there is a high rate of unnecessary ND with its associated morbidity. Another question concerns the appropriate type of ND to be performed. Even if required after chemoradiation, selective ND is oncologically feasible with minimal morbidity. Lastly, robust data from a randomized trial demonstrating the superiority of one approach vs. the other are lacking. After conducting a review of recent literature on the subject, the authors conclude that planned ND is not necessary for patients with complete response because of the availability of improved diagnostic follow up modalities, and the increased sensitivity to CRT of HNSCC, particularly HPV associated tumors.

Advances in the management of squamous cell carcinoma of the head and neck

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide. The main risk factors for cancers of the oral cavity, larynx, oropharynx, and hypopharynx are alcohol and tobacco use. In addition, the human papillomavirus (HPV) is an established cause of oropharyngeal cancer. An experienced multidisciplinary team is necessary for adequate management and optimal outcome. The treatment of locally advanced disease generally requires various combinations of radiotherapy, surgery, and systemic therapy, but despite this aggressive multimodal treatment, 40% to 60% of the patients will relapse. In this report, we will discuss recent advances in the management of SCCHN, including new developments in molecular biology, imaging, and treatment.

Hypoxia-guided adaptive radiation dose escalation in head and neck carcinoma: A planning study

Abstract Objective. To evaluate from a planning point of view the dose distribution of adaptive radiation dose escalation in head and neck squamous cell carcinoma (HNSCC) using 18F-Fluoroazomycin arabinoside (FAZA) positron emission tomography/computed tomography (PET-CT). Material/methods. Twelve patients with locally advanced HNSCC underwent three FAZA PET-CT before treatment, after 7 fractions and after 17 fractions of a carboplatin-5FU chemo-radiotherapy regimen (70 Gy in 2 Gy per fraction over 7 weeks). The dose constraints were that every hypoxic voxel delineated before and during treatment (newborn hypoxic voxels) should receive a total dose of 86 Gy. A median dose of 2.47 Gy per fraction was prescribed on the hypoxic PTV defined on the pre-treatment FAZA PET-CT; a median dose of 2.57 Gy per fraction was prescribed on the newborn voxels identified on the first per-treatment FAZA PET-CT; a median dose of 2.89 Gy per fraction was prescribed on the newborn voxels identified on the second per-treatment FAZA PET-CT. Results. Ten of 12 patients had hypoxic volumes. Six of 10 patients completed all the FAZA PET-CT during radiotherapy. For the hypoxic PTVs, the average D50% matched the prescribed dose within 2% and the homogeneity indices reached 0.10 and 0.12 for the nodal PTV 86 Gy and the primary PTV 86 Gy, respectively. Compared to a homogeneous 70 Gy mean dose to the PTVs, the dose escalation up to 86 Gy to the hypoxic volumes did not typically modify the dose metrics on the surrounding normal tissues. Conclusion. From a planning point of view, FAZA-PET-guided dose adaptive escalation is feasible without substantial dose increase to normal tissues above tolerance limits. Clinical prospective studies, however, need to be performed to validate hypoxia-guided adaptive radiation dose escalation in head and neck carcinoma.

A Randomized Trial on the Optimization of 18F-FDG Myocardial Uptake Suppression: Implications for Vulnerable Coronary Plaque Imaging

