Randomized Trial of Postoperative Radiation Therapy After Wide Excision of Neurotropic Melanoma of the Head and Neck (RTN2 Trial 01.09).

BACKGROUND: Cutaneous neurotropic melanoma (NM) of the head and neck (H&N) is prone to local relapse, possibly due to difficulties widely excising the tumor. This trial assessed radiation therapy (RT) to the primary site after local excision. METHODS: Participants from 15 international centers were randomized to observation or RT. The participants were required to have microscopically negative excision margins 5 mm wide or wider and no evidence of disease elsewhere. The primary outcome was time to local relapse. The secondary outcomes included time to any recurrence, overall survival (OS), and toxicity. RESULTS: The trial ceased prematurely due to slow recruitment and the COVID-19 pandemic. During 2009-2020, 50 participants were randomized: 23 to observation and 27 to RT. The most common NM subsites were scalp (32%), midface (22%), and lip (20%). The median depth of invasion was 5 mm, and desmoplasia observed in 69%. The median duration from randomization to last contact was 4.8 years. Four participants (8%) experienced local relapse as a first recurrence during the study period: 3 in the observation arm and 1 in the RT arm (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.03-2.76; p = 0.279). No statistically significant difference in time to any relapse or OS was observed. More than 6 months after randomization, grade 3 or greater toxicity was experienced by 10% of the participants in the observation arm and 12.5% of the participants in the RT arm of the study. CONCLUSION: Due to low accrual, the role of adjuvant RT for cutaneous NM of the H&N excised with microscopically negative margins 5 mm wide or wider remains undefined. Its routine use cannot be recommended. Local relapse might be less common than previously anticipated based on retrospective reports.

A systematic review and meta-analysis of utility estimates in melanoma.

BACKGROUND: Health-related quality of life (HRQOL) in melanoma is affected by cancer stage. Previous studies have reported limited data on utility-based HRQOL. OBJECTIVES: To determine pooled estimates of utility-based HRQOL (utilities) for people with American Joint Cancer Committee stage I/II, III or IV melanoma for use in economic evaluations. METHODS: We performed a systematic review, meta-analysis and metaregression of utilities for patients with melanoma. HRQOL scores reported with the QLQ-C30, SF-36, SF-12, FACT-G and FACT-M instruments were converted to utilities using published mapping algorithms. Meta-analysis was used to calculate mean utilities. Metaregression was used to examine the effects of baseline patient and study characteristics. RESULTS: We identified 33 studies reporting 213 utilities. From meta-analyses, the mean utility for stage I/II melanoma was 0·97 [95% confidence interval (CI) 0·90-0·98]; for stage III melanoma it was 0·77 (95% CI 0·70-0·83); for stage III/IV 0·76 (95% CI 0·76-0·77); and for stage IV melanoma 0·76 (95% CI 0·71-0·81). The difference in utility between stage III and stage IV was not statistically significant (P = 0·52). For patients with stage I/II, the utility estimate at the time of surgery was 0·77 (95% CI 0·75-0·79), and at 3-12 months postsurgery it was 0·85 (95% CI 0·84-0·86). Utility estimates for patients with stage IV melanoma were 0·65 (95% CI 0·62-0·69) during the first 3 months of treatment and 0·83 (95% CI 0·81-0·86) at 4-12 months on treatment. For patients with stage IV melanoma treated with chemotherapy, the utility estimate was 0·52 (95% CI 0·51-0·52), while for those treated with targeted therapy it was 0·83 (95% CI 0·82-0·85). CONCLUSIONS: These robust, evidence-based estimates of health state utility can be used in economic evaluations of new treatments for patients with early-stage or advanced-stage melanoma.

Radiotherapy for lentigo maligna: a literature review and recommendations for treatment.

