Neck Oncology Cooperative Group Research Articles

Can Epstein-Barr virus DNA load in nasopharyngeal brushings or whole blood predict recurrent nasopharyngeal carcinoma in a non-endemic region? A prospective nationwide study of the Dutch Head and Neck Oncology Cooperative Group.

This study estimated the value of quantitative measurements of EBV markers in the clinical management of nasopharyngeal carcinoma in a non-endemic area. The aim was to predict prognosis and detect recurrent and residual disease. In 72 patients, EBV DNA load in blood and nasopharyngeal brushes, and IgA VCA-p18 and EBNA1 in plasma were measured at different time points. At diagnosis and post-treatment, a cut-off value was used for detecting disease [positive (PPV) and negative (NPV) predictive value]. The markers were correlated as a continuous variable with tumor stage, disease-free survival (DFS) and overall survival (OS). The Cox hazard ratio model assessed hazard ratios. At diagnosis, the markers were above the COV in 45, 92, 85 and 83% of the patients, respectively. Post-treatment, DNA load test in blood and brush had the best discriminating power (blood DNA load test: PPV 39% and NPV 97%, brush for local disease: PPV 75% and NPV 99%). Post-treatment, DNA load in blood was the best predictor for OS and DFS [hazard ratio 3.2 (95% CI 1.51-3.5) and 2.3 (95% CI 1.72-5.8)]. Assessing the EBV DNA load in blood has significant prognostic value, although the clinical value is for discussion. The EBV DNA load in the brush might improve early detection of local failures post-treatment.

Response evaluation after chemoradiotherapy for advanced staged oropharyngeal squamous cell carcinoma: a nationwide survey in the Netherlands.

Following failure of chemoradiotherapy (CRT) for advanced staged oropharyngeal squamous cell carcinomas (OPSCC), residual tumor can often be treated successfully with salvage surgery, if detected early. Current clinical practice in the VU University Medical Center is to perform routine response evaluation, i.e., examination under general anesthesia (EUA), 12 weeks after treatment. However, in the Netherlands there is no consensus on response evaluation in patients with advanced oropharyngeal cancer. Questionnaire on current clinical practice concerning response evaluation after CRT for advanced OPSCC in all eight head and neck cancer centers of the Dutch Head and Neck Oncology Cooperative Group. The response rate was 100%. Response evaluation was routinely performed with various methods in five institutions (62.5%) and in one institute (12.5%) only if clinical evaluation was difficult. Two centers (25%) did not perform response evaluation. In case of suspicion of residual disease during follow-up, six centers (75%) performed imaging prior to EUA and two centers (25%) only if clinical evaluation was difficult. Diagnostic techniques used prior to EUA were MRI (87.5%), diffusion-weighted MRI (37.5%), 18F-FDG-PET-CT (75-87.5%) and CT (37.5%). This survey shows a substantial variation in the diagnostic policy concerning response evaluation after CRT for advanced OPSCC in the Netherlands. There is a need for guidelines for response evaluation in patients with advanced oropharyngeal cancer.

Indications and extent of elective neck dissection in patients with early stage oral and oropharyngeal carcinoma: nationwide survey in The Netherlands

Different strategies are available for the management of patients with early (i.e. tumour stage one or two) oral or oropharyngeal carcinoma and a clinically negative neck. In 2006, a questionnaire was sent to the eight head and neck cancer centres of the Dutch Head and Neck Oncology Cooperative Group. This questionnaire covered: the factors influencing the decision to perform an elective neck dissection; the neck staging procedure; and the types of neck dissection undertaken. All eight questionnaires were returned completed. Respondents indicated that the site (n = 6), size (n = 7) and thickness (n = 6) of the primary tumour were important in decisions regarding elective neck dissection. Ultrasound-guided fine needle aspiration cytology was the most frequently used diagnostic technique (n = 7). Depending on the site and stage of the primary tumour presented, in the different cases 3-7 of the centres would perform an elective neck dissection. Selective neck dissections (i.e. levels I to III/IV) were more frequently performed than modified radical neck dissections. There was no uniformity regarding management of the clinically negative neck in patients with early stage oral and oropharyngeal carcinoma, within The Netherlands.

