Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma.

BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

Effects of the COVID-19 pandemic on the diagnosis of malignant melanoma: a retrospective study

Background: The COVID-19 pandemic has influenced health care services all around the globe, which is also reflected in the diagnosis and management of malignant melanoma (MM). Objectives: We performed a retrospective assessment of the impact of the COVID-19 pandemic on the diagnosis of MM in order to evaluate the effects of the pandemic on MM care. Materials & Methods: The Breslow thickness of excised MM and total number of patients with newly diagnosed MM who underwent surgery during the first year of the pandemic (March, 2020 to February, 2021; 227 subjects) were compared relative to a control period the year before (March, 2019 to February, 2020; 201 subjects), based on a retrospective study design. Results: There was no significant decrease in the total number of excisions (227 subjects in the pre-COVID cohort vs. 201 in the COVID cohort). However, the mean Breslow thickness increased significantly from 1.1±1.4 mm in the pre-COVID group to 1.8±2.3 mm in the COVID group. Conclusion: We conclude that, due to several restrictions in the early phase of the pandemic, melanomas were diagnosed at a more advanced stage.

Advanced-Stage Melanoma at Presentation Following the Peak of the Pandemic: A COVID-19 Cancer Canary in a Coal Mine.

BACKGROUND: For melanoma patients, timely identification and tumor thickness are directly correlated with outcomes. COVID-19 impacted both patients' ability and desire to see physicians. We sought to identify whether the pandemic correlated with changes in melanoma thickness at presentation and subsequent treatment timeline. METHODS: Retrospective chart review was performed on patients who underwent surgery for melanoma in an academic center surgical oncology practice from May 2019 to September 2021. Patients were split into two cohorts: "pre-pandemic" from May 2019 to May 2020 and "pandemic," after May 2020, representing when these patients received their initial diagnostic biopsy. Demographic and melanoma-specific variables were recorded and analyzed. RESULTS: A total of 112 patients were identified: 51 patients from the "pre-pandemic" and 61 from the "pandemic" time period. The pandemic cohort more frequently presented with lesions greater than 1 mm thickness compared to pre-pandemic (68.8% v 49%, p = 0.033) and were found to have significantly more advanced T stage (p = 0.02) and overall stage disease (p = 0.022). Additionally, trends show that for pandemic patients more time passed from patient-reported lesion appearance/change to diagnostic biopsy (5.7 ± 2.0 v 7.1 ± 1.5 months, p = 0.581), but less time from biopsy to operation (42.9 ± 2.4 v 52.9 ± 5.0 days, p = 0.06). CONCLUSIONS: "Pandemic" patients presented with thicker melanoma lesions and more advanced-stage disease. These results may portend a dangerous trend toward later stage at presentation, for melanoma and other cancers with rapid growth patterns, that will emerge as the prolonged effects of the pandemic continue to impact patients' presentation for medical care.

Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial.