Lentigo maligna (LM) incidence is increasing. LM frequently involves the face near critical anatomical structures and as a consequence clinical management is challenging. Nonsurgical therapies, including radiotherapy (RT), are increasingly used. Evidenced-based treatment guidelines are lacking. We conducted a review of previously published data analysing RT treatment of LM. A search of PubMed, Embase and Medline databases to June 2012 identified nine clinical studies that examined the use of RT for LM treatment in at least five patients. Nine studies described 537 patients with LM treated with definitive primary RT, between 1941 and 2009, with a median reported follow-up time of 3 years. Eight articles could be reviewed for oncological outcome data. There were 18 recurrences documented in a total of 349 assessable patients (5%). Salvage was successful in the majority of recurrent LM cases by using further RT, surgery or other therapies. Progression to LM melanoma (LMM) occurred in five patients (five out of 349, 1.4%) who all had poor outcomes. There were five marginal recurrences documented out of 123 assessable patients (4%). There were eight in-field recurrences documented with either LM (five) or LMM (three) out of 171 assessable patients (5%). A series of recommendations were then developed for RT parameters for treatment of LM. These parameters include treatment volume, dose, dose per fraction and outcome measures. These may be of use in prospective data collection.

Surveillance for treatment failure of lentigo maligna with dermoscopy and in vivo confocal microscopy: new descriptors.

BACKGROUND: Nonsurgical treatment (radiotherapy, imiquimod) is increasingly employed for the management of lentigo maligna (LM). While the diagnosis of LM remains difficult, the detection of treatment failure is even more challenging. OBJECTIVES: To describe the sensitivity and specificity for the diagnosis of LM of individual features and methods using dermoscopy and in vivo reflectance confocal microscopy (RCM) to aid in the detection of treatment failure of LM following nonsurgical treatment. METHODS: A retrospective study of dermoscopy and RCM images (blinded to the correlation with pathology) in patients with biopsy-confirmed LM who were undergoing nonsurgical treatment in two referral institutions - one in Sydney, Australia, and the other in Barcelona, Spain. Ninety-eight patients were treated nonsurgically for LM during the period 2006-2012. Thirty-one patients had abnormal dermoscopy or RCM evaluation, and had a biopsy that identified LM recurrence in 15 patients and nonmelanoma diagnoses in 16 patients (one Bowen disease, 15 solar changes). RESULTS: The diagnosis of treatment failure was difficult with dermoscopy, with a sensitivity of 80% and specificity of 56%, even with the interpretation of an expert. The best criterion was asymmetric hyperpigmented follicular openings, but this was present in only 47% of treatment failure LM. Isolated, very fine brown dots ('dust' appearance) correlated highly with the diagnosis of treatment failure LM (73% sensitivity and 88% specificity) and with pagetoid cells seen with RCM. The LM score, comprising six criteria, had a specificity of 94% and sensitivity of 100%. CONCLUSIONS: These methods and descriptors should help to manage the diagnosis of treatment failure.

Human papillomavirus modifies the prognostic significance of T stage and possibly N stage in tonsillar cancer.

BACKGROUND: Despite the association with more advanced nodal stage, patients with human papillomavirus (HPV) positive oropharyngeal cancers have better outcomes. We examined whether the HPV can modify the effect of known prognostic factors in tonsillar cancer. PATIENTS AND METHODS: A total of 489 patients from 10 centres were followed up for recurrence or death for a median of 3.2 years. Determinants of the rate of locoregional recurrence, death from tonsillar cancer and overall survival were modelled using Cox regression. RESULTS: The prognostic value of T and N stages were modified by HPV as indicated by statistically significant interaction terms. After adjusting for age, gender and treatment, T stage appeared relevant only for HPV-positive cancers (where a higher T stage was associated with worse outcomes). There was some evidence that N stage was a more relevant prognostic factor for HPV-negative than -positive cancers. There was no evidence that the HPV modifies the effect of age, gender or grade on outcomes. CONCLUSIONS: This study suggests that the prognostic significance of the conventional staging system in tonsillar cancer is modified by HPV.

The utility of magnetic resonance imaging in the detection of brain metastases in the staging of cutaneous melanoma.

