Search

Purpose: To evaluate if correction of low hemoglobin (Hb) levels by means of darbepoetin alfa improves the outcomes of radiotherapy in patients with squamous cell carcinoma of the head and neck (HNSCC)., Patients and Methods: Patients eligible for primary radiotherapy and who had Hb values below 14.0 g/dl were randomized to receive accelerated fractionated radiotherapy with or without darbepoetin alfa. Patients also received the hypoxic radiosensitizer nimorazole. Darbepoetin alfa was given weekly during radiotherapy or until the Hb value exceeded 15.5 g/dl., Results: Following a planned interim analysis which showed inferiority of the experimental treatment the trial was stopped after inclusion of 522 patients (of a planned intake of 600). Of these, 513 were eligible for analysis (254 patients treated with darbepoetin alfa and 259 patients in the control group). Overall, the patients were distributed according to the stratification parameters (gender, T and N staging, tumor site). Treatment with darbepoetin alfa increased the Hb level to the planned value in 81% of the patients. The compliance was good without excess serious adverse events. The results showed a poorer outcome with a 5-year cumulative loco-regional failure rate of 47% vs. 34%, Hazard Ratio (HR): 1.53 [1.16-2.02], for the darbepoetin alfa vs. control arm, respectively. This was also seen for the endpoints of event-free survival (HR: 1.36 [1.09-1.69]), disease-specific death (HR: 1.43 [1.08-1.90]), and overall survival (HR: 1.30 [1.02-1.64]). There was no enhanced risk of cardio-vascular events observed in the experimental arm or any significant differences in acute or late radiation related morbidity. All univariate analyses were confirmed in a multivariate setting., Conclusion: Correction of the Hb level with darbepoetin alfa during radiotherapy of patients with HNSCC resulted in a significantly poorer tumor control and survival., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Purpose: Evaluate the prognostic and predictive impact of HPV-associated p16-expression and assess the combined prognostic impact of p16 and smoking on altered fractionated radiotherapy (AFRT) for oropharyngeal cancer (OPC) within the frames of the update of the Meta-Analysis of Radiotherapy in Carcinomas of Head and neck (MARCH)., Materials and Methods: Patients with OPC, known tumor p16-status and smoking history were identified from the MARCH update, resulting in a dataset of 815 patients from four randomized trials (RTOG9003, DAHANCA6&7, RTOG0129, ARTSCAN). Analysis was performed using a Cox model stratified by trial and adjusted on gender, age, T-stage, N-stage, type of radiotherapy fractionation, p16, smoking. Primary endpoint was progression-free survival (PFS)., Results: In total, 465 patients (57%) had p16-positive tumors and 350 (43%) p16-negative. Compared to p16-negative, p16-positive patients had significantly better PFS (HR = 0.42 [95% CI: 0.34-0.51], 28.9% absolute increase at 10 years) and OS (HR = 0.40 [0.32-0.49], 32.1% absolute increase at 10 years). No interaction between p16-status and fractionation schedule was detected. Smoking negatively impacted outcome; in the p16-positive subgroup, never smokers had significantly better PFS than former/current smokers (HR = 0.49 [0.33-0.75], 24.2% survival benefit at 10 years)., Conclusions: No predictive impact of p16-status on response to AFRT could be detected but the strong prognostic impact of p16-status was confirmed and especially p16-positive never smoking patients have superior outcome after RT., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: HPV is found in head and neck cancer from all sites with a higher prevalence in oropharynx cancer (OPC) compared to non-OPC. HPV/p16-status has a significant impact on radiotherapy (RT) outcome in advanced OPC, but less is known about the influence in non-OPC. We analyzed HPV-associated p16-expression in a cohort of patients with stage III-IV pharynx and larynx cancer treated with primary, curatively intended (chemo-)RT, aiming to test the hypothesis that the impact of HPV/p16 also extends to tumors of non-oropharyngeal origin., Material and Methods: 1294 patients enrolled in previously conducted DAHANCA-trials between 1992 and 2012 were identified. Tumors were evaluated by p16-immunohistochemistry and classified as positive in case of staining in >70% of tumors cells., Results: Thirty-eight percent (490/1294) of the tumors were p16-positive with a significantly higher frequency in OPC (425/815) than in non-OPC (65/479), p<.0001. In OPC p16-positivity significantly improved loco-regional control (LRC) (adjusted HR [95% CI]: 0.43 [0.32-0.57]), event-free survival (EFS) (HR 0.44 [0.35-0.56]), and overall survival (OS) (HR: 0.38 [0.29-0.49]), respectively, compared with p16-negativity. In non-OPC no prognostic impact of p16-status was found for either endpoint: LRC (HR: 1.13 [0.75-1.70]), EFS (HR: 1.06 [0.76-1.47]), and OS (HR: 0.82 [0.59-1.16])., Conclusions: The independent influence of HPV-associated p16-expression in advanced OPC treated with primary RT was confirmed. However, RT-outcome in the group of non-OPC did not differ by tumor p16-status, indicating that the prognostic impact may be restricted to OPC only., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Aim: EGFR and HPV-associated p16 are among the most investigated biomarkers in head and neck cancer. The aim was to investigate the correlation and interaction between these two markers and to evaluate their potential prognostic significance when combined., Materials and Methods: 336 Oropharyngeal carcinomas treated with primary radiotherapy (66-68 Gy, 2fx/day, 10-12 Gy/week) and with known EGFR/p16-status estimated semiquantitatively by immunohistochemistry were included in the study. Data were evaluated by EGFR-expression (high/low) and p16-status (positive/negative) consequently dividing tumours into four groups by combination of the biomarkers. Patient/tumour characteristics and complete 5-year follow-up were available., Results: Low EGFR-expression was significantly more common in p16-positive tumours compared to p16-negative, p < 0.0001. p16 positivity showed a strong prognostic impact (p < 0.0001, HR = 0.22 [0.13-0.38]), whereas EGFR was a weak prognostic marker when local control was used as endpoint (p = 0.03, HR = 0.53 [0.29-0.94]). Combination of EGFR/p16 did not add significant information to p16 alone and by multivariable analysis only p16 showed significant prognostic information for all evaluated endpoints., Conclusions: Both EGFR and p16 bear prognostic information in oropharyngeal cancer, although p16 is, by far, the strongest prognostic factor. The markers seem to be correlated and this might have influence when evaluating the effect of EGFR inhibition in oropharyngeal tumours., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Hypoxia is a cause of resistance to radiotherapy, especially in patients with head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to evaluate (18)F-fluoroazomycin arabinoside (FAZA) positron emission tomography (PET)/computed tomography (CT) hypoxia imaging as a prognostic factor in HNSCC patients receiving radiotherapy., Material and Methods: Forty patients with HNSCC treated with radiotherapy (66-76 Gy) were included. Static FAZA PET/CT imaging 2h post injection was conducted prior to irradiation. The hypoxic volume (HV) was delineated using a tumor-to-muscle value ≥ 1.4. In 13 patients, a repetitive FAZA PET/CT scan was conducted during the radiotherapy treatment., Results: A hypoxic volume could be identified in 25 (63%) of the 40 tumors. FAZA PET HV varied considerably with a range from 0.0 to 30.9 (median: 0.3) cm(3). The T(max)/M(med) ranged from 1.1 to 2.9 (median: 1.5). The distribution of hypoxia among the Human Papillomavirus (HPV) positive (12/16) and negative (13/24) tumors was not significant different. In the FAZA PET/CT scans performed during radiotherapy, hypoxia could be detected in six of the 13 patients. For these six patients the location of HV remained stable in location during radiotherapy treatment, though the size of the HV decreased. In 30 patients a positive correlation was detected between maximum FAZA uptake in the primary tumor and the lymph node. During a median follow up of 19 months a significant difference in disease free survival rate with 93% for patients with non hypoxic tumors and 60% for patients with hypoxic tumors could be detected., Conclusion: This study emphasizes the role of FAZA PET/CT imaging as a suitable assay with prognostic potential for detection of hypoxia in HNSCC., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To validate the predictive impact of a hypoxia gene expression classifier in identifying patients with head and neck squamous cell carcinoma (HNSCC) having benefit from hypoxic modification of radiotherapy., Patients and Methods: Gene expressions were quantified from formalin-fixed, paraffin-embedded tumour biopsies of 323 HNSCC patients randomized for placebo or nimorazole in conjunction with radiotherapy in the DAHANCA 5 study. Tumours were classified as either "more" or "less" hypoxic with a classifier constituting of 15 hypoxia responsive genes. The predictive impact was evaluated by analysing the response to nimorazole vs. placebo in terms of loco-regional tumour control (LRC) and disease-specific survival (DSS) in the two classified groups., Results: Hundred and fourteen patients (35%) were classified as having "more" hypoxic tumours. These patients had a significant benefit of hypoxic modification with nimorazole compared with placebo in terms of LRC (5-year actuarial values 49% vs. 18%; p=0.001) and DSS (48% vs. 30%; p=0.04). "Less" hypoxic tumours had no significant effect of hypoxic modification (LRC: 50% vs. 44%; p=0.39, DSS: 57% vs. 51%; p=0.49) and generally an