BACKGROUND: Pembrolizumab prolongs progression-free and overall survival among patients with advanced melanoma and recurrence-free survival in resected stage III disease. KEYNOTE-716 assessed pembrolizumab as adjuvant therapy in patients with completely resected, high-risk, stage II melanoma. We report results from the planned first and second interim analyses for recurrence-free survival. METHODS: In this double-blind, randomised, placebo-controlled phase 3 study, involving 160 academic medical centres and hospitals in 16 countries (Australia, Belgium, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Poland, South Africa, Spain, Switzerland, the UK, and the USA), patients aged 12 years or older with newly diagnosed, completely resected stage IIB or IIC melanoma (TNM stage T3b or T4 with a negative sentinel lymph node biopsy) were recruited. Eligible patients were randomly assigned (1:1), in blocks of four and stratified by T-category (3b, 4a, and 4b) and paediatric status (age 12-17 years vs ≥18 years), using an interactive response technology system to intravenous pembrolizumab 200 mg (2 mg/kg in paediatric patients) or placebo every 3 weeks for 17 cycles or until disease recurrence or unacceptable toxicity. All patients, clinical investigators, and analysts were masked to treatment assignment. The primary endpoint was investigator-assessed recurrence-free survival (defined as time from randomisation to recurrence or death) in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment). The primary endpoint was met if recurrence-free survival was significantly improved for pembrolizumab versus placebo at either the first interim analysis (after approximately 128 patients had events) or second interim analysis (after 179 patients had events) under multiplicity control. Safety was assessed in all patients randomly assigned to treatment who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03553836, and is closed to accrual. FINDINGS: Between Sept 23, 2018, and Nov 4, 2020, 1182 patients were screened, of whom 976 were randomly assigned to pembrolizumab (n=487) or placebo (n=489; ITT population). The median age was 61 years (IQR 52-69) and 387 (40%) patients were female and 589 (60%) were male. 874 (90%) of 976 patients were White and 799 (82%) were not Hispanic or Latino. 483 (99%) of 487 patients in the pembrolizumab group and 486 (99%) of 489 in the placebo group received assigned treatment. At the first interim analysis (data cutoff on Dec 4, 2020; median follow-up of 14·4 months [IQR 10·2-18·7] in the pembrolizumab group and 14·3 months [10·1-18·7] in the placebo group), 54 (11%) of 487 patients in the pembrolizumab group and 82 (17%) of 489 in the placebo group had a first recurrence of disease or died (hazard ratio [HR] 0·65 [95% CI 0·46-0·92]; p=0·0066). At the second interim analysis (data cutoff on June 21, 2021; median follow-up of 20·9 months [16·7-25·3] in the pembrolizumab group and 20·9 months [16·6-25·3] in the placebo group), 72 (15%) patients in the pembrolizumab group and 115 (24%) in the placebo group had a first recurrence or died (HR 0·61 [95% CI 0·45-0·82]). Median recurrence-free survival was not reached in either group at either assessment timepoint. At the first interim analysis, grade 3-4 treatment-related adverse events occurred in 78 (16%) of 483 patients in the pembrolizumab groups versus 21 (4%) of 486 in the placebo group. At the first interim analysis, four patients died from an adverse event, all in the placebo group (one each due to pneumonia, COVID-19-related pneumonia, suicide, and recurrent cancer), and at the second interim analysis, one additional patient, who was in the pembrolizumab group, died from an adverse event (COVID-19-related pneumonia). No deaths due to study treatment occurred. INTERPRETATION: Pembrolizumab as adjuvant therapy for up to approximately 1 year for stage IIB or IIC melanoma resulted in a significant reduction in the risk of disease recurrence or death versus placebo, with a manageable safety profile. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.

Influence of COVID-19 confinement on the size of malignant skin tumours surgically removed at a Spanish hospital.

The COVID-19 pandemic required people to confine themselves to their homes where possible, and disrupted normal hospital activities. We examine whether this lockdown generated changes in the size of the tumours. We compared the dimensions of the surgically removed malignant skin tumours from the first 150 patients treated after the confinement ended in Spain (22 May 2020) with those of the last 150 patients to receive such treatment before the confinement began (13 March 2020). Data on tumour surface area were collected from pathology reports. Overall, no significant difference was seen in the tumour sizes. However, among men, the tumours removed after confinement were significantly larger (P < 0.05). Controversy exists over how the reduction in the number of tumours diagnosed during lockdowns might have influenced the characteristics of tumours. In this study, no overall difference was seen in the size of the tumours removed, although those removed from men after confinement were larger.

Effects of COVID-19 Lockdown on Tumour Burden of Melanoma and Cutaneous Squamous Cell Carcinoma.

The aim of this study was to compare tumour burden in patients who underwent surgery for melanoma and cutaneous squamous cell carcinoma during nationwide lockdown in Spain due to COVID-19 (for the period 14 March to 13 June 2020) and during the same dates in 2019 before the COVID-19 pandemic. In addition, associations between median tumour burden (Breslow thickness for melanoma and maximum clinical diameter for cutaneous squamous cell carcinoma) and demographic, clinical, and medical factors were analysed, building a multivariate linear regression model. During the 3 months of lockdown, there was a significant decrease in skin tumours operated on (41% decrease for melanoma (n = 352 vs n = 207) and 44% decrease for cutaneous squamous cell carcinoma (n = 770 vs n = 429)) compared with the previous year. The proportion of large skin tumours operated on increased. Fear of SARS-CoV-2 infection, with respect to family member/close contact, and detection of the lesion by the patient or doctor, were related to thicker melanomas; and fear of being diagnosed with cancer, and detection of the lesion by the patient or relatives, were related to larger size cutaneous squamous cell carcinoma. In conclusion, lockdown due to COVID-19 has resulted in a reduction in treatment of skin cancer.

Obesity is not associated with disease-free interval, melanoma-specific survival, or overall survival in patients with clinical stage IB-II melanoma after SLNB.

