Survival analysis of head and neck squamous cell carcinoma: influence of smoking and drinking.

BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) are associated with tobacco and alcohol; however, the prognostic relevance of these substances is unclear. METHODS: Univariate and multivariate survival analyses were performed for patients with (n = 1829) and without (n = 183) substance use. RESULTS: HNSCC-specific survival (death due to primary-HNSCC or recurrent HNSCC) and HNSCC/second primary tumor-specific survival (death due to primary-HNSCC or recurrent HNSCC or second primary tumor) were not significantly different for patients who smoked and drank alcohol (hazard ratio [HR], 1.26; 95% confidence interval [CI], 0.86-1.85) and those who did not (HR, 1.34; 95% CI, 0.96-1.88). Overall survival was significantly affected; HR for patients who smoked and drank alcohol was 1.50 (95% CI, 1.16-1.93). CONCLUSION: Although tobacco and alcohol use are the main risk factors for development of HNSCC, disease outcome was comparable in patients who did or did not use these substances. Tobacco and alcohol use affected overall survival, which emphasizes the importance of substance use cessation.

Local therapy of cancer with free IL-2.

This is a position paper about the therapeutic effects of locally applied free IL-2 in the treatment of cancer. Local therapy: IL-2 therapy of cancer was originally introduced as a systemic therapy. This therapy led to about 20% objective responses. Systemic therapy however was very toxic due to the vascular leakage syndrome. Nevertheless, this treatment was a break-through in cancer immunotherapy and stimulated some interesting questions: Supposing that the mechanism of IL-2 treatment is both proliferation and tumoricidal activity of the tumor infiltrating cells, then locally applied IL-2 should result in a much higher local IL-2 concentration than systemic IL-2 application. Consequently a greater beneficial effect could be expected after local IL-2 application (peritumoral = juxtatumoral, intratumoral, intra-arterial, intracavitary, or intratracheal = inhalation). Free IL-2: Many groups have tried to prepare a more effective IL-2 formulation than free IL-2. Examples are slow release systems, insertion of the IL-2 gene into a tumor cell causing prolonged IL-2 release. However, logistically free IL-2 is much easier to apply; hence we concentrated in this review and in most of our experiments on the use of free IL-2. Local therapy with free IL-2 may be effective against transplanted tumors in experimental animals, and against various spontaneous carcinomas, sarcomas, and melanoma in veterinary and human cancer patients. It may induce rejection of very large, metastasized tumor loads, for instance advanced clinical tumors. The effects of even a single IL-2 application may be impressive. Not each tumor or tumor type is sensitive to local IL-2 application. For instance transplanted EL4 lymphoma or TLX9 lymphoma were not sensitive in our hands. Also the extent of sensitivity differs: In Bovine Ocular Squamous Cell Carcinoma (BOSCC) often a complete regression is obtained, whereas with the Bovine Vulval Papilloma and Carcinoma Complex (BVPCC) mainly stable disease is attained. Analysis of the results of local IL-2 therapy in 288 cases of cancer in human patients shows that there were 27% Complete Regressions (CR), 23% Partial Regressions (PR), 18% Stable Disease (SD), and 32% Progressive Disease (PD). In all tumors analyzed, local IL-2 therapy was more effective than systemic IL-2 treatment. Intratumoral IL-2 applications are more effective than peritumoral application or application at a distant site. Tumor regression induced by intratumoral IL-2 application may be a fast process (requiring about a week) in the case of a highly vascular tumor since IL-2 induces vascular leakage/edema and consequently massive tumor necrosis. The latter then stimulates an immune response. In less vascular tumors or less vascular tumor sites, regression may require 9-20 months; this regression is mainly caused by a cytotoxic leukocyte reaction. Hence the disadvantageous vascular leakage syndrome complicating systemic treatment is however advantageous in local treatment, since local edema may initiate tumor necrosis. Thus the therapeutic effect of local IL-2 treatment is not primarily based on tumor immunity, but tumor immunity seems to be useful as a secondary component of the IL-2 induced local processes. If local IL-2 is combined with surgery, radiotherapy or local chemotherapy the therapeutic effect is usually greater than with either therapy alone. Hence local free IL-2 application can be recommended as an addition to standard treatment protocols. Local treatment with free IL-2 is straightforward and can readily be applied even during surgical interventions. Local IL-2 treatment is usually without serious side effects and besides minor complaints it is generally well supported. Only small quantities of IL-2 are required. Hence the therapy is relatively cheap. A single IL-2 application of 4.5 million U IL-2 costs about 70 Euros. Thus combined local treatment may offer an alternative in those circumstances when more expensive forms of treatment are not available, for instance in resource poor countries.