Detecting hypothyroidism after treatment for laryngeal or hypopharyngeal carcinomas: a nationwide survey in The Netherlands

A survey to evaluate the management of thyroid function testing was performed in the major institutions treating head and neck cancer in The Netherlands. In July 2006, a questionnaire considering laboratory tests, selection of patients, scheme and treatment of hypothyroidism was sent to physicians who treat head and neck cancer patients in 19 hospitals in the Netherlands including all eight head and neck centers of the Dutch Head and Neck Oncology Cooperative Group (Nederlandse Werkgroep Hoofd-Halstumoren; NWHHT). Thirty-two of thirty-nine (84%) questionnaires were returned. Twenty-four (75%) physicians tested only when symptoms were mentioned, 42% tested all patients treated with different treatment modalities (radiotherapy, chemotherapy or surgery). Most physicians screened annually (32%) or every 6 months (24%) on hypothyroidism. All physicians screened for TSH, 18 physicians (69%) tested free T4 as well. Fifty-eight percent of physicians referred their patients to another department for supplementation therapy when thyroid function is tested abnormal. Twenty physicians (65%) would appreciate guidelines on screening although 75% are aware of the guidelines of the Dutch Head and Neck Oncology Cooperative Group. There is a need for more clear and detailed guidelines in which recommendations on patients' selection, intervals and laboratory measurements of screening for hypothyroidism and its treatment are provided.

The prognostic role of comorbidity in salivary gland carcinoma

Patients with head and neck cancer are prone to develop significant comorbidity mainly because of the high incidence of tobacco and alcohol abuse, both of which are etiologic and prognostic factors. However, to the authors' knowledge little is known regarding the prognostic relevance of comorbidity in patients with salivary gland cancer. A retrospective cohort of 666 patients with salivary gland cancer was identified within the Dutch Head and Neck Oncology Cooperative Group database. For multivariate analysis, a Cox proportional hazards model was used to study the effect of comorbidity on overall survival and disease-specific survival. According to the Adult Comorbidity Evaluation-27 (ACE-27) index, 394 patients (64%) had grade 0 comorbidity, 119 patients (19%) had grade 1 comorbidity, 71 patients (12%) had grade 2 comorbidity, and 29 patients (5%) had grade 3 comorbidity. In multivariate analysis for overall survival, the ACE-27 comorbidity grade was a strong independent prognostic variable. The hazards ratio (HR) of death, including all causes, was 1.5 (95% confidence interval [CI], 1.1-2.1) for patients with ACE-27 grade 1 comorbidity versus grade 0 comorbidity (P < .007). The HR was 1.7 (95% CI, 1.2-2.5) for grade 2 comorbidity (P = .003) and 2.7 (95% CI, 1.5-4.7) for grade 3 comorbidity versus grade 0 comorbidity (P = .001). In the current analysis, ACE-27 comorbidity grade was not an independent prognostic factor for disease-free survival. To the authors' knowledge, this is the first study concerning the prevalence and relevance of the prognostic comorbidity variable ACE-27 grade in patients with salivary gland cancer. Overall survival, but not disease-free survival, was correlated strongly with ACE-27 grade. Compared with other studies that investigated the effect of comorbidity on patients with head and neck cancer, patients with salivary gland cancer had less comorbidity. Their comorbid status appeared to be reasonably comparable to that of patients with other nonsmoking- and nonalcohol-related cancers.

A randomized trial of PET scanning to improve diagnostic yield of direct laryngoscopy in patients with suspicion of recurrent laryngeal carcinoma after radiotherapy

The RELAPS study (REcurrent LAryngeal carcinoma PET Study) was designed to determine whether FDG–PET is of value in the selection of patients for direct laryngoscopy under general anesthesia in patients with suspicion of recurrent laryngeal carcinoma after radiotherapy. In a randomized controlled clinical trial the current diagnostic practice, i.e. all patients undergo direct laryngoscopy, will be compared to a strategy in which FDG–PET selects the patients for laryngoscopy. All eight head and neck cancer centers of the Dutch Head and Neck Oncology Cooperative Group NWHHT will participate in this multicenter trial. The study population consists of patients with clinical suspicion of recurrent T2–T4 laryngeal carcinoma after radiotherapy (without obvious signs of tumor) in whom a direct laryngoscopy under general anesthesia with taking of biopsies is indicated by the local physician. The primary efficacy endpoint is the difference in the number of futile indications for direct laryngoscopy between the conventional diagnostic arm and the FDG–PET based diagnostic arm. An indication for laryngoscopy is classified as futile if this laryngoscopy was negative and no recurrence was diagnosed within 6 months follow-up (gold standard). The FDG–PET based strategy may increase the risk of missing recurrent tumor compared to current practice. Safety endpoints include survival and morbidity due to laryngoscopy with taking of biopsies. Survival rates of both groups will have to be collected outside the time frame of the funded trial. Resectability of recurrent tumor and tumor negative surgical margins after total laryngectomy will be used as proxy endpoints. The trial will also compare quality of life and direct medical costs between both arms.