18F-FDG PET/CT can be used to detect arterial atherosclerotic plaque inflammation. However, avid myocardial glucose uptake may preclude its use for visualizing coronary plaques. Fatty acid loading or calcium channel blockers could decrease myocardial 18F-FDG uptake, thus assisting coronary plaque inflammation identification. The present prospective randomized trial compared the efficacies of different interventions for suppressing myocardial 18F-FDG uptake. We also investigated whether circulating free fatty acid (cFFA) levels predicted the magnitude of myocardial 18F-FDG uptake. Methods: Thirty-six volunteers ate a high-fat low-carbohydrate meal, followed by a 12-h fasting period. They were then randomized to 1 of 4 intervention groups. Group 1 received no additional preparation and served as a reference. Groups 2 and 3, respectively, received a commercial high-fat solution containing 43.8 g of lipids or 50 mL of olive oil 1 h before 18F-FDG injection to evaluate the impact of fatty acid loading on myocardial 18F-FDG uptake. Group 4 received verapamil to evaluate the effect of calcium channel blockers. Cardiac PET/CT was performed after administration of 370 MBq of 18F-FDG. Myocardial uptake suppression was assessed using a qualitative visual scale and by measuring the myocardial maximum standardized uptake value (SUVmax). Insulin, glucose, and cFFA were serially measured. Results: The qualitative visual scale showed good myocardial 18F-FDG uptake suppression in 8 of 9, 5 of 9, 4 of 9, and 8 of 9 subjects of groups 1, 2, 3, and 4, respectively (P = 0.09). SUVmax did not significantly differ between groups (P = 0.17). Interestingly, cFFA levels were higher in volunteers with good suppression (0.80 ± 0.31 mmol/L) than in those with poor suppression (0.53 ± 0.15 mmol/L; P = 0.011). We found an inverse correlation between cFFA level (measured at 18F-FDG injection) and the SUVmax (R = 0.61). Receiver-operating-characteristic curve analysis identified 0.65 mmol/L cFFA as the best cutoff value to predict adequate 18F-FDG uptake suppression (positive predictive value, 89%). Conclusion: A high-fat low-carbohydrate meal followed by a 12-h fasting period effectively suppressed myocardial 18F-FDG uptake in most subjects. Neither complementary fatty acid loading nor verapamil administered 1 h before 18F-FDG injection conferred any additional benefit. Myocardial 18F-FDG uptake was inversely correlated with cFFA level, representing an interesting way to predict myocardial 18F-FDG uptake suppression.

Tumour response and safety of cetuximab in a window pre-operative study in patients with squamous cell carcinoma of the head and neck.

BACKGROUND To investigate the safety and activity of cetuximab in the pre-operative treatment of squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS Cetuximab was administered for 2 weeks before surgery to 33 treatment-naïve patients selected for primary surgical treatment. Tumour biopsies, 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography ((18)FDG-PET) and imaging were carried out at baseline and before surgery. The primary aim of the study was safety and the secondary aims included metabolical, radiological and pathological tumour response. Five untreated patients were included as controls. RESULTS Cetuximab given 24 h before surgery was safe. Ninety percent of patients had (18)FDG-PET partial response (EORTC guideline) in the cetuximab group versus 0% in the control group. Delta maximal standardized uptake values (ΔSUVmax) were correlated with tumour cellularity on the surgical specimens (P < 0.0001). For patients with ΔSUVmax less than -25% or less than -50%, Ki67 was significantly decreased by cetuximab (P = 0.01 and 0.003). Cetuximab induced down-regulation of pEGFR (P = 0.0004) and pERK (P = 0.003). CONCLUSIONS Short-course pre-operative administration of cetuximab is safe and shows a high rate of (18)FDG-PET response. (18)FDG-PET response was correlated with residual tumour cellularity suggesting that (18)FDG-PET deserves further investigation as a potential early marker of cetuximab activity in SCCHN.

PET imaging biomarkers in head and neck cancer

In locally advanced head and neck squamous cell carcinoma (HNSCC), the role of imaging becomes more and more critical in the management process. In this framework, molecular imaging techniques such as PET allow noninvasive assessment of a range of tumour biomarkers such as metabolism, hypoxia and proliferation, which can serve different purposes. First, in a pretreatment setting they can influence therapy selection strategies and target delineation for radiation therapy. Second, their predictive and/or prognostic value could help enhance the therapeutic ratio in the management of HNSCC. Third, treatment modification can be performed through the generation of a molecular-based heterogeneous dose distribution with dose escalation to the most resistant parts of the tumour, a concept known as dose painting. Fourth, they are increasingly becoming a tool for monitoring response to therapy. In this review, PET imaging biomarkers used in the routine management of HNSCC or under investigation are discussed.

