Assessing the Potential for Patient-led Surveillance After Treatment of Localized Melanoma (MEL-SELF): A Pilot Randomized Clinical Trial.

IMPORTANCE: Patient-led surveillance is a promising new model of follow-up care following excision of localized melanoma. OBJECTIVE: To determine whether patient-led surveillance in patients with prior localized primary cutaneous melanoma is as safe, feasible, and acceptable as clinician-led surveillance. DESIGN, SETTING, AND PARTICIPANTS: This was a pilot for a randomized clinical trial at 2 specialist-led clinics in metropolitan Sydney, Australia, and a primary care skin cancer clinic managed by general practitioners in metropolitan Newcastle, Australia. The participants were 100 patients who had been treated for localized melanoma, owned a smartphone, had a partner to assist with skin self-examination (SSE), and had been routinely attending scheduled follow-up visits. The study was conducted from November 1, 2018, to January 17, 2020, with analysis performed from September 1, 2020, to November 15, 2020. INTERVENTION: Participants were randomized (1:1) to 6 months of patient-led surveillance (the intervention comprised usual care plus reminders to perform SSE, patient-performed dermoscopy, teledermatologist assessment, and fast-tracked unscheduled clinic visits) or clinician-led surveillance (the control was usual care). MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of eligible and contacted patients who were randomized. Secondary outcomes included patient-reported outcomes (eg, SSE knowledge, attitudes, and practices, psychological outcomes, other health care use) and clinical outcomes (eg, clinic visits, skin surgeries, subsequent new primary or recurrent melanoma). RESULTS: Of 326 patients who were eligible and contacted, 100 (31%) patients (mean [SD] age, 58.7 [12.0] years; 53 [53%] men) were randomized to patient-led (n = 49) or clinician-led (n = 51) surveillance. Data were available on patient-reported outcomes for 66 participants and on clinical outcomes for 100 participants. Compared with clinician-led surveillance, patient-led surveillance was associated with increased SSE frequency (odds ratio [OR], 3.5; 95% CI, 0.9 to 14.0) and thoroughness (OR, 2.2; 95% CI, 0.8 to 5.7), had no detectable adverse effect on psychological outcomes (fear of cancer recurrence subscale score; mean difference, -1.3; 95% CI, -3.1 to 0.5), and increased clinic visits (risk ratio [RR], 1.5; 95% CI, 1.1 to 2.1), skin lesion excisions (RR, 1.1; 95% CI, 0.6 to 2.0), and subsequent melanoma diagnoses and subsequent melanoma diagnoses (risk difference, 10%; 95% CI, -2% to 23%). New primary melanomas and 1 local recurrence were diagnosed in 8 (16%) of the participants in the intervention group, including 5 (10%) ahead of routinely scheduled visits; and in 3 (6%) of the participants in the control group, with none (0%) ahead of routinely scheduled visits (risk difference, 10%; 95% CI, 2% to 19%). CONCLUSIONS AND RELEVANCE: This pilot of a randomized clinical trial found that patient-led surveillance after treatment of localized melanoma appears to be safe, feasible, and acceptable. Experiences from this pilot study have prompted improvements to the trial processes for the larger trial of the same intervention. TRIAL REGISTRATION: http://anzctr.org.au Identifier: ACTRN12616001716459.

BRAF mutation testing for patients diagnosed with stage III or stage IV melanoma: practical guidance for the Australian setting.

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAFV600 mutation testing does not need to be requested by the treating clinician). When performed in centres with appropriate expertise and experience, immunohistochemistry (IHC) using the anti-BRAF V600E monoclonal antibody (VE1) can be a highly sensitive and specific means of detecting BRAFV600E mutations, and may be used as a rapid and relatively inexpensive initial screening test. However, VE1 immunostaining can be technically challenging and difficult to interpret, particularly in heavily pigmented tumours; melanomas with weak, moderate or focal BRAFV600E immunostaining should be regarded as equivocal. It must also be remembered that other activating BRAFV600 mutations (including BRAFV600K), which account for ∼10-20% of BRAFV600 mutations, are not detected with currently available IHC antibodies. For these reasons, if available and practicable, we recommend that DNA-based BRAF mutation testing always be performed, regardless of whether IHC-based testing is also conducted. Advice about tissue/specimen selection for BRAF mutation testing of patients diagnosed with stage III or IV melanoma is also offered in this article; and potential pitfalls when interpreting BRAF mutation tests are highlighted.

