Associations between skin rash, treatment outcome, and single nucleotide polymorphisms in head and neck cancer patients receiving the EGFR-inhibitor zalutumumab: results from the DAHANCA 19 trial.

PURPOSE: To study the associations between development of moderate to severe skin rash, clinical outcome, and single nucleotide polymorphisms (SNPs) in candidate genes in head and neck cancer patients from the DAHANCA 19 trial receiving the EGFR-inhibitor zalutumumab concurrently with radiation treatment. MATERIAL AND METHODS: 310 patients were included from the zalutumumab-arm of the DAHANCA 19 study. Nine SNPs in the candidate genes EGFR, EGF, AREG, FCGR2A, FCGR3A, and CCND1 were successfully determined in 294 patients. Clinical endpoints were moderate to severe skin rash within the first 3 weeks of treatment, loco-regional failure (LRF), disease-specific survival (DSS), and overall survival (OS). RESULTS: During the first 3 weeks of treatment, 86% of the patients experienced any grade of rash and 17% experienced a moderate to severe rash. Development of moderate to severe rash was not associated with LRF or DSS but was associated with improved OS, HR 0.40 (95% CI: 0.19-0.82). The effect was similar for patients with p16-negative or p16-positive tumors (p = .90). After adjustment for comorbidity and performance status, the minor alleles of SNPs rs9996584 and rs13104811 located near the AREG gene were significantly associated with increased risk of moderate to severe rash with per-allele odds ratios of 1.61 (1.01-2.54) and 1.56 (1.00-2.44). SNP rs11942466 located close to rs9996584 had a borderline significant association, and none of the other SNPS were significantly associated with risk of skin rash. CONCLUSIONS: Moderate to severe skin rash after zalutumumab during radiation treatment was associated with improved OS, independent of HPV/p16-status. Genetic variants in AREG (member of the EGF family) may be associated with increased risk of skin rash.

DAHANCA 10 - Effect of darbepoetin alfa and radiotherapy in the treatment of squamous cell carcinoma of the head and neck. A multicenter, open-label, randomized, phase 3 trial by the Danish head and neck cancer group.

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.

Oncocytic carcinoma of the salivary glands: A Danish national study.

OBJECTIVES: To present a Danish national series of oncocytic carcinoma (OC) patients, including data on treatment, recurrence and survival. METHODS: From the national Danish database of salivary gland carcinomas, all patients diagnosed with OC from 1990 to 2005 were identified and data concerning demographics, tumor site, clinical stage and treatment profiles were extracted. A follow-up was carried out. RESULTS: Of the 15 cases of salivary gland OC, eight were female. The incidence was 0.02/100.000 inhabitants per year in Denmark, 13 patients presented with OC in the parotid gland and two patients with OC in the submandibular gland. Eight patients had nodal involvement at the time of diagnosis. None of the patients had distant metastases at the time of diagnosis. All patients were treated with primary surgery and seven patients received adjuvant radiotherapy. Half of the patients had recurrence. Six patients were alive at 5 years follow up and one patient was alive without recurrence at 10 years follow up. CONCLUSIONS: This study is the first to report a national incidence of oncocytic carcinoma in the salivary glands. The results confirm oncocytic carcinoma to be a salivary gland carcinoma with a poor prognosis. All patients experiencing recurrence died of the disease. Treatment must be aggressive. National registries are necessary to achieve further knowledge for future treatment recommendations.

Incidence of and survival after glottic squamous cell carcinoma in Denmark from 1971 to 2011-A report from the Danish Head and Neck Cancer Group.

AIM: To describe the incidence, disease-specific mortality (DSM), and overall survival (OS) of patients with glottic squamous cell carcinomas (SCC) in Denmark from 1971-2011 in a national population-based cohort of consecutive patients. MATERIALS AND METHODS: All patients diagnosed with glottic SCC stage I-IV between 1971 and 2011 in Denmark were included. Patients were identified from the Danish Head and Neck Cancer database, which has a coverage of approximately 100% of registered glottic cancer in Denmark. Information on vital status and cause of death were updated using patient charts and national registries. RESULTS: In total 5132 patients with glottic SCC were included. The yearly number of new cases increased from 107 in the 1970s to 139 in the 2000s. Overall, the incidence increased from 1.9 to 2.6 per 100,000, with a more prominent increase in men (3.5 to 4.7) compared with women (0.4 to 0.6). The 5-year DSM was 16% (15-17%) and the 5-year OS was 63% (61-64). The hazard rate of DSM adjusted for patient characteristics, tumour characteristics and waiting-time was significantly lower in the 2000s (p < 0.01), and the hazard rate of OS was significantly higher (p < 0.01) compared to the earlier decades. Longer waiting-time for treatment (>25 d) significantly increased DSM and reduced OS. CONCLUSION: Despite being highly avoidable with smoking cessation, the incidence of glottic SCC increased in Denmark from 1971-2011. The adjusted hazard rate of DSM and overall death after glottic SCC was significantly lower in the 2000s compared to previous decades. Waiting-time for treatment significantly influenced DSM and OS.