Evolution of [18F]fluorodeoxyglucose and [18F]fluoroazomycin arabinoside PET uptake distributions in lung tumours during radiation therapy

Abstract Background: Dose painting (DP) aims to improve radiation therapy (RT) outcome by targeting radioresistant tumour regions identified through functional imaging, e.g., positron emission tomography (PET). Importantly, the expected benefit of DP relies on the ability of PET imaging to identify tumour areas which could be consistently targeted throughout the treatment. In this study, we analysed the spatial stability of two potential DP targets in lung cancer patients undergoing RT: the tumour burden surrogate [18F]fluorodeoxyglucose (FDG) and the hypoxia surrogate [18F]fluoroazomycin arabinoside (FAZA). Materials and methods: Thirteen patients with unresectable lung tumours underwent FDG and FAZA 4D-PET/CT before (pre), and during the second (w2) and third (w3) weeks of RT. All PET/CT were reconstructed in their time-averaged midposition (MidP) for further analysis. The metabolic tumour volume (MTV: FDG standardised uptake value (SUV) > 50% SUVmax) and the hypoxic volume (HV: FAZA SUV >1.4) were delineated within the gross tumour volume (GTVCT). The stability of FDG and FAZA PET uptake distributions during RT was subsequently assessed through volume-overlap analysis and voxel-based correlation analysis. Results: The volume-overlap analysis yielded median overlapping fraction (OF) of 0.86 between MTVpre and MTVw2 and 0.82 between MTVpre and MTVw3. In patients with a detectable HV, median OF was 0.82 between HVpre and HVw2 and 0.90 between HVpre and HVw3. The voxel-based correlation analysis yielded median Spearman’s correlation coefficient (rS) of 0.87 between FDGpre and FDGw2 and 0.83 between FDGpre and FDGw3. Median rS was 0.78 between FAZApre and FAZAw2 and 0.79 between FAZApre and FAZAw3. Conclusions: FDG and FAZA PET uptake distributions were spatially stable during the 3 first weeks of RT in patients with unresectable lung cancer, both based on volume- and voxel-based indicators. This might allow for a consistent targeting of high FDG or FAZA PET uptake regions as part of a DP strategy.

Methodology for adaptive and robust FDG-PET escalated dose painting by numbers in head and neck tumors

Objective. To develop a methodology for using FDG PET/CT in adaptive dose painting by numbers (DPBN) in head and neck squamous cell carcinoma (HNSCC) patients. Issues related to noise in PET and treatment robustness against geometric errors are addressed. Methods. Five patients with locally advanced HNSCC scheduled for chemo-radiotherapy were imaged with FDG-PET/CT at baseline and 2–3 times during radiotherapy (RT). The GTVPET was segmented with a gradient-based method. A double median filter reduces the impact of noise in the PET uptake-to-dose conversion. Filtered FDG uptake values were linearly converted into a voxel-by-voxel prescription from 70 (median uptake) to 86 Gy (highest uptake). A PTVPET was obtained by applying a dilation of 2.5 mm to the entire prescription. Seven iso-uptake thresholds led to seven sub-levels compatible with the Tomotherapy HiArt® Treatment Planning System. Planning aimed to deliver a median dose of 56 Gy and 70 Gy in 35 fractions on the elective and therapeutic PTVs, respectively. Plan quality was assessed with quality volume histogram (QVH). At each time point, plans were generated with a total of 3–4 plans for each patient. Deformable image registration was used for automatic contour propagation and dose summation of the 3 or 4 treatment plans (MIMvista®). Results. GTVPET segmentations were performed successfully until week 2 of RT but failed in two patients at week 3. QVH analysis showed high conformity for all plans (mean VQ = 0.95 93%; mean VQ = 1.05 3.9%; mean QF 2.2%). Good OAR sparing was achieved while keeping high plan quality. Conclusion. Our results show that adaptive FDG-PET-based escalated dose painting in patients with locally advanced HNSCC is feasible while respecting strict dose constraints to organs at risk. Clinical studies must be conducted to evaluate toxicities and tumor response of such a strategy.

