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.

Olfactory neuroblastoma: a single-center experience.

Olfactory neuroblastoma (ONB) is a potentially curable disease, despite being an aggressive malignancy with a poor natural history. Our goal was to evaluate management outcomes for patients with ONB treated at our institution. Our prospective database for brain tumors and the pathology registry of head and neck cancers at Oslo University Hospital were searched to identify all patients treated for ONB between 1998 and 2016. Variables extracted from these databases, supplemented by retrospective chart reviews, underwent thorough analysis. All cases were formally re-examined by a dedicated head and neck pathologist. Twenty patients were identified. Follow-up was 100%. Mean follow-up was 81.5 months for the entire cohort and 120.3 months for patients with no evidence of disease. Fourteen patients underwent treatment of choice including craniofacial resection (CFR) with or without radiotherapy (XRT). Six patients could only receive less extensive treatment; three patients underwent lateral rhinotomy (LR) with or without XRT after being deemed medically unsuitable for CFR, while another three patients received only supportive, non-surgical treatment (due to positive lymph node status in two and to extensive tumor size in one case). Overall and disease-specific survival rates were 100% after 10 years of follow-up when negative surgical margins were achieved by CFR. Positive margins were associated with poorer outcome with no patients surviving longer than 44 months. Long-term survival was also achieved in two cases among patients not eligible for CFR: one case after radical LR and one case after radio-chemotherapy. Advanced disease at presentation (tumor size ≥40 mm, Kadish grades C and D, or TNM IVa and IVb) and positive surgical margins were correlated to significantly dismal survival. Our study suggests that CFR with or without adjuvant XRT is safe and leads to excellent long-time overall and disease-specific survival. Negative surgical margins, tumor size <40 mm, Kadish stage A/B, and TNM stages I-III are independent prognostic predictors of outcome.

Patterns of local-regional recurrence after conformal and intensity-modulated radiotherapy for head and neck cancer.

AIM: To evaluate the patterns of loco-regional recurrences in head and neck cancer patients METHODS: Twenty-six out of 112 patients treated with primary or postoperative 3D CRT or IMRT for their primary and recurrent disease between 2007 and 2013 were included. The CT images of recurrent disease were rigidly registered with the primary CT images for each patient. To assess overlaps and overlap localization, the recurrence volume overlapping with the primary target volume was identified. For relapses occurring in the regional lymph nodes, the epicenter distance in recurrences and primary volumes and dose in recurrences were also identified. The recurrences were defined as in-field, marginal or out-of-field. RESULTS: The majority of the failures occurred within 1 year after completed primary treatment. The dose differences in recurrence volume were not statistically significant when patients were treated with IMRT or 3D CRT. Recurrence in 15/26 of the included patients occurred in the regional lymph nodes located fully or partly inside the primary target volume or the elective lymph node region. The majority of recurrences were recognized as in-field, independent of the primary treatment. CONCLUSION: Recurrence in the majority of the patients occurred in the regional lymph nodes located in high dose area. The cause of recurrence may be due to inadequate total dose in the primary treatment and/or lack of optimal primary diagnosis leading to inadequate primary target delineation.

Risk of Recurrence in Laryngeal Cancer.

A cohort study was undertaken to analyze the risk of recurrence among 1616 patients with primary squamous cell carcinoma of the larynx from 1983 to 2010 at a single, tertiary academic center in Oslo, Norway. The cohort was followed from the date of diagnosis to September 2011. Competing risk regression analysis assessed the association between various risk factors and the risk of recurrence, where death was considered a competing event. Recurrence was observed in 368 patients (23%) during the study period. The majority (71%) of recurrences involved the location of the primary tumor. The overall risk of recurrence during the first three years after initiating treatment was 20.5%. Increased risk of recurrence was observed in patients with supraglottic cancer, younger patients, those with T2-T3 tumors and in patients treated in the earlier part of the study period. Significant factors for recurrence in glottic carcinomas were age, treatment in the earlier part of the study and T-status, whereas age was a significant factor in supraglottic cancer. N-status appeared less significant. In conclusion, follow-up of laryngeal squamous cell carcinoma should place particular emphasis on the site of the primary tumor, younger patients, cases of supraglottic cancer and T2-T4 primary tumors, especially during the first three years after treatment. More studies are needed to assess the impact of surgical versus non-surgical treatment, and eventually the significance of recurrence, for disease-specific and overall survival in cases of advanced laryngeal squamous cell carcinoma.