Prevention of Frey syndrome in parotid gland surgery.

OBJECTIVE: This study discusses the anatomy and surgical techniques for the prevention of Frey syndrome. By performing only a partial superficial parotidectomy, we probably preserve the connection between the auriculotemporal nerve and the facial nerve. By suturing the remainder of the parotid gland tissue and the superficial musculoaponeurotic system (SMAS) back to the sternocleidomastoid muscle, an interposition is made. Furthermore, by extending the incision not too far cranially, the auriculotemporal nerve cutaneous branch is spared. We also tried to preserve part of the great auricular nerve (GAN). DESIGN: Descriptive study. SETTING: One main institute (a tertiary referral centre) and one affiliated secondary centre. METHODS: Patients operated on for parotid gland tumours in our hospitals during the last 3 years underwent starch-iodine testing after at least 1 year of follow-up. MAIN OUTCOME MEASURES: The number of patients developing Frey syndrome. We hypothetically explored the importance of preserving both the auriculotemporal and the great auricular nerve. RESULTS: Eighty-one patients were operated on for a parotid gland tumour. Forty-five (56%) of these patients could be followed up for more than 1 year. Four patients had a positive starch-iodine test. Two of these underwent revision surgery and had symptoms already before our procedure. About half of the patients had a SMAS interposition performed. All four patients with Frey syndrome did not have a SMAS interposition. CONCLUSION: We advocate our technique in primary benign tumours. Further research to clarify the parasympathetic and sympathetic function of the great auricular nerve and the cutaneous branch of the auriculotemporal nerve is necessary.

Do magnetic resonance imaging and ultrasound add anything to the preoperative workup of parotid gland tumors?

PURPOSE: To assess the additional value of magnetic resonance imaging (MRI) and ultrasound (US) to physical examination (PE) and fine needle aspiration cytology (FNAC) in the preoperative determination of the location and histology of parotid gland tumors. PATIENTS AND METHODS: Prospectively, 99 patients with 77 benign and 22 malignant lesions were included; 82 underwent parotidectomy. FNAC was performed in 88 patients. On PE, the location of the tumor was predicted. Eighty-nine patients had MRI and 47 US. Various characteristics and the presumed diagnosis were assessed. Furthermore, the location of the tumor in relation to the facial nerve was predicted. The results were compared with the definite histology and the location during surgery. RESULTS: Of the MRI characteristics, incomplete demarcation from normal parotid gland tissue showed the highest positive predictive value (PPV) for malignancy of 0.48. Of the US characteristics, enlarged lymph nodes yielded the highest PPV for malignancy of 0.5. Cytology correctly predicted the benign or malignant nature of the tumor in all cases. Superficial location was well predicted on PE with a PPV of 0.8, slightly better on MRI (PPV of 0.87), and worse on US (PPV of 0.7). CONCLUSION: FNAC is the only accurate investigation for classifying a parotid gland tumor as benign or malignant. Palpation and MRI are superior to US in predicting tumor location. Because the results for palpation and MRI are almost equal, MRI should only be reserved for specific cases, and not routinely requested.

The effect of age on survival and quality of life in elderly head and neck cancer patients: a long-term prospective study.

Little is known about long-term treatment outcome of elderly head and neck cancer patients and their quality of life (QOL). One hundred and eighteen older (>or=70 years) and 148 younger (45-60 years) patients with head and neck cancer were followed up for 3-6 years. In the long-term follow-up 33 younger and 24 older patients completed the EORTC QLQ-C30 and H&N35 and a questionnaire about depression. The survival rate after 3-6 years for younger patients was 36%, as compared to 31% in the older patient group. Higher tumour stages, more co-morbidity and non-standard treatment showed to be independent prognostic factors for mortality. No independent prognostic value of age could be found. The global QOL score remains roughly comparable. Even up to 6 years after treatment, we found no significant differences in survival or overall QOL between older and younger head and neck cancer patients.

Grading facial nerve function: why a new grading system, the MoReSS, should be proposed.

