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.

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.

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.

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.

Technique for axillary radiotherapy using computer-assisted planning for high-risk skin cancer.

High-risk skin cancer arising on the upper limb or trunk can cause axillary nodal metastases. Previous studies have shown that axillary radiotherapy improves regional control. There is little published work on technique. Technique standardization is important in quality assurance and comparison of results especially for trials. Our technique, planned with CT assistance, is presented. To assess efficacy, an audit of patients treated in our institution over a 15-month period was conducted. Of 24 patients treated, 13 were treated with radical intent, 11 with this technique. With a follow up of over 2 years, the technique had more than a 90% (10/11) regional control in this radical group. Both of the radical patients who were not treated according to the technique had regional failure. One case of late toxicity was found, of asymptomatic lymphoedema in a radically treated patient. This technique for axillary radiotherapy for regional control of skin cancer is acceptable in terms of disease control and toxicity as validated by audit at 2 years.

Characterization of the expression and activation of the epidermal growth factor receptor in squamous cell carcinoma of the skin.

BACKGROUND: Locally advanced skin cancers including squamous cell carcinoma (SCC) of the skin are increasing in incidence. Patients are often elderly with significant comorbidities and therapy can be difficult. New targeted therapies, such as treatment directed at the epidermal growth factor receptor (EGFR), may be effective and less toxic in these patients. However, before designing appropriate clinical trials it is necessary to characterize the expression and activation of targets such as the EGFR to evaluate the rationale of using EGFR inhibitors (EGFRIs) in the treatment of this type of cancer. OBJECTIVES: To characterize the expression and activation by phosphorylation of EGFR in SCC of the skin by quantitative Western blotting using the LiCor immunofluorescence detection system with validation by immunohistochemistry. Secondary objectives were to evaluate downstream targets of EGFR expression and activation in SCC of the skin and to examine the associations between EGFR, pathological features and clinical behaviour of these tumours. METHODS: Twenty-one mainly locally advanced skin SCCs collected in our institution and stored in our tissue bank over a 4-year period were used for the study. RESULTS: Nine of 21 (43%) tumours expressed EGFR above background. Of those nine, five expressed phosphorylated EGFR. There was no correlation with downstream activation of canonical signalling pathways, pathological features or clinical behaviour. CONCLUSIONS: EGFR is expressed in a minority of tumours and then is not always activated. These results show that, before designing a trial with a targeted agent such as an EGFRI in SCC of the skin, it is important to verify the presence of the appropriate target to maximize the best outcome.

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.

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.

Quality assurance in a Radiation Oncology Unit: the Chart Round experience.

Quality assurance ensures that planned treatments eventuate. Programmes must include feedback loops to promptly correct any shortfall in predetermined standards. In March 1999, a weekly Chart Round was introduced to verify that certain items relevant to quality care were being completed for patients of the Head and Neck Radiotherapy Unit at the Peter MacCallum Cancer Institute. The experience was reviewed after 1 year and it was found that the initiation of Chart Rounds has assisted in raising the level of item completion from 80% to 99% in similar groups of patients treated before and after the initiation of the Chart Round. Initiation of the Chart Round has also provided a useful forum for in-house peer-review, education and effective real-time communication between medical and allied health personnel, all of which has further added to the quality of patient care.