Melanoma is a public health issue due to its increasing incidence and young age of diagnosis. There are three types of malignant melanoma: cutaneous, uveal and mucosal.
Cutaneous malignant melanoma is the most common melanoma subtype of the three aforementioned, accounting for 90% of cases of melanoma(1). Melanoma is reported as the 19th most common type of cancer worldwide, with estimated age-standardized incidence rates of 2.8-3.1 per 100,000(2). There is a variation in its incidence between countries, with the highest rates in Australia (37 per 100,000) and with a lower rate in South-Central Asia (0.2 per 100,000). This trend of varying incidence is possible due to variations in racial skin phenotype, differences in sun exposure and custom of use of UV protection around the world. The American Cancer Society’s estimates for melanoma in the United States of America for 2020 are about 100,350 cases of new melanomas to be diagnosed.
Europe is, in terms of incidence rates, behind Australia and the USA. Even within Europe, incidence rates vary widely(3).
The incidence of cutaneous malignant melanoma around the world has been rising annually faster than that of any other solid malignancy. This fact is of concern due to younger patients, with a median age at diagnosis of 57 years old.
The prognostic factors in cutaneous melanoma include histopathological and immunohistochemistry characteristics, patients’ characteristics, biochemical measures, and genetic mutations.
Another type of melanoma is represented by uveal melanoma – the most common primary ophthalmic malignancy in adults – with poor prognosis and resistance to available treatments. The incidence of uveal melanoma in Europe has been estimated between 2 and 8 per million(4), and the median age at presentation ranges from 55 to 60 years old(5,6).
Mucosal melanoma represents the least common of the three melanoma subtypes, accounting for less than 1.5% of all melanomas(1,7).
There is a lot of research in melanoma population management, starting with surgery type, continuing with radiotherapy and systemic treatments.
The current guidelines recommend surgery for earlier stages, followed by sentinel lymph node biopsy in tumours with Breaslow over 0.8 mm, with lymph node area evaluation by ultrasound in specialised clinics or lymph node basin dissection, where ultrasound evaluation is not possible. If there is an enlargement in locally lymph nodes, surgery is recommended, as well as for resectable metastatic lesions. Adjuvant treatment includes in stage IIB interferon, in stage III or stage IV, without evidence of disease (resected R0 stage IV), immunotherapy represented by nivolumab or targeted therapy – only for BRAF mutated tumours – represented by combination of dabrafenib with trametinib. For metastatic stages, there are a lot of approved drugs: ipilimumab in combination with nivolumab or immunotherapy monotherapy represented by pembrolizumab, nivolumab or ipilimumab. Targeted therapy approved for BRAF-positive tumours is represented by: dabrafenib and trametinib, vemurafenib and cobimetinib, encorafenib with binimetinib. In later lines, chemotherapy can be used.
Radiotherapy is used in metastatic setting for palliation and in adjuvant setting for lymph node basin.
Some malignant melanoma treatments – including chemotherapy, targeted therapies, immunotherapy and radiation – can change the immune response(8). People who have weakened immune systems or lung problems due to radiotherapy pneumonitis or immune-mediated pneumonitis or lung metastases have a much higher risk of complications if they are infected with SARS-CoV-2. For most people, the immune system recovers within a couple of months after completing these treatments, so those who have been treated for melanoma in the past don’t necessarily have a higher risk of severe illness(9).
On the 20th of April 2020, there were reported 2,444,209 coronavirus cases and 167,986 deaths(10).
There are a lot of recommendations amidst COVID-19 pandemic on diagnosis and treatment of patients with different kinds of solid tumours.
The ethical principle that should guide our medical decisions should be primum non nocere, respecting patient’s wish and trying to do what is best for him/her with fair allocation of resources.
Unanswered questions – such as: Do cancer patients have a higher risk of contracting the infection or of developing severe infection?, Which is the best approach for the treatment of cancer patients in the middle of COVID-19 outbreak? or What therapies can be delayed and what would be the impact on survival? – remain.
We want to evaluate and reinforce the recommendations on melanoma patients management by searching for different medical societies recommendation.