Self-reported Symptoms to Monitor Recurrent Head and Neck Cancer-Analysis of 1,678 Cases.

AIM: The aim of this article was to study the clinical significance of subjective symptoms of recurrence in patients treated for primary head and neck cancer. MATERIALS AND METHODS: Clinical data of 1,678 patients with squamous cell carcinoma of the head and neck admitted at the Department of Oto-rhino-laryngology-Head and Neck Surgery, Oslo University Hospital during a period of 15 years (1983-1997) were analyzed. RESULTS: A total of 525 (31%) patients had recurrence during follow-up, 74% of these within the first two years after primary treatment. Subjective symptoms indicating recurrent disease were reported by 67%. The remaining recurrences were detected in asymptomatic patients at scheduled consultations. Prognosis was better among patients with subjective symptoms of recurrent disease after treatment for primary tumors of the oral cavity and larynx. Those with recurrence from other tumor sites had no difference in prognosis between symptomatic and asymptomatic patients. CONCLUSION: The high proportion of patients with subjective symptoms indicates that there is a potential to make follow-up routines more effective. Individualized and flexible procedures, taking into account patient's self-reported symptoms, may help speed-up the process and thus improve prognosis. This could also lead to a more efficient use of resources by reducing the number of redundant examinations of low-risk patients.

The DAHANCA 6 randomized trial: Effect of 6 vs 5 weekly fractions of radiotherapy in patients with glottic squamous cell carcinoma.

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 46days, respectively. The primary endpoint was loco-regional failure. RESULTS: Median follow-up time was 14.5years. Of the 177 failures, 167 involved T-site. The cumulative incidence of loco-regional failure (LRF) was 21.6% in the 6fx/w group and 29.3% in the 5fx/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 6fx/w group compared to the 5fx/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 6fx/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.

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.

Significance of self-reported symptoms as part of follow-up routines in patients treated for oral squamous cell carcinoma.

BACKGROUND: There is little evidence to prove that frequent out-patient consultations lead to better prognosis in patients treated for oral squamous cell carcinoma. Furthermore, there is no consensus regarding the timing and number of follow-up consultations or the duration of monitoring after completed therapy. MATERIALS AND METHODS: We prospectively recorded demographic and clinical data of 537 patients treated over a period of 15 years with complete follow-up of 18 years in a tertiary academic Center. RESULTS: Out of 537 patients considered free of disease after treatment, 196 (36%) developed recurrent disease during follow-up. Self-reported symptoms led to diagnosis of the recurrence in 78% of the cases. Only 22% of recurrences were detected through physical examination of asymptomatic patients. There was no difference in disease-free survival in-between these two groups. CONCLUSION: Follow-up routines are indispensable as part of cancer treatment but can be more cost-efficient when patients are educated and encouraged to report subjective symptoms. Trained personnel in collaboration with head and neck specialists can handle parts of follow-up routines.

Factors associated with acute and late dysphagia in the DAHANCA 6 & 7 randomized trial with accelerated radiotherapy for head and neck cancer.

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.

A gel tumour phantom for assessment of the accuracy of manual and automatic delineation of gross tumour volume from FDG-PET/CT.