OBJECTIVE: To compare the interobserver variability of a new grading system to the currently recommended House-Brackmann Grading Scale. STUDY DESIGN: Prospective case-control study. SETTING: Tertiary referral center. PATIENTS: All patients with a facial nerve paresis/paralysis (whatever the cause). INTERVENTION: All patients were evaluated for their facial nerve function by three observers, independently, using both the new system and the House-Brackmann Grading Scale. MAIN OUTCOME MEASURE: The level of agreement between the three observers using both scales. RESULTS: With the movement, rest, secondary defects, and subjective scoring grading scale, a higher percentage of agreement between the observers was noticed than with the House-Brackmann Grading Scale. CONCLUSION: The movement, rest, secondary defects, and subjective scoring grading system is more useful for grading facial nerve dysfunction in clinical practice than the House-Brackmann Grading Scale.

Morbidity of parotid gland surgery: results 1 year post-operative.

Patients operated on for parotid gland tumours were evaluated prospectively to study morbidity after this procedure. Nowadays, major complications such as recurrence of tumour and permanent facial nerve paresis are rare after primary surgery. Therefore, this study especially takes minor complications such as Frey's syndrome and sensory deficits into account. The study documents morbidity in 45 patients who completed a 1 year follow-up. Among those with primary benign tumours, we found no recurrences and no permanent paresis, nor did starch-iodine testing reveal any cases of Frey's syndrome. However, two patients who had previously been operated on multiple times did test positive for Frey's syndrome, as did two others after surgery for malignancy. Furthermore, we found that patients whose posterior branch of the great auricular nerve was sacrificed had a larger area of sensory deficit than those whose nerve was preserved. We conclude that the morbidity of parotid gland surgery can be reduced further by giving minor complications more attention.

Why to start the concomitant boost in accelerated radiotherapy for advanced laryngeal cancer in week 3.

PURPOSE: We analyzed toxicity and the local control rates for advanced laryngeal cancer, treated with two accelerated fractionation schedules. The main difference between the schedules was the onset of the concomitant boost, in Week 3 or Week 4. Overall treatment time and total dose were equivalent. METHODS AND MATERIALS: In a prospective, nonrandomized study of T3, T4, and advanced T2 laryngeal cancer, concomitant boost schedules were used in 100 patients. Thirty patients received a schedule of twice daily 1.2 Gy in Weeks 1-3, followed by twice daily 1.7 Gy in Weeks 4 and 5; total dose was 70 Gy (the hyperfractionated accelerated schedule [HAS] regimen). Seventy patients were treated with 5 times 2 Gy in Weeks 1 and 2, followed by daily 1.8 Gy and 1.5 Gy (boost) in Weeks 3-5; total dose 69.5 Gy (the accelerated schedule only [ASO] regimen). Distribution of T stage was 47%, 40%, and 12% for T2, T3, and T4, respectively. In 24% of the patients, lymph nodes were positive. Pretreatment tracheotomy or stridor or both occurred in 8 patients. The distribution of prognostic factors was not significantly different between the two fractionation schedules. Acute and late toxicity was assessed. Results were estimated by the use of actuarial methods. For late toxicity and local control univariate and multivariate analyses were performed. Tumor control probability analysis was used to model cure rate differences. RESULTS: Overall acute mucositis score was equal for both schedules. Acute mucositis started and decreased significantly earlier in the HAS regimen. In all patients acute mucositis healed completely. The treatment was completed within 38 days in all patients. The regional control rate was 100% for clinical N0, and 75% for the clinical N+ patients. The 3-year local control rate was 59% and 78% for the HAS and ASO regimens, respectively (p = 0.05); the ultimate local control was 80% and 94%, respectively. In multivariate analysis, besides the fractionation schedule (relative risk [RR], 2.6 for HAS vs. ASO), pretreatment tracheotomy/stridor (RR 4.3, yes vs. no), and local tumor response 3-6 weeks after radiotherapy (RR 5.1, no vs. yes) were independent factors for local control. Tumor control probability analysis indicated that the onset of repopulation may be about 4-6 days earlier for the HAS regimen. The onset of repopulation in the HAS regimen is probably at the end of the second week or at the beginning of the third week. Severe late toxicity was observed in the HAS group and ASO group in, respectively, 11% and 16%. In multivariate analysis this toxicity related significantly to the field size and pretreatment tracheotomy/stridor. CONCLUSIONS: In our study the timing of the boost in accelerated radiotherapy for advanced laryngeal cancer was an independent factor for local control, favoring the use of a concomitant boost in Week 3. This finding may indicate that accelerated repopulation of tumor cells starts early in the treatment phase.