Improved Risk Prediction Calculator for Sentinel Node Positivity in Patients With Melanoma: The Melanoma Institute Australia Nomogram.

PURPOSE: For patients with primary cutaneous melanoma, the risk of sentinel node (SN) metastasis varies according to several clinicopathologic parameters. Patient selection for SN biopsy can be assisted by National Comprehensive Cancer Network (NCCN) and ASCO/Society of Surgical Oncology (SSO) guidelines and the Memorial Sloan Kettering Cancer Center (MSKCC) online nomogram. We sought to develop an improved online risk calculator using alternative clinicopathologic parameters to more accurately predict SN positivity. PATIENTS AND METHODS: Data from 3,477 patients with melanoma who underwent SN biopsy at Melanoma Institute Australia (MIA) were analyzed. A new nomogram was developed by replacing body site and Clark level from the MSKCC model with mitotic rate, melanoma subtype, and lymphovascular invasion. The predictive performance of the new nomogram was externally validated using data from The University of Texas MD Anderson Cancer Center (n = 3,496). RESULTS: The MSKCC model receiver operating characteristic curve had a predictive accuracy of 67.7% (95% CI, 65.3% to 70.0%). The MIA model had a predictive accuracy of 73.9% (95% CI, 71.9% to 75.9%), a 9.2% increase in accuracy over the MSKCC model (P < .001). Among the 2,748 SN-negative patients, SN biopsy would not have been offered to 22.1%, 13.4%, and 12.4% based on the MIA model, the MSKCC model, and NCCN or ASCO/SSO criteria, respectively. External validation generated a C-statistic of 75.0% (95% CI, 73.2% to 76.7%). CONCLUSION: A robust nomogram was developed that more accurately estimates the risk of SN positivity in patients with melanoma than currently available methods. The model only requires the input of 6 widely available clinicopathologic parameters. Importantly, the number of patients undergoing unnecessary SN biopsy would be significantly reduced compared with use of the MSKCC nomogram or the NCCN or ASCO/SSO guidelines, without losing sensitivity. An online calculator is available at www.melanomarisk.org.au.

Adjuvant therapy with high dose vitamin D following primary treatment of melanoma at high risk of recurrence: a placebo controlled randomised phase II trial (ANZMTG 02.09 Mel-D).

BACKGROUND: Patients with primary cutaneous melanomas that are ulcerated and >2 mm in thickness, >4 mm in thickness and those with nodal micrometastases at diagnosis, have few options for adjuvant treatment. Recent studies have suggested a role for vitamin D to delay melanoma recurrence and improve overall prognosis. METHODS/DESIGN: This is a pilot placebo-controlled randomised phase II trial to assess the feasibility, safety and toxicity of an oral loading dose of Vitamin D (500,000 IU) followed by an oral dose of 50,000 IU of Vitamin D monthly for 2 years in patients who have been treated for cutaneous melanoma by wide excision of the primary. Patients aged 18-79 years who have completed primary surgical treatment and have Stage IIb, IIc, IIIa (N1a, N2a) or IIIb (N1a, N2a) disease are eligible for randomisation 2:1 to active treatment or placebo. The primary endpoints are sufficiency of dose, adherence to study medication and safety of the drug. The secondary endpoints are participation and progression free survival. The study has been approved by the Ethics Review Committee (RPAH Zone) of the Sydney Local Health District, protocol number X09-0138. DISCUSSION: Effective, non-toxic adjuvant therapy for high risk primary melanoma is not currently available. Favorable outcomes of this phase II study will form the basis for a multi-centre phase III study to assess whether the addition of oral high-dose vitamin D therapy in patients who have completed primary treatment for melanoma and are at high risk of recurrence will: 1. prolong time to recurrence within 5 years 2. improve overall survival at 5 years and 3. be both safe and tolerable. 62 patients have been randomised since the study commenced in December 2010. Target accrual for the study has been met with 75 patients randomised between December 2010 and August 2014.The Mel-D trial is conducted by the Australia and New Zealand Melanoma Trials Group (ANZMTG 02.09) TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry (ANZCTR) ACTRN12609000351213.