INTRODUCTION: Our primary aim was to make a phantom for PET that could mimic a highly irregular tumour and provide true tumour contours. The secondary aim was to use the phantom to assess the accuracy of different methods for delineation of tumour volume from the PET images. MATERIAL AND METHODS: An empty mould was produced on the basis of a contrast enhanced computed tomography (CT) study of a patient with a squamous cell carcinoma in the head and neck region. The mould was filled with a homogeneous fast-settling gel that contained both (18)F for positron emission tomography (PET) and an iodine contrast agent. This phantom (mould and gel) was scanned on a PET/CT scanner. A series of reference tumour contours were obtained from the CT images in the PET/CT. Tumour delineation based on the PET images was achieved manually, by isoSUV thresholding, and by a recently developed three-dimensional (3D) Difference of Gaussians algorithm (DoG). Average distances between the PET-derived and reference contours were assessed by a 3D distance transform. RESULTS: The manual, thresholding and DoG delineation methods resulted in volumes that were 146%, 86% and 100% of the reference volume, respectively, and average distance deviations from the reference surface were 1.57 mm, 1.48 mm and 1.0, mm, respectively. DISCUSSION: Manual drawing as well as isoSUV determination of tumour contours in geometrically irregular tumours may be unreliable. The DoG method may contribute to more correct delineation of the tumour. Although the present phantom had a homogeneous distribution of activity, it may also provide useful knowledge in the case of inhomogeneous activity distributions. CONCLUSION: The geometric irregular tumour phantom with its inherent reference contours was an important tool for testing of different delineation methods and for teaching delineation.

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.

Does transfusion improve the outcome for HNSCC patients treated with radiotherapy? - results from the randomized DAHANCA 5 and 7 trials.

BACKGROUND: Patients with head and neck squamous cell carcinoma (HNSCC) and a low level of hemoglobin often have a poor response to radiation that may be related to hypoxia-induced radioresistance. We have previously published the importance of hemoglobin level and the effect of transfusion by the results from the randomized DAHANCA 5 trial, including 414 patients in the analysis. Aim of the current analysis was to gain additional power by adding patients from the continued subrandomization in the DAHANCA 7 trial, now including a total of almost 1200 patients. MATERIAL AND METHODS: Patients were randomized to treatment in the DAHANCA 5 and 7 study (nimorazole vs. placebo and five fx/week vs. six fx/week), and in addition, patients with "low" pre-irradiation hemoglobin values (females <13 g/dl; males <14.5 g/dl) were subrandomized to plus or minus transfusion. Transfusion was given with packed red blood cells with the aim to achieve a hemoglobin level in the "high" value range. RESULTS: A total of 1166 patients were included, 701 patients had high hemoglobin levels and 465 had low hemoglobin levels. Among the low hemoglobin patients, 235 were randomized to receive transfusion. Patient characteristics and treatment arms were well balanced. In the majority of patients, transfusion resulted in increased hemoglobin levels although this decreased slightly throughout treatment as in the non-transfused patients. Overall, the patients with low hemoglobin level had a significant reduced probability of locoregional control, disease-specific and overall survival. In the low hemoglobin group, transfusion did not improve the outcome in locoregional control, disease-specific or overall survival. In multivariate analyses, HPV/p16 status, T and N classification were significant factors for all outcome measures, whereas there was no significant influence of transfusion or hemoglobin level on endpoints. CONCLUSION: Transfusion prior to and during radiation treatment did not improve the outcome in patients with HNSCC and low hemoglobin values, but may have a negative impact on survival.

Prevention and treatment of trismus in head and neck cancer: A case report and a systematic review of the literature.