Effectiveness of adenotonsillectomy in children with mild symptoms of throat infections or adenotonsillar hypertrophy: open, randomised controlled trial.

OBJECTIVE: To assess the effectiveness of adenotonsillectomy in children with mild symptoms of throat infections or adenotonsillar hypertrophy. DESIGN: Open, randomised controlled trial. SETTING: 21 general hospitals and three academic centres in the Netherlands. PARTICIPANTS: 300 children aged 2-8 years requiring adenotonsillectomy. INTERVENTION: Adenotonsillectomy compared with watchful waiting. MAIN OUTCOME MEASURES: Episodes of fever, throat infections, upper respiratory tract infections, and health related quality of life. RESULTS: During the median follow up period of 22 months, children in the adenotonsillectomy group had 2.97 episodes of fever per person year compared with 3.18 in the watchful waiting group (difference -0.21%, 95% confidence interval -0.54 to 0.12), 0.56 throat infections per year compared with 0.77 (-0.21, -0.36 to -0.06), and 5.47 upper respiratory tract infections per person year compared with 6.00 (-0.53, -0.97 to -0.08). No clinically relevant differences were found for health related quality of life. Adenotonsillectomy was more effective in children with a history of three to six throat infections than in those with none or two. 12 children had surgery related complications. CONCLUSION: Adenotonsillectomy in children with mild symptoms of throat infections or adenotonsillar hypertrophy has no major clinical benefits over watchful waiting.

Elderly patients with head and neck cancer: the influence of comorbidity on choice of therapy, complication rate, and survival.

PURPOSE OF REVIEW: Comorbidity may be an important reason for head and neck surgeons to treat elderly patients less intensively. This article provides an overview of the influence of age and comorbidity on choice of therapy, postoperative complications, and survival. RECENT FINDINGS: Several retrospective studies show that elderly patients can undergo surgery if they do not have severe comorbid disorders. Severe comorbidity influences the rate of postoperative complications, and the higher complication rate in older patients reported in some studies is probably due to a higher level of comorbidity. Comorbidity also affects the survival of cancer patients, but several studies have failed to detect a relation between age and survival after correction for comorbidity. Thus, although severe comorbidity may influence the choice of treatment, patient age as such should not be a reason to exclude patients from intensive therapy. SUMMARY: If severe comorbidity is not present, elderly patients should receive standard treatment for head and neck cancer. Treatment choice should be based on medical findings and patient preference, not on chronologic age.

Quality of life in elderly patients with head and neck cancer one year after diagnosis.

BACKGROUND: Little is known about quality of life (QOL) in elderly patients. METHODS: Seventy-eight older (> or =70 years) and 105 younger patients (45-60 years) with carcinoma of the oral cavity, pharynx (stage > or =II), or larynx (stage > or =III) completed the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire and EORTC Head and Neck Cancer Quality of Life Questionnaire before treatment. Fifty-one older and 70 younger patients completed all follow-up questionnaires at 3, 6, and 12 months. RESULTS: Before and after treatment, the physical functioning of the older patients was worse than that of younger patients. This difference remained relatively constant during follow-up and is probably related to normal aging. At baseline and 3 months, no other differences were found between both groups. At 6 months, younger patients reported more pain, but at 12 months no relevant differences were found. CONCLUSIONS: Treatment did not affect QOL differently in older and younger patients. Therefore, standard treatment should always be considered, irrespective of the patient's age.

Effectiveness of adenotonsillectomy in children with mild symptoms of throat infections or adenotonsillar hypertrophy: open, randomised controlled trial.

OBJECTIVE: To assess the effectiveness of adenotonsillectomy in children with mild symptoms of throat infections or adenotonsillar hypertrophy. DESIGN: Open, randomised controlled trial. SETTING: 21 general hospitals and three academic centres in the Netherlands. PARTICIPANTS: 300 children aged 2-8 years requiring adenotonsillectomy. INTERVENTION: Adenotonsillectomy compared with watchful waiting. MAIN OUTCOME MEASURES: Episodes of fever, throat infections, upper respiratory tract infections, and health related quality of life. RESULTS: During the median follow up period of 22 months, children in the adenotonsillectomy group had 2.97 episodes of fever per person year compared with 3.18 in the watchful waiting group (difference -0.21, 95% confidence interval -0.54 to 0.12), 0.56 throat infections per person year compared with 0.77 (-0.21, -0.36 to -0.06), and 5.47 upper respiratory tract infections per person year compared with 6.00 (-0.53, -0.97 to -0.08). No clinically relevant differences were found for health related quality of life. Adenotonsillectomy was more effective in children with a history of three to six throat infections than in those with none to two. 12 children had complications related to surgery. CONCLUSION: Adenotonsillectomy has no major clinical benefits over watchful waiting in children with mild symptoms of throat infections or adenotonsillar hypertrophy.