Dynamic contrast-enhanced computed tomography to assess early activity of cetuximab in squamous cell carcinoma of the head and neck

Abstract Background. Cetuximab, a monoclonal antibody targeting the Epidermal Growth Factor Receptor (EGFR), has demonstrated activity in various tumor types. Using dynamic contrast-enhanced computed tomography (DCE-CT), we investigated the early activity of cetuximab monotherapy in previously untreated patients with squamous cell carcinoma of the head and neck (SCCHN). Methods. Treatment-naïve patients with SCCHN received cetuximab for 2 weeks before curative surgery. Treatment activity was evaluated by DCE-CT at baseline and before surgery. Tumor vascular and interstitial characteristics were evaluated using the Brix two-compartment kinetic model. Modifications of the perfusion parameters (blood flow Fp, extravascular space ve, vascular space vp, and transfer constant PS) were assessed between both time points. DCE data were compared to FDG-PET and histopathological examination obtained simultaneously. Plasmatic vascular markers were investigated at different time points. Results. Fourteen patients had evaluable DCE-CT parameters at both time points. A significant increase in the extravascular extracellular space ve accessible to the tracer was observed but no significant differences were found for the other kinetic parameters (Fp, vp or PS). Significant correlations were found between DCE parameters and the other two modalities. Plasmatic VEGF, PDGF-BB and IL-8 decreased as early as 2 hours after cetuximab infusion. Conclusions. Early activity of cetuximab on tumor interstitial characteristics was detected by DCE-CT. Modifications of plasmatic vascular markers are not sufficient to confirm anti-angiogenic cetuximab activity in vivo. Further investigation is warranted to determine to what extent DCE-CT parameters are modified and to evaluate whether they are able to predict treatment outcome.

Correlation analysis of [18F]fluorodeoxyglucose and [18F]fluoroazomycin arabinoside uptake distributions in lung tumours during radiation therapy

Abstract Background: PET-guided dose painting (DP) aims to target radioresistant tumour regions in order to improve radiotherapy (RT) outcome. Besides the well-known [18F]fluorodeoxyglucose (FDG), the hypoxia positron emission tomography (PET) tracer [18F]fluoroazomycin arabinoside (FAZA) could provide further useful information to guide the radiation dose prescription. In this study, we compare the spatial distributions of FDG and FAZA PET uptakes in lung tumours. Material and methods: Fourteen patients with unresectable lung cancer underwent FDG and FAZA 4D-PET/CT on consecutive days at three time-points: prior to RT (pre), and during the second (w2), and the third (w3) weeks of RT. All PET/CT were reconstructed in their time-averaged midposition (MidP). The metabolic tumour volume (MTV: FDG standardised uptake value (SUV) > 50% SUVmax), and the hypoxic volume (HV: FAZA SUV > 1.4) were delineated within the gross tumour volume (GTVCT). FDG and FAZA intratumoral PET uptake distributions were subsequently pairwise compared, using both volume-, and voxel-based analyses. Results: Volume-based analysis showed large overlap between MTV and HV: median overlapping fraction was 0.90, 0.94 and 0.94, at the pre, w2 and w3 time-points, respectively. Voxel-wise analysis between FDG and FAZA intratumoral PET uptake distributions showed high correlation: median Spearman’s rank correlation coefficient was 0.76, 0.77 and 0.76, at the pre, w2 and w3 time-points, respectively. Interestingly, tumours with high FAZA uptake tended to show more similarity between FDG and FAZA intratumoral uptake distributions than those with low FAZA uptake. Conclusions: In unresectable lung carcinomas, FDG and FAZA PET uptake distributions displayed unexpectedly strong similarity, despite the distinct pathways targeted by these tracers. Hypoxia PET with FAZA brought very little added value over FDG from the perspective of DP in this population.