Introduction Trismus, or limited mouth opening, is a well-known complication of head and neck cancer and its treatment. It may be caused by tumour infiltration into the masticatory muscles or by treatment like surgery and radiotherapy. A limited mouth opening may have a negative effect on nutrition, phonation, dental hygiene and treatment, and quality of life. The severity of this complication depends on the location of the tumour, the type of reconstruction, the total radiation dose, fractionation, and treatment techniques. If there is no intervention, these changes may be progressive and persist for life. There are no specific treatments for trismus. Current strategies emphasize prevention and, in instances of existing trismus, collaboration between health care professionals to establish pain control, prevent the progression of trismus, and restore function. The prevalence of trismus in head and neck cancer patients ranges from 5% to 38%. Despite numerous studies, reliable data on the aetiology of trismus and appropriate treatment for it are scarce. Case report We describe a patient with squamous cell carcinoma of the oropharynx who developed trismus after surgery and radiotherapy. A multidisciplinary treatment strategy including analgesics, regional blocks, hyperbaric oxygenation therapy, external dynamic bite opener and physiotherapy, increased the mouth opening from 5 mm to 22 mm, however, the patient still suffered from xerostomia and had problems with intake of solid food. Material and methods A systematic literature search (starting January 1., 1980, and ending June 1., 2009) was performed to identify evidence-based interventions for the treatment of trismus in head and neck cancer patients. A total of 244 articles were identified from the databases. Of these, eight were excluded because of the absence of an English abstract and 214 were excluded because they were of marginal relevance to the inclusion criteria. The remaining 22 articles were evaluated independently by two experts using the Scottish Inter-collegiate Guidelines Network criteria for quality and evidence. Results There were few studies of good methodological quality on this topic. Two systematic reviews and two RCTs were identified. The other reports involved cohorts, case series, and expert opinions. Discussion Evidence in the form of clinical studies on therapeutic interventions is scarce. Numerous pharmacological treatment modalities have been described, but few are supported by the results of comparative trials involving control groups. Few studies have documented therapeutic effects for longer than a year. Better evidence was found for non-pharmacological methods, especially for physical therapy with passive and active stretching exercises, an important first-line strategy. The interincisal distance criterion for trismus varies between authors from 15 to 40 mm, which renders comparison between studies difficult. The absence of a standardized assessment protocol may also have contributed to variation between studies. An interincisal distance of 35 mm has been proposed as a definition of trismus. Explicit and precise treatment algorithms could not be established based on the available literature. However, a coordinated multidisciplinary approach in order to estimate and understand patient dysfunction is recommended; a systematic treatment plan should result in good symptom control and patient care. Prevention of trismus is more desirable than treatment for trismus.

Reduced risk of head and neck second primary tumors after radiotherapy.

BACKGROUND AND PURPOSE: With radiotherapy of primary tumors of the head and neck, a significant dose reaches the surrounding mucosa. The field cancerization and second field tumor theories state that premalignant lesions are present in the mucosa even at the time of primary tumor treatment. We tested the hypothesis that exposure to irradiation stabilizes subclinical premalignant lesions. This would reduce the rate of second primary tumors in the upper aerodigestive tract (UADT). MATERIALS AND METHODS: The cohort consisted of 346 patients treated for small localized squamous cell carcinoma of the oral cavity (T1-2, N0, and M0). The rate of UADT second primary tumors was compared between 247 patients exposed to radiation (case subjects) and 99 patients unexposed to radiation (control subjects). RESULTS: Median time to UADT second primary tumor was 8.6 years for irradiated patients and 3.9 years for controls (p=0.007). Through the first 5 years after the treatment of the primary tumor, the relative risk of developing a new UADT tumor for irradiated patients compared to controls was 0.12 (p<0.001). After 5 years the risk increased for irradiated cases. A corresponding change in risk was not found for controls. CONCLUSIONS: A slower rate of second primary tumors was seen within UADT mucosa exposed to irradiation. This could suggest a preventive effect by radiation on malignant transformation of subclinical premalignant foci.

The influence of resection and aneuploidy on mortality in oral leukoplakia.