Prognosis in salivary gland cancer. Results of the dutch head and neck oncology cooperative group (NWHHT)

Prognosis in salivary gland cancer. Results of the dutch head and neck oncology cooperative group (NWHHT)

The role of radiotherapy in the treatment of malignant salivary gland tumors

We analyzed the role of primary and postoperative low linear energy transfer radiotherapy in 538 patients treated for salivary gland cancer in centers of the Dutch Head and Neck Oncology Cooperative Group, in search for prognostic factors and dose response. The tumor was located in the parotid gland in 59%, submandibular gland in 14%, oral cavity in 23%, and elsewhere in 5%. In 386 of 498 patients surgery was combined with radiotherapy, with a median dose of 62 Gy. Median delay between surgery and radiotherapy was 6 weeks. In the postoperative radiotherapy group, adverse prognostic factors prevailed. Elective radiotherapy to the neck was given in 40%, with a median dose of 50 Gy. Primary radiotherapy (n = 40) was given for unresectable disease or M(1), with a dose range of 28-74 Gy. Postoperative radiotherapy improved 10-year local control significantly compared with surgery alone in T(3-4) tumors (84% vs. 18%), in patients with close (95% vs. 55%) and incomplete resection (82% vs. 44%), in bone invasion (86% vs. 54%), and perineural invasion (88% vs. 60%). Local control was not correlated with interval between surgery and radiotherapy. No dose-response relationship was shown. Postoperative radiotherapy significantly improved regional control in the pN(+) neck (86% vs. 62% for surgery alone). A rating scale for different sites, T stage, and histologic type may be applied to calculate the risk of disease in the neck at presentation, and so indicate the need for elective neck treatment. A marginal dose-response was seen, in favor of a dose > or =46 Gy. A clear dose-response relationship was shown for patients treated with primary radiotherapy. Five-year local control was 50% with a dose of 66-70 Gy. Postoperative radiotherapy with a dose of at least 60 Gy is indicated for patients with T(3-4) tumors, incomplete or close resection, bone invasion, perineural invasion, and pN(+). In unresectable tumors, a dose of at least 66 Gy is advisable.

Salivary gland carcinoma: independent prognostic factors for locoregional control, distant metastases, and overall survival: results of the Dutch head and neck oncology cooperative group.

We analyzed the records of patients with malignant salivary gland tumors, as diagnosed in centers of the Dutch Head and Neck Oncology Cooperative Group, in search of independent prognostic factors for locoregional control, distant metastases, and overall survival. In 565 patients, we analyzed general results and looked for the potential prognostic variables of age, sex, delay, clinical and pathologic T and N stage, site (332 parotid, 76 submandibular, 129 oral cavity, 28 pharynx/larynx), pain, facial weakness, clinical and pathologic skin involvement, histologic type (WHO 1972 classification), treatment, resection margins, spill, perineural and vascular invasion, number of neck nodes, and extranodal disease. The median follow-up period was 74 months; it was 99 months for patients who were alive on the last follow-up. The rates of local control, regional control, distant metastasis-free and overall survival after 10 years were, respectively, 78%, 87%, 67%, and 50%. In multivariable analysis, local control was predicted by clinical T-stage, bone invasion, site, resection margin, and treatment. Regional control depended on N stage, facial nerve paralysis, and treatment. The relative risk with surgery alone, compared to surgery plus postoperative radiotherapy, was 9.7 for local recurrence and 2.3 for regional recurrence. Distant metastases were independently correlated with T and N stage, sex, perineural invasion, histologic type, and clinical skin involvement. Overall survival depended on age, sex, T and pN stage, site, skin and bone invasion. Several prognostic factors for locoregional control, distant metastases, and overall survival were found. Postoperative radiotherapy was found to improve locoregional control.

