Elo Andersen

Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6&7 randomised controlled trial

BACKGROUND Although head and neck cancer can be cured by radiotherapy, the optimum treatment time for locoregional control is unclear. We aimed to find out whether shortening of treatment time by use of six instead of five radiotherapy fractions per week improves the tumour response in squamous-cell carcinoma. METHODS We did a multicentre, controlled, randomised trial. Between January, 1992, and December, 1999, of 1485 patients treated with primary radiotherapy alone, 1476 eligible patients were randomly assigned five (n=726) or six (n=750) fractions per week at the same total dose and fraction number (66-68 Gy in 33-34 fractions to all tumour sites except well-differentiated T1 glottic tumours, which were treated with 62 Gy). All patients, except those with glottic cancers, also received the hypoxic radiosensitiser nimorazole. Analysis was by intention to treat. FINDINGS More than 97% of the patients received the planned total dose. Median overall treatment times were 39 days (six-fraction group) and 46 days (five-fraction group). Overall 5-year locoregional control rates were 70% and 60% for the six-fraction and five-fraction groups, respectively (p=0.0005). The whole benefit of shortening of treatment time was seen for primary tumour control (76 vs 64% for six and five fractions, p=0.0001), but was non-significant for neck-node control. Six compared with five fractions per week improved preservation of the voice among patients with laryngeal cancer (80 vs 68%, p=0.007). Disease-specific survival improved (73 vs 66% for six and five fractions, p=0.01) but not overall survival. Acute morbidity was significantly more frequent with six than with five fractions, but was transient. INTERPRETATION The shortening of overall treatment time by increase of the weekly number of fractions is beneficial in patients with head and neck cancer. The six-fractions-weekly regimen has become the standard treatment in Denmark.

Cervical lymph node metastases from unknown primary tumours Results from a national survey by the Danish Society for Head and Neck Oncology

BACKGROUND AND PURPOSE The management of patients with cervical lymph node metastases from unknown primary tumours is a major challenge in oncology. This study presents data collected from all five oncology centres in Denmark. MATERIAL AND METHODS Of the 352 consecutive patients with squamous cell or undifferentiated tumours seen from 1975 to 1995, a total of 277 (79%) were treated with radical intent. The general treatment policy at all centres during the entire study period has been to treat all suitable candidates with radiotherapy to both sides of the neck and include elective irradiation of the mucosal sites in nasopharynx, and larynx, hypopharynx and larynx (81%). Irradiation of the ipsilateral neck only was done in 26 patients (10%). Radical surgery was the only treatment in 23 N1-N2 patients (9%). RESULTS The 5-year estimates of neck control, disease-specific survival and overall survival for radically treated patients were 51, 48 and 36%, respectively. The emergence of the occult primary was observed in 66 patients (19%). About half of the emerging primaries were within the head and neck region with oropharynx, hypopharynx and oral cavity being the most common sites. Emerging primaries outside the head and neck region were primarily located in the lung (19 patients) and oesophagus (five patients). The frequency of emerging primary in the head and neck was significantly higher in patients treated with surgery alone, the actuarial risks at 5-year being 54+/-1% (no RT) vs. 15+/-3% (with RT), P<0.0001. The most important factor for neck control was nodal stage (5-year estimates 69% (N1), 58% (N2) and 30% (N3)). Other important parameters for neck control and disease-specific survival included haemoglobin, gender and overall treatment time. Patients treated with ipsilateral radiotherapy had a relative risk of recurrence in the head and neck region of 1.9 compared with patients treated to both neck and mucosa. At 5 years, the estimated control rates were 27% (ipsilateral) and 51% (bilateral; P=0.05). The 5-year disease-specific survival estimates were 28 and 45%, respectively (P=0.10). CONCLUSIONS This study has confirmed that patients with neck node metastases from occult head and neck cancer have clinical features and prognosis similar to other head and neck malignancies. Extensive irradiation to both sides of the neck and the mucosa in the entire pharyngeal axis and larynx resulted in significantly less loco-regional failures compared with patients treated with ipsilateral techniques, but only a trend towards better survival. A prospective randomized trial is required to determine the optimal strategy in terms of locoregional control, survival and morbidity.

The influence of HPV-associated p16-expression on accelerated fractionated radiotherapy in head and neck cancer: Evaluation of the randomised DAHANCA 6&7 trial

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.

