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.

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.

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.

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.