BACKGROUND AND OBJECTIVES: Clinicopathologic characteristics have prognostic value in clinical stage IB-II patients with melanoma. Little is known about the prognostic value of obesity that has been associated with an increased risk for several cancer types and worsened prognosis after diagnosis. This study aims to examine effects of obesity on outcome in patients with clinical stage IB-II melanoma. METHODS: Prospectively recorded data of patients with clinical stage IB-II melanoma who underwent sentinel lymph node biopsy (SLNB) between 1995 and 2018 at the University Medical Center of Groningen were collected from medical files and retrospectively analyzed. Cox-regression analyses were used to determine associations between obesity (body mass index> 30), tumor (location, histology, Breslow-thickness, ulceration, mitotic rate, SLN-status) and patient-related variables (gender, age, and social-economic-status [SES]) and disease-free interval (DFI), melanoma-specific survival (MSS), and overall survival (OS). RESULTS: Of the 715 patients, 355 (49.7%) were women, median age was 55 (range 18.6-89) years, 149 (20.8%) were obese. Obesity did not significantly affect DFI (adjusted hazard ratio [HR] = 1.40; 95% confidence interval [CI] = 0.98-2.00; p = 0.06), MSS (adjusted HR = 1.48;95%CI = 0.97-2.25; p = 0.07), and OS (adjusted HR = 1.25; 95% CI = 0.85-1.85; p = 0.25). Increased age, arm location, increased Breslow-thickness, ulceration, increased mitotic rate, and positive SLN-status were significantly associated with decreased DFI, MSS, and OS. Histology, sex, and SES were not associated. CONCLUSION: Obesity was not associated with DFI, MSS, or OS in patients with clinical stage IB-II melanoma who underwent SLNB.

Management of melanoma patients during COVID-19 pandemic in an Italian skin unit.

Due to the COVID-19 crisis, many scheduled medical and surgical activities have been suspended. This interruption to the healthcare system can negatively affect the diagnosis and management of melanoma. Neglecting melanoma throughout the outbreak may be associated with increased rates of mortality, morbidity, and healthcare expenses. We performed a retrospective review of all dermatological and surgical activity performed in our Melanoma Skin Unit between 23 February 2020 and 21 May 2020 and compared these data with those from the same period in 2019. During the lockdown period, we observed a decrease in dermatologic follow-up (DFU) (-30.2%) and in surgical follow-up (SFU) (-37%), and no modification of melanoma diagnosis (-3%). Finally, surgical excisions (SE) (+ 31.7%) increased, but sentinel lymph node biopsy (SLNB) (-29%) and lymph node dissections(LND) (-64%) decreased compared to the same period in 2019. Our experience supports the continuation of surgical and diagnostic procedures in patients with melanoma during the COVID-19 pandemic. Surgical and follow-up procedures for the diagnosis and treatment of melanoma should not be postponed considering that the pandemic is lasting for an extended period.

Expression of the COVID-19 receptor ACE2 in the human conjunctiva.

SARS-CoV-2 is assumed to use angiotensin-converting enzyme 2 (ACE2) and other auxiliary proteins for cell entry. Recent studies have described conjunctival congestion in 0.8% of patients with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and there has been speculation that SARS-CoV-2 can be transmitted through the conjunctiva. However, it is currently unclear whether conjunctival epithelial cells express ACE2 and its cofactors. In this study, a total of 38 conjunctival samples from 38 patients, including 12 healthy conjunctivas, 12 melanomas, seven squamous cell carcinomas, and seven papilloma samples, were analyzed using high-throughput RNA sequencing to assess messenger RNA (mRNA) expression of the SARS-CoV-2 receptor ACE2 and its cofactors including TMPRSS2, ANPEP, DPP4, and ENPEP. ACE2 protein expression was assessed in eight healthy conjunctival samples using immunohistochemistry. Our results show that the SARS-CoV-2 receptor ACE2 is not substantially expressed in conjunctival samples on the mRNA (median: 0.0 transcripts per million [TPM], min: 0.0 TPM, max: 1.7 TPM) and protein levels. Similar results were obtained for the transcription of other auxiliary molecules. In conclusion, this study finds no evidence for a significant expression of ACE2 and its auxiliary mediators for cell entry in conjunctival samples, making conjunctival infection with SARS-CoV-2 via these mediators unlikely.

Surgical decision-making and prioritization for cancer patients at the onset of the COVID-19 pandemic: A multidisciplinary approach.

In the midst of the coronavirus disease 2019 (COVID-19) pandemic, governmental agencies, state medical boards, and healthcare organizations have called for restricting "elective" operations to mitigate the risk of transmission of the virus amongst patients and healthcare providers and to preserve essential resources for potential regional surges of COVID patients. While the fear of delaying surgical care for many of our patients is deeply challenging for us as cancer care providers, we must balance our personal commitment to providing timely and appropriate oncologic care to our cancer patients with our societal responsibility to protect our patients (including those on whom we are operating), co-workers, trainees, families, and community, from undue risks of contracting and propagating COVID-19. Herein, we present guidelines for surgical decision-making and case prioritization developed among all adult disease specialties in the MD Anderson Cancer Center Departments of Surgical Oncology and Breast Surgical Oncology in Houston, Texas.