AIMS: To retrospectively evaluate the use of brain magnetic resonance imaging (MRI) in the initial staging of patients with cutaneous melanoma in our melanoma unit. MATERIALS AND METHODS: The radiology request forms for brain MRI for melanoma staging for 193 consecutive patients were reviewed. Patient hospital records were also retrospectively reviewed. Patients with no histological confirmation of a cutaneous primary or patients whose scan was to primarily investigate their neurological symptoms were excluded. Records were also searched for incidental symptoms that may have been associated with brain metastases. RESULTS: One hundred patients were eligible. No patients were upstaged by MRI. Of a total of 33 patients already graded as stage IV by prior staging, 11 (33%) were found to have brain metastases. No patients graded less than stage IV were found to have brain metastases on MRI. Six out of 12 patients with incidental symptoms had metastases. Five patients graded as stage IV had asymptomatic brain metastases. CONCLUSION: We recommend brain MRI only for patients with stage IV disease and for other patients with melanoma contemplating further adjuvant therapy where brain metastases would change management.

Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma.

The anti-PD-1 antibodies nivolumab and pembrolizumab are active in metastatic melanoma; however, there is limited data on combining anti-PD-1 antibody and radiotherapy (RT). We sought to review clinical outcomes of patients receiving RT and anti-PD-1 therapy. All patients receiving anti-PD-1 antibody and RT for metastatic melanoma were identified. RT and systemic treatment, clinical outcome, and toxicity data were collected. Fifty-three patients were included; 35 patients received extracranial RT and/or intracranial stereotactic radiosurgery (SRS) and 21 received whole brain radiotherapy (WBRT) (three of whom also received SRS/extracranial RT). Patients treated with extracranial RT or SRS received treatment either sequentially (RT then anti-PD-1, n = 11), concurrently (n = 16), or concurrent "salvage" treatment to lesions progressing on anti-PD-1 therapy (n = 15). There was no excessive anti-PD-1 or RT toxicity observed in patients receiving extracranial RT. Of six patients receiving SRS, one patient developed grade 3 radiation necrosis. In 21 patients receiving WBRT, one patient developed Stevens-Johnson syndrome, one patient developed acute neurocognitive decline, and one patient developed significant cerebral edema in the setting of disease. Response in irradiated extracranial/intracranial SRS lesions was 44% for sequential treatment and 64% for concurrent treatment (p=0.448). Likewise there was no significant difference between sequential or concurrent treatment in lesional response of non-irradiated lesions. For progressing lesions subsequently irradiated, response rate was 45%. RT and anti-PD-1 antibodies can be safely combined, with no detectable excess toxicity in extracranial sites. WBRT and anti-PD-1 therapy is well tolerated, although there are rare toxicities and the role of either anti-PD-1 or WBRT in the etiology of these is uncertain.

Radiation recall reaction following gemcitabine.

A case of dermatitis and myositis in the upper thorax following administration of gemcitabine in a 65-year-old woman with metastatic non small cell lung cancer (NSCLC) is described. The reaction and time course suggest a radiation recall phenomenon. This report joins a small but increasing number of radiation recall events related to gemcitabine. The possibility of a radiation recall reaction should be borne in mind when a patient develops symptoms in a previously irradiated site without evidence of disease progression at that site. Cessation of the precipitating drug is the most important step in management and systemic steroids may hasten symptomatic relief.

The measurement of total filtration of diagnostic X-ray tubes.

New data based on calculated X-ray spectra for X-ray tubes of different target angles and various magnitudes of kilovoltage ripple are presented. Currently available published data relating the total filtration of diagnostic X-ray tubes to the measured half-value thickness (HVT) are of limited use to those carrying out such measurements. Electronic penetrameters are now widely available, which allow improved accuracy in the measurement of tube kilovoltage, and the monitoring of waveforms. This has highlighted the necessity to refer to data which apply to the correct waveform ripple value, and to the correct tube target angle. A wide range of data referring to 10 degrees and 16 degrees target angles has been calculated. An experimental example is presented where measured values of HVT on nine X-ray tubes are converted to values of total filtration, using the calculated data.

Primary melanoma of the oesophagus well palliated by radiotherapy.

A case of a 16 cm primary melanoma of the mid oesophagus in a Caucasian male is reported. Radiological investigations at presentation revealed asymptomatic mediastinal and lower oesophageal metastases. The patient was treated with hypofractionated radiotherapy and achieved durable local disease control and excellent palliation of his dysphagia and chest pain until his death from widespread metastatic disease 5 months after treatment. The role of external beam radiotherapy in the treatment of primary oesophageal melanoma is reviewed.