Almost all professional societies try to identify the optimal protocols for cancer facilities to minimize the risk of SARS-CoV-2 infection in both inpatient and outpatient settings. The Romanian National Society of Medical Oncology wrote also a statement reported on the health ministry page(11).
Zhang et al. described the characteristics and outcomes of 28 patients with COVID-19 and cancer from three hospitals in Wuhan, China(6), in a retrospective cohort study published in Annals of Oncology and showed that cancer patients were at higher risk for severe events and mortality. As a response to his article, William K. Oh, MD of Icahn School of Medicine at Mount Sinai, recommended caution in interpreting findings reported from China. He reported a 1.7-fold increased prevalence than in the Chinese population of the same age that is observed in American population, and a mortality rate in these patients more than 10 times higher in American population from New York than that reported in all COVID-19 patients in China(12).
The countries affected will need to make decisions and to balance the demands of responding to SARS-CoV-2 infection and to coordinate actions to maintain essential health service delivery.
Routine checkups, elective, unnecessary surgeries and other procedures have been cut back or delayed in these new pandemic times to help minimize exposure to the new coronavirus that has already infected more than 2.4 million people.
NCCN Short-Term Recommendations for Cutaneous Melanoma Management During COVID-19 Pandemic recommends to defer follow-up screening/clinical surveillance visits in surgically resected, asymptomatic patients with localized melanoma (stages 0, I, II) and imaging surveillance (e.g., chest X-ray, CT, FDG PET/CT in stage IIB/IIC patients) in asymptomatic stage IIB/IIC patients for at least 3-6 months.
Modifying surgery aspects in the time of COVID-19 pandemic include recommendations from medical societies such as The Society of Surgical Oncology, The European Society of Medical Oncology, and NCCN.
The Society of Surgical Oncology (SSO) recommends to delay wide local excision of in situ disease for three months and all lesions with negative margins on initial biopsy should be delayed for reexcision for obtaining oncological secure margins, if resources become scarce. If a significant delay in definite excision is anticipated, the precise location of the biopsy site should be documented (e.g., photography), recommendations reinforced by NCCN Short-Term Recommendations for Cutaneous Melanoma Management During COVID-19 pandemic(21).
The surgical management of T3/T4 melanomas (>2 mm thickness) should take priority over T1/T2 melanomas (≤2 mm thickness). The exception is any melanoma that is incompletely biopsied with large clinical residual lesion, and gross complete resection is recommended to be done in this case. The high priority is given by ESMO recommendations to T3 and T4, and medium to T1 and T2.
Sentinel lymph node biopsy should be reserved for patients with lesions >1 mm and, if necessary, due to scarce of resources, could be delayed for three months.
The metastatic resections should be placed on hold, unless the patient is symptomatic or unresponsive to systemic therapies.
NCCN recommends for stage III (regional nodal) to defer therapeutic lymphadenectomy when regional nodes are clinically palpable, and offer neoadjuvant systemic therapy immune checkpoint blockade (ICB) or BRAF/MEK inhibitors instead. Exceptions are when metastatic node(s) are invading a vital structure like the carotid artery.
From the ESMO point of view, the high priority is represented by new diagnosis of invasive primary melanoma, unless wide excision has been performed or tumour is Tis or T1a, postoperative complications and stage III melanomas.
High/medium priority: wide excision and sentinel lymph node biopsy for new diagnosis of invasive primary melanoma T1b or higher, but SSO also recommends that delaying surgery is acceptable, as this was not shown to influence survival(13,14).
For systemic therapy, the recommendations like interim treatment change options during the COVID-19 pandemic, being based on clinical opinion from members of the Chemotherapy Clinical Reference Group and cancer pharmacist and endorsed by NHS England and NHS Improvement. They recommend for melanoma patients to give oral therapy as first-line treatment for BRAF-positive patients in preference to immunotherapy in order to reduce admission for i.v. therapy and the time spent in the oncology clinics, for lowering the risk of infection, and to stop immunotherapy doublet (ipilimumab and nivolumab) and switch to single agent nivolumab or pembrolizumab to reduce toxicity and need for hospitalization(19).
