C. Terhaard

Improved Recurrence-Free Survival with ARCON for Anemic Patients with Laryngeal Cancer

Purpose: Anemia is associated with poor tumor control. It was previously observed that accelerated radiotherapy combined with carbogen breathing and nicotinamide (ARCON) can correct this adverse outcome in patients with head and neck cancer. The purpose of this study was to validate this observation based on data from a randomized trial. Experimental Design: Of 345 patients with cT2-4 laryngeal cancer, 174 were randomly assigned to accelerated radiotherapy and 171 to ARCON. Hemoglobin levels, measured before treatment, were defined as low when <7.5 mmol/L for women and <8.5 mmol/L for men. The hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. Data were analyzed 2 years after inclusion of the last patient. Results: Pretreatment hemoglobin levels were available and below normal in 27 of 173 (16%) accelerated radiotherapy and 27 of 167 (16%) ARCON patients. In patients with normal pretreatment, hemoglobin levels treatment with ARCON had no significant effect on 5-year loco-regional control (LRC, 79% versus 75%; P = 0.44) and disease-free survival (DFS, 75% vs. 70%; P = 0.46) compared with accelerated radiotherapy. However, in patients with low pretreatment, hemoglobin levels ARCON significantly improved 5-year LRC (79% vs. 53%; P = 0.03) and DFS (68% vs. 45%; P = 0.04). In multivariate analysis including other prognostic factors, pretreatment hemoglobin remained prognostic for LRC and DFS in the accelerated radiotherapy treatment arm. No correlation between pretreatment hemoglobin levels and pimonidazole uptake was observed. Conclusion: Results from the randomized phase III trial support previous observations that ARCON has the potential to correct the poor outcome of cancer patients with anemia (ClinicalTrials.gov number, NCT00147732). Clin Cancer Res; 20(5); 1345–54. ©2014 AACR.

Epidermal growth factor receptor expression in laryngeal cancer predicts the effect of hypoxia modification as an additive to accelerated radiotherapy in a randomised controlled trial

Accelerated radiotherapy (AR) improves the poor prognosis associated with epidermal growth factor receptor (EGFR) overexpression frequently seen in head and neck carcinomas. Combining AR with carbogen and nicotinamide (ARCON) counteracts enhanced tumour cell proliferation- and hypoxia-related radioresistance. The purpose of this study was to investigate if EGFR expression levels are associated with response to ARCON in patients with carcinoma of the larynx. Patients (N=272) with advanced stage larynx carcinoma were randomised between AR alone and ARCON. Paraffin-embedded biopsies from these patients were processed for immunohistochemical staining of EGFR. EGFR fraction was quantitated by automated image analysis and related to clinical outcome. A large variation was observed in EGFR fraction between tumours with expression levels ranging from 0 to 0.93 (median fraction 0.4). No difference in 5-year locoregional control was found between low and high EGFR expressing tumours in the AR arm (69% versus 75%), which is in line with the established effect of AR in EGFR overexpressing tumours. There was, however, a significant association in the ARCON arm: patients with low EGFR levels had a better 5-year locoregional control (88% versus 72% p=0.02) and disease-specific survival (92% versus 77% p=0.01). ARCON improved locoregional control relative to AR only in patients with low EGFR expression (hazard ratio (HR) 0.34 p=0.009). In conclusion, only in tumours with a low EGFR fraction, adding hypoxia modification to AR has an additive beneficial effect on outcome. EGFR expression is a predictive biomarker for the selection of patients that will or will not respond to ARCON.

Validated guidelines for tumor delineation on magnetic resonance imaging for laryngeal and hypopharyngeal cancer

Abstract Background: Validation of magnetic resonance imaging (MRI) and development of guidelines for the delineation of the gross tumor volume (GTV) is of utmost importance to benefit from the visibility of anatomical details on MR images and to achieve an accurate GTV delineation. In the ideal situation, the GTV delineation corresponds to the histopathologically determined ‘true tumor volume’. Consequently, we developed guidelines for GTV delineation of laryngeal and hypopharyngeal tumors on MRI and determined the accuracy of the resulting delineation of the tumor outline on histopathology as gold standard. Material and methods: Twenty-seven patients with T3 or T4 laryngeal/hypopharyngeal cancer underwent a MRI scan before laryngectomy. Hematoxylin and eosin sections were obtained from surgical specimens and tumor was delineated by one pathologist. GTV was delineated on MR images by three independent observers in two sessions. The first session (del1) was performed according to clinical practice. In the second session (del2) guidelines were used. The reconstructed specimen was registered to the MR images for comparison of the delineated GTVs to the tumor on histopathology. Volumes and overlap parameters were analyzed. A target margin needed to assure tumor coverage was determined. Results: The median GTVs (del1: 19.4u2009cm3, del2: 15.8u2009cm3) were larger than the tumor volume on pathology (10.5u2009cm3). Comparable target margins were needed for both delineation sessions to assure tumor coverage. By adding these margins to the GTVs, the target volumes for del1 (median: 81.3u2009cm3) were significantly larger than for del2 (median: 64.2u2009cm3) (pu2009≤u20090.0001) with similar tumor coverage. Conclusions: In clinical radiotherapy practice, the delineated GTV on MRI is twice as large as the tumor volume. Validated delineation guidelines lead to a significant decrease in the overestimation of the tumor volume.