BACKGROUND: Although the standard treatment of oral leukoplakia ranges from watchful waiting to complete resection, the value of these approaches is unknown. METHODS: We studied the relations among resection, ploidy status, and death from cancer in 103 patients with diploid dysplastic oral leukoplakia, 20 patients with tetraploid lesions, and 27 patients with aneuploid lesions. Data on cancer-specific mortality and treatment were obtained from the Cancer Registry of Norway, Statistics Norway, and chart reviews. RESULTS: Primary oral carcinoma developed in 47 of the 150 patients with leukoplakia (31 percent)--5 with diploid, 16 with tetraploid, and 26 with aneuploid leukoplakia--during a mean follow-up of 80 months (range, 4 to 237). The margin status of the initial leukoplakia resection had no relation to the development of oral cancer (P=0.95). Twenty-six of the 47 patients in whom cancer developed (4 with prior tetraploid and 22 with prior aneuploid lesions) had recurrences (55 percent); the recurrences were more frequently multiple and distant (within the oral cavity) among patients with aneuploid lesions than among those with tetraploid or diploid lesions. All 47 patients underwent a standard regimen of surgery and radiation, followed by chemotherapy in the 26 with recurrent cancer. Only patients with aneuploid leukoplakia died of oral cancer; the five-year rate of death from cancer was 72 percent. Aneuploidy-related first carcinomas were diagnosed at a more advanced stage than were carcinomas originating from diploid or tetraploid leukoplakia (P=0.03) and were more likely to be lethal regardless of the stage. CONCLUSIONS: Complete resection of aneuploid leukoplakia does not reduce the high risk of aggressive carcinoma and death from oral cancer.

Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 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.

Different prognostic indices in 310 patients with tonsillar carcinomas.

BACKGROUND: Several modifications of the TNM system have been reported as better prognostic tools than the original classification in head and neck cancer, but none of these modifications has been tested in a large series of tonsillar carcinomas. These studies did not examine host and treatment factors as predictors in addition to TNM. METHODS: Three hundred and ten consecutively untreated patients with squamous cell carcinoma of the tonsillar region admitted to the Norwegian Radium Hospital and/or the National Hospital between 1960 and 1996 were included. RESULTS: The five reported TN-based stage modifications were all highly significant predictors of survival. Four clinical variables indicating shorter disease-specific survival were identified: age > 60, male gender, total radiation dose < 70 Gy, and duration of radiotherapy > 50 days. CONCLUSIONS: Earlier reported TNM-based stage modifications are all very useful predictors of survival in tonsillar carcinomas. In addition, age, gender, total radiation dose, and duration of radiotherapy were important prognostic factors. We propose that both host and treatment factors should be tested carefully when building new prognostic indices in tonsillar carcinomas.

Side effects and quality of life after inadvertent radiation overdosage in brachytherapy of head-and-neck cancer.

PURPOSE: By comparing our old (DP5, in use from 1978 to 1994) and new (Plato, Nucletron) dose planning system, we found that the old system underestimated doses by 20-25%. To study the possible consequences for the patients treated between 1978 and 1994, all who were still alive were invited to undergo an examination with respect to side effects and quality of life (QOL). MATERIALS AND METHODS: The degree of overdosage was calculated by comparing the isodose distribution generated on the two dose planning systems. Eighty-four patients were then invited to undergo an examination with respect to side effects and QOL. The side effects were scored according to the LENT SOMA system and QOL according to European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30), and EORTC Quality of Life Questionnaire-Head & Neck 35 (QLQ-H&N35). RESULTS: The mean overdosage of brachytherapy was 19.3%. No association was found between overdosage and side effects or QOL. For implants in the lateral border of the tongue, we found a statistically significant correlation between osteoradionecrosis and the following parameters: linear activity, total activity, dose rate, and extrapolated response dose. By multivariate analysis, only total implanted activity and the use of lead protection during brachytherapy were found to be of prognostic significance with respect to development of osteoradionecrosis. CONCLUSION: The incidence of side effects after brachytherapy at the Norwegian Radium Hospital seems to have been somewhat higher in the period under investigation than at other institutions. There may be several explanations, including the use of external beam radiotherapy before brachytherapy and departure from the Paris system among others. However, the side effects were not associated with the overdosage that was the basis for the study. As opposed to the general consensus of opinion, long-term QOL was found to be worse after brachytherapy than after external beam radiotherapy. This calls for increased awareness and a systematic prospective registration of the long-term side effects of brachytherapy.