For stage III melanoma, as the NCCN Melanoma Panel and ESMO recommends, adjuvant therapy may be initiated up to 12 weeks from the moment of definitive surgical resection, and there should be chosen regimens that expose least the health care giver and the patient, including: nivolumab 480 mg i.v. every 4 weeks for one year, pembrolizumab 200 i.v. every 3 weeks for one year, pembrolizumab 400 mg i.v. every 6 weeks for one year(15).
The continuation of already started adjuvant therapy is of high priority, as well as for ESMO(17).
The beginning of adjuvant immunotherapy or targeted therapy for stage III disease is recommended for patients with high-risk stage III disease (sentinel lymph node deposit of more than 1 mm and AJCC 8th edition stage >IIIA) as high priority and low priority for sentinel lymph node deposit of less than 1 mm or stage AJCC 8th edition IIIA.
With less frequent clinic visits/infusions, telehealth interval symptom checks by staff are recommended.
NCCN Short-Term Recommendations for Cutaneous Melanoma Management During COVID-19 Pandemic include, for stage IV melanoma, considerations regarding toxicity of the regimen selected, thus decisions about ICB should be individualised. There should be a preference for agents with the lowest toxicity profile.
Single-agent anti-PD-1 should be preferred over combination of anti-CTLA4/anti-PD-1 now, taking into consideration the substantial inflammation/possible exacerbation of COVID-19, the need for steroids/other immunosuppressants to treat immune adverse events (AE) that may affect SARS-CoV-2-infected individuals. Patients on IO showing signs of pneumonitis on CT scans should be tested for COVID-19 also. The CheckMate 511 regimen (IPI 1 mg/kg and NIVO 3 mg/kg) should be discussed on a case-by-case basis (ESMO recommendation).
It is currently unknown how patients infected with SARS-CoV-2 on ICB will react to the expected immune-related adverse events (irAEs), even though there are some articles that propose a pathophysiological mechanism(22-25). It is possible for patients on ICB to experience severe treatment-related AEs during their treatment course and may adversely affect SARS-CoV-2-infected individuals(26). We should pay attention to symptoms of immune gastrointestinal toxicities that could overlap with digestive symptomatology due to SARS-CoV-2 infection.
Skin adverse immune reaction secondary to ICI therapy can appear at the clinical exam, such as vasculitis and erythematous skin rash observed in some cases of SARS-CoV-2 infection. It is recommended to evaluate also the SARS-CoV-2 infection if there is needed immunosuppressive therapy.
Also, in metastatic setting, consider regimens like: nivolumab 480 mg i.v. every 4 weeks, or pembrolizumab 400 mg i.v. every 6 weeks.
A regimen of ipilimumab 1 mg/kg and nivolumab 3 mg/kg every 3 weeks for 4 infusions, with subsequent consideration for nivolumab monotherapy, is associated with lower rates of immune-mediated toxicity compared to the FDA standard, and is recommended to be taken into consideration by ESMO and NCCN, and should be discussed on a case-by-case basis(17).
Drug resources could become limited over the course of the pandemic, and maybe we are in the position to make the following recommendations: encorafenib/binimetinib or vemurafenib/cobimetinib combinations can be substituted for dabrafenib/trametinib in the adjuvant setting in USA, as NCCN recommends, or single-agent BRAF inhibitor can be used in the event of MEK inhibitor shortages in European countries and in the USA.
For chemotherapy regimens, oral temozolomide is the preferred option, due to limited resource utilization and contact with the medical care provider.
The Society of Surgical Oncology recommends single-dose palliative radiation to be considered for bulky disease to alleviate symptoms, if surgical capacity is scarce(20). High priority according to ESMO is represented by situations such as stereotactic radiosurgery for brain metastases, threatening lesions like risk of fracture or bleeding, and spinal cord compression. Low priority are adjuvant radiotherapy post-radical lymphadenectomy and irradiation of asymptomatic and not threatening metastases, therefore those therapies could be postponed(17).
We should take into consideration all the recommendations when we treat melanoma patients, and to treat them best in accordance with their needs and available guidelines. n
Conflict of interests: The authors declare no conflict of interests.