PO-0943: Dutch national head and neck plan comparison significantly improved treatment planning quality

Conclusion: Rigid (PLA) and flexible (Ninjaflex) bolus materials provide build-up characteristics within 5% of Solid Water. When incorporated into treatment planning calculations, planned dose for 3D bolus agrees with OSLD measured dose to within 2% on average, and 3D printed bolus gives lower variability in the agreement of the delivered to planned dose. In summary, 3D printed chestwall bolus may be produced in an automated fashion and gives improved consistency of delivered dose accuracy compared to standard sheet bolus.

PV-0516: Guideline development for tumor delineation on MR-images for laryngeal and hypophargeal cancer

Conclusion: In all modalities, delineated GTVs overestimated tumor volume. Nevertheless, some tumor volume was missed in all cases. Automated delineation on PET resulted in the smallest target volume compared to manual delineation on CT and MRI, while covering an equivalent amount of tumor. This study suggests that delineation or segmentation inaccuracies can be corrected using a margin between 5.6 and 8.7 mm.

OC-0068: Comparison of GTV delineations on CT, MRI and FDG-PET of laryngeal and hypopharyngeal carcinoma with histopathology

increasingly used for response monitoring and prediction. In this study the diagnostic potential of DCE-MRI for treatment response assessment in esophageal cancer is investigated. Materials and Methods: In 12 patients receiving nCRT, DCEMRI studies were performed before treatment (pre), after 813 fractions (per) and 5-7 weeks after completion of nCRT, prior to surgery (post). After resection pathologic assessment of the tumor regression grade (TRG) was performed following the Mandard score. For analysis a distinction was made between a group of good responders (GR), defined as pCr (TRG 1) or near-pCr (TRG 2), and poor responders (noGR) with TRG ≥ 3. The primary tumor was delineated on the T2W images before, during and after nCRT. This delineated volume was contracted with an isotropic margin of 2 mm to account for residual motion and partial volume effects. Within this contracted volume mean, median and 75 percentile (P75) of the AUC of the contrast agent concentration was calculated. Here, the AUC was defined as the integral over the concentration curve (60 seconds, starting at inflow of contrast agent). Results: In 4 patients (33%) pCR was found and a total of 5 patients (42%) showed a good response. Initial P75 AUC values were the same across GR and noGR. Relative changes in mean, median and P75 AUC between pre and per treatment were all found to be significant across the two groups, while the same parameters comparing pre and post treatment were not significant. All noGR showed an increase in AUC comparing relative changes between pre and per treatment (fig. A), while 80% of GR remained similar or decreased. The ΔP75 pre-per was found to be most predictive (-6%±29% for GR [mean ± SD] vs. 76%±58% for noGR, p=0.005) (fig B). With a cut-off value of 17.4% an area under the ROC curve of 0.97, sensitivity of 80%, specificity of 100%, positive predictive value (PPV) of 100% and a negative predictive value (NPV) of 88% is found.

PD-0093: CT-based tumour volume as a predictor of outcome in laryngeal cancer: results of the phase 3 ARCON trial

Materials and Methods: The inclusion criteria for this multi-center prospective study are (1) biopsy-proven NPC, (2) no distant metastasis, (3) in clinical remission after curative treatment (radiotherapy ± chemotherapy), (4) within 3 year after finishing radiotherapy. pEBV DNA concentration is monitored every 3 months. Detailed staging workups areperformed when abnormal pEBV DNA detected. All tumor recurrences are documented by imaging studies along with pathological verification if the lesions are accessible and patients agree. Results: From August 2011 to October2012, 252 patients were enrolled and 33 patients had abnormal pEBV DNA during follow-up visit. Thirty of 33 (91%) patients with elevated pEBV DNA have been proven as tumor relapse, whereas the remaining 219 patients with normal pEBV DNA level are showing no evidence of disease (P<0.0001). In addition, two-thirds (20/30) relapsed patients were detected in a symptomless state. Conclusions: pEBV DNA assay is a very encouraging tool in monitoring NPC patients after treatment.