Polymorphous low-grade adenocarcinoma: A Danish national study.

OBJECTIVES: To present a national series of polymorphous low-grade adenocarcinoma (PLGA) patients, including survival rates and an analysis of prognostic factors. MATERIALS AND METHODS: By merging three Danish nationwide registries, 73 patients diagnosed with PLGA from 1990 to 2005 were identified. Histological slides were reviewed and data concerning demographics, tumour site, clinical stage, treatment profiles and follow-up were retrieved. Survival estimates and prognostic factors were evaluated by comparing Kaplan-Meier plots using the Mantel-Haenszel log-rank test. RESULTS: Of the 73 patients, 47 (64%) were female. Median age was 58years. The most common location was the palate (73%). Median latency was five months. Recurrence was seen in 13% of patients. Overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) rates after 10years were 73%, 99% and 83%, respectively. Univariate analyses suggested that free resection margins significantly improve RFS. CONCLUSION: PLGA usually has an excellent survival outcome even in cases of advanced stage disease and locoregional recurrence. Primary choice of treatment should be complete surgical excision. Although there is no convincing evidence for the efficacy of adjuvant radiotherapy, it should still be considered, particularly in cases of involved resection margins and advanced stage disease. Late recurrences are common and respond well to salvage therapy.

Salivary duct carcinoma: a Danish national study.

BACKGROUND: To present the first national series of salivary duct carcinoma patients, including survival rates and an analysis of prognostic factors. METHODS: By merging three Danish nationwide registries that encompass an entire population, 34 patients diagnosed with salivary duct carcinoma from 1990 to 2005 were identified. Histological slides were reviewed, and data concerning demographics, tumour site, clinical stage, treatment profiles and follow-up were retrieved. Survival estimates and prognostic factors were evaluated by comparing Kaplan-Meier plots using the Mantel-Haenszel log-rank test. RESULTS: Salivary duct carcinoma showed an incidence of 0.04/100.000 inhabitants/year. Distant recurrence was seen in 52% of patients. Five-year overall survival, disease-specific survival and recurrence-free survival were 32%, 42% and 35%, respectively. Univariate analyses suggested that overall stage (III/IV) and vascular invasion have a negative impact on all survival measures. Involved resection margins correlated with a poorer overall survival and disease-specific survival, whereas adjuvant radiotherapy improved overall survival and recurrence-free survival. CONCLUSIONS: Salivary duct carcinoma incidence averages to two episodes per year in the entire Kingdom of Denmark. With half of patients in this study experiencing distant recurrences and only a third surviving at 5 years, prognosis is dismal. Advanced overall stage, vascular invasion and involved resection margins all seem to correlate with a poorer survival, while adjuvant radiotherapy significantly improved outcome. Extensive T-site surgery, neck dissection and adjuvant radiotherapy are therefore recommended.

Locally advanced head and neck cancer treated with accelerated radiotherapy, the hypoxic modifier nimorazole and weekly cisplatin. Results from the DAHANCA 18 phase II study.

PURPOSE/OBJECTIVE: A phase II clinical trial evaluating the feasibility and outcome of treating locally advanced head and neck squamous cell carcinoma (HNSCC) with accelerated radiotherapy, the hypoxic modifier nimorazole and weekly cisplatin. MATERIAL AND METHODS: A total of 227 patients with stage III or IV HNSCC of the larynx, oropharynx, hypopharynx, or oral cavity where included between January 2007 and December 2010. The prescribed radiotherapy (RT) dose was 66-68 Gy in 2 Gy fractions, 6 F/W. The hypoxic radiosensitiser nimorazole was given orally at a dose of 1200 mg/m(2) before each fraction. Concomitant cisplatin (40 mg/m(2)) i.v. was given once a week for a maximum of six cycles. Outcome data were evaluated in terms of loco-regional tumour control (LRC), event-free survival (EFS) and overall survival (OS). Morbidity data were evaluated based on the DAHANCA routine registration. Human papillomavirus (HPV)-status was estimated by immunohistochemical staining of p16. RESULTS: Included were 178 (78%) men and 49 (22%) women with a median age of 57 years. All except five patients received RT as prescribed. At least five series of cisplatin was given to 164 (72%) of the patients, and 149 patients (66%) received the full dose of nimorazole. The five-year actuarial LRC, EFS and OS rates were 80%, 67% and 72%, respectively. The LRC rates according to site were: oropharynx: 88%, larynx: 77%, hypopharynx 72% and oral cavity 49%, respectively. HPV/p16 staining was obtained in 141 of the 150 oropharyngeal cancers. Of these, 112 (79%) were p16 pos and 29 (21%) were p16 neg. LRC for the p16 neg oropharyngeal cancers was poorer than for the p16 pos (74% vs. 91%; p = 0.02). Tube feeding during treatment was necessary for 146 (64%) patients. At 12 months this number was reduced to 6%. CONCLUSION: The treatment was tolerable in this cohort of locally advanced HNSCC patients. Acute and late toxicity was comparable to similar studies of chemoradiotherapy, and the outcome superior to the data reported in the literature. This strongly indicates that RT of advanced head and neck cancer must include as well hypoxic modification, accelerated fractionation as chemoradiotherapy to yield optimal outcome.