Elderly patients with head and neck cancer: physical, social and psychological aspects after 1 year.

OBJECTIVE: Elderly patients with head and neck cancer often receive non-standard treatment for reasons other than comorbidity. In this prospective study we investigated how elderly patients fare 1 year after treatment in comparison with their younger counterparts. MATERIAL AND METHODS: Seventy patients aged 45-60 years and 51 patients aged > or = 70 years with cancer of the oral cavity, pharynx (stage II-IV) or larynx (stage III-IV) participated in the study before treatment and 1 year later. Each patient was interviewed and given a questionnaire concerning physical functioning, social contacts, depressive symptoms, satisfaction with treatment and future expectations. RESULTS: At 12 months, patients in both age groups reported significantly more depressive symptoms and less social support than before treatment, and their Karnofsky Performance Score was lower. However, there were no differences between elderly and younger patients. Approximately 90% of those in both age groups said that they would choose the same treatment again, and there was no age difference regarding the impact of treatment or expectations for the future. CONCLUSION: This study shows that the impact of treatment on quality of life did not differ between elderly and younger patients with head and neck cancer. Therefore, standard treatment should be considered in elderly patients if no severe contraindications exist.

Waiting times for radiotherapy: consequences of volume increase for the TCP in oropharyngeal carcinoma.

BACKGROUND AND PURPOSE: Waiting lists for radiotherapy have become longer over the past years. Apart from the psychological distress for the patient we are concerned about tumour growth during this waiting time, which may worsen prognosis. The purpose of this pilot study was to investigate tumour growth in the waiting time and to obtain an indication of its clinical consequences for patients with oropharyngeal carcinoma. A tumour control probability (TCP) model was applied to evaluate consequences for outcome. METHODS AND MATERIALS: Increase in tumour volume was measured for 13 patients with oropharyngeal carcinoma by outlining the tumour on the diagnostic as well as on the treatment planning CT scan. Waiting time was defined as time between histopathological diagnosis and start of radiotherapy. For each tumour we calculated the increase in tumour volume and the tumour doubling time. The potential increase in TCP was calculated for each tumour for the situation without treatment delay. RESULTS: The mean increase in tumour volume was 70%. The mean waiting time was 56 days. Expected TCP with incorporation of delay was 47%, without delay it might have been 63-66%. CONCLUSION: This study shows tumour progression during the time between the diagnostic CT scan and the treatment planning CT scan in oropharyngeal cancer. As a consequence of waiting time, which allows tumour volume increase, there may be an average control loss of 16-19 % for these tumours during the total waiting time before radiotherapy.

Carcinoma of the larynx: the Dutch national guideline for diagnostics, treatment, supportive care and rehabilitation.

PURPOSE: This evidence based guideline aims to facilitate proper management and to prevent diverging views concerning diagnosis, treatment and follow-up of carcinoma of the larynx between the major referral centers for head and neck cancer in The Netherlands. METHOD: A multidisciplinary committee was formed representing all medical and paramedical disciplines involved in the management of laryngeal cancer and all head and neck oncology centers in The Netherlands. This committee reviewed the literature and formulated statements and recommendations based on the level of evidence and consistency of the literature data. Where reliable literature data were not available, recommendations were based on expert opinion. RESULTS: Strict criteria have been proposed for the radiological diagnostic procedures as well as for the pathology report. For carcinoma in situ and severe dysplasia, microsurgery, preferably by laser, is proposed. For all other stages of invasive carcinoma, a full course of radiotherapy as a voice conserving therapy is the treatment of choice. Only in cases with massive tumor volumes with invasion through the laryngeal skeleton, primary surgery is inevitable. For rehabilitation and supportive care, minimal criteria are described. Due to the complexity of therapy and relative rarity of larynx carcinoma, all patients should be seen at least once in a dedicated head and neck clinic. CONCLUSION: This guideline for the management of larynx carcinoma was produced by a multidisciplinary national committee and based on scientific evidence wherever possible. This procedure of guideline development has created the optimal conditions for nationwide acceptance and implementation of the guideline.