Abstract 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.
Defining margins around the Gross Tumour Volume (GTV) to create a Clinical Target Volume (CTV) for head and neck cancer radiotherapy has traditionally been based on presumed knowledge of anatomical ...routes of spread. However, using a concentric geometric expansion around the GTV may be more reproducible. The purpose of this study was to analyse the inter-observer consistency of geometric CTV delineation with adaptation for anatomical boundaries versus anatomically defined CTVs.
Radiation oncologists at four Danish cancer centres delineated high, intermediate and elective dose CTVs (CTV1, CTV2 and CTV3, respectively) in a patient-case template (stage IV squamous cell carcinoma of the oropharynx), first using mainly anatomical margins (original standard) and then using concentric geometric expansion (new standard). Each centre made a dummy-run radiotherapy plan based on the delineated CTVs. The difference between the CTV contours and the radiotherapy plans was evaluated across the centres.
Anatomy-based contours were significantly more heterogenous and showed larger volume differences between centres than geometric margins. Dice similarity coefficient increased by 0.29 and mean surface distance decreased by 4mm for CTV1. Use of consistent CTV volumes resulted in more consistent irradiated volumes between centres.
Introduction of geometric margins resulted in more uniform CTV1 and CTV2 delineation. Geometric CTV expansion was easier, left less room for misinterpretation, and resulted in more uniform treatment plans with similar irradiated high and intermediate dose volumes across all centres.
Abstract Background Comorbidity is common in head and neck squamous cell carcinoma (HNSCC) patients due to the etiology of the disease being primarily smoking. The aim of this study was to ...investigate the impact of comorbidity on survival in a national population-based cohort study on 9388 HNSCC-patients treated with radiotherapy (RT), to re-evaluate the prognostic impact of individual diseases within the Charlson Comorbidity Index (CCI), and to develop a revised head and neck comorbidity index (HN-CCI). Material and methods A national cohort of 9388 HNSCC-patients treated with curative intended RT diagnosed from 1992 to 2008 was identified from the DAHANCA-database. Data on comorbidity prior to HNSCC-diagnosis was obtained from the National Patient Registry and adapted to the CCI. Results By dividing the patients into two groups, we tested and validated which type of comorbidities within the CCI affected overall survival (OS) and cancer specific death (CSD). In total, 36% of patients had comorbidity. Six comorbid conditions within the CCI significantly reduced five-year OS probability: congestive heart failure, cerebrovascular disease, chronic pulmonary disease, peptic ulcer disease, liver disease, and diabetes, and based on these conditions the new head and neck specific comorbidity index was developed, the HN-CCI. Comorbidity according to HN-CCI had a highly significant impact on OS, whereas it was not associated with CSD. Chronological age was not associated with increased risk of CSD after controlling for comorbidity. Conclusions Comorbidity is frequent in HNSCC patients and negatively impacts OS. Therefore assessment of comorbidity will be of great importance, both in order to treat/optimize patient’s health before radiotherapy, but also in order to be able to stratify/control for comorbidity in randomized trials to avoid bias. Re-evaluation of the CCI revealed that only six conditions had an impact on survival, and a new modified index to assess comorbidity for HNSCC-patients was developed. The performance of HN-CCI to stratify patients on survival was good and HN-CCI is highly recommended for future assessment of comorbidity and prognostic staging of radiotherapy-treated HNSCC-patients.
Highlights • A national Danish study presenting 201 patients with adenoid cystic carcinoma. • 10-year disease specific survival was 75%. • 36% experienced recurrence during follow-up (median 7.5 ...years). • The treatment of choice is surgery with free margins. • Adjuvant radiotherapy should be considered in selected patients.