Salivary gland carcinoma in Denmark 1990-2005: outcome and prognostic factors. Results of the Danish Head and Neck Cancer Group (DAHANCA).

To describe outcome and prognostic factors in a national Danish series of patients treated for salivary gland carcinoma. From three Danish nation-wide registries and supplementary patient records, 871 patients diagnosed with primary major or minor salivary gland carcinoma in the period from 1990 to 2005 were identified. A total of 796 (91%) histological specimens were revised according to the WHO 2005 classification. The median follow-up time was 78 months. Three hundred and thirty-four patients (38%) experienced recurrence. Crude survival, disease-specific survival and recurrence-free survival after 5 and 10 years were 66%, 76%, 64% and 51%, 69%, 58%, respectively. In multivariate analysis age, latency, stage, microscopic margins, vascular invasion and histological grade were all independent prognostic factors with regards to crude and disease-specific survival. Stage, microscopic margins, vascular invasion and histological grade were independent prognostic factors for recurrence-free survival. Age over 61 years, latency under 8 months, stage 3+4 disease, involved or close microscopic margins, vascular invasion and high histological grade are all independent prognostic factors with a negative impact on survival in salivary gland carcinoma patients. This knowledge can be helpful in guiding clinicians in daily work and choice of treatment across the large variety of salivary gland carcinoma subtypes.

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.

The Danish national guidelines for treatment of oral squamous cell carcinoma.

The treatment strategy for oral squamous cell carcinoma in Denmark has traditionally varied between the different head and neck oncology centres. A study group within the Danish Society for Head and Neck Oncology (DSHHO) was formed with the aim of optimising and standardising the treatment strategy. The approach was to use single modality treatment for stage I, stage II and some stage III and combined modality treatment for stage III and IV. Surgery was the preferred treatment when it was considered possible to perform a radical excision of the tumour and possible lymph node metastases with acceptable aesthetic and functional outcome. The implementation of a recognised national guideline facilitates prospective studies on a large well-characterised cohort. This increases the possibility of obtaining valid data on parameters such as morbidity, loco-regional control and survival. In addition the establishment of a reference program facilitates national monitoring of the treatment using defined indicators and standards.

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

OBJECTIVE: 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. PATIENTS: A total of 472 consecutive patients undergoing postirradiation salvage laryngectomy in the period July 1, 1987-June 30, 1997 were recorded at the five head and neck oncology centers in Denmark. Age ranged from 36 to 84 years, median 63 years, 405 men and 67 women. Primary tumor site was glottic larynx (n = 242), supraglottic larynx (n = 149), other larynx (n = 45), pharynx (n = 27), and other (n = 9). All patients had received prior radiotherapy. RESULTS: Median time between radiotherapy and laryngectomy was 10 months (range, 1-348 months). A total of 89 fistulae lasting at least 2 weeks were observed, corresponding to an overall average fistulae risk of 19%. The number of performed laryngectomies per year decreased linearly (from 58 to 37), whereas the annual number of fistulae increased slightly (from 7 to 11), which meant that the corresponding estimated fistulae risk increased significantly from 12% in 1987 to 30% in 1997. Other significant risk factors for fistulae in univariate analysis included younger patient age, primary advanced T and N stage, nonglottic primary site, resection of hyoid bone, high total radiation dose, and large radiation fields. Multiple logistic regression analysis of these parameters suggested that nonglottic tumor site, late laryngectomy period (1987-1992 vs 1993-1997), and advanced initial T stage were independent prognostic factors for fistulae risk. Surgical parameters like resection of thyroid/tongue base/trachea or radiotherapy parameters like overall treatment time or fractions per week did not influence fistulae risk. CONCLUSIONS: The risk of fistulae is especially high in patients initially treated with radiotherapy for nonglottic advanced stage tumors. A significant decrease in the number of performed salvage laryngectomies over the 10 years was seen. Over the same time period, the annual number of fistulae remained almost constant. The resulting more than doubling of fistulae rate could thus in part be explained by less surgical routine.