outcome, which was similar to "more" hypoxic tumours treated with nimorazole. In contrast to HPV-negative tumours, HPV-positive tumours had a substantially better outcome in response to radiotherapy, which was irrespective of hypoxic modification., Conclusions: A predictive 15-gene hypoxia classifier could identify patients associated with improved outcome after combining radiotherapy with hypoxic modification and underlines the relevance of such therapy. The impact of the classifier was limited to HPV-negative tumours., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Tumour HPV-positivity is a favourable prognostic factor in the radiotherapy of HNSCC, but the optimal radiotherapy regimen for HPV-positive HNSCC is not yet defined. Reducing overall treatment time is known to improve outcome in the radiotherapy of HNSCC as was also demonstrated in the randomised DAHANCA 6&7 trial. We aimed to assess the influence of tumour HPV-status, expressed by p16, on the response to accelerated fractionated radiotherapy in HNSCC through evaluation of the DAHANCA 6&7 trial., Materials and Methods: Immunohistochemical detection of HPV-associated p16-expression was performed on FFPE-pre-treatment tumour-tissues from 794 patients enrolled in the DAHANCA 6&7 trial. The influence of tumour p16-status on loco-regional tumour control and survival as a function of fractionation schedule (5Fx/week vs 6Fx/week) was evaluated 5years after the completion of radiotherapy., Results: The significant and independent prognostic value of tumour p16-positivity in HNSCC radiotherapy was confirmed, with adjusted hazard ratios (HR) of 0.58 [0.43-0.78], 0.47 [0.33-0.67] and 0.54 [0.42-0.68] for loco-regional control, disease-specific and overall survival, respectively. Accelerated radiotherapy significantly improved loco-regional tumour control compared to conventional radiotherapy, adjusted HR: 0.73 [0.59-0.92] and the benefit of the 6Fx/week regimen was observed both in p16-positive (HR: 0.56 [0.33-0.96]) as well as in p16-negative tumours (HR: 0.77 [0.60-0.99]). Disease-specific survival was also significantly improved with accelerated radiotherapy in the group of p16-positive tumours (adjusted HR: 0.43 [0.22-0.82])., Conclusion: Accelerated radiotherapy significantly improves outcome in HNSCC compared to conventional fractionation. The observed benefit is independent of tumour p16-status and the use of a moderately accelerated radiotherapy regimen seems advantageous also for HPV/p16-positive HNSCC., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The profound influence of Human papillomavirus (HPV) on the epidemiological pattern and clinical course of head and neck cancer (HNSCC) has led to a change in the traditional understanding of this disease entity. Separate therapeutic strategies based on tumour HPV status are under consideration and in this light provision of knowledge concerning the influence of tumour HPV on the radiation response in HNSCC appears highly relevant. This review provides a summary of the current understanding of the role of HPV in head and neck cancer with specific focus on the viral impact on radiotherapy outcome of HNSCC., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: HPV/p16-positive head and neck cancers (HNSCC) show superior response to radiotherapy, compared with virus-negative tumours. Tumour hypoxia induces radioresistance and the randomised DAHANCA 5 trial found that the hypoxic cell radiosensitiser nimorazole significantly improved the outcome in HNSCC. Using p16-status as a retrospective stratification parameter, we aimed to assess the influence of p16-expression on the response to nimorazole in HNSCC., Materials and Methods: Pre-treatment tumour blocks were available from 331 of the 414 patients in the DAHANCA 5 trial and evaluated by immunohistochemistry for p16-expression. The influence of p16-expression on outcome was analysed as a function of treatment group (nimorazole/placebo) 5 years after radiotherapy., Results: Overall, patients treated with nimorazole had significantly better loco-regional control than did those given placebo: hazard ratio (HR) 0.70 [95% CI 0.52-0.93]. Positive expression of p16 also significantly improved outcome after radiotherapy (0.41 [0.28-0.61]). In the subgroup of patients with p16-negative tumours, loco-regional failure was more frequent in the placebo group than in the nimorazole group (0.69 [0.50-0.95]). However, in the p16-positive group, patients treated with nimorazole had a loco-regional control rate similar to patients given placebo (0.93 [0.45-1.91])., Conclusions: HPV/p16-expression significantly improved outcome after radiotherapy in HNSCC. Hypoxic modification improved outcome in HPV/p16-negative tumours but was of no significant benefit in HPV/p16-positive tumours, suggesting that hypoxic radioresistance may not be clinically relevant in these tumours., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)