Plasma cell infiltration of the upper aerodigestive tract treated with radiation therapy.

A case of chronic, fluctuating plasma cell gingivostomatitis that progressed despite chemotherapy and surgery is reported. This is the first case reported of treatment with radiation therapy, and one of the few cases reported where the infiltrate has reached the larynx. After receiving low dose radiation therapy, via a conformal technique encompassing the respiratory mucosal lining from the base of tongue to carina, there has been symptomatic improvement.

The assessment of emotional distress experienced by people with an intellectual disability: a study of different methodologies.

The assessment of emotional disorders such as anger, depression and stress among people with an intellectual disability has traditionally used one of three methodologies: ratings by a significant other, a clinical interview or self-report. Despite the widespread use of all three methodologies, there is little research into their equivalence. This paper assesses the convergence among these three approaches for 147 people with a mild or moderate intellectual disability across the affective domains of anger, depression and stress. The results showed the overlap among the three methods to be consistently low, although limited convergence was found between self-report and clinical interview. Ratings by work supervisors discriminated least clearly between anger, depression and stress while self-report was the most discriminating between these three overlapping but conceptually distinct states. Suggestions are made for ongoing research into the methodologies of assessing affective states among people with an intellectual disability.

Measuring stress in the mildly intellectually handicapped: the factorial structure of the Subjective Stress Scale.

The Subjective Stress Scale (SSS) was developed by Bramston and Bostock (1994) to provide a sensitive measure of stress for people with intellectual disabilities. This study examined the underlying structure of the SSS by analysing responses of 221 intellectually disabled people to the questionnaire. Exploratory factor analysis of the interitem correlation matrix yielded at least three solutions that were quite interpretable: a one-factor, a two-factor, and a four-factor solution. Factors in all three solutions bore a strong resemblance to stress dimensions reported for the general population using other stress measures. The results suggest that although the actual stressors vary, persons with mild intellectual disability are affected by the same major stress dimensions as the general population. The results also suggest that the SSS can be used as a much needed measure of subjective stress levels in people with mild intellectual disabilities.

Validation of the Lifestress Inventory for people with a mild intellectual disability.

The Subjective Stress Scale (SSS; Bramston & Bostock, 1994) was developed to measure stress in people with a mild intellectual disability. In previous research, the SSS was found to measure two broad dimensions of stress (a) a General Worry factor and (b) a factor that tapped concerns about Negative Interpersonal Relations (Bramston & Fogarty, 1995). The present study sought to continue this line of research by introducing a slightly modified form of the SSS, to be known as the Lifestress Inventory (LI) and examining the psychometric properties of the scale when administered to a new sample of 221 people with mild intellectual disabilities. Confirmatory factor analysis indicated that three underlying factors corresponding to General Worry, Negative Interpersonal Relations, and Coping were sufficient to account for the correlations among the items in the LI. Rasch analysis indicated some improvements to the scoring format for the LI and also showed that the most easily experienced stressors were associated with the Negative Interpersonal Relations dimension. The refinements introduced by the LI and the further demonstration that some of the broad stress dimensions identified in the general population can also be found in people with an intellectual disability represent important milestones for researchers interested in exploring reactions to stress among this population.

Symposium on teacher stress. Occupational stress among vocational teachers.

There is a widespread belief that work related stress among teachers is serious, with implications for teachers' health status and performance. The difficulty with interpreting data on teacher stress is that the measuring instruments used are often neither standardised nor sometimes focused on stressors pertinent to the occupational roles of teachers. This study, therefore, uses a recently developed test instrument called the Occupational Stress Inventory (OSI) which concisely measures occupational stress, strain and coping resources. Data were obtained, using the OSI, from a group of vocational teachers and compared to a group of professional non-teachers. Overall the results showed a significantly higher level of teacher stress, although only one of 10 stress and strain measures contributed to this effect. The implications for teachers, in terms of occupational role, are discussed.