Salivary gland carcinoma in Denmark 1990–2005: A national study of incidence, site and histology. Results of the Danish Head and Neck Cancer Group (DAHANCA)

To describe the incidence, site and histology (WHO 2005) of salivary gland carcinomas in Denmark. Nine hundred and eighty-three patients diagnosed from 1990 to 2005 were identified from three nation-wide registries. The associated clinical data were retrospectively retrieved from patient medical records. Histological revision was performed in 886 cases (90%). Based on histological revision, 31 patients (3%) were excluded from the study leaving 952 for epidemiological analysis. The mean crude incidence in Denmark was 1.1/100,000/year. The male vs. female ratio was 0.97 and the median age was 62 years. The parotid gland was the most common site (52.5%) followed by the minor salivary glands of the oral cavity (26.3%). The most frequent histological subtypes were adenoid cystic carcinoma (25.2%), mucoepidermoid carcinoma (16.9%), adenocarcinoma NOS (12.2%) and acinic cell carcinoma (10.2%). The revision process changed the histological diagnosis in 121 out of 886 cases (14%). The incidence of salivary gland carcinoma in Denmark is higher than previously reported. More than half of salivary gland carcinomas are located in the parotid gland with adenoid cystic carcinoma being the most frequent subtype. Histological classification of salivary gland carcinomas is difficult and evaluation by dedicated pathology specialists might be essential for optimal diagnosis and treatment.

Salvage laryngectomy and pharyngocutaneous fistulae after primary radiotherapy for head and neck cancer: a national survey from DAHANCA

In 1998, the Danish Society for Head and Neck Oncology decided to conduct a nationwide survey at the five head and neck oncology centers with the aim of evaluating the surgical outcome of salvage laryngectomy after radiotherapy with special emphasis on identifying factors that could contribute to the development of pharyngocutaneous fistulae.

Impact of HPV-associated p16-expression on radiotherapy outcome in advanced oropharynx and non-oropharynx cancer

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.

The impact of comorbidity on outcome in 12 623 Danish Head and Neck Cancer Patients: A population based study from the DAHANCA database

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.

Prevalence and peak incidence of acute and late normal tissue morbidity in the DAHANCA 6&7 randomised trial with accelerated radiotherapy for head and neck cancer

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.

Evaluation of comorbidity in 9388 head and neck cancer patients: a national cohort study from the DAHANCA database.

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 patients 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.

High serum levels of YKL-40 in patients with squamous cell carcinoma of the head and neck are associated with short survival

YKL‐40 is a glycoprotein secreted by macrophages, neutrophils and malignant tumor cells. Elevated serum levels of YKL‐40 are associated with poor prognosis in several malignancies. In this study, we examined the prognostic value of serum YKL‐40 before treatment and during follow‐up in patients with squamous cell carcinoma of the head and neck (HNSCC). YKL‐40 was determined by ELISA retrospectively in serum from 173 patients with primary HNSCC before treatment and up to 2 years after treatment. Median follow‐up time was 7.9 years. YKL‐40 protein expression in tumor biopsies was assessed by immunohistochemistry in 50 patients. Pretreatment serum YKL‐40 was elevated in 53%. Patients with high serum YKL‐40 had shorter survival than patients with normal serum YKL‐40 (33 vs. 84 months; p = 0.008). Multivariate Cox analysis including pretreatment serum YKL‐40, age, sex, primary tumor site, TNM classification and treatment demonstrated that TNM classification (HR = 2.61, p = 0.02) and serum YKL‐40 (log‐transformed continuous variable: HR = 1.55, p < 0.0001) were independent prognostic variables of overall survival (OS). Multivariate Cox analysis demonstrated that TNM classification (HR = 5.77, p = 0.001) and serum YKL‐40 (dichotomous variable: HR = 2.75, p = 0.01) were independent predictors of recurrence‐free survival. During follow‐up after radiotherapy, a high serum YKL‐40 (log‐transformed continuous variable) in patients with TNM Stage III and IV disease predicted poorer OS within 6 months (HR = 1.95, p < 0.0001). Immunohistochemical analysis showed YKL‐40 expression in the malignant tumor cells. In conclusion, serum YKL‐40 was demonstrated to be an independent prognostic biomarker of recurrence‐free and overall survival in patients with HNSCC.