Improved prognosis in most common cancer at all stages

Malignant melanoma is one of the most common malignant tumors, especially in adolescent age groups. However, given the state of knowledge on the proliferation and antigenicity pattern of tumor cells, an ideal use of modern immunotherapeutic and targeted approaches is offered. Meanwhile, expansion of treatment options to early stages and in the neoadjuvant setting has improved recurrence- and progression-free survival.

Malignant melanoma (MM) has shown an ominously increasing frequency of morbidity and mortality in recent decades. The most common cancer represents the prototype of an immunogenic malignant tumor, the development of which is partly subject to endogenous and partly to exogenous factors. Every year, around 55,000 people die from this aggressive skin tumor. MM is so dangerous because it has a propensity to metastasize lymphogenically and hematogenically and can spread throughout the body via the lymph nodes. Therefore, it is very important for the prognosis to remove the sentinel lymph node and to examine it for the presence of micrometastases.

Known risk factors for its development include. a.o. an increased, v. a. intermittent UV exposure, tanning bed attendance, a fair skin type, frequent childhood sunburns, and a positive family history. It is now known that UV radiation has a direct mutagenic effect with the formation of point mutations and structural changes in the genetic material. In addition, free radicals are formed, which cause further genetic changes. These transformations permanently activate proto-oncogenes such as BRAF and cell cycle control genes. This subsequently results in sustained activation of cellular signaling pathways such as the mitogen-activated protein kinase (MAPK), phosphoinositol (PI3K), and mTOR signaling pathways. Molecular genetic classification of tumors has shown that approximately 50% of melanomas have a BRAF mutation, and 25% have an NRAS mutation and 15% have an NF1 mutation.

Advances in therapy management

Improved understanding of molecular pathological mechanisms has been instrumental in the development of immunotherapy and targeted treatment. Thus, significant improvement in relapse-free, progression-free, and overall survival was achieved. For example, in the presence of a BRAF mutation, clinical trials have demonstrated significantly prolonged relapse-free survival in stage III with adjuvant immunotherapy (ICI) or targeted therapy (TT). Recent long-term data demonstrate the benefit of adjuvant ICI therapy, and long-term clinical benefit was also observed in BRAF-mutated stage III melanoma patients with TT.

The Merkel cell carcinoma
Merkel cell carcinoma (MCC) is a rare and aggressive tumor of the skin with a high recurrence rate, frequent metastatic spread throughout the body, and associated high mortality. It occurs predominantly in elderly patients over the age of 70 and those with a weakened immune system. Accordingly, the most important risk factors for the development of MCC are considered to be age over 50 years, fair skin color, sun/UV radiation exposure, and immunosuppression. The tumor tends to metastasize early and returns rapidly despite intensive chemotherapy and radiotherapy. The prognosis of those affected is therefore often unfavorable.

For some time now, an increase in MCC cases has been recorded. This is thought to be due to its close association with Merkel cell polyomavirus. In about 80% of patients, the virus can be detected within the tumor tissue. Stem cells of the epidermis and dermis as well as early B cells of the immune system are currently considered as possible starting points for MCC.

Key features of Merkel cell carcinoma (AEIOU):
A asymptomatic/painless
E expanding rapidly/rapidly growing
I Immunosuppression
O older/older than 50 years
U UV exposure/light skin

The treatment is carried out according to the stage. However, the first priority is always surgical resection of the primary tumor and the performance of a sentinel lymph node biopsy and, if necessary, removal of lymph nodes. This is followed by radiation therapy and systemic tumor treatments such as immunotherapy and chemotherapy. Immunotherapies with PDL1 inhibitors show good success especially in patients with distant metastases.

In patients with advanced, unresectable tumors, immunotherapy consisting of CTLA-4/PD-1 inhibition and monotherapy with a PD-1 inhibitor significantly prolonged progression-free and overall survival. Targeted therapy also shows significant benefit in progression-free and overall survival in melanoma patients with unresectable advanced disease. Patients with advanced BRAF-mutated melanoma also appear to benefit more from sequence therapy, starting with CTLA-4/PD-1 inhibition and followed by targeted therapy at progression, in terms of longer overall survival than from sequence therapy starting with targeted therapy. Initial results of the combination treatment of LAG-3/PD-1 inhibition demonstrated significantly prolonged progression-free survival in patients with unresectable advanced melanoma compared to PD-1 monotherapy. It seems that the combination of LAG-3/PD-1 inhibition may be a good alternative to the current CTLA-4/PD-1 inhibition.

In the neoadjuvant therapeutic approach, the focus is on systems therapy followed by surgical resection. In this way, an early systemic effect can be achieved. Patients with complete pathologic response in the index lymph node without further systemic therapy had a recurrence-free survival of 93.3% at two years and 100% distant metastasis-free survival with this approach.