Abstract
Background. Head and neck squamous cell carcinoma (HNSCC) is primarily caused by smoking and alcohol. Besides having a carcinogenic effect, smoking also leads to other diseases and thus ...contributes to a high prevalence of comorbidities among HNSCC patients. Furthermore, the world population is becoming older resulting in more elderly patients with HNSCC. The aim of this study was to investigate the prevalence and impact of comorbidity in a retrospective nationwide population-based study of all Danish HNSCC patients diagnosed from 1992 to 2008. Material and methods. A total of 12 623 patients diagnosed with HNSCC in the period from 1992 to 2008 were identified through the Danish Head and Neck Cancer group (DAHANCA) database. By linking to the Danish registers, information on somatic comorbidity present prior to the HNSCC diagnosis was obtained and adapted to the Charlson Comorbidity Index (CCI). The influence of comorbidity on overall survival and cancer specific death was evaluated and the type and prevalence of comorbidity described. Results. In total, 36% of patients had comorbidity according to CCI. Increasing age was significantly associated with increasing CCI. In multivariate analyses, the CCI score remained a strong independent prognostic factor for overall survival, the HR being 1.16 (95% CI 1.08; 1.25), 1.34 (1.22; 1.46), 1.63 (1.51; 1.80) for patients with CCI score 1, 2, and 3+, respectively. The CCI score did not influence cancer specific death. Conclusion. Comorbidity is common among HNSCC patients and has a negative prognostic impact on overall survival. Cancer specific death was not affected by comorbidity suggesting that patients die from their comorbidities rather than their cancer. In the future, more elderly patients with comorbidity will require treatment which will demand a change in the healthcare system with a multidisciplinary approach required in order to take care of both their cancer and their comorbidities.
Abstract 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 (5 Fx/week vs 6 Fx/week) was evaluated 5 years 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 6 Fx/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.
Abstract Purpose The DAHANCA 6 trial evaluated tumor response and morbidity after moderate accelerated radiotherapy compared to conventional fractionated radiotherapy in patients treated for glottic ...squamous cell carcinoma (SCC). Further, the failure pattern and incidence of new primary tumors were explored. Patients and methods Six hundred and ninety-four patients with non-metastatic glottic SCC were randomized between six or five weekly fractions (fx/w) of radiotherapy to the same total dose. The median treatment time was 38 and 46 days, respectively. The primary endpoint was loco-regional failure. Results Median follow-up time was 14.5 years. Of the 177 failures, 167 involved T-site. The cumulative incidence of loco-regional failure (LRF) was 21.6% in the 6 fx/w group and 29.3% in the 5 fx/w group and the corresponding hazard rate (HR) of LRF was 0.72 (CI: 0.53–0.97, p = 0.04). The effect of acceleration on LRF was especially evident in well differentiated tumors (HR = 0.42 (CI: 0.23–0.75) and in T1–2 tumors (HR = 0.60 (CI: 0.41–0.89)). The HR of laryngectomy was 0.72 (CI: 0.50–1.04) in the 6 fx/w group compared to the 5 fx/w group. The hazards of disease-specific death, event-free survival, and overall survival were comparable between the two groups. Significantly more patients experienced severe acute mucositis in the 6 fx/w group but the incidence of late morbidity was comparable between the groups. New primary tumors occurred in 22.5% of the patients. Conclusion Moderate accelerated radiotherapy significantly improved loco-regional control in patients with glottic SCC.
Abstract Background and purpose The aim of this report was to describe the incidence and prevalence of acute and late morbidity in the DAHANCA 6&7 multicentre randomised trial with accelerated ...radiotherapy for squamous cell carcinoma of the head and neck. Materials and methods The DAHANCA 6&7 study included 1476 patients eligible for primary radiotherapy alone. Patients were randomised between five or six weekly fractions of conventional radiotherapy. The prescribed dose was 66–68 Gy in 33–34 fractions. All patients were seen weekly during treatment and at regular intervals after completion where detailed morbidity recording was done. Reports from 1468 patients were available for analysis of treatment related morbidity. Results Accelerated radiotherapy caused a significant ( p < 0.05) increase in the peak incidence of: use of analgesics (53% vs. 65%), dysphagia (35% vs. 45%), mucosal oedema (52% vs. 59%), and mucositis (33% vs. 53%). All acute reactions were reversible and healed within three months after radiotherapy. Loss of taste, xerostomia, and acute skin reaction was not different between the two groups. For all late endpoints except fibrosis and atrophy a decline in prevalence was observed in the years after radiotherapy, there was no significant difference between randomisation arms in any of the late endpoints. Conclusions Six fractions per week, resulting in a one-week reduction in overall treatment time relative to conventional radiotherapy increased acute but not late morbidity. Since acceleration improves loco-regional tumour control, the schedule represents a significant improvement of the therapeutic ratio for head and neck radiotherapy and might be close to the maximal gain possible with accelerated fractionation alone.
Abstract Purpose To describe the pattern of failure in a national consecutive cohort of patients with glottic squamous cell carcinomas (SCC) treated with primary radiotherapy (RT) with curative ...intent over a 41-year period. Materials and methods All patients undergoing curative treatment for a glottic SCC diagnosed in Denmark between 1971 and 2011 were included and followed from the first contact with the oncology center to death or February 15, 2015. Results 5001 patients were identified of whom 98% had primary RT. The median follow-up was 9.1 years/5.7 years (patients alive/patients who died). Ten patients were lost to follow-up. In total 1511 failures were observed; of these 93%, 11% and 5% included T site, N site, and M site, respectively. For patients diagnosed in the 70s and the 00s, respectively, the five-year incidences were: local failure (32% vs 19%), loco-regional failure (34% vs 21%), laryngectomy (26% vs 10%), laryngectomy-free survival (48% vs 62%), disease-free survival (62% vs 68%), and overall survival (62% vs 68%). The five-year incidence of ultimate failure (13–16%) remained statistically unchanged. Conclusion From the 70s to the 00s a continually improving primary disease-control was observed with a concurrent decrease in the incidence of laryngectomy. The survival rate was significantly higher in the 00s compared to the previous three decades.
Abstract
Background. Dysphagia is a common and debilitating side effect in head and neck radiotherapy (RT). Prognostic factors are numerous and their interrelationship not well understood. The aim of ...this study was to establish a multivariate prognostic model for acute and late dysphagia after RT, based on information from a prospective trial. Material and methods. The DAHANCA 6&7 randomized study included 1476 patients with head and neck cancer eligible for primary RT alone. Patients were randomized between 5 and 6 weekly fractions of conventional RT, and received 62-70 Gy in 31-35 fractions. Patients were scored for dysphagia weekly during treatment and at regular intervals until five years after treatment. Dysphagia scores were available from 1461 patients. Results. Acute dysphagia according to DAHANCA grades 1, 2, 3 and 4 occurred in 83%, 71%, 43% and 23%, respectively. Severe dysphagia occurred in 47% and 38% of patients receiving accelerated or conventional radiotherapy, respectively (p = 0.001). At one, two, three, four and five years the prevalence of chronic dysphagia above grade 0, was 46%, 32%, 29%, 24%, 23%, respectively with no difference between 5 and 6 fractions. In multivariate analysis, the following parameters were independent factors for severe acute dysphagia: T3-T4 tumors, N-positive disease, non-glottic cancer, age> median, baseline dysphagia > 1 and accelerated radiotherapy. The following factors were prognostic factors for late dysphagia: non-glottic cancer, T3-T4, N-positive disease and baseline dysphagia > 1. The data confirmed previously published predictive models, as it was possible to separate patients in groups with low, medium and high risk of dysphagia, respectively, based on pre-treatment risk scores. Conclusion. Prognostic models were established to characterize patients at risk of developing acute or late dysphagia in the DAHANCA 6&7 trial. The results may be useful to identify patients at risk of dysphagia and thus candidates for prophylactic measures against swallowing dysfunction.
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