Results and patterns of care in 893 patients treated for hypopharyngeal cancer: a report by the Dutch Head and Neck Oncology Co-operative Group

Objective. The majority of all new cancer cases occur in men and women 65 years of age and older. As the population is ageing and the incidence of cancer rises with age, the number of new malignancies in the elderly is increasing. As it is well understood that a relationship exists between age at diagnosis and the type of treatment received, age-specific patterns of care and results of treatment for patients diagnosed with a hypopharyngeal cancer were studied. Patients and methods. All patients registered in the Netherlands between 1985 and 1995 by the NWHHT were included in this study. The patients were divided into three age categories: < 50 years, 50–69 years, and ≥ 70. Age-specific differences in treatment for these age categories were analysed using chi-square analysis. Disease-free and survival curves were estimated using Kaplan-Meier estimators as product-limit estimators. Multivariate analysis was performed using the Cox's proportional hazard model. Results. A significant correlation could be observed between the different patient groups and the N-stage of the neck (P = 0.001). Additionally, a significant correlation could be observed between the different patient groups and stage of disease (P = 0.019). A significant correlation could be observed between age and the decision to treat according to the protocol (P = 0.001). Additionally, a significant correlation was observed between age and the type of administered treatment policy (P = 0.002). Uni– and multivariate analysis failed to reveal a significant difference in survival between the different patient groups. Conclusion. Chronological age alone should not influence the type of treatment.

Clinical staging of oropharyngeal carcinoma

An alternative to the International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) stage grouping system was proposed for patients with oropharyngeal carcinoma by Hart et al. (1995) on behalf of the Dutch Head and Neck Oncology Cooperative Group. The system was created by regrouping the T, N, and M categories without redefining the categories themselves. Data related to epidemiology, treatment, and survival from 224 previously untreated patients with oropharyngeal carcinoma were analyzed. Staging was performed according to the 1992 UICC/AJCC criteria and according to the proposed stage grouping system. Kaplan-Meier estimates of overall survival were compared for both staging systems; and in a Cox proportional hazards regression analysis, the influence of the variables age, gender, subsite and side of tumor location, histopathologic grade, form of treatment, and stage distribution (according to 1992 UICC criteria and that proposed by Hart et al.) on overall survival was determined. The proposed staging system showed a more balanced distribution of patients (16% in Stage I, 37% in Stage II, 14% in Stage III, and 33% in Stage IV compared with 5% in Stage I, 7% in Stage II, 21% in Stage III, and 67% in Stage IV according to UICC/AJCC 1992 staging). Furthermore, the proposed staging system showed better prognostic discrimination for overall survival (5-year survival rates according to the staging system of Hart et al. were 59% in Stage I, 31% in Stage II, 28% in Stage III, and 16% in Stage IV, vs. 61% in Stage I, 59% in Stage II, 32% in Stage III, and 24% in Stage IV according to UICC/AJCC 1992 staging). The results are in concordance with the results published by the Dutch Head and Neck Oncology Cooperative Group. It is possible to improve the current staging system by regrouping the T, N, and M categories. [See editorial on pages 1611-2, this issue.]

T3 laryngeal cancer: A retrospective study of the dutch head and neck oncology cooperative group: Study design and general results : CHJ Terhaard, GJ Hordijk, P Van Den Broek, et al. Clin Otolaryngol 17:393–402, 1992

T3 laryngeal cancer: A retrospective study of the dutch head and neck oncology cooperative group: Study design and general results : CHJ Terhaard, GJ Hordijk, P Van Den Broek, et al. Clin Otolaryngol 17:393–402, 1992

T3 laryngeal cancer: a retrospective study of the Dutch Head and Neck Oncology Cooperative Group: study design and general results.

511 Patients with T3 N0-3 M0 squamous cell carcinoma of the larynx, treated in the Netherlands from 1975 until 1984, were retrospectively analysed. Four different treatment policies were followed: primary surgery, planned combination of radiotherapy and surgery, primary radical radiotherapy, and selective radiotherapy. General results are presented. Local control rate was 72%. Regional control rate was 90% for clinically N0 patients and 78% for clinically N+ patients. Salvage therapy was overall successful in 38%. Surgical salvage for local radiation failures (with regional relapse) was successful in 69%, and for regional failures (without local relapse) in 46%. Ultimate locoregional control was 78% and, due to 8% distant metastases, 5-year actuarial corrected survival was 70%. Prognosis did not improve over the years. Corrected survival was independently correlated with tumour extension, involvement of neck nodes and treatment strategy. Corrected survival was similar for primary radiotherapy and primary surgery, but significantly better for planned combined therapy. Multiple primary tumours occurred significantly more often in male (19.5%) than in female patients (7.3%) (P = 0.05), the bronchus being most commonly affected. Cumulative actuarial risk for metachronous tumour was 15% after 5 years and 30% after 10 years so prevention and early detection of these second tumours may play the most important role